Page Synopsis: The previous page on CFS was so full of new topics I didn't want to crowd the page and put the focus on Mitochondria here as well as an integrative model of disease mechanisms in the Chronic Fatigue Syndrome


On a personal note I've been taking Venlafaxine, though I would like to tapper off and perhaps that would improve CFS (seeing as stopping Cymbalta marked my greatest improvement to date)


I will have to stop Venlafaxine anyways (and likely  switch to a different SSRI or SSnRI) in order to trial Amantadine, the drug that shows the most promise. Note to those taking SSRI's and SSnRi's DO NOT casually stop taking such medicines as the withdrawals are DRAMATIC, and should only be done so with adequate and ample supervision


I've been taking Tadalafil every 2 to 3 days for personal reasons (ED), though it (and sildefinil) is a recommended medicine for CFS helps. Though it helps with focus, I find it anxiety inducing and I question effects of long term use


Drugs interested in trying for CFS are listed on the personal plan page



Skill Level  1

Relevance:1 Technical Level:1

This is mostly a launch page for the medicine pages that follow, except for Vyvanse


page 14

page 16



Lisdexamfetamine Vyvanse for chronic fatigue syndrome

User Reviews for Lisdexamfetamine to treat Chronic Fatigue Syndrome

9.2/10 average rating

15 ratings from 16 user reviews


User Louis Cyphre·Taken for 5 to 10 years·September 5, 2020

“I have ADHD, fibromyalgia, chronic fatigue syndrome, and narcolepsy. Vyvanse is a lifesaver. It is the only medication that improves my quality of life. Not only does it help my concentration, it also helps with the pain. I hope that Shire starts making doses higher than 70mg, as it does cause tolerance to increase. The only way around that is to take a day or two off the medication every week. My doctor prescribes me 10mg instant release dexamphetamine tablets to take on those days so I don’t suffer such a hard crash. All in all, it is a consistent medication with few side effects. Yes, it can be abused by people who do not have any medical reasons for taking it. But for those of us that do have medical conditions, it vastly improves quality of life. I am very tired of the demonization of amphetamines, and people equating this to crystal meth. Under the care of a doctor, there is little chance that someone will abuse or become addicted to this drug.”

9 / 10



User purplebutterfly·May 29, 2010

Vyvanse (lisdexamfetamine): “I have tried several medications for chronic fatigue syndrome and nothing seems to help more than an hour or two. Vyvanse is a wonderful medication for chronic daytime sleepiness and fatigue. I could not believe the amount of work I was able to get done. It does not make you feel "drugged" like other medications do. I felt like my old self again, before the days of CFS.”

10 / 10



User Charlotte·Taken for 1 to 6 months·October 2, 2020

“Having Chronic Fatigue Syndrome (CFS) for 4 years completely destroyed my life. Spent 15k trying to recover finally decided to go to a psychiatrist and ask for Vyvanse (I found this through my own research) Well its like night and day. I can function like a normal person. I do have 5mg of instant release dexedrine in the afternoon as a booster. I also have 2 or 3 days off each week so I avoid tolerance. This has absolutely saved my life I wish I could take it everyday..If you're suffering get a psychiatrist and give it a go”

10 / 10



User TAR·Taken for 1 to 2 years·December 12, 2018

“My life has absolutely changed. I've been bed ridden for years. I missed a day and a half at a very important client meeting because I couldn't move to get out of bed. Vyvanse 40 mg. has given me my life back. I can't begin to express my gratitude. Because some doctors are unaware of this study however, the doctor that took over for my current practitioner wouldn't refill my RX. I only have a few days left and am terrified to go back to my old way of life, or lack there of. I would highly recommend Vyvanse for Chronic Fatigue and Fibromyalgia. I feel so much better!”

10 / 10



User Anonymous·Taken for 1 to 6 months·October 15, 2016

“This medicine is a truly life saver. Even with my depression well treated, i kept physicaly tired the whole day. I wanted to do things but my body felt like i spent 3 hours at the gym. 30mg of it, 6am changed the whole game. I can go on really motivated the whole day and still get a great night of sleep. NO SIDE EFFECTS besides some stomach cramps on the first days There's no comparsion with other meds i've tried before (provigil and Focalin) I can finally say that i'm capable of doing anything if i truly want to.”

10 / 10



User nenagh·Taken for 1 to 6 months·August 28, 2017

“I was utterly shattered and didn't know what to do before I started this drug. I had bone crushing chronic fatigue and felt I had tried everything. I was so tired for so long I was planning on ending my life. I am on 50mg and it has made a huge difference. I have very little fatigue now, I still have some problems with anxiety an depression but I always had those. Overall I am much better on the drug. I had tried other stimulants like Concerta, Ritalin and Provigil before with little effect. If you are suffering from chronic fatigue please give lisdexamphetamine a try as it can make a big difference.”

9 / 10



User Love1another·Taken for less than 1 month·December 27, 2013

“I have been living with chronic fatigue for over 9 years now. I have gone to so many different doctors and have been put on so many different kinds of medicines that never worked. I finally was put on Vyvanse 30 mg. I can not tell you how much this Medicean has changed my life for the better. I would have to force myself out of bed in the mornings and come back home after taking the kids to school and tell myself I would just rest for 20 mins and then get up. I would fall back to sleep for hours and could not figure out what was wrong with me. I hated feeling so tired all the time. I've been on vyvanse now for 1 week and it is a miracle drug for me. I have energy and my life back. I only wish I would have known about this 9 years ago.”

10 / 10



User PC·September 18, 2019

“Used Adderall XR a few years and wasn't helping with physical/mental energy, unmotivated & unfocused, even lost my job. Doc switched me to Vyvance 10 or 20mg and took even longer to work. I know reviews here are positive, but I didn't get benefits with Vyvance and went back. Barely noticed any change like taking nothing at all. Maybe doc gave too low dose? Now trying Armodafinil 250mg. Doc said break 1/2 and did 1st week+ and didn't help much. Then 3/4 sometimes full 250. Not great. I'm frustrated I can't find anything to help with mental/physical energy. I was vivacious, hard working, driven til mid 40s. I'm sure it's partially hormonal but I'm a drained person. Can't think, tired all the time, disorganized, foggy, unmotivated. Adderall helped me get out of bed but no physical energy or mental focus. Everything tried, I move around like a saggy robot without passion. Projects undone, papers piled up. I don't know what to try anymore. Looking online for other possible treatments.”

3 / 10



User Anonymous·August 19, 2011

Vyvanse (lisdexamfetamine): “I have suffered from narcolepsy, chronic fatigue syndrome and ADHD all my life. The ONLY thing that has allowed me to feel 'normal" enough to participate in my own life again is Vyvanse. Unfortunately, I have recently moved from AZ to CA and due to different laws, I have been unable to fill or receive a new prescription in CA (even with all of my doctors records and recommendations) and I have been severely depressed due to all the old symptoms returning. BUT VYVANSE SAVED MY LIFE AND I HIGHLY RECOMMEND IT.”

10 / 10



User Alice·Taken for 6 months to 1 year·August 27, 2020

“I was diagnosed with CFS/ME 5 years ago. Although I learned how to manage it better through pacing, I still felt very limited in what I could do in one day. Nine months ago, I started on Vyvanse - 10mg for 2 weeks, 20 mg for two weeks and then settled in with a dose of 30mg daily. It did give me more energy but I had to be careful to still pace myself and not over do it. I felt more motivated and more positive. It also helped with general pain. I did not like the side effects of dry mouth and I felt almost like a clenching of my muscles so my doctor reduced me to 20mg two weeks ago. My fatigue and pain are back and worse than before. I’m feeling discouraged and will likely go back to the 30mg. It’s worth the side effects to have more energy and to feel positive and creative.”

8 / 10



User Laurenapolis·Taken for 6 months to 1 year·May 6, 2016

“This drug changed my life- I would have to take 4 hour naps during the day, on top of 8-10 hours of sleep in order to get through a a day but now I can stay awake and it helps me FOCUS. Upon taking it I feel an overwhelming sense of positivity almost a "high" and it lasts for hours. I can accomplish anything I want to. The drug lasts for the whole work day and I'm back to being my sleepy self by night time. I take 60mg and weigh 145. I would definitely recommend this drug.”

10 / 10



User TR·Taken for 1 to 6 months·April 19, 2018

“I can’t even begin to tell you how much better I’m feeling. I’d gone on a business trip to see a multi billion dollar corporation for 3 days. After a day and a half I had to tell them I was so ill that I needed to leave. By the next day, I couldn’t move to get out of bed. I’d never felt that bad before. That’s when I decided I had enough of feeling exhausted, tired and foggy all the time. I researched CFS medications and found this forum along with double blind studies. I started on 30 mg. Initially I felt shaky and my heart was pounding. I found that if I ate with the Vyvanse that didn't happen. I felt great and had energy all day long. I also have fibromyalgia and ehlers-Danlos and it’s helped my pain tremendously. I sleep great band cause of all the energy I burn. I haven’t lost any weight or my appetite. I am so grateful for this medication. 10 Stars!”

10 / 10



User Finally something works·Taken for 1 to 2 years·October 14, 2014

“I finally got diagnosed with Lupus two years ago after going to many doctors that couldn't find anything wrong with me. I knew that my extreme chronic fatigue wasn't normal. After 5 years of different doctors one did an ANA test and my Lupus was 1:674 which is very high. I started the vyvanse 20 for a month and didn't help then went to 40 for about a year now on 50mg. I take it at 7 am and I can feel it kick in about 9:30. It keeps me awake and able to do what needs to be done. Some days I feel the vyvanse work better than others. If I eat a high protein breakfast it always does better. No OJ or acid drinks or fruit. It makes the vyvanse not work well. It's expensive if u don't have insurance, try Adderral 20 instant its the same & cheaper”

9 / 10



User Cindy·Taken for 1 to 6 months·September 6, 2019

“My 6 year old son has struggled with severe anxiety, sensory processing, and ADHD nearly his entire life. This is the 5th or 6th medication we have tried after having terrible results with the others. He is truly a different child on this medication. His impulsiveness has decreased tremendously, his anxiety is almost nonexistent, his outbursts, rages, and tantrums are nearly gone. And the best part is, that we can actually see his true personality for the first time EVER. Hallelujah! His symptoms are so controlled now that he can express himself, be creative, problem-solve, and do well in school. I am so grateful for his pediatrician for recommending this. It has changed the lives of our entire family.”

10 / 10



User absent minded mommy·Taken for 1 to 2 years·March 8, 2016

“I suffered a traumatic brain injury in 2003 at the age of 17. Comatose for 28 days and about one year ago I finally got someone to listen and give me something vyvanse helped a ton at first with my waves of fatigue. My daughter was recently diagnosed ADHD and she also takes vyvanse worked great in the beginning but both of us it seems to have just stopped? Focus an concentration are worse than before meds. And when it does kick in it maybe lasts 6 hours. Also believe I am suffering from post traumatic narcolepsy. Wish this med worked as well now as in the beginning. I was upped to 50 mg recently she complained it wasn't helping but making me feel worse and all that did was make me grind my teeth even more and worsen my insomnia”



User Dcb·Taken for less than 1 month·March 8, 2022

“lisdexamfetamine was a game changer for me after 8 years of dealing with Chronic Fatigue Syndrome CFS due to a relapse of a mononucleosis infection. I have been taking Ritalin before this drug which wasn't bad but not very great either. The difference between lisdexamphetamine and Ritalin is day and night for me. I can finally get a good night sleep at nights even after a hard day of work. It boosted my energy and concentration like nothing else would with almost no side effects. I take 30 mg daily and the only thing that worries me is that there comes a day when I wouldn't have access to it. I also take Doxepin 25mg and Clonazepam 1mg before bed to improve my sleep quality and Paroxetine 20mg to manage my depression and anxiety.”

10 / 10


What Medicines Treat Chronic Fatigue Syndrome

Some people are prescribed stimulants, like the ones used to treat ADHD. These medicines help ease fatigue and problems with memory and concentration. But they are tricky for chronic fatigue syndrome. They may give you energy and focus, which could cause you to get stuck in a cycle of overdoing it and then “crashing.” That would make your condition worse.


Since people with ME/CFS are very sensitive to any medicines that affect the brain, some people experience irritation and agitation taking stimulants, in conventional doses. They should be prescribed in low doses, by doctors who frequently prescribe them and know how to handle the side effects

User Reviews for Lisdexamfetamine to treat Narcolepsy


                         User Reviews for Lisdexamfetamine to treat NarcolepsySleepyDude·March 14, 2019“I was terrified to start Vyvanse (lisdezamfedamine) because of my awful experiences with other stimulants; I had extreme anxiety that lasted for several weeks on 6 days of Adderall XR 5mg, and Concerta XR made me even more drowsy. Amphetamines metabolize too slowly and methylphenidates don't work correctly, according to a genetic test I took. Though Vyvanse is in the amphetamine class, the fact that it's a pro-drug (meaning it's inactive until the body converts it to amphetamine), my body doesn't seem to hang onto it like it did with Adderall. Combined with modafinil 200mg and a coffee a day, it works very well with keeping me awake and weirdly has actually reduced my anxiety. If you took a genetic test and it showed up with having problems metabolizing amphetamines too slowly and causing problems, you might do better on Vyvanse instead. Side effects for me are dry mouth and cold toes/fingers, and my deductible makes it $240 after a $60 off vyvanse coupon, but it's worth it in my opinion.”9 / 10  Babs·Taken for less than 1 month·June 29, 2019“I tried everything for my Narcolepsy- closest I came to feeling “ok” was on Concerta but it seemed like my body burned through it very quickly and I was able to sleep on it without much effort (I even used it during a sleep study) no increased focus, my mind was scattered all day, and I was very irritable coming down off it. Concerta lasted at most 1-2 hrs for me before I started to crash with painful exhaustion. Not this. This I took 10 hours ago- 10!!!- and I still am going strong. This is the best medication I have ever been prescribed for my Narcolepsy. My husband has noticed a huge change in my behavior, mood, and well being. I recommend this to anyone who was losing hope like I was. I take 70 mg a day.”10 / 10  JRTuttle4·June 29, 2009Vyvanse (lisdexamfetamine): “I was constantly struggling to stay awake (sometimes when driving too) and I'm pretty sure I almost lost my new job (started in 02/2009) before training ended. I'm also sure that they doubted I'd be very effective on the phones after training. Also, at the end of training, we had to make an 85% on the final exam to continue to be employed there and I'm sure they thought I would fail. Right before the exam, I quit taking Lyrica, which decreased the severity of the sleep narcolepsy, but didn't eliminate it. Vyvanse has greatly improved my effectiveness at work and I even got a promotion less than 3 weeks after I began taking it! I've had basically no side effects and now with not having to fight to stay awake, Vyvanse relieves a lot of stress and anxiety!”9 / 10  Sleepymomof2·November 11, 2013“I was prescribed Vyvanse 50 mg for the treatment of my narcolepsy w/o cataplexy & hypersomnia. The first 2 weeks were great but I found my body quickly adjusted to this medicine making it almost completely ineffective by the end of the first month. The 2nd month, I went to 60 mg. this month, I'm on 70mg. I'm not falling asleep while driving, however I am still having episodes of extreme sleepiness and sleeping extremely deeply at times. I'm also going between sleeping 5 hours to 15 a night. My main concern is: I'm on the maximum dose so just where do I go from here?! I also have bipolar disorder/anxiety & I've found my need for anxiety medicine to be almost nonexistent, which is a great bonus.”6 / 10  Ceigeme·March 28, 2010Vyvanse (lisdexamfetamine): “I have sleep apnea, and somewhere in the last 7 months developed narcolepsy. I almost lost my job, and spent 4.5 months on disability because I couldn't stay awake at my desk. I was falling asleep in my car, as a passenger and a driver, falling asleep at diner, on the phone, everywhere. So when I went back to work, I thought I was better, I had been treating my bi-polar with a lot of good medications, so I really felt ready to go back to work. Well about 2 days back to work I was falling asleep again. It was miserable. My sleep Dr wanted me to take a stimulant, and my Psychiatrist prescribed Vyvanse. The first 60 mg pill did nothing. I was falling asleep again. So my doctor advised me to take another 60 mg pill. It worked! I'm doing much better.”10 / 10  Anonymous·November 7, 2011Vyvanse (lisdexamfetamine): “Its my 3rd day and I love the fact I can function and take care of my 5 month old without struggling. I'm on the 30 mg only reason I didn't give it a ten is I take it at 6 am and by 2pm I'm super tired again...other than that love it.”8 / 10  Anonymous·Taken for 1 to 2 years·March 25, 2014“My experience with this medicine has helped me through school very well and I don't fall asleep in school, I pay attention very well. It doesn't wear off until I get home. Then I'm really tired but the really tired part is okay I don't really mind. This is my key for school. I don't take it in the summer and whenever it's time for school. My Vyvanse is a really big help.”10 / 10  Kelp·Taken for 2 to 5 years·August 22, 2021“I originally was put on this medication for my ADHD. I was on it for 2-3 years. I didn’t take it for a week & that’s when my narcolepsy symptoms started. I couldn’t get on a schedule to take it. I would wake up late & didn’t want to take it & then stay up late. The bright side is that incident lead to my narcolepsy diagnosis. Taking Vyvanse covered up my narcolepsy symptoms. Prior I was diagnosed with hypersomnia AND insomnia… Anyway, my side effects are dry mouth, thirst, lack of appetite/forget to eat and in the first 2 hours I can be a little more emotional (not sure if that’s really related). I have taken from 90mg-30mg. What worked best for me was 30mg @ A.M. & then 40mg at lunch. This helped with the eating & making sure it lasted the whole day. I would say it lasts 10+ hours. But when I was only on 40mg I felt it just lasted maybe 6 hours. Overall great drug”10 / 10  napqueen967·Taken for 1 to 6 months·November 11, 2021“31y F. Suffered from EDS for last 5yrs, finally got appropriate sleep studies two months ago. Have tried Provigil, Nuvigil, Sunosi, all did not do very much for me. Started Vyvanse and now take 50mg in AM, 20mg around midday. Big difference though it is more difficult to get out of bed in the AM now. Takes about an hour to kick in then I'm good until next dose. I metabolize it quickly so it doesn't last as long as its should even with the xtra 20mg in the PM as a booster. I've tried Adderall ER in PM as booster but makes me feel woozy for first 2 hours so switched to the 20mg Vyvanse. Will be replacing the 20mg Vyvanse with Wakix soon though because I'm falling asleep driving home still and 70mg is max dose. I work 2 jobs and need to stay awake from 5am to at least 8pm. Better than my life before, though not quite where I need to be. I also notice I can get more agitated easier now. Other than that and feeling very sluggish upon waking up in AM, I have no side effects.”8 / 10  Anonymous·June 8, 2017“I'm doing well at my job and able to drive. 60mg. I sweat on occasion.”9 / 10  Gypsy Dreamer·Taken for 2 to 5 years·June 9, 2016“Helps me get things done and to focus. No adverse side affects.”8 / 10                                                                                                                                       click to closeback to top of article

Staphylococcus Vaccine as medicine for CFS

Interesting PhoenixRising forum discussion here


Mitochondrial Disease Research


Virtually all chronic complex diseases have mitochondrial dysfunction5. This means that over half of all Americans—over 150 million people—will suffer with a chronic disease that can be traced to mitochondrial dysfunction. Even the aging process itself has been found to be controlled by mitochondrial function. Diseases like diabetes, heart disease, chronic fatigue syndrome (CFS), Parkinson, Alzheimer, mental health disorders like bipolar disorder, major depression, and post-traumatic stress disorder (PTSD), traumatic brain injury (TBI), autoimmune diseases like lupus and multiple sclerosis (MS), and childhood disorders like autism, ADHD, asthma, and many more all have been shown to have mitochondrial dysfunction

Breakthroughs in the Cause and Treatment of Autism and Chronic Fatigue Syndrome


It was clear to us since 1995 that the major setbacks in mitochondrial diseases like Leigh and Alpers syndromes were associated not with the start of a metabolic stress like an infection, but were most common and most severe later, during the healing phase that came after the initial stress or injury. In pivotal collaborative studies conducted from 2003-2008 with the brilliant inventor and laser physicist, Dr.  Paul Gourley at Sandia National Laboratories in Albuquerque, NM (Figure 5), we studied the biophysics of the cellular and mitochondrial response to stress.  That work showed that any kind of stress—environmental, genetic, or a combination of both led to profound changes in mitochondrial structure and function.  We next began a series of breakthrough studies in collaboration with the renowned immunologist and trailblazer in regenerative medicine, Dr. Ellen Heber-Katz, then at the Wistar Institute in Philadelphia (Figure 6).  In experiments from 2005-2009, we drilled down into the molecular mechanisms of healing in the super-healer MRL mouse. These “mighty mouse” studies led to the discovery that healing from any injury requires both a mitochondrial reserve capacity and the ability to shift from one kind of mitochondrial function to another under times of stress or injury. These properties were abundant in the MRL mouse, and in other animals during fetal development, but are missing in children with   inherited forms of mitochondrial disease, and are gradually lost with aging. These studies on the role of mitochondria in stress and healing set the stage for all our next studies in complex disorders like ASD and ME/CFS


Chronic Health Disorders (that) have increased (between) 2-100 times since the 1980s.  Forty percent of children born in the US today and 60 percent of adults under 65 live with at least one chronic illness


The goal is to adress more than symptoms


Exposomics and Metabolomics

In 1985, 5-10% of children born in the US lived with a chronic disease.  Today, just thirty years later, 40% of children live with chronic disease.  Many diseases have increased 2-10 times from 1985 to 2015 (Figure 1).  Children with chronic disease grow up to be adults with disabilities and disease.  This increase in chronic disease is not due to a change in our genes, or a failure in our healthcare system.  The increase in disease is the result of measureable chemical changes in our food chain, air, water, and soil.  The Environmental Protection Agency (EPA) was given the task of protecting human health by protecting the environment, but economic cuts have handicapped it since its last major contribution to public health, the banning of leaded gasoline in 1996

We didn’t need to think about preserving a healthy environment much in past centuries because the number of humans on the planet was not enough to permanently intoxicate and degrade the natural resources of the biosphere.  This situation reached a tipping point in 19882-5.  In 1988, there were 5.1 billion people on Earth.  In that year, the human population consumed resources and released waste products at a rate the Earth could renew and recycle sustainably.  After that, we began to live on biological principle.  In 2016, the human population is 7.4 billion.  Ever since 1988, we have been consuming natural resources faster than they can be replaced, and releasing waste that is accumulating in both obvious in less obvious places.  The Great Pacific Garbage patch is a slow moving swirl of plastics and non-biodegradable detritus that is now twice the size of Texas and continuously releasing pesticides and organic pollutants on a global scale6.


Nanoscale chemical waste is the natural cast-off of an unregulated industrial economy.  Many of these chemicals can be shown to produce neurodevelopmental disease during fetal development and in the newborn period.  Whole ecosystems have begun to sicken7-9.  The Naviaux Lab is developing new mass spectrometry methods that will enable the rapid and regular testing of our environment and food chain to give scientists and policy makers the data needed to crack down on companies and practices that endanger the health of our children, the health of our nation, and the health of the natural world.


Empowering the EPA—Keeping Americans Safe from Pollution

1. Establish a permanent Office of Pollution Monitoring (OPM) and an associated observatory network consisting of 50 sentinel cities, with outlying factories, farms, forests, lakes, rivers, and marine coastal sites throughout the United States.


2. Create a list of the specific samples to be collected at each of the 50 sentinel sites.  These will include GIS-tagged samples of: air, water (from municipal tap and waste, rivers, lakes, well/aquifer/groundwater, and ocean samples), sediments (from specific parks, lakes, reservoir, and marine coastal samples), and regional sentinel foods such as organic and non-organic cow’s milk, honey, corn, soybeans, rice, wheat, oats, fruit (grapes, apples, pears, cherries), strawberries, blueberries, spinach, kale, celery, tomatoes, peanuts, walnuts, almonds, beef, pork, poultry, and fish.


3. Collect GIS-tagged samples annually for sites with municipal populations > 1 million, and every 2 years for sites < 1 million, and measure the chemicals, including antibiotics, antifungal drugs, and common pharmaceuticals.


4. Create a publicly-accessible electronic database with the results of these surveys as a congressionally-mandated public service.

5. Work with the US Department of Agriculture (USDA), National Institutes of Health (NIH) and the American Medical Association (AMA) to correlate the trends of environmental chemical concentrations and the activities that produce them, with the trends of chronic illness in children in the sentinel areas.


6. Generate a biannual report that prioritizes for US Congressional action, the chemicals that are found to be associated with the greatest health risks.



1. Needleman, H.L. The removal of lead from gasoline: historical and personal reflections. Environmental research 84, 20-35 (2000).

2. Wackernagel, M., et al. Calculating national and global ecological footprint time series: resolving conceptual challenges. Land Use Policy 21, 271-278 (2004).

3. Landrigan , et al. The Lancet Commission on pollution and health. The Lancet In press, (2017).

4. Stoglehner, G. Ecological footprint – a tool for assessing sustainable energy supplies. Journal of Cleaner Production 11, 267-277 (2003).

5. Wackernagel, M. & Yount, J.D. The ecological footprint: An indicator of progress toward regional sustainability. Environmental Monitoring and Assessment 51, 511-529 (1998).

6. Rios, L.M., Jones, P.R., Moore, C. & Narayan, U.V. Quantitation of persistent organic pollutants adsorbed on plastic debris from the Northern Pacific Gyre’s “eastern garbage patch”. Journal of environmental monitoring : JEM 12, 2226-2236 (2010).

7. Katagi, T. Bioconcentration, bioaccumulation, and metabolism of pesticides in aquatic organisms. Reviews of environmental contamination and toxicology 204, 1-132 (2010).

8. Bonefeld-Jorgensen, E.C. Biomonitoring in Greenland: human biomarkers of exposure and effects – a short review. Rural and remote health 10, 1362 (2010).

9. Joyce, S. The dead zones: oxygen-starved coastal waters. Environmental health perspectives 108, A120-125 (2000


About Naviaux Labs

Dr. Naviaux has been tracking over 30 chronic diseases that have increased 2-100 times since the 1980s. Some of these are illustrated in Figure 7. In the case of ASD, the prevalence has risen from 1 in 5000 (20 in 100,000) in the 1970s to 1 in 59 (1700 in 100,000; an 84-times increase) in 20146. It has been calculated that 60% of the apparent increase can be explained by changes in the diagnostic criteria for ASD over the past 40 years7. However, even with this conservative correction, the adjusted prevalence of ASD of 1 in 59 children today represents an absolute increase of 34 times (84 x 0.4 = 34) from the 1970s. A similar calculation and correction for ME/CFS shows that there has been a 62-fold increase since 1985. Our DNA cannot change this fast. Therefore, the rise in the prevalence of chronic illness in the past 30-40 years is not caused by DNA, but by a change in the environment and the interaction of our DNA with the environment—cogenetic factors. Over 7,000 chemicals are used in the United States at amounts of 25,000 to over 1 million pounds per year. These include pesticides, plasticizers, lubricants, flame retardants, Teflon’s, food additives, preservatives, dyes, sunscreens, veterinary antibiotics and antifungal medication, and many others. Fewer than 5% of these have ever been tested for developmental toxicity. These chemicals have entered the human food chain, water, and air. In 2005, study conducted by the Environmental Working Group found that the umbilical cord blood of newborn babies in the United States already contained an average of 287 pesticides, pollutants and other environmental chemicals8. Using a combination of LC and GC mass spectrometry, the Naviaux Lab has developed new methods in “exosomes” that allow us to measure the chemicals in blood that can cause chronic illness, and the chemicals that can lower our resistance to chronic illness


An unanswered question in the biology of ME/CFS is, “Why do patients who are able to recover still have a life-long risk of recurrence?”. Dr.Naviaux believes that life experiences and exposures to environmental chemicals and biotoxins come together with genes to create a “perfect storm” that causes ME/CFS. Even after recovery, this perfect storm leaves a mark—a metabolic and epigenetic memory that changes how the network of chemicals in the blood is regulated and how it responds to future exposures. In 2020, we will launch a new study to examine the network connections between the metabolome and exposome. Using advanced machine learning and network dynamic analysis, this new study will help pave the way for the  future  suramin  ME/CFS  treatment  trial. Other  exciting  studies  include  a  new collaboration with the brilliant virologist, Dr. Bhupesh Rusty at the University of Würzburg, Germany. Using a new, cell-based assay system, we are hot on the trail of both the identity and the biological control of the activity in ME/CFS blood that causes fatigue. This “fatigue factor” looks like it could be the same thing that coordinates the mitochondrial and metabolic features of the cell danger response (CDR) and inflammation5, changes impedance in the nanoneedle10, inhibits recovery from illness by blocking the healing cycle9, induces a Dauer-like state11, and triggers collagen remodeling over time that can cause acquired forms of Ehlers Danlos-like syndromes. If successful, these studies will help fill in missing details in how suramin, copaxone, and elamipretide (SS31) might work to treat ME/CFS.


launch the SAT2 in the summer or fall of 2020. If the SAT2 is successful, it will open up the possibility of using antipurinergic drugs like suramin in several other disorders. Dr. Naviaux wants to conduct clinical trials in ME/CFS and primary forms of mitochondrial disease like NARP. If these are successful, nearly 20 other disorders may also benefit. If ATP-related cell signaling is found to be a fundamental cause of blocks in the healing cycle9, then many investigators and drug companies will launch programs of drug discovery to find new medicines that work like suramin,


                        Integrative model of disease mechanisms in the Chronic Fatigue Syndrome (Possible to 'reset' so that antibodies attack only correct things, smell type marker in protein enzyme or surface not recognizing or marking correctly) possible too much 'trash' mTor cleaning up? My immune system is confused, and possibly attacking itself...along with inflammation. Once the immune system becomes overwhelmed and confused about what is an invader and what is not, a "reset" needs to take place to properly orient it to harmful and safe substances). From: Reviving the Broken Marionette: Treatments for CFS/ME and Fibromyalgia CFS/ME is not generally considered an autoimmune illness, but autoimmunity could still contribute to its symptoms. Several autoantibodies have been detected more commonly compared to healthy controls. These include e.g. gangliosides; phospholipids; serotonin. 9 Antinuclear antibodies (ANA) are found in a subset of CFS/ME patients. In one study over 50% of CFS/ME patients had autoantibodies to muscarinic cholinergic receptors.10 Here we review the potential sources of autoimmunity which are observed in people with ME/cfs. The increased levels of pro-inflammatory cytokines, e.g., interleukin-1 and tumor necrosis factor-α, and increased levels of nuclear factor-κB predispose to an autoimmune environment. Many cytokine abnormalities conspire to produce a predominance of effector B cells and autoreactive T cells. The common observation of reduced natural killer cell function in ME/cfs is a source of disrupted homeostasis and prolonged effector T cell survival. B cells may be pathogenic by playing a role in autoimmunity independent of their ability to produce antibodies. The chronic or recurrent viral infections seen in many patients with ME/cfs can induce autoimmunity by mechanisms involving molecular mimicry and bystander activation. Increased bacterial translocation, as observed in ME/cfs, is known to induce chronic inflammation and autoimmunity. Low ATP production and mitochondrial dysfunction is a source of autoimmunity by inhibiting apoptosis and stimulating necrotic cell death. Self-epitopes may be damaged by exposure to prolonged O&NS, altering their immunogenic profile and become a target for the host’s immune system. Nitric oxide may induce many faces of autoimmunity stemming from elevated mitochondrial membrane hyperpolarization and blockade of the methionine cycle with subsequent hypomethylation of DNA. Here we also outline options for treatment involving rituximab and endotherapia. From: The Emerging Role of Autoimmunity in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/cfs) Abstract The World Health Organization classifies myalgic encephalomyelitis/chronic fatigue syndrome (ME/cfs) as a nervous system disease. Together with other diseases under the G93 heading, ME/cfs shares a triad of abnormalities involving elevated oxidative and nitrosative stress (O&NS), activation of immuno-inflammatory pathways, and mitochondrial dysfunctions with depleted levels of adenosine triphosphate (ATP) synthesis. There is also abundant evidence that many patients with ME/cfs (up to around 60 %) may suffer from autoimmune responses. Awide range of reported abnormalities in ME/cfs are highly pertinent to the generation of autoimmunity. Here we review the potential sources of autoimmunity which are observed in people with ME/cfs. The increased levels of pro-inflammatory cytokines, e.g., interleukin-1 and tumor necrosis factor-α, and increased levels of nuclear factor-κB predispose to an autoimmune environment. Many cytokine abnormalities conspire to produce a predominance of effector B cells and autoreactive T cells. The common observation of reduced natural killer cell function in ME/cfs is a source of disrupted homeostasis and prolonged effector T cell survival. B cells may be pathogenic by playing a role in autoimmunity independent of their ability toproduce antibodies. Thechronic orrecurrent viral infections seen in many patients with ME/cfs can induce autoimmunity by mechanisms involving molecular mimicry and bystander activation. Increased bacterial translocation, as observed in ME/cfs, is known to induce chronic inflammation and autoimmunity. Low ATP production and mitochondrial dysfunc-tion is a source of autoimmunity by inhibiting apoptosis and stimulating necrotic cell death. Self-epitopes may be damaged by exposure to prolonged O&NS, altering their immunogenic profile and become a target for the host’s immune system. Nitric oxide may induce many faces of autoimmunity stemming from elevated mitochondrial membrane hyperpolarization and blockade of the methionine cycle with subsequent hypomethylation of DNA. Here we also outline options for treatment involving rituximab and endotherapia Introduction Myalgic encephalomyelitis/chronic fatigue syndrome (ME/cfs) is characterized as a nervous system disease according to the World Health Organization, including the International Classification of Diseases (ICD-10, G93-3) [1, 2]. One defining characteristic of the disease is a global worsening of symptoms or a prolonged state of relapse following even trivial increases in cognitive or physical activity, i.e., post-exertional malaise/ fatigue (PEM) [3–5]. The pathology overlaps with what is observed in other neurological diseases such as multiple sclerosis and Parkinson’s disease, which are underpinned by a triad of abnormalities involving activated microglia raised oxidative and nitrosative stress (O&NS) and mitochondrial dysfunction. Morris and Maes [1, 6] detailed the mechanisms by which prolonged pathogen infection leads to a chronic immunoinflammatory environment in the periphery and ultimately results in activated microglia, raised O&NS, and mitochondrial dysfunctions. The vast majority of ME/cfs patients report multiple recurrent or persistent bacterial and viral infections [7–9]. The multiplicity of infections correlates positively with the number and severity of symptoms in people with ME/cfs. Interestingly, this relationship also extends to neurological symptoms [10]. Concurrent infections appear to globally worsen symptoms [11]. Several authors have reported reduced CD56 bright natural killer cell (NKC) function in ME/cfs [12–14]. Reduced NKC functioning has been a consistent finding with several research teams detecting impaired NKC activity in ME/cfs patients [12, 14, 15]. Strong evidence of T cell exhaustion has been reported in ME/cfs patients by many different teams of workers [15, 16]. Many studies using peripheral blood measures have shown redox dysregulation, indexed by decreased levels of antioxidants, e.g., zinc, coenzyme Q10, and glutathione [17–20] in ME/cfs and increased O&NS by-products, including higher levels of peroxides and thiobutyric acid, increased isoprostane levels, and elevated protein carbonyl levels [5, 17, 20–22]. A number of studies have demonstrated that oxidative stress measures correlate significantly and positively with symptom severity [5, 17, 19–22]. Other findings of increased O&NS in ME/cfs involve reports demonstrating active expression of immuno-inflammatory pathways known to promote free radical generation and oxidative damage, such as increases in pro-inflammatory cytokines, e.g., interleukin (IL)-1β, tumor necrosis factor (TNF)-α, nuclear factor (NF)-κB, cyclo-oxygenase-2 (COX-2), and inducible nitric-oxide synthase (iNOS) [18, 23–27]. Dysregulation of both pro-inflammatory and anti-inflammatory cytokines may occur in ME/cfs [18, 23–26]. In many ME/cfs patients, however, the role of pro-inflammatory cytokines is dominant [13, 28–30]. AbnormalitiesinIL-6andtransforminggrowthfactor(TGF)β-1 are also commonly reported [1]. Lowered levels of ω3-polyunsaturated fatty acids in ME/cfs may further increase the inflammatory potential [31]. Prolonged elevated levels of O&NS and pro-inflammatory cytokines play a role in the abnormalities in mitochondrial function reported by several teams of workers [20, 32–34]. Patients with ME/cfs reach perceived exhaustion at a much earlier time point than healthy controls. They display increased lactate and diminished adenosine triphosphate (ATP) production compared to healthy controls which is even more evident upon repeat exercise testing in both brain and striated muscle. Impairments in oxidative metabolism result in a marked acceleration of glycolysis in striated muscle and a prolonged recovery time needed to restore pre-exercise levels of ATP [35] state [32, 36]. Increasing leptin levels in people suffering from ME/cfs [37] using low-dose cortisone appears to be of benefit [38]. Low levels of leptin are found in people with clinical depression [39], although higher leptin levels have been shown to predict the development of de novo depression [40]. Recently, we have provided evidence that increased production of pro-inflammatory cytokines, immune activation, activated O&NS pathways, and increased lactate and diminished ATP production in ME/cfs may conspire to cause PEM [1, 5, 6, 28]. All the abovementioned abnormalities can conspire to create multiple sources of autoimmune responses and pathology in ME/cfs. The aim of this paper is to review the different types of autoimmune responses in ME/cfs, the etiological factors that play a role in the onset of those autoimmune reactions in ME/ cfs and putative treatments of the autoimmune reactions. Autoimmunity in ME/cfs Not all patients with ME/cfs suffer from autoimmunity or emerging autoimmune responses. The percentage of positive ME/cfs patients showing autoimmune responses is difficult to establish; however, estimates vary from 30 to 60 % and around 40–50 % show the development of autoimmune reactions directed against a multitude of different neoepitopes [27]. B Cells in ME/cfs Increases in the number of mature CD19 B cells have been reported in ME/cfs patients [41–43]. Klimas et al. [15] reported elevated number of CD20 and CD21 B cells in their trial population. In a recent study, Bradley et al. [44] reported an extremely large and significant increase in the number of naive B cells, which express CD19 and CD20, as a percentage of total lymphocytes and B cells in ME/cfs. The authors also detected significantly greater numbers of transitional B cells and a markedly depleted plasma blast population which they opined pointed to a state of autoimmunity in the patients examined. Autoimmunity in ME/cfs Autoantibodies against neurotransmitter receptors, including 5hydroxytryptamine receptor 1A (HTR1A), dopamine receptor D2 (DRD2) and muscarinic cholinergic receptor 1 (CHRM1), and mu-opioid receptor (OPRM1), have been reported in patients with ME/cfs. Patients with ME/cfs show a higher antiCHRM1 antibody index and presence of antinuclear antibodies [45]. Antineuronal antibody levels are particularly elevated in ME/cfs patients with neurologic abnormalities [46]. The presence of autoimmune antibodies in the systemic circulation may result in muscular and or mental fatigue by binding with calcium channels and acetylcholine receptors or antigens in the CNS [47]. Large subgroups of ME/cfs patients display indicators of autoimmune responses directed against antilamine, microtubule-associated proteone, ssDNA, phospholipids, gangliosides, 5-HT, and 68/48kd proteone [48–51]. Table 1 reviews the different autoimmune findings in ME/cfs. Neoepitopes in ME/cfs IgM-mediated immune responses directed against endogenous moleculesare presentinME/cfs patients. These molecules have been damagedundergoing changesinconformationduetohigh levels of O&NS damage and have become immunogenic as a result. Consequently, autoimmune responses are generated against by-products of lipid peroxidation, such as azelaic acid and malondialdehyde (MDA), corrupted anchorage molecules, including oleic, palmitic, and myristic acid and S-farnesyl-Lcysteine, and NO-modified amino acids and proteins, including NO-phenylalanine, NO-arginine, NO-tyrosine, NOtryptophan, NO-cysteinyl, and NO-albumin [17]. The concentrations of these damaged molecules correlate significantly and positively with symptom severity. Raised serum IgM levels directed against membrane constituents and anchorage molecules additionally correlate with increases in muscular fatigue and a flu-like malaise [17]. Factors that Contribute to Autoimmune Responses in ME/cfs Role of NK Cells in Autoimmunity NKCs, via their rapid response and their ability to destroy infected cells, are the primary defense against pathogen invasion and are active before the adaptive immune system comes into play [52, 53]. They also interact with other immune cells, however, and also perform a major role in immune regulation particularly in controlling excessive T cell proliferation and regulating the activation and differentiation of myeloid dendritic cells. NKCs facilitate dendritic cell (DC) development and T cell differentiation, but NKCs can also inhibit (auto)immune responses by destroying autologous myeloid and lymphoid cells. Table 1 Signs and drivers of autoimmunity in myalgic encephalomyelitis/chronic fatigue syndrome (MS/cfs) Signs of autoimmune responses in ME/cfs• Numbers of CD19, CD20, and CD21 B cells• Anti-serotonin (5-HT) antibodies• Anti-5-HTA receptor antibodies• Anti-D2 receptor antibodies• Anti-muscarinic cholinergic receptor antibodies• Antinuclear antibodies• Antineuronal antibodies• Antilamine antibodies• Microtubule-associated proteone antibodies• ssDNA• Anti-phospholipid antibodies• Ganglioside antibodies• 68/48kd proteone• IgM against oxidatively modified neoepitopes• IgM against nitric oxide adducts• Positive clinical response to treatment with rituximab• Drivers of autoimmune responses in ME/cfs• Reduced numbers and functions of natural killer cells• Viral infections through molecular mimicry and bystander effects• Mitochondrial apoptosis and necrosis pathways and shortfalls in ATP• Elevated levels of nuclear factor-κB• Cytokines inducing T helper 17 phenotype differentiation• Bacterial translocation with lipopolysaccharide-associated molecular mimicry• Formation of immunogenic oxidatively and nitrosatively modified neoepitopes• Increased concentrations of homocysteine and DNA hypomethylation Activated mammalian target of rapamycin, e.g., via increased nitric oxide NKCs resident in peripheral blood may be subdivided into two subsets, i.e., those that express CD56 or CD16 receptors. CD56dimCD16+NKCsmakeupapproximately90%ofNKCs found in blood. These NKCs attack and kill target cells with great efficiency but secrete only very low levels of cytokines. CD56brightCD16− NKCs, however, constitute less than 10 % of the entire NKCs population and are found in much greater concentrations in secondary lymphoid tissues [54]. This NKC subset, when activated produces a range cytokines, including interferon (IFN)-γ, TNF-α, and granulocyte-macrophage colony-stimulating factor (GM-CSF), but need to be activated before they are able to exert a cytotoxic function [55]. There is also a growing understanding of the role of NKCs in the genesis of autoimmunity [56, 57]. Some studies report that NKCs impede or impair autoimmune responses [58, 59]. Others, however, suggest that NKCs have an enabling role in autoimmunity, possibly due to their innate ability to supply an early source of cytokines with subsequent activation of antigen presentation cells (APCs) and hence the development of inflammatory and ultimately pathogenic Th1 (and Th17) responses [60, 61]. The weight of evidence suggests that NKCs can regulate inflammation and induce loss of self-tolerance at a number of different levels during immune activation and, thus, suggest that NKCs play quite different roles in different kinds of autoimmunity. It appears that their roles also vary during different stages of the processes which ultimately cumulate in the development of autoimmune diseases. NKC functions (and sometimes numbers) decline in majority of autoimmune diseases as the diseases progress [62]. There has been a great deal of debate regarding a primary role for NKCs in engendering autoimmunity [57, 62]. The weight of evidence indicates that NKCs promote the creation of autoreactive Th1 cells and subsequent disease at a relatively early stage in the genesis of autoimmune disease [60, 61]. Once autologous T cells come into play, NKCs are controlled by cytokines (in particular IL-21) secreted by these cells which lead to a functional deficiency and even a partial deletion of the NKCs in question [63]. IL-21 can stimulate the activation and differentiation of T and NKC populations, but can also induce the death of those cells [64, 65]. The effect of IL-21 on NKCs seems dependent on the functionality of the cells [64, 65]. T cells appear to have two different contrasting kinds of influence on NKCs. Firstly, T cells act to support NKC activity under conditions of chronic infections, via the provision ofIL-2. Secondly, Tcells attenuate NKC activity via the release of IL-21 [63]. The bidirectional interaction or cross talk between NKCs and Tcells is facilitated by colocalization [66, 67] and dendritic cells act as communicative bridges between the two cell types [63, 68]. Numerous studies have reported that people with autoimmune diseases like systemic lupus erythematosus (SLE) and multiple sclerosis (MS) have depleted numbers of NKCs compared to controls and that those cells display grossly impaired functions [69, 70]. The results of four magnetic resonance imaging (MRI) studies involving intravenous daclizumab in MS provide very strong evidence supporting the role of NKCs in disease pathology [71]. Daclizumab (Zenapax®) is a humanized monoclonal anti-CD25 antibody that was first approved in renal allograft rejection and later examined in clinical trials in MS [71]. The numbers of CD16-NKCs increased in the peripheral blood of patients treated with daclizumab. Moreover, the reduction in disease activity, measured by MRI, correlated significantly and positively with the expansion of this NKC subset [72]. NKCs obtained from the blood of patients during therapy destroyed autologous-activated T cells, while NKCs taken from the same patients before therapy did not [72]. This supports the notion that reduced numbers and function of CD56 bright CD16-NKCs contribute to the development or maintenance of the disease [54]. By inference, the frequently reported finding that NKCs and NKC activity are significantly lowered in ME/cfs may play a role in the onset of autoimmunity in that disorder. Role of Viral Infections in Autoimmunity Viral infections lead to the synthesis of IFN-α and IFN-β. If the levels of IFN-α and IFN-β are high enough, subsequent activation of IL-12 and NKCs is blocked [73, 74]. With some viruses, however, this IFN response is not sufficient to block high levels of IFN-γ and IL-12 [74] and this situation may lead to autoimmunity. Bystander activation, molecular mimicry, and chronic viral infection possibly involving epitope spreading are potential processes that may generate immunoreactivity eventually producing autoimmunity. Virus Infections and Molecular Mimicry Molecular mimicry involves the presence of a shared epitope between a virus or other pathogen and a host [75]. Crossreactivity between viruses and hosts are commonplace. In order for overt autoimmune disease to emerge, the crossreactivity must involve an epitope which has a crucial part to play in biochemical cascades, and damage to its structure can lead to pathology. If no such epitope is involved, a state of autoimmune responsivity may exist but no disease emerges [75].Chronic viral infections may cause immune- and O&NSmediated damage because of the chronic presence of viral antigens activating the immune system. For example, numerous viruses are associated with the onset and maintenance of MS. Approximately two dozen different viruses are isolated from the CNS of MS patients, including herpesviruses, paramyxoviruses, andretroviruses, etc. [76, 77]. Numerous studies have reported exacerbation of disease activity following virus infections [78, 79]. Despite the isolation of those viral entities, none have been definitively established as being the causative pathogen [80]. Viral antigens may display very similar if not identical three-dimensional structure and/or sequence homology to host epitopes [75]. Such viral infections can ultimately lead to primed or activated preexisting self-reacting T cells leading to autoimmunity. Such preexisting autologous T cells would in the case of MS include a T cell population which is reactive to myelin. Myelin-specific Tcells have been detected in patients with MS and healthy controls [81]. This is essentially the mechanism of autoimmunity induced by molecular mimicry. Infection by viruses lacking homologous structures may cause autoimmunity via the bystander activation mechanism. This involves a localized intense cytokine response resulting in the proliferation and migration of self-reactive T cells into the CNS [82]. This will be dealt with in more detail in a subsequent section. Viral Infections and Bystander Effects Bystander T cell activation produces functional and phenotypic changes in T cells without the need for engagement of the T cell receptor (TCR) [83]. While other receptors on cell membranes may be involved [84], cytokines alone are capable of provoking this mode of activation [85]. Tcells are normally activated via the engagement of highly specific TCRs and MHC molecules [86, 87]. These cells may also be activated unconventionally by TCR independent or bystander signaling [83]. Bystander Tcell occurs in herpes simplex virus, LCMV, and HIV infections leading to polyclonal expansion of memory T cells and subsequent production of protective or pathological cytokines. The underlying mechanism of bystander IFN-γ activationis dependent onpro-inflammatorycytokines, mainly IL-12 and IL-18 [88]. For example, a role for bystander activation may account for the cell death resulting from HIV infection which cannot be explained by direct infection of T cells [89]. Activation of immuno-inflammatory pathways has been proposed as a major cause of cell death [90], a proposal supported by a considerable body of evidence [90]. Virus infections also provoke activation of dendritic cells and macrophages. These activated antigen-presenting cells can also activate preprimed autoreactive T cells, which in turn may drive autoimmune responses. Additionally, T cells which are virus-specific might also instigate bystander activation. Briefly, CD8+ T cells recognize virally infected cells at sites of infection and secrete toxic granules causing the death of these cells. The apotopic fragments, the CD8+ T cells and macrophages then generate cytokines, such as TNF-α, and NO, which drive bystander destruction of cells in the immediate vicinity even when not infected. This produces exaggerated immunopathology at the sites of viral infection [77]. Mitochondrial Apoptosis Pathways and Autoimmunity Apoptosis and Necrosis Identification of apoptotic cells by phagocytes drives the production of anti-inflammatory cytokines, e.g., IL-10, prostaglandins, and TGF-β1 [90, 91] and actively restrains the activity of pro-inflammatory cytokines generated by engagement of Tolllike receptors (TLRs) [92]. Apoptotic cells may block TLRdependent release of pro-inflammatory cytokines and chemokines, processes which are regulated at the transcriptional level [93]. Thus, the stimulation of phagocyte receptors not only results in the immune silent removal of dying cells but produces signals leading to the production of anti-inflammatory agents which generate an immunosuppressive milieu during the elimination of apoptotic cells. During necrotic cell death, on the other hand, the uncoordinated and massive release of cell contents may cause profound immuno-inflammatory responses. The other homeostatic process involved in apoptotic elimination is the generation of anti-inflammatory compounds, which inhibit immuno-inflammatory pathways and enable the removal of apoptosed cells. Failure to efficiently remove apoptotic cells can generate autoimmunity [94]. Impaired apoptotic clearance means that apoptotic cells can undergo necrotic death which involves the lysis of cells releasing their contents thus provoking activation of immuno-inflammatory pathways directed against the voided intracellular antigens and DNA [95, 96]. This provides an immunogenic impetus involved in the etiopathology of several human autoimmune disorders notably systemic lupus erythematosus and rheumatoid arthritis [97]. In the extrinsic pathway, released ligands (signaling molecules) bind to death receptors such as Fas on the target cell resulting in the induction of apoptosis [98]. Apoptotic signals triggered by Fas (Apo1/CD95) can be transmitted via two pathways depending on cell type [99]. Fas excitation activates caspase-8 in type 1 cells by express formation of the DISC3 (death activating complex) [100, 101], which subsequently activates caspase-3, once again resulting in apoptosis. In type 2 cells, DISC formation is less marked and alterations in mitochondrial membrane potential (DCm) occur before the activation of caspase-8 and caspase-3. Active caspase-8 can also regulate the escape of cytochrome c in the intrinsic pathway [101, 102]. The intrinsic pathway is activated by cellular stress, especially elevated free radicals and elevated O&NS. Once the stress signal is received, proapoptotic proteins such as BAX and BID induce the release of cytochrome c together with other contents from the mitochondria [103] into the cytoplasm. Once released, cytochrome c interacts with ATP to form a complex that ultimately activates caspase-9, one of the apoptosis initiator proteins [104]. Consequently, an apoptosome is formed, which ultimately activates a final effector protein that initiates capase-3 degradation [104]. Low ATP concentrations, as are frequently observed in ME/ cfs, inhibit this apoptotic pathway. Mitochondrial ATP, Apoptosis, Necrosis, and Autoimmunity A number of studies have reported that depletion of intracellular ATP completely inhibits Fas-mediated apoptosis and that ATP-dependent steps occur down- and upstream of caspase-3like protease activation [105]. Hence, a shortfall of ATP can inhibit the intrinsic as well as the extrinsic pathway. It is not surprising, therefore, to learn that the ATP concentration is a major determinant of cell demise by apoptosis and necrosis [105]. Moreover, apoptotic signals are communicated to the cell nucleus via an ATP-dependent mechanism [106]. Indeed, this active transport mechanism is vital for generating apoptotic changes of the nucleus [107]. Necrosis is regarded as a form of highly regulated programmed death enabled by communication between an array of ATP-dependent kinase enzymes [108, 109]. Death receptor signaling is regarded as a major driver of ATP-dependent necrosis and may occur without any perceptible depletion in cellular ATP. This pathway is regulated by a series of protein kinases with one particular threonine kinase namely RIP-1 being the key regulator. Energy availability is a key driver of different types of necrosis [110]. Below a certain ATP threshold, an instigated apoptopic response fails but necrosis takes over. Hence, the level of ATP depletion is involved in the type of cell death [111]. We conclude that shortfalls in ATP may either drive programmed cell death (PCD) towards the necrotic pathway or indeed inhibit cellular death altogether or dramatically increase the survival time of effector T cells in the immune system. In either case, a shortfall of ATP may be a driver of autoimmunity and chronic inflammation. Another cause (or indeed consequence) of chronic inflammation is activated NF-κB which we will discuss in the next subsection. Role of NF-κB in Generating Autoimmunity NF-κB and Generation of Chronic Inflammation The increased levels of NF-κB, which are frequently observed in ME/cfs [24], may also play a role in the generation of autoimmunity. The activation of NF-κB initiates a number of transcriptional eventsleadingto autoregulationofinflammatory cascades via modulation of NF-κB activation [112]. NF-κB can beactivatedbynumerousstimuli.Suchstimuliincludebacterial endotoxins [113], TNF-α, IL-1β [1, 114], elevated O&NS [1, 115], mitogens, and viral proteins [114]. NF-κB activation stimulates the transcription of TNF-α and IL-1β, both of which in turn are known activators of NF-κB [1]. An inflammatory stimulus such a bacterial endotoxin leads to the activation of NF-κB, which enhances TNF-α and IL-1β production resulting in the amplification of the initial inflammatory signal [112]. NF-κB during an inflammatory response activates the synthesis of iNOS that produces NO [116]. NF-κB and Autoreactive B Cells Elevated levels of NF-κB additionally increase survival of autoreactive B cells [117]. A further contribution made by elevation of NF-κB to autoimmunity is the consequent upregulation of B cell activating factor (BAFF), a crucial cytokine in the survival of B cells and resting mature B cells [118, 119]. BAFF is not only a crucial survival factor during B cell development but is also an essential factor in the development of B cell tolerance. Breakdown of the mechanisms regulating BAFF expression results in exaggerated BAFF synthesis that diminishes B cell tolerance and drives B cell hyperplasia and leads to autoimmune phenomena [120]. NF-κB and Cell Death There are two NF-κB pathways involved in the regulation of cell survival or cell death [121]. The classical pathway is activated by bacterial or viral infections or elevated levels of pro-inflammatory cytokines [122]. This is the pathway which is normally involved in the inhibition of PCD [123, 124]. The second or alternative pathway is stimulated by a range of TNF molecules [125] and is particularly important in premature B cellsurvival[126].Twowell-illuminated pathwaysleadtoPCD [127], i.e.,the mitochondrial or intrinsic pathway and,secondly, the death receptor (DR) or extrinsic pathway [128]. Both pathways are caspase-dependent [128, 129]. NF-κB suppresses both PCD types [130, 131] and exerts this prosurvival activity through different anti-apoptotic proteins [123, 132]. NF-κB promotes the expression of different compounds of the Bcl-2 family which impede apoptosis through mitochondrial mechanisms involving caspase-8-governed Bid cleavage and cytochrome c release [123, 132]. NF-κB and c-Jun activating kinase (JNK) are activated simultaneously under a variety of stress conditions. Conversely, sustained activation of NF-κB inhibits cytokine-induced JNK activation [133]. Whereas temporary activation of JNK following TNF treatment promotes cell survival, chronic JNK activation encourages cell demise. NF-κB activation restrains the chronic phase of JNK activation and therefore protects cells against cytotoxicity induced by TNF-α [134]. Multiplepositivefeedbackloopsexistbetweentheinstigators of cellular death, O&NS, caspases, and JNK. Crucially, NF-κB suppresses these positive feedback loops by activating caspase inhibitors, BCl-2 compounds, and antioxidants. Hence, elevation of NF-κB leads to a depletion of reactive oxygen species (ROS) and caspase inhibition. NF-κB activation additionally inhibits sustained JNK activity which explains the prosurvival activityofNF-κB[135].NF-κB,cytokines,andelevatedO&NS are conspirational partners in producing a chronic immunoinflammatory state and consequent immune sequelae involving a number of different mechanisms [1]. We now turn to causes of autoimmunity produced by abnormal levels of cytokines and O&NS, two other characteristics of ME/cfs. Cytokines and T Cell-Mediated Autoimmunity IL-6 in combination with TGF-β induces the production of Th17 cells [136]. Several cytokines apart from TGF-β1 and IL-6 support the differentiation of naive T cells towards the Th17 phenotype. These cytokines include IL-1β, IL-21, and IL-23 [136, 137]. IL-6 actually orchestrates the differentiation of Th17 cells by activating STAT-3 leading to the subsequent production of IL-21 and IL-23 [138]. These latter cytokines are activators of RORyt, the transcription factor governing the shift of naive T towards Th17 cells. IL-21 is essential to this process and may drive Th17 differentiation in the absence of IL-6 [136, 139]. IL-23 is not essential for the differentiation of Th17 T cells but is vital for their survival and their function. Hence,Th17Tcells are not pathogenic inthe absence ofIL-23 [136, 140]. IL-1 amplifies the generation of Th17 cells induced by TGF-β1 and IL-6 and may cause a Th17 shift in the absence of IL-6 [136, 139, 140]. IL-1 overproduction results in the conversion of FOXP3 T regulatory (Treg) into Th17 cells [141, 142]. It is noteworthy that while elevated levels of IL-2 normally suppress the generation of Th17 cells, elevations of IL-2 in the presence of elevated IL-1 have a stimulatory effect [143]. IL-6 has another pivotal role in the production of Th17 cytokines by inhibiting the differentiation and function of FOXP3 regulatory Tcells. FOXP3 inhibits the transcription of ROR gamma and hence suppresses Th17 differentiation [144]. Th17 cells are encephalitogenic in the presence of IL-23 and readily cross the blood–brain barrier (particularly if inflamed) and induce neuroinflammation [140] via a number of mechanisms. These mechanisms include the secretion of granzyme B causing neuron damage and stimulating the recruitment of CD4 + T cells, neutrophils, and dendritic cells into the CNS [145]. Th17 most readily cross the blood barrier if it is already inflamed. Elevated levels of IL-1β and TNF-α lead to the disruption of endothelial tight junctions in the blood–brain barrier [146, 147] and the gut [148, 149]. These pro-inflammatory cytokinesmaynotonly facilitate neuroinflammation bycausing disruption of the blood–brain barrier (BBB), but also do so by increasing the permeability of tight junctions in the gut and allowing translocation of bacteria and endotoxins into the bloodstream. Bacterial Translocation, Neuroinflammation, and Autoimmunity Increased bacterial translocation, a new pathway in ME/cfs [17, 30], is another factor that may cause autoimmunity in ME/cfs. IL-1β and TNF-α cause an increase in intestinal endothelial cell permeability via the activation of NF-κB [149] and disrupt endothelial cell tight junctions allowing the translocation of gram-negative bacteria and LPS or endotoxins into the mesenteric lymph nodes or the circulation leading to activation of immuno-inflammatory responses [18, 30, 150]. The microvascular endothelial tight junctions in the BBB are very similar to those in the intestine, and hence, molecular entities such as Th17 T cells which can damage the tight junctions in the intestine may also damage the tight junctions in the brain. Circulating bacterial LPS disrupt the integrity of the BBB [151] and lead to the activation of microglia [152]. Microglia are responsible for activating and propagating the immune response in the CNS following pathogen invasion [153, 154]. Microglia (and astrocytes) are able to “perceive” pathogens via their pattern recognition receptors. Binding of pathogens promotes recruitment and antigen-specific activation of infiltrating leucocytes [154]. Activation of microglia and subsequent activation of astrocytes result in neuropathological changes, eventually leading to the development of neuroinflammation of neurodegenerative disease [1, 6]. Bacterial LPS can also generate neurological diseases which are autoimmune in origin. For example, the central oligosaccharides of the LPS of Campylobacter jejuni demonstrate a high degree of mimicry with gangliosides [155]. Cross-reactivity between anti-LPS and anti-ganglioside antibodies plays a pivotal role in the etiology of Guillain–Barré syndrome [18, 156]. LPS appears to stimulate the release of glutamate, ultimately removing the voltage-sensitive Mg2+ block of NMDA receptors, promoting excitotoxicity [157]. LPS molecular mimicry resulting from gram-negative bacteria associated with Alzheimer’s disease (beta-amyloid), AIDS dementia (gp120 and gp41), or multiple sclerosis (myelin basic protein) may well explain the transient neurological and neuropsychiatric symptoms often associated with these diseases [157]. Some authors suggest that LPS-associated molecular mimicry may in fact cause MS and Parkinson’s disease [158, 159] and that increased intestinal permeability plays a role in both disorders [160, 161]. We have discussed a number of mechanisms whereby autoimmunity in the periphery could induce a state of autoimmunity in the CNS. Indeed the existence of autoantibodies to neurotransmitters and anchorage molecules has been repeatedly demonstrated in ME/cfs. The next section concentrates on autoimmunity induced by elevated O&NS. The basic principle underpinning this data is that epitopes may be damaged by exposure to prolonged O&NS and thus lose their immunogenic tolerance and become a target for the hosts’ immune system [17]. Autoantibodies Resulting from O&NS-Modified Epitopes IgM-related immune responses have been reported in ME/cfs patients directed towards corrupted components of lipid membranes and anchorage molecules, such as oleic, palmitic, and myristic acid, and S-farnesyl-L-cysteine [17, 29]. IgM autoantibodies are also produced against derivatives of lipid peroxidation, e.g., azelaic acid and malondialdehyde (MDA), and nitrosatively modified amino acids or proteins, such as NOtyrosine, NO-phenylalanine, NO-arginine, NO-tryptophan, NO-cysteinyl, and NO-albumin. Interestingly, IgM-mediated immune responses directed against the same neoepitopes (e.g., lipid membrane fatty acids, anchorage molecules and NO-adducts) and comparable immuno-inflammatory and O&NS processes have been observed in major depression [18, 27, 50]. Recently, we have reviewed that these shared immuno-inflammatory, O&NS and autoimmune pathways may underpin the comorbidity between ME/cfs and major depression [50]. These secondary autoimmune responses directed against neoepitopes are significantly greater in ME/cfs than in major depression [27]. Lipid peroxidation induced by elevated ROS leads to the genesis of highly reactive aldehydes, including 4hydroxynonenal (4-HNE) and MDA. These entities can engage in covalent bonding with proteins, modifying their structure, which in turn affects their biological functions [162] potentially making them highly immunogenic [163, 164]. The importance of NO in disease etiology lies with generation of superoxide, ultimately leading to the production of peroxynitrite (ONOO−). This entity is a powerful nitrating and oxidizing agent which for example reacts with tyrosine residues to produce nitrotyrosine (NT) [165]. Elevated NT levels have been found in many pathologies [166, 167]. Additionally, modifications of DNA and proteins by peroxynitrite may amplify their immunogenicity, causing a break in immune tolerance [163, 167, 168]. The role of elevated O&NS in the generation of antibodies is therefore one mechanism by which these signaling molecules underpin the development of autoimmunity. The next section deals withautoimmunepathology initiatedbyelevated NO, which are frequently observed in ME/cfs [17, 29]. The section will be a brief and simple summary of the molecular pathways involved. Nitric Oxide, the Methionine Cycle, and Autoimmunity Nitrous oxide irreversibly inhibits methionine synthase, the enzyme responsible for the remethylation of homocysteine to methionine, via the oxidation of the essential cofactor cobalamin [169]. This inhibition leads to elevated levels of homocysteine and depleted concentrations of methionine. Increased concentrations of homocysteine and S-adenoylhomocysteine in the intracellular space result in hypomethylation of DNA [170]. This state can lead to the overexpression of many genes involved in autoimmunity [171, 172]. Such hypomethylation of DNA is observed in a number of autoimmune diseases [173], e.g., rheumatoid arthritis [174], SLE [172], and inflammatory arthritis [175]. Hypomethylation of lymphocyte DNA produces an increase in self reactivity in antigen-specific T cells [176] and stimulates the production and proliferation of autologous B cells [177]. The increase in autoreactive B cells numbers and function is considered to be a major contributing element in autoimmunity induced by abnormalities in this lymphocyte population which will be considered in the final section of the paper. Before considering this area in detail, however, the next section focuses on the role of NO as a regulator of mitochondrial membrane potential and the mammalian target of rapamycin (mTOR). NO acts as a signaling molecule which regulates mitochondrial membrane potential [178]. Prolonged elevated NO concentrations lead to mitochondrial membrane hyperpolarization [179] and subsequent stimulation of mTOR [180]. mTOR is a serine/threonine protein kinase and a monitor of the mitochondrial transmembrane potential which controls protein synthesis, cell growth, cell proliferation, and survival [181]. mTOR is additionally a major regulator of T cell homeostasis [182] and chronic activation disrupts the regulation of the immune response producing effects predisposing to autoimmunity. These effects include increased proliferation of autoreactive T cells coupled with an increase in B cell autoantibody production [183]. Activated mTOR drives the differentiation of naive T lymphocytes towards the effector phenotype [184] and inhibits Treg differentiation and FOXP3 expression thus not only reducing Treg numbers but also Treg cell function [182, 185, 186]. Natural CD4 + FOXP3 Treg cells are not terminally differentiated and display developmental plasticity. Activated mTOR “reprograms” natural Tregs into Th17 or Th1 T lymphocytes [185]. mTOR also controls the activation and maturation of plasmacytoid dendritic cells [184, 187]. The net effect of activated mTOR is the increase in IFN-α produced by plasmacytoid dendritic cells and an increase in the costimulatory capacity of myeloid dendritic cells [187]. Elevated levels of leptin, a cytokine heavily involved in energy regulation, also activates mTOR [188]. It is perhaps not surprising therefore that elevated levels of leptin are found in many autoimmune conditions [189]. The following section examines the effects of elevated levels of this cytokine on different players involved in the immune response. Leptin and Autoimmunity Leptin levels are elevated by prolonged activation of proinflammatory cytokines [190] and subsequently have profound effects on the immune system further predisposing to an autoimmune environment. Leptin exerts a stimulatory effect on NO production [191] and further upregulates the activity of proinflammatory cytokines [183, 192]. Elevated levels of leptin potentiate the production of IL-12, IFN-γ, and IL-2 and suppress the synthesis of IL-10 and IL-4 [193, 194]. Activated T cell survival and proliferation are both enhanced by leptin [195, 196], while the proliferation of FOXP3 CD4 + CD25+ Tregs is inhibited by this cytokine [183]. Evidence suggests that elevated levels of leptin leads to the activation and improved survival of resting T and B lymphocytes with subsequent secretion of TNF-αandIL-6bybothcelltypes[197].Leptinalsomodulates the secretion of pro-inflammatory cytokines and chemokines by macrophages [193], monocytes [198], and eosinophils [199]. Dendritic cell survival and Th1 priming are both increased by elevated leptin levels as is their production of proinflammatory and Th1 cytokines [200]. All in all, elevated levels of leptin may induce a de novo autoimmune environment by inducing the activation of Tand B cells while driving T cell differentiation towards the Th1 or Th17 phenotype or by potentiating the deleterious effects of an already chronically activated immune system. In the forthcoming final section, we consider the management role of B cells and their contribution to autoimmune pathology which exists quite independently of their ability to produce antibodies. Antibody-Independent Generation of Autoimmunity by B Lymphocytes B cells synthesize cytokines in response to a wide range of extracellular signals. These signals include microbial endotoxins, antigens, and T cells [201, 202]. In individuals with autoimmune disorders, cytokine-producing B cells are found in the blood and primary lymphoid tissues [201, 203]. Cytokines produced by B cells are able to modulate the development and function of many pivotal immune cells, including T, NK, and dendritic cells [204]. This management role of B cells probably explains the immunoregulatory antibodyindependent activities of B cells [205]. Interestingly, rituximab therapy induces prolonged remission in several autoimmune diseases without any significant depletion of serum autoantibody titers [206]. Rituximab (Rituxan® or MabThera®) is a monoclonal antibody which targets CD20 (a B cell surface marker) and consequently causes a profound B cell depletion [206]. The CD20 monoclonal antibody modulates the titer and functions of Treg and effector Tcells in many autoimmune diseases [204, 207]. This observation adds to the accumulating body of evidence that B cells may be pathogenic independently of their ability to produce antibodies [201, 205]. The mechanisms that regulate B cell cytokine synthesis are therefore a focus of interest. B cells are able to differentiate into Th-1-like and Th-2-like effector subsets that produce distinct cytokines, such as IFN-γ and IL-4, respectively [204, 205, 208–210]. B cells may produce chemokines and cytokines independently or in response to antigen, TLR ligands, T cells, or combinations of these stimuli [201, 202]. B cell cytokine production is heavily context-dependent and is the result of the balance of signals received by the B cell receptor and the CD40 antigen. CD40 and BCR signaling results in the proliferation of B cells secreting TNF-α and IL-6. These cytokines act in an autocrine manner to further accelerate B cell differentiation and amplifies the immune response via the generation and maintenance of a positive feedback loop. CD40 stimulation alone activates B cells which generate IL-10 only [211]. As stated above, the cytokines made by B cells have a management role as they are involved in modulating the activation or function of CD4+ T cells [201]. Regulatory B cells or Bregs for example act to inhibit pro-inflammatory cytokines and effector T cell differentiation and promote the differentiation of Tregs via the production of IL-10 or TGF-β1 and hence dampen down a hyperaggressive immune response [203]. Reduced numbers or functions of these regulatory subsets are evident in a number of different autoimmune diseases [212, 213]. Similarly, TGF-β-expressing B cells stimulate the conversion of CD25 + CD4+ T cells into FOXP3+ Treg cells [214]. Thus, cytokines synthesized by B cells can suppress T cell immune responses directly or can promote a predominance of Treg cells which attenuate effector T cell proliferation and functions. B cells may be categorized based on their pattern of cytokine secretion into B effector-1 and effector-2 cells (Be-1 and Be-2 cells). B cells in the presence of Th1-like cytokines and primed by T cells or TLR ligands secrete Th1-like cytokines, including IFN-γ. These Be-1 cells produce minimal levels of IL-4 or IL-13 but do secrete IL-10, TNF-α and IL-6 [208, 210].In contrast, B cells in the presence ofTh2-type cytokines and primed by T cells/antigen secrete IL-2, IL-4, and IL-13, but low levels of IFN-γ and IL-12 [209, 210]. These Be-2 cells may also release IL-10, TNF-α, and IL-6. Finally, regulatory B cells [215] produce IL-10 following stimulation with antigen combinations, CD40L and TLR ligands [204, 216]. Hence, in the predominant cytokine environment present in people with ME/cfs, one would expect an imbalance of Be-1– Be-2 effector cells and Bregs. CD40 and BCR signaling would be expected in an environment containing high levels of pro-inflammatory cytokines and antigens, and hence, effector B cells would be expected to greatly outnumber regulatory B cells and make a major contribution to the breakdown of immune homeostasis evidenced in this disease. Conclusions and Future Directions We have endeavored to describe the many potential sources of autoimmunity in people with ME/cfs. Low NKC function is a source of disrupted homeostasis and prolonged effector T cell survival. Low ATP production and mitochondrial dysfunction is a source of autoimmunity by inhibiting apoptotic and stimulating necrotic cell death pathways and hence decreasing immunosuppression at the termination of the immune response and increasing inflammation. Elevated levels of proinflammatory and other cytokine species conspire together to impair the normal homeostatic mechanisms which govern T and B cell activation differentiation and survival. This leads to an imbalance of regulatory and effector lymphocytes. Elevated O&NS damage lipids and proteins leading to the formation of neoepitopes which become immunogenic leading to the disruption of many essential cellular processes. Elevated levels of NF-κB not only contribute to prolonged lymphocyte survival but also increase the generation of autoreactive B cells. Elevated levels of pro-inflammatory cytokines result in elevated levels of NO and leptin. Both entities lead to disruption of homeostatic mechanisms via interaction of mTOR. Elevated levels of NO lead to blockade of the methionine cycle and hypomethylation of DNA. Finally, increased levels of pro-inflammatory cytokines and NF-κB conspire to disrupt epithelial tight junctions in the intestine allowing the potential translocation of bacterial LPS into the general circulation. This can have dire consequences and is a crucial element underpinning the pathology in a number of neuro-autoimmune disorders. Rituximab has recently been evaluated as a treatment for ME/cfs and has displayed considerable efficacy [217]. In a study, 30 patients with ME/cfs were randomized to rituximab or placebo, in a placebo-controlled double-blind study and monitored for a year. Significant positive responses were recorded in 67 % of the rituximab-treated patients and 13 % of the placebo arm. The intervention produced a global improvement in symptoms without the production of any serious side effects. The positive response to rituximab experienced by patients was delayed by between 2 and 7 months, and this phenomenon convinced the authors that ME/cfs was, at least partly, an autoimmune disease. Rituximab is gathering momentum as a treatment of many autoimmune diseases [218] particularly where the patients are unresponsive to first and second line treatments [219]. When taken together, the trial data demonstrates that the great majority of patients respond well to rituximab. The benefit applies to people with a wide range of autoimmune diseases which are licensed indications such as rheumatoid arthritis [220] and other autoimmune diseases such as SLE [221] and Sjorgens syndrome [222] where the drug is prescribed off license. Concerns have been raised regarding the side effect profile of rituximab probably because of its historical success in successfully treating certain cancers. However, an exhaustive review of all peer-reviewed data undertaken by Gurcan et al. [219] concluded that the incidence of serious or severe unwanted effects was very low. Rituximab reduces T and B cells [223]. It must be stressed that the effectiveness of rituximab is not dependent on secreted antibody as rituximab does not alter plasma cell numbers in serum or CSF [224]. This observation suggests that rituximab may have effects other than as a monoclonal antibody. Perhaps one of the most surprising effects is the inhibition of Th17 Tcell production [225]. Th17 Tcells are pivotal players in producing chronic inflammation and neurotoxicity in several other autoimmune diseases such as MS. Rituximab also reduces IL-2 levels directly and thus may help to suppress a chronically activated immune system [226]. Rituximab may also achieve the inhibition of the immune response by inhibiting the activation of NF-κB [227], which is another driver of autoimmunity. Rituximab also improves the function of Treg cells [228]. Impaired Treg function is also another element in the induction autoimmunity and neurotoxicity. The contribution of B cells to pathology in MS is evidenced by the effectiveness of rituximab [229]. T lymphocytes from relapsing remitting MS patients show an attenuated response to stimulation by antigen following treatment with rituximab [230]. This observation supports the hypothesis that B cell activity is also required to maintain active disease processes in this illness [230]. The drug has also delivered clinically important benefits when used as a treatment in a number of peripheral neurological diseases [231]. Another potentially synergistic approach may well be the use of endotherapia. Endotherapia (GEMSP) has recently been successfully trialed as a treatment of MS [232]. Endotherapia is an immunopathological strategy addressing pathology which seems to underpin chronic incurable diseases whose etiology is multifactorial. It involves the combination of an evaluation of circulating immunoglobulins directed against specific neoepitopes that created ROS elevation. GEMSP is a preparation of numerous small molecules, including fatty acids, anchorage molecules, antioxidants, radical scavengers, amino acids, ligated to linear chain of poly-L-lysine (PLL) which are nonimmunogenic [232] and inhibit inflammation and O&NS processes. Each individual linkage affords significant advantages. Importantly, it prevents metabolic degradation of the linked molecules and enables a long half-life and confers stability on the various linked chemical entities. Membrane permeability is increased and the induction of various viral and bacterial components. These features combine to induce neuroprotection From: 'What Causes Chronic Fatigue Syndrome? Clues as to Causes for CFS' Several studies have shown irregularities in the immune systems of people with ME/CFS, but researchers have not found a consistent pattern of abnormalities. Among the most common are allergies and an overactive immune system. Some studies have reported that a majority of ME/CFS patients are allergic to things including pollen, foods and metals such as nickel and mercury. That's led to a theory that allergens may trigger a series of immune abnormalities which then lead to ME/CFS. One theory is that allergies, stress and infection may combine to deplete a chemical called adenosine triphosphate (ATP), which stores energy in cells. Some ME/CFS patients show evidence of decreased ATP production. Some ME/CFS patients have high levels of a substance called cytokines, which scientists theorize could cause symptoms of ME/CFS, including fatigue and muscle aches. Various studies have reported T cell imbalances in people with ME/CFS, but other studies have not confirmed the T cell and cytokine abnormalities. Chronic fatigue syndrome appears to have a few features in common with autoimmune diseases such as lupus or multiple sclerosis, in which the immune system mistakenly attacks healthy parts of the body. A growing body of research suggests ME/CFS may be autoimmune. From book: 'Immune Dysfunction and Autoimmune' There is an abundance of scientific evidence to suggest that people who have CFS have immune dysfunction. A high percentage of sufferers have elevated circulating cytokines, altered T lymphocyte numbers, and low natural killer cell cytotoxicity. In basic terms, these people have immune systems that are under functioning. This explains why people with CFS tend to frequently pick up coughs and colds. They also have trouble fighting off what they pick up. They are more susceptible to and affected by invaders such as viruses, bacteria, parasites, Candida, and toxins. People with CFS also have a higher occurrence of allergies than the healthy population. The Autoimmune diet book and stop inflammation by avoiding nightshades! Including Potatos. In the comments section mentioned even a tiny bite is a night and day difference ( Inflammation is a “hot” topic in medicine. It appears connected to almost every known chronic disease—from heart disease to cancer, diabetes to obesity, autism to dementia, and even depression. Other inflammatory diseases such as allergies, asthma, arthritis, and autoimmune disease are increasing at dramatic rates. As physicians we are trained to shut off inflammation with aspirin, anti-inflammatory medication such as Advil or Motrin, steroids, and increasingly more powerful immune suppressing medication with serious side effects. But we are not trained to find and treat the underlying causes of inflammation in chronic disease. Hidden allergens, infections, environmental toxins, an inflammatory diet, and stress are the real causes of these inflammatory conditions. Autoimmune diseases, specifically, now affect 24 million people and include rheumatoid arthritis, lupus, multiple sclerosis, thyroid disease, inflammatory bowel disease, and more. These are often addressed by powerful immune suppressing medication and not by addressing the cause. That’s like taking a lot of aspirin while you are standing on a tack. The treatment is not more aspirin or a strong immune suppressant, but removing the tack. If you want to cool off inflammation in the body, you must find the source. Treat the fire, not the smoke. In medicine we are mostly taught to diagnose disease by symptoms, not by their underlying cause. Functional medicine, the emerging 21st century paradigm of systems medicine, teaches us to treat the cause, not only the symptoms, to ask the question why are you sick, not only what disease do you have. I recently participated in a group discussion with a conventional doctor, a rheumatologist, and patient with an autoimmune disease, and one of my patients who was cured of a complex autoimmune disease by addressing the causes. The focus of the other doctors, however, was on how to suppress the inflammation with medication, not finding and treating the cause. Functional medicine is a different way of thinking about disease that helps us understand and treat the real causes of inflammation instead of finding clever ways to shut it down. Medicine as it is practiced today is like taking the battery out of a smoke detector while a fire burns down your house! Autoimmune conditions are connected by one central biochemical process: A runaway immune response also known as systemic inflammation that results in your body attacking its own tissues. When my patient described how he cured his autoimmune disease by finding and eliminating the causes of inflammation in his diet and environment, it was dismissed as a “spontaneous remission.” In the face of a paradigm-shattering medical case, these doctors were hardly curious and quickly dismissive, describing what was shared as anecdotal. My patient on that panel, a hard-working 46-year old father of three, was once so inflamed he could barely function. By treating the underlying causes of his inflammation he is now in vibrant good health, enjoying his life with his kids and fully capable of caring for them. Stories like these (and the many others I have shared in my blogs, books, and on television) are not anecdotes but a giant compass pointing us in the direction we should be looking to find answers to our health problems. In today’s blog, I will explain what autoimmunity is, how inflammation spirals out of control, describe some of the underlying causes for these fires in the body, and provide you with nine steps to cool the fires of inflammation and overcome conditions that range from allergies to arthritis and more. Autoimmunity: What it is and How it Occurs We are facing an epidemic of allergic (60 million people), asthmatic (30 million people), and autoimmune disorders (24 million people). Autoimmune diseases include rheumatoid arthritis, lupus, multiple sclerosis, psoriasis, celiac disease, thyroid disease, and the many other hard-to-classify syndromes in the 21st century. These are all autoimmune conditions, and at their root they are connected by one central biochemical process: A runaway immune response also known as systemic inflammation that results in your body attacking its own tissues. Your immune system is your defense against invaders. It is your internal army and has to clearly distinguish friend from foe—to know you from others. Autoimmunity occurs when your immune system gets confused and your own tissues get caught in friendly cross-fire. Your body is fighting something—an infection, a toxin, an allergen, a food or the stress response—and somehow it redirects its hostile attack on your joints, your brain, your thyroid, your gut, your skin, or sometimes your whole body. This immune confusion results from what is referred to as molecular mimicry. Conventional approaches don’t have a method for finding the insult causing the problem. Functional medicine provides a map to find out which molecule the cells are mimicking. Interestingly, autoimmune disorders occur almost exclusively in developed countries. People in poor nations without modern amenities like running water, flush toilets, washing machines, and sterile backyards don’t get these diseases. If you grew up on a farm with lots of animals, you are also less likely to have any of these inflammatory disorders. Playing in the dirt, being dirty, and being exposed to bugs and infections trains your immune system to recognize what is foreign and what is “you.” In this country, autoimmune diseases, when taken all together, are a huge health burden. They are the eighth leading cause of death among women, shortening the average patient’s lifespan by eight years. The annual health care cost for autoimmune diseases is $120 billion a year representing nearly twice the economic health care burden of cancer (about $ 70 billion a year). (i) Unfortunately, many of the conventional treatments available can make you feel worse. Anti-inflammatory drugs like Advil, steroids, immune suppressants like methotrexate, and the new TNF-alpha blockers like Enbrel or Remicade can lead to intestinal bleeding, kidney failure, depression, psychosis, osteoporosis, muscle loss, and diabetes, not to mention overwhelming infection and cancer.(ii) When used selectively these drugs can help people get their lives back. But they are not a long-term solution. They shouldn’t be the end of treatment, but a bridge to cool off inflammation while we treat the root cause of the disease. There is another way to deal with autoimmune conditions. Let me share the same story I told the doctors on that panel. Recovering from Autoimmunity: Addressing the Root Causes of Inflammation My patient Sam ended up on a long misadventure through the medical system before he came to see me. For years he went from doctor to doctor getting all kinds of labels for his problems but no real help in treating them. This hard-working, once healthy trade professional had suddenly developed a series of inflammatory conditions including chronic sinus and prostate infections. Many doctors gave him many antibiotics for these infections. Shortly thereafter, he developed severe chest pains and went to the emergency room. While he was there, doctors found swollen lymph nodes and told him he had lymphoma, a form of cancer. For three weeks he lived in despair until the biopsy results came back. It turned out he didn’t have cancer but an autoimmune disease. Which autoimmune disease? The doctors weren’t quite sure… He had many abnormal blood test results—like low white blood cell and platelet counts, high levels of auto-antibodies of all types (antibodies that attack our own tissues), high immunoglobulins (the foot soldiers of the immune system), and autoimmune thyroid disease. But doctors had a hard time putting their finger on what was wrong. They couldn’t label him. Meanwhile, Sam developed metabolic syndrome and weight gain (pre-diabetes) as a result of the runaway inflammation in his body. Here is a quote from one his specialist’s notes: “Whether he has lupus or Sjogren’s syndrome is a bit unclear. Regardless, he merely needs observation and no therapeutic intervention at this time.” This unfortunately is all too common. What exactly did they plan to observe, how bad he felt? Or would they just wait for him to get worse before intervening? That’s when he came to me. Using a functional medicine approach, a new way of thinking about the underlying causes and imbalances in chronic disease, I began by asking Sam some simple questions. Then I went hunting for toxins, allergens, and infections—all common causes of inflammation—and found the real causes of his symptoms. He had taken so many antibiotics that altered his gut flora or bacteria and promoted yeast overgrowth. Fungus and yeast flourished in his body, growing between his toes, on his toenails, in his crotch, and scalp. He had Helicobacter pylori bacteria in his gut. He had a leaky gut and reacted to many foods, including dairy and gluten. He was exposed to toxins at his job and had high levels of mercury. And he had chronic sinus infections. So we went to work cleaning house. I treated his yeast with anti-fungals and the H. pylori with antibiotics, got rid of his food allergies, fixed his gut, detoxified him from metals and cleaned up his sinuses. Then I helped heal his immune system by supporting it with nutrients. I gave him zinc, fish oil, vitamin D, herbs, and probiotics, and put him on a clean, whole-foods, allergen-free, anti-inflammatory diet. At his next follow-up visit, I asked Sam how he was doing, expecting him to say that he felt a little better. However, his response surprised even me. He said he felt fine. “What about the fatigue?” I asked. “I have great energy.” “What about the bloating and gas?” “Nope.” “What about the reflux?” “Gone.” “What about your sinuses and chronic phlegm?” “All clear.” “What about your memory and concentration problems?” “All better.” And he lost 15 pounds. When his labs came in, they confirmed what he told me—they were all back to normal. His white cells increased and his immune markers calmed way down. Sam’s results simply reflect the application of a new model of thinking about problems called functional medicine—it’s a way to get to the root of health problems and treat the underlying causes of what ails you instead of suppressing symptoms with medications. If you have an autoimmune disease, here is what you need to think about and do. Nine Steps to Treating Autoimmune Disease 1. Check for hidden infections—yeast, viruses, bacteria, Lyme, etc.—with the help of a doctor, and treat them. 2. Check for hidden food allergens with IgG food testing or just try The UltraSimple Diet, which is designed to eliminate most food allergens. 3. Get tested for celiac disease, which is a blood test that any doctor can do. 4. Get checked for heavy metal toxicity. Mercury and other metals can cause autoimmunity. 5. Fix your gut. For details, see my blog on irritable bowel syndrome. 6. Use nutrients such as fish oil, vitamin C, vitamin D, and probiotics to help calm your immune response naturally. 7. Exercise regularly—it’s a natural anti-inflammatory. 8. Practice deep relaxation like yoga, deep breathing, biofeedback, or massage, because stress worsens the immune response. 9. Tell your doctor about Functional Medicine and encourage him or her to get trained—go to for more information and to get a copy of the Textbook for Functional Medicine. Give these steps a try—and see if you don’t start feeling less inflamed. As I said earlier, the answers are right in front of you. Treat the underlying causes of your illness and you will begin to experience vibrant health once more. Now I’d like to hear from you… Have you been diagnosed with an autoimmune disease? How is your doctor treating you? Have you been frustrated by the medical advice that you’ve been given? What steps have you taken to get to the root of the problem, and what have your results been? Please leave your thoughts by adding a comment below—but remember, we can’t offer personal medical advice online, so be sure to limit your comments to those about taking back our health! chart Autoimmune epidemic in USA skyrockets: We are destroying our gut microbes and wondering what is wrong Learn more: Autoimmune disease, the body's betrayal - How to healLearn more: Inflammation and Autoimmune reaction - Everyday Foods that Fan the Flames of Inflammation I spent a lot of time in the last chapter giving you the rundown of what dangerous things may be coming along with your food. But if you’re like most people, some of the foods you eat may be harmful for your health in and of themselves. In today’s fad diet world, it’s probably no surprise to hear that what you eat is important to creating homeostasis in the Wellness Model of Health™. The food you consume has far more of an impact on you than just the weight it may add to your frame. Beyond the obvious, certain foods can create an excess of inflammation within the body, triggering pain and ill-health. The impact of inflammation on the body is enormous. For example, inflammation in joints causes stiffness and pain. Inflammation in the back and muscles results in trigger points. Arterial inflammation is associated with heart disease, and fascia-related inflammation is linked strongly to fibromyalgia. In fact, multiple studies have proven that inflammation is connected to nearly every major disease we suffer from today. And it starts with the food you eat every single day—the third cornerstone of the Complete Healing Formula™, your diet. By now, you know that diet has an impact on our physical and mental wellbeing. No matter what kind of pain or illness you’re suffering from, you’re going to make your whole situation and state of homeostasis better by improving your diet. There are specific conditions that many people suffer from—like chronic joint pain—that can be alleviated by following simple dietary guidelines. An obvious example, as Dr. Mark Wiley cites in his book, Arthritis Reversed, is that if you are carrying around excess weight, it places a compressive load on your joints that is three times the actual weight. That means for every fifteen pounds you are overweight, your hips and knees are under stress to move a forty-five-pound load. If you are thirty to forty pounds or more overweight, the effects can be staggering. Changing the way you eat to reduce your level of chronic inflammation will most likely lead to weight loss, which will in turn result in the relief of excess pressure on your body. And this is only one superficial way that inflammation impacts our larger health ecosystem. In addition to eating well, there are specific foods you can avoid and others you can consume to preserve and improve your body’s defense against inflammation, your natural state of homeostasis, and consequently, your health conditions. This chapter will review how food causes pain and inflammation, which foods affect inflammation, and how you can ease pain and discomfort with a diet of healthy whole foods. How Food Causes Pain and InflammationWhen it comes to pain and inflammation, the food you consume plays a key role. Food is a critical piece of the puzzle when it comes to controlling energy draining health symptoms.Unfortunately, the typical American diet consists of excess fat, tons of sugar, loads of factory-farmed red meat, and a frightening amount of processed foods. Is it any wonder there are so many people suffering from chronic pain and illness? These foods cause inflammation, block the bowels, drain the immune system, and deplete the blood of dense nutrients. “Bad” FoodsWhen it comes to pain and illness, several categories of food should be avoided, including nightshades, dairy-based products, and high-fructose corn syrup. Dr. Wiley covers a number of these in his book. Excess nightshade fruits and vegetables are particularly troublesome for those suffering from conditions like chronic joint pain. This family of food includes white potatoes, eggplant, sweet and hot peppers, tomatoes, tomatillos, tamarillos, pepinos, pimentos, goji berries, ground cherries, Cape gooseberries, garden huckleberries, and paprika. These foods can cause calcification, bone spurs, and inflammation. Such side effects are harmful to those suffering pain and illness because they amplify the existing inflammation and joint problems rather than alleviating them. In cases of people who are sensitive or allergic to nightshades, they can even cause nerve damage, muscle tremors, and impeded digestion. Excess dairy products are also troublesome for those suffering from chronic ailments. They are often high in cholesterol and saturated fat, and can contribute to obesity. And as we learned, being overweight by even fifteen pounds can have disastrous effects on arthritic joints. But the problem with dairy goes a lot deeper than weight issues. Products like milk, yogurt, ice cream, cheese, cottage cheese, and various sauces can contribute to an increase in phlegm-rheum. Phlegm-rheum is a classification of thick, sticky fluids in the body that include mucus. These thick and sticky fluids pool around joints and collect toxins and bacteria, and become either damp or hot, depending on other factors. This increases inflammation, swelling, bone degeneration, loss of range of motion, and pain. The sweetener known as high-fructose corn syrup (HFC) has been called the main culprit in the rise in youth obesity in the United States, and obesity is one of the key risks for chronic health issues. High-fructose corn syrup is corn syrup that has undergone enzymatic processing to convert its glucose into fructose. This fructose has then been mixed with regular corn syrup, which is 100 percent glucose, and the result is a sweet liquid known as high-fructose. This liquid is the sweetener found in just about every cold beverage in your local convenience store, including iced tea, sodas, and energy drinks. Not only that, but it is also found in so-called healthy foods like tomato soup and yogurt, as well as less healthful items such as salad dressings and cookies. The FDA did a thirty-year study and found a correlation between HFC and obesity, stating that it is worse for your health than plain sugar—which isn’t good for those with pain and inflammation either. Worst of all, even as the public begins to awaken to the dangers of HFC, the food industry is now peddling equally dangerous chemical sugar substitutes and all the additional toxins that come with them. Excess processed or refined grains are also to be avoided. These are found in flour, cereals, breads, baked goods, and snack foods. Usually they’re listed as “enriched” flour or anything other than “whole” grains. In essence, refined grains have been broken down for you, so your body doesn’t have to do the work. Since the grain then breaks down too quickly in the body and the intestines, it releases hormones that promote inflammation. Even eating “whole” grains can still be problematic for many people. Not only are those whole grains still processed, but many grains—especially wheat—trigger inflammatory responses in the body. Acidic FoodsOther foods that negatively affect our health include those that are acidic. As strange as it may sound, your body, its fluids, and your blood can become excessively acidic. Just as acidic fruits like lemons can “eat” the enamel off your teeth, and acid can corrode a battery casing, your body can become overly acidic when your natural pH is off kilter. Even the conventional medical community agrees that the human body was not designed to withstand chronic acidic states. When the body is off-kilter long enough, out of its natural state of homeostasis, it starts to break down. Signs and symptoms of an excessively acidic body can be seen and/ or felt externally, with the onset of headaches, body pain, and skin rashes. In the acidic range, the immune system is compromised, leading to easily contracted sinus infections, allergies, colds, and the flu, and placing you at risk for progressing autoimmune diseases and rheumatoid arthritis. Moreover, an excessively acidic interior environment can lead to muscle contraction that can restrict the free flow of blood and inhibit the exchange of nutrients and waste products from muscle cells. This can cause soreness, cramping, fatigue, degenerative cellular diseases, and even cellular death. Dr. Wiley offers a pH balance guide in his book, reproduced here. Chart 12.1: pH Balance GuideAcid0 Battery Acid1 Stomach Acid2 Lemon Juice, Vinegar3 Orange Juice, Soda4 Tomato Juice, Beer5 Black Coffee6 Saliva, Cow’s MilkNeutral 7 Pure WaterAlkaline8 Sea Water9 Baking Soda10 Antacid11 Ammonia12 Soapy Water13 Bleach, Oven Cleaner14 Drain Cleaner Chronic pain is related to pH imbalance and the accumulation of acid deposits in the joints of the neck, hips, wrists, and hands. It is this accumulated acid that damages cartilage. When the cells that produce lubricating synovial fluids and bursa fluids are acidic, this condition causes a dryness that irritates and swells the joints. When uric acid builds up, it tends to deposit in the form of crystals that can feel like broken glass in the feet, hands, knees, and back. Thankfully, you don’t have to worry about this when your body is kept within the alkaline range of 7.0 - 7.4. In fact, while in this range it is impossible for disease to sustain itself, because the immune system is strong and the acidic environment necessary for diseases like cancer, gout, and arthritis no longer exists. Chart 12.1 will help you see just how the foods you eat and the beverages you drink contribute to an unhealthy internal environment. Acidity and StressAn imbalanced pH or acid/alkaline interior environment is one of the hidden causes of disease and one of the states that makes our existing health symptoms worse. So how does the body become too acidic (and thus, unhealthy) and place you at risk for negative health symptoms? Well, excess stress is a big one. As I discussed in chapter 2, stress, or the effects of being in the “fight or flight” response for too long a period of time, releases stress hormones into the body, flooding the blood stream with protective chemicals. These chemicals, like cortisol, were necessary during the times of our ancestors who had to run for their lives from wild beasts or rival tribes. These days, this stress response is caused by different types of stressors, like emotional upset, physically demanding work, and overwhelming psychological issues that we deal with at home and at work. There are too many of these happening throughout the day. It is no wonder we are under chronic states of stress, are not well, and are in a constant acidic state. Our modern diet is also a huge contributor to our chronic acidic interior environment. When food reaches your digestive tract, it is broken down and either leaves an alkaline or an acidic residue behind. If you eat foods that are organic, whole, and fresh, and drink plenty of pure water, the body can easily maintain an alkaline state. However, consuming excess sugar, refined grains, preservatives, pesticides, dairy products (like cow’s milk, cheese, yogurt, and ice cream), red meat, chocolate, coffee, soda and alcohol turns the body acidic. One of the main effects of a poor diet is inflammation, which is also the main symptom of chronic pain and illness. Ph is a measure of the potential hydrogen or residue a food leaves behind, as being either alkaline or acidic. And this is not directly related to the acidic nature of a food before it is digested. Lemons, for example, are highly acidic. If you squeeze the juice of a lemon on an open wound, it will burn. However, when ingested and digested, lemon is very alkalizing for the body, and lemon juice can help reduce acidic levels. A diet that is low in acidic foods and packed full of nutrient-dense alkalizing foods will make you healthier, while also reducing the symptoms of your chronic pain or illness. If you have pain or chronic disease, you more than likely have a predisposition to infection, and it is likely that a pH imbalance is present in your body. To be sure, you can purchase pH testing strips or rolls in your local drug store. These are thin paper items that gauge your pH level when dipped either into your saliva or urine stream, first thing in the morning before anything is eaten or drunk. You should strive to have your pH in in the alkaline range, and if you aren’t at that level, you should try to move closer to it each day. Good FoodsNow for the good news. There are plenty of foods that you can add to your daily diet to make you strong and keep you in homeostatic balance. A diet high in fiber and whole foods, low in preservatives and unhealthy fat, and infused with blood-invigorating aromatic spices can help reduce pain and inflammation. It is essential to any healthful diet that you consume as many fresh, organic, whole foods as possible. Eating foods in or close to their original state is one of the keys to being healthy, preventing self-induced diet-based inflammation, and reducing the inflammation you are experiencing as a result of your pain or illness. Dr. Wiley’s book, Arthritis Reversed, gives a concise list of the best foods known to prevent and help reduce inflammation and pain. These should be eaten throughout the day as part of balanced wholesome meals.• Wild fish (example: Alaskan salmon)• Fresh whole fruits• Bright colored vegetables (except nightshades)• Green and white tea• Purified and distilled water• Healthy oils (coconut, olive, flax, hemp, safflower, hazelnut)• Beef and poultry that is certified organic, grass fed, soy free, and free range• Nuts, legumes, and seeds• Dark green leafy vegetables• Organic oatmeal (regular, not instant)• Aromatic spices (turmeric, ginger, cloves, garlic, onion, coriander, and ground mustard seed) I want to stress the importance of making sure your meat comes from animals that are grass fed, soy free, free range, and certified organic. It is a sad truth that a lot of the meat that is commercially available today comes from sick animals, who are kept in awful, unhealthy, and cruel conditions. These animals are usually stuffed and packed into barns so tightly they can barely move and they get little to no natural light. They are also often given growth hormones and overfed with foods they wouldn’t eat normally, like corn for cows and, in some cases, even dead, sick animals. These conditions obviously make the animals sick, and then they need antibiotics. At the end of this cycle, the unhealthy, antibiotic-ridden, hormone-laced meat from a sick animal finds its way into our bodies. That’s why it’s so important to choose your meat with care. As you can see, a diet high in whole foods and low in preservatives and unhealthy fat is an essential part of any pain and illness relief plan. Not only do the above-listed foods actually work to reduce pain and inflammation, but they also support proper nerve function, and muscle and bone health. Remember, the acid/alkaline or pH level of your body (which can cause or prevent inflammation), is related to the foods you consume. Using the chart reproduced from Dr. Wiley’s Arthritis Reversed below, see how what you consume on a daily or monthly basis may be contributing to the worsening of your chronic health condition. Chart 12.2: pH SpectrumCredit: Green Tea Dr. Wiley did a significant amount of research on green tea. He found that green tea, like all true tea, comes from the leaves of the Camellia Sinensis tree, and 90 percent of the world’s tea supply is produced in China. What makes green tea so powerful is a chemical compound called polyphenol, which occurs naturally in plants and works as an antioxidant. Polyphenols work to protect the body from the oxidative stress that causes diseases. Specifically, the polyphenol Epigallocatechin gallate (EGCG) is an extremely powerful antioxidant. In fact, EGCG antioxidant activity is more powerful than the antioxidants found in vitamins C and E. After fifteen years of working with green tea in his cancer research, Dr. Hasan Mukhtar started looking at the possible benefits this drink could have for people with rheumatoid arthritis. Realizing that both disorders were inflammatory in nature, his team began testing to see if green tea would have the same healing effect on rheumatoid arthritis as it does on cancer and cardiovascular disease. His first paper, “Prevention of Collagen-Induced Arthritis in Mice by a Polyphenolic Fraction of Green Tea,” was presented to the National Academy of Sciences in April 2005. The results were astounding. Out of the eighteen mice that were given green tea extract, ten never developed any arthritic symptoms. What’s more, symptoms in the remaining eight showed that they developed a much milder form of arthritis. The amount given was the equivalent of drinking just four cups of green tea a day! Lead author of the paper, Dr. Tariq M. Haqqi said, “Taken together, our studies suggest that a polyphenolic fraction from green tea that is rich in antioxidants may be useful in the prevention and onset and severity of arthritis.” Three independent and controlled experiments were conducted. Using a widely accepted animal model that is very similar to rheumatoid arthritis, the mice were injected with collagen to induce arthritis. Two groups were studied for forty days, while a third was examined for eighty-five days to verify that the green tea did not simply delay the onset of the disease. Green tea, unlike the more widely used black version, is not fermented. Instead of crushing the tea leaves, thereby removing the polyphenols, green tea is first dried, and then heated. One teaspoon steeped in hot (not boiling) water contains anywhere from 100 to 200mg of EGCG. Milk should not be added, as it negates the tea’s beneficial properties. According to this study and others that were done for other diseases, two to four cups a day is usually recommended. Human trials are currently being developed. In the meantime, however, Drs. Mukhtar and Haqqi both strongly encourage people to start drinking green tea. Nobody has shown any form of toxicity associated with tea, and with the tremendous amount of data showing its many beneficial qualities, it is a wise and wholesome preventive measure. MushroomsMushrooms should also be a part of your daily diet, as they are full of nutrients and are power immune boosters. There are many reasons that mushrooms are so powerful and essential to our health. They are an excellent dietary staple and health booster, containing nine of the essential amino acids our bodies need, along with 30 percent of the high-quality proteins we require. Plus, with virtually no unsaturated fat, they include more minerals than most meat and vegetables. Even more important than their nutritional content, mushrooms are rich in enzymes that are critical to reducing inflammation throughout the body. For this reason, mushrooms are known to be useful in alleviating rheumatoid arthritis symptoms, hypertension and heart disease, diabetes, and even some cancers. With so much going for them, and all their amazing health benefits, what’s not to love? So go ahead and give mushrooms a big welcome in your home. Add them to your meals where you can. You will feel a whole lot better because of it. TurmericIn cultures that are thousands of years old, such as in India, there are deep traditions of cooking daily meals with medicinal roots and herbs. These herbs act as preventive measures for sustaining good health, and prevention is the cornerstone of India’s traditional Ayurvedic medicine. Turmeric is one such medicinal root that has made its way into a vast number of Indian recipes. Aside from your standard chicken or goat curries, there is a whole list of Indian dishes that contain flavorful thermogenic ingredients like cardamom, coriander, ginger, cloves, and turmeric. Not only are these recipes tasty, the ones containing turmeric are especially healthful because of one of its components, called curcumin. Research conducted by Sarker et al. notes the powerful anti-inflammatory, antitumor, and antioxidant properties of curcumin. Moreover, the US National Library of Medicine and the National Institutes of Health say: “Laboratory and animal research has demonstrated anti-inflammatory, antioxidant, and anti-cancer properties of turmeric and its constituent curcumin.” Unlike aspirin or ibuprofen, turmeric’s curcumin reduces inflammation naturally, without damaging the liver or kidneys. It has been found especially helpful in treating conditions like arthritis, sports injuries, irritable bowel syndrome, Crohn’s disease, tendonitis, and various autoimmune diseases. Some research even suggests that curcumin may also help those suffering asthma, inflammatory bowel disease, and yes, even cancer. Since curcumin is an anti-inflammatory as well as an antioxidant, it is used for treating arthritis, wounds, digestive disorders, liver issues, and in the prevention of cancer. It also helps reduce the side effects of chemotherapy. Statistics show that Asian children experience less incidence of leukemia than their Western counterparts, and a diet rich in turmeric may be the reason why. With no negative effects, there’s no reason not to include more turmeric in your diet. You can try to eat more Indian and Malaysian food or buy the ground powder and use it in your own cooking. Since the flavor can be strong, some people prefer to purchase a high-quality curcumin supplement. In any case, make turmeric and curcumin part of your diet and start reducing your body’s inflammation. Inflammation FreeBeing aware of what you’re eating and how it affects your body. Think about this in the larger context of the Wellness Model of Health™. This is the first step toward becoming free of inflammation. By tweaking your diet to avoid certain foods and adding some new ones, you can live an overall healthier and happier life. And good food isn’t the only tool you have at your disposal when it comes to building better wellness. In the next chapter, I’ll talk about the power of hydration and show you how simple water has the power to change your life. Chapter Review• Inflammation is associated with nearly every major disease we suffer from today.• The typical American diet is filled with foods that cause inflammation.• Acidic foods are another cause of inflammation. Stress can cause additional acidity in the body.• A diet high in fiber and whole foods, low in preservatives and unhealthy fat, and infused with blood-invigorating aromatic spices can help reduce pain and inflammation.• Green tea, mushrooms, and turmeric are extra-strong foods for battling inflammation. Recommended ResourcesArthritis Reversed by Dr. Mark WileyYou can get a detailed list of the best and worst foods for inflammation in Dr.Mark Wiley’s book, Arthritis Reversed at It's important to drink 8 glasses a day. But not all water created equally. Make sure you drink the water that doesn't kill you just as fast. For example, tap water is full of chemicals, chlorine, lye, fluoride etc. Even bathing and showering without shower filter is dangerous.... Filtered Reverse Osmosis and bottled water is very acidic and very oxidant. Your body is 70% water, brain is 80 and blood is 90. Imagine what happens when the water you drink is burning and rusting you inside? That’s why more and more people switching to Kangen 9.5 pH water. Its anti-acidic, anti-oxidant and anti-inflammatory. The immune system is initially depressed by too much cortisol. Whenever further cortisol surges occur, the immune system is further depressed, and over time, it can be damaged and function poorly. The deterioration of gut function and gut flora worsens the immune dysfunction. Seventy to eighty percent of your immune system is in your gut, so gut dysfunction severely reduces the effectiveness of your immune system. Leaky gut, poor glutathione production, and opportunistic viral, bacterial, fungal, and parasitic infections all place further pressure on the immune system and leave it unable to cope. From: The Emerging Role of Autoimmunity in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/cfs)  The World Health Organization classifies myalgic encephalomyelitis/chronic fatigue syndrome (ME/cfs) as a nervous system disease. Together with other diseases under the G93 heading, ME/cfs shares a triad of abnormalities involving elevated oxidative and nitrosative stress (O&NS), activation of immuno-inflammatory pathways, and mitochondrial dysfunctions with depleted levels of adenosine triphosphate (ATP) synthesis. There is also abundant evidence that many patients with ME/cfs (up to around 60 %) may suffer from autoimmune responses. A wide range of reported abnormalities in ME/cfs are highly pertinent to the generation of autoimmunity. Here we review the potential sources of autoimmunity which are observed in people with ME/cfs. The increased levels of pro-inflammatory cytokines, e.g., interleukin-1 and tumor necrosis factor-α, and increased levels of nuclear factor-κB predispose to an autoimmune environment. Many cytokine abnormalities conspire to produce a predominance of effector B cells and autoreactive T cells. The common observation of reduced natural killer cell function in ME/cfs is a source of disrupted homeostasis and prolonged effector T cell survival. B cells may be pathogenic by playing a role in autoimmunity independent of their ability to produce antibodies. The chronic or recurrent viral infections seen in many patients with ME/cfs can induce autoimmunity by mechanisms involving molecular mimicry and bystander activation. Increased bacterial translocation, as observed in ME/cfs, is known to induce chronic inflammation and autoimmunity. Low ATP production and mitochondrial dysfunction is a source of autoimmunity by inhibiting apoptosis and stimulating necrotic cell death. Self-epitopes may be damaged by exposure to prolonged O&NS, altering their immunogenic profile and become a target for the host’s immune system. Nitric oxide may induce many faces of autoimmunity stemming from elevated mitochondrial membrane hyperpolarization and blockade of the methionine cycle with subsequent hypomethylation of DNA.TH2 Immune System Dominance and Heterogeneity in ME/CFS | Page 2 | Phoenix Rising ME / CFS Forums From: The role of TNF-alpha in T-cell-mediated inflammation depends on the Th1/Th2 cytokine balance.The role of tumor necrosis factor-alpha (TNF-alpha) in tuberculosis is paradoxical because although there is much evidence for a protective role, there is also evidence that it plays a part in the tissue damage that characterizes human disease. We have shown previously that TNF-alpha frequently induces necrosis when injected into sites undergoing delayed-type hypersensitivity (DTH) responses to mycobacterial antigen. This is dependent on CD4+ T cells. However the presence of this sensitivity to TNF-alpha-induced necrosis depended on the immunization protocol. We have tested the hypothesis that sensitivity to TNF-alpha depends on the cytokine profile of the induced T-cell response. All subcutaneous doses of mycobacterial immunogen used (10(7) to 10(9) organisms) primed spleen cells so that they secreted interferon-gamma (IFN-gamma) and interleukin-2 (IL-2) when cultured in vitro with soluble antigen. However priming for production of IL-4 was dose dependent as in other systems, and was produced at all times from 7 to 30 days after immunization with 10(9) organisms. Time-course studies over 30 days showed that sensitivity to TNF-alpha was found in DTH sites of animals primed for IL-4 and IFN-gamma production, but not in animals primed only for the Th1 cytokines. We suggest therefore that the paradoxical role of TNF-alpha can be resolved. In 'pure' Th1 responses it may act as an additional macrophage-activating factor. In mixed Th1 + Th2 or Th0 responses it may cause tissue damage. This mixed pattern is characteristic of tuberculosis, and of the late stage of many chronic infections where elimination of the infecting organism is failing, and chronic tissue damage is seen. From: Research clearly shows one of the most common imbalances in patients with chronic fatigue syndrome is within the immune system. Cytokines are the hormonal messengers responsible for most of the effects in the immune system. Although there are many, cytokines can be functionally divided into two groups: those that are pro-inflammatory and those that are anti-inflammatory but that promote allergic responses. A certain type of immune cell, called Helper T cells, are regarded as being the most prolific cytokine producers. This subset of immune cells can be further subdivided into Th1 and Th2, and the cytokines they produce are known as Th1-type cytokines and Th2-type cytokines. Th1- and Th2-helper cells direct different immune response pathways. Th1 cells drive the type-1 pathway (referred to as “cellular immunity”) to fight viruses and other intracellular pathogens. Th2 cells drive the type-2 pathway (referred to as “humoral immunity”) and up-regulate antibody production to fight extracellular organisms. Over-activation of either pattern can cause disease, and either pathway can down-regulate the other. And it has been theorised that certain conditions are a Th 1 or Th 2 state. Some research suggests CFS is primarily  a Th2 dominant state. But the hypothesis has major inconsistencies; human cytokine activities rarely fall into exclusive pro- Th1 or -Th2 patterns. The Th1 pathway, when it is overreactive, can generate organ-specific autoimmune disease (e.g., arthritis, multiple sclerosis, type 1 diabetes). The Th 2 pathway is seen as underlying allergy and related IgE-based disease, and predisposing to systemic autoimmune disease. But these stereotypes have proven to be over-simplistic, with the result that the hypothesis is increasingly criticised. A number of natural compounds have a tendency to push either side of the Th1/Th2 balance. Green tea is one such substance. However others have a balancing beneficial effect. For example, the long chain omega-3 fatty acids EPA and DHA  significantly benefit diverse inflammatory and autoimmune conditions without any specific Th1/Th2 effect. Th1 stimulating compounds • Echinacea• astragalus• Licorice root• Beta-sitosterol• Ashwaganda• Panax ginseng• Mushrooms (Maitake, Reishi, Shiitake)• Chlorella• Grape seed extract Th2 stimulating compounds • Green tea• Resveratrol• Pycnogenol• Curcumin• Genistein• Quercetin Interestingly pregnancy is a Th 2 dominant state and this may be why individuals may experience complete resolution of symptoms in certain conditions such as Rheumatoid Arthritis (thought to be a Th 1 dominant state). Also, several studies have demonstrated decreased prevalence of allergic diseases (a Th 2 dominant state) in patients with Rheumatoid Arthritis. However, The findings from various human and animal studies do not support such a clear-cut role for Th1 as the driving force in RA. Other Highlights From The Research Glutathione, Oxidative Stress and CFS Depletion of glutathione…results in lowered Th1 activity and higher Th2 activity; GSH repletion had just the opposite effect. Thus, it seems immune activity can have Th1 or Th2 character depending on the relative antioxidant status of the cells directing the process. It does seem increased oxidative stress may favour a Th2-dominated immune state. We at Conquering Fatigue Successfully frequently see low glutathione levels and increased levels of oxidative stress in our clients. Also, Mercury depletes glutathione and polarizes toward Th2 dominance. Parasites, glutathione and CFS Because parasite infections will often modestly deplete glutathione, the human Th 2 orientation to parasites could be an adaptation based on a glutathione depletion DHEA & Th 1/2 balance Dehydroepiandrosterone (DHEA) is produced by the adrenal glands. As one of the effectors of the hypothalamic-pituitary- adrenal (HPA) axis, DHEA supports the body’s adaptive stress responses. It may also be involved in immune regulation. DHEA’s involvement in immune homeostasis is anti-Th2/pro-Th1. Progesterone May up-regulate Th2. Selenium When selenium deficient animals are supplemented with selenium, IL-2 action (a Th1 cytokine) is enhanced. This is likely to benefit the type-1 pathway and thereby improve antiviral, antibacterial, and antifungal resistance. Zinc IL- 2 status (Th1 cytokine) in these subjects and found that IL- 2 and IFN-gamma declined during the depletion phase and was corrected by repletion. Probiotics Probiotics may also down-regulate conditions linked to Th 2 over-activation. Both type-1 and type-2 cytokine patterns can be partially restored. But Be Warned Research is very mixed on this topic and we can not say convincingly that CFS is a Th 2 dominant state. What we can say is that it appears to be more common, but there are CFS patients who are Th 1 dominant. We at Conquering Fatigue Successfully, recommend (a) working with an experienced practitioner and (b) testing to investigate which ‘side’ of the immune system is more active. There is real risk of exacerbating symptoms by taking products that stimulate the wrong branch of the immune system. This may be one of those topics where we also have to remember to “first, do no harm”. The following quotes highlight the complexity of this topic: published studies on Th1/Th2 dominance often downplay the dendritic cells (DCs), monocyte-macrophages, and other antigen-presenting cells Meaning there are other immune cells that may influence Th1/Th2 balance which need to be considered. many other dynamic factors influence Th1/Th2 maturation. Among these are: antigen dose, nature of the antigen, direct cell-to-cell interaction with APCs, the diversity and relative intensity of these interactions, and the cytokine receptors available on the naive cell. Meaning there are many other variables to consider when on the topic of Th1/2 balancing and these include things like the virus or bacteria that may be initiating an immune response. Whether right or wrong, the Th1/Th2 hypothesis is a “top-down” model of cell interaction that assumes one class of immune cells is especially equipped to supervise the others. Many lines of evidence indicate this model is overly simplistic and requires major modification to satisfy the discordant data. Meaning we can’t rely on this theory! The below quote provides clarity on what can be considered moving forward. Supporting the immune system through lifestyle medicine is a safe and effective strategy. One advantage inherent in the more collective model for immune functioning is that keeping the immune system healthy and mobilizing it against disease would depend more on giving the body systemic support than on deploying tailored magic immunotherapeutics. Proven  immunomodulators such as mushroom extracts take on significant relevance. Fish oils, vitamin C, glutathione, and other antioxidants, as well as numerous plant extracts can further enhance immune cell functionality. In managing immune hypofunction or other dysfunction, it is crucial to manage all forms of stress. Rooks reported diverse stressors, including sleep deprivation, calorie restriction, excessive exercise, examination stress, and cardiopulmonary bypass surgery, down-regulate Th1 and up-regulate Th2 activity. These effects are mediated mainly by glucocorticoids, but also by the catecholamine hormones epinephrine and norepinephrine. As heroic efforts to tailor technological immune therapies go forward, the best immune intervention tools continue to be lifestyle modification, vitamins, minerals, orthomolecules, and selected nontoxic phytotherapies. Stress is key concept to understand and we recommend reading our articles on this topic: click here and here. Chronic Fatigue Syndrome – A Th2 dominant condition? Summary We cannot say with 100% certainty that CFS is a Th2 dominant state, but current research suggests the majority of patients are. Based on the fact that some patients are in a Th1 dominant state, and that stimulating the pathway can significantly worsen the condition, testing is of the upmost importance if wanting to explore this path. Past health history may shed further light on this, as mentioned improvements during pregnancy may provide compelling evidence, but testing would still be beneficial to confirm any suspicions and also is an effective method of monitoring any interventions put in to place.From: Can sustained arousal explain the Chronic Fatigue Syndrome? | Behavioral and Brain Functions | Full Text an integrative model of disease mechanisms in the Chronic Fatigue Syndrome (CFS), unifying empirical findings from different research traditions. Based upon the Cognitive activation theory of stress (CATS), we argue that new data on cardiovascular and thermoregulatory regulation indicate a state of permanent arousal responses – sustained arousal – in this condition. We suggest that sustained arousal can originate from different precipitating factors (infections, psychosocial challenges) interacting with predisposing factors (genetic traits, personality) and learned expectancies (classical and operant conditioning). Furthermore, sustained arousal may explain documented alterations by establishing vicious circles within immunology (Th2 (humoral) vs Th1 (cellular) predominance), endocrinology (attenuated HPA axis), skeletal muscle function (attenuated cortical activation, increased oxidative stress) and cognition (impaired memory and information processing). Finally, we propose a causal link between sustained arousal and the experience of fatigue. The model of sustained arousal embraces all main findings concerning CFS disease mechanisms within one theoretical framework. Summary Review: The Dysfunctional Autonomic Nervous System in ME/CFSAnd some tips that might help address these problemsBy Charlotte Stephens, 24th January 2018. Two research studies recently reported similar findings relating to the autonomic nervous system in people with ME/CFS. Both related to sleep and build on existing evidence suggesting that a dysfunctional autonomic nervous system (also known as dysautonomia) is perhaps creating or exacerbating some of the symptoms that may be associated with ME/CFS. In this ME Association summary review, I hope to explain: 1. the autonomic nervous system and how it functions 2. the latest research findings in relation to sleep, and,2. suggest some things you can do to help address these problems. Altered autonomic nervous system (ANS) functioning has been frequently reported in patients with ME/CFS (Johnson, 2017). Symptoms that are related to ANS dysfunction in ME/CFS include: • Dizziness, light-headedness and feeling faint on standing (postural hypotension)• Orthostatic intolerance (being unable to stand for long periods)• Palpitations• Cold hands and feet• Irritable bladder symptoms• Gastric and irritable bowel type symptoms – including nauseaA condition known as postural orthostatic tachycardia syndrome (POTS) also occurs in a sub-group of people with ME/CFS. Something called heart rate variability (HRV) – see below – can be used as a measure of autonomic function and this was used in the two studies published last month. Although the studies were small, they concluded that there is an apparent dysfunction, or imbalance, in the ANS during sleep and when awake, with one study looking at the effects before and after an exercise and cognitive challenge. Each study concluded that HRV in CFS is lower than controls during sleep, suggesting higher sympathetic nervous system activity and lower parasympathetic nervous system activity (see below). Note: for the purposes of this review, we might regard high sympathetic nervous system activity as ‘bad’, as it means a higher state of arousal, and the body being on a heightened state of alert, which if sustained, can produce symptoms associated with ME/CFS. What is the ANS (Autonomic Nervous System)?The nervous system spans the whole body, connecting all our organs and tissues with each other and the brain, sending messages between them. It is split into two systems: The central nervous system and the peripheral nervous system. The autonomic nervous system (ANS) is the involuntary branch of the peripheral nervous system. Involuntary means that it controls most of our unconscious actions, that, most of the time, we aren’t aware are happening; such as breathing, digestion and the beating of our heart, so it’s like an auto-pilot system. However, it is also possible to take the system out of auto-pilot and into manual, as we can control the actions of the ANS to some extent, and with practise (I’ll return to this later). The ANS has influence over muscles and glands throughout the body and controls a whole range of things, including heart rate, breathing, salivation, digestion, perspiration (sweating) and urination. The ANS is further subdivided into two opposing sections; the sympathetic and the parasympathetic nervous systems. These two divisions have a sort of yin-yang relationship; they both act on the same parts of the body but produce completely opposite effects. The sympathetic nervous system (SNS) likes to speed everything up (get you ‘hyped’) and is best known for stimulating the ‘flight or fight’ response, having effects such as increased heart rate, increased breathing, dilated pupils, slowed digestion, and increasing blood-flow to the muscles in preparation for movement. On the other hand, the parasympathetic nervous system (PNS) likes to calm you down (relax you) and is known for the ‘rest and digest’ response, having opposite effects to the SNS, such as slowing your breathing, reducing your heart rate, constricting pupils, and encouraging digestion. Personal side-note on pupil dilation: I find this effect particularly interesting as, when I am feeling a crash coming on, my family have often mentioned how big (dilated) my pupils have gone, and it is a tell-tale sign that I am going downhill. This makes sense to the theory that my SNS is in overdrive. It would be interesting to see how many others have noticed this. When in balance, these two systems work together well in the body. However, they are selfish systems as when one is working, the other one cannot; one must be ‘switched off’ in order for the other to work – they cannot both work at the same time. Understandably, the sympathetic nervous system is very energy demanding, whilst the parasympathetic nervous system, is energy conserving. There’s a good YouTube video that explains the ANS in a simple, fun (but fast!) way, here: Interestingly, the ANS stems mainly from the ganglion, an area which has been mentioned in M.E. research as being dysfunctional; there is a hypothesis based on post mortem research that inflamed neurons in the dorsal root ganglion are interfering with proper autonomic nervous system functioning. MRI studies have found that symptoms of fatigue in CFS subjects were associated with reduced responsivity of the basal ganglia (Unger et al. 2012; Miller et al. 2014). A post mortem of a patient with M.E. revealed inflammation in and around the dorsal root ganglion, with the authors hypothesising that dysfunction of the sensory and the autonomic nervous system may lead to abnormal neural activity and explain some of the symptoms of M.E. (Lacerda et al. 2010). What is Heart Rate Variability (HRV)? Heart rate variability (HRV) is the variation in the time between each heart beat and can be measured via an ECG or some chest strap heart rate monitors. Your heart rate is not meant to stay the same speed all the time; it changes depending on your activity and emotions. HRV is a very good measure of the efficiency and performance of the cardiovascular system (Papaioannou et al. 2013). Having high HRV is preferable as it means your body can efficiently adapt and change your heart rate depending on your activity. Studies suggest that people who have a higher HRV are healthier and live longer with less risk of disease. Hillebrand et al. (2013) found that low HRV is associated with a 32-45% increased risk of a cardiovascular event. Heart rate variability may also be a marker of how well your body can handle stress. This is because it can act as a measure of the relative activity of the sympathetic and parasympathetic divisions of the ANS. Meeuset al. (2013) measured HRV in CFS patients and found that increased sympathetic activity was present in CFS patients at night (not good- we don’t want to be ‘hyped up’ and ‘on alert’ when trying to sleep!). ANS problems and ME/CFS Many studies have found the ANS to be dysfunctional, or ‘out of balance’ in ME/CFS patients (called ‘dysautonomia’). Robinson et al. (2015) found evidence of dysautonomia in almost 90% of CFS patients. ANS imbalance can also impact the length, type and quality of sleep, with evidence suggesting that reduced HRV (showing increased sympathetic activity) in patients with ME/CFS is most prominent during sleep (Boneva et al. 2007). An overactive sympathetic system has been associated with poor sleep, cognitive decline, inflammation and increased pain, and so it could play a role in many of the symptoms of ME/CFS (Fisher et al. 2010) – see table 1 below. One research group said, "We have studied autonomic function in CFS for some time and our findings clearly indicate a loss of integrity in stress-responsive systems in CFS. Patients with this condition are hyper-responsive to challenges arising both from within the body and from the environment. Even while asleep, their stress-responsive neural systems are on high alert, signalling that it is not safe to relax.” (Beaumont et al. 2012). ME/CFS patients tend to have reduced parasympathetic activity, and increased sympathetic activity, known as “sympathetic nervous system predominance” (Martinez et al. 2014). This same ANS dysfunction is seen in healthy people after engaging in acutely fatiguing tasks, and the lack of parasympathetic activity appears to correlate to feelings of fatigue. The difference is that in CFS, the ANS dysfunction happens after much lower levels of stress or activity (Tanaka et al. 2015). In simple terms, people with ME/CFS are hyper-sensitive to anything from infections and pain within the body to stimuli outside the body, such as noise, heat or emotional stress. The body is stuck in a high-alert – ‘we need to defend ourselves from all threats’ – mode (otherwise known as the ‘fight or flight response’, stemming from the sympathetic nervous system). Symptoms of Sympathetic dominance Excessive FatigueExercise intoleranceNausea/ poor appetiteConstipationPoor Digestion/indigestionAnxiety/nervousnessShallow breathingFast/slow/irregular heart rateLow blood pressureLight-headedness/dizziness upon standingWeaknessInsomnia/ Poor quality sleepIncreased agitation/irritabilityConcentration/memory problems   Increased muscle tensionNight sweatsDecreased LibidoIncreased inflammationIncreased susceptibility to infectionsTemperature regulation problemsCold hands/feetHyper-sensitivity (to light/noise)HeadachesTremorsFrequent urinationChronic painJoint painBody aches  Naturally, being on a constant state of high alert, quickly drains the body of energy and can result in other problems, such as gastrological symptoms, as digestion is not a priority in this state. The sympathetic system puts many organs and processes into overdrive and deprives other areas of blood and oxygen, so this is not an ideal state to spend most of your time in! “Sympathetic nervous system predominance is common in chronic fatigue syndrome and measures should be taken to regain autonomic balance” Martinez et al. (2014). Overview of the latest research on ANS and sleep The First Paper (by Cvejic et al. 2017): This study explored changes in autonomic functioning, sleep, and physical activity during a period of post-exertional symptom exacerbation, induced by physical or cognitive challenge in participants with chronic fatigue syndrome (CFS). Thirty-five participants with CFS (meeting the Fukuda definition) reported fatigue levels 24hrs before, immediately before, immediately after, and 24hrs after the completion of a physical (stationary cycling) or cognitive (simulated driving) challenge. Participants also provided ratings of their sleep quality and duration for the night before, and after, the challenge. Continuous ECG and physical activity was recorded from 24hrs prior, until 24hrs after, the challenge. To be recruited to this study, the CFS patients were required to have a steady level of symptoms, with no major fluctuations in severity, as well as a good sleep schedule (consistent sleep and rise times and minimised daytime napping). Medications affecting autonomic functioning (including beta-blockers and corticosteroids), or any other contraindications (untreated anxiety, uncontrolled cardiovascular complaints) were exclusionary. Participants were only allowed to take part in the physical challenge if they were shown able to carry out regular low-intensity exercise, without symptom exacerbation, and were physically capable of performing moderate-intensity aerobic exercise for at least 25 min. Although this was clearly in the best interest of the health of the participants, this may mean that this ‘challenge’ was within their activity levels and did not bring about a big enough PEM response to observe noticeable differences. The paper even comments on the suitability of their participants: “although experiencing significant impairment, they may have been more functional than others who are unable to undertake outpatient treatment or tolerate challenge protocols. It is possible that individuals with more severe fatigue and functional disability would have greater symptom exacerbation in response to challenges, accompanied by more prominent alterations in autonomic parameters”. In other words, it seems reasonable to assume that monitoring a more severely-affected cohort of patients would show even greater autonomic dysfunction and dysautonomia. Both physical and cognitive challenges induced an immediate increase in fatigue, which remained elevated 24hrs post-challenge. And, after completing the challenges, participants spent a greater proportion of the day lying down, but did not experience significant changes in sleep quality or sleep duration. Heart rate and heart-rate variability (HRV) were found to be reduced slightly post-challenge in the CFS group. Everyone’s HRV should increase when they’re asleep, compared to when they’re awake, which was the case for the patients with CFS. However, the amount of increase in the HRV between wake and sleep was significantly reduced after completing the challenge, suggesting reductions in nocturnal parasympathetic activity during the period of post-exertional malaise (PEM). High HRV is associated with better quality of sleep, but HRV during sleep was reduced post-challenge or during the period of PEM. However, CFS patients did not report a significant reduction in quality of sleep post-challenge to accompany the drop in HRV. The authors comment, “this might reflect a lack of sensitivity in subjective sleep quality measures”. It could also be that because these patients were mild, it may not have induced significant PEM and so didn’t affect their quality of sleep. The paper concluded: “Preliminary evidence of reduced nocturnal parasympathetic activity, and increased periods of inactivity, were found during post-exertional fatigue in a well-defined group of participants with CFS. Larger studies employing challenge paradigms are warranted to further explore the underlying pathophysiological mechanisms of post-exertional fatigue in CFS.” The second Paper (by Orjatsalo et al. 2017): This study looked at the nocturnal (night-time) cardiac autonomic nervous system (via heart-rate variability (HRV)) in different sleep stages in 8 patients (meeting the 2015 Institute of Medicine ME/CFS diagnostic criteria) and 8 “tired” controls. HRV, blood pressure and heart rate were studied in all sleep stages. The amount of sympathetic activity was higher for patients with CFS in all sleep stages compared to controls. The amount of Parasympathetic activity was lower in deep sleep in the patients with CFS than for the controls. Patients with CFS had higher overall nocturnal mean Blood Pressure and lower heart rate than controls. The paper concluded: “The results suggest a nocturnal dysfunction of the cardiac ANS in CFS, presenting as lower parasympathetic tone in deep sleep and higher sympathetic tone asleep.” So, what can we do about it?there is no drug or ‘quick fix’ to help restore a state of balance (or homeostasis) within the autonomic nervous system that might help relieve some of the symptoms we have seen are associated with dysautonomia. The Vagus nerve is a large nerve in the back of the neck that controls parasympathetic activity (the ‘rest and digest’ system). People with CFS and other chronic illness are said to have ‘low vagal tone’ and by increasing this, it is possible that you can increase your parasympathetic activity and help towards reducing symptoms. There are some medical innervations designed for resetting the ANS by stimulating the Vagus nerve, by surgically implanting an electrode in the neck region, or by applying an electrode to the surface of the ear (Clancy et al. 2014), which are reported to have been successful in several disorders. However, these techniques are invasive, not widely used and are currently not on offer to patients with ME/CFS (Johnson, 2014). There are several self-help measures that have been reported as being helpful ways to increase vagal tone, which in themselves seem simple, although incorporating them as a regular part of your life may prove difficult. These mainly involve techniques that induce the relaxation response which, over time, affects autonomic nervous system functioning (Nick Earle, 2017). They are summarised below. Whilst good breathing techniques and relaxation may well be helpful, it must be noted that there is currently no research evidence to indicate that increasing vagal tone is a safe and effective form of treatment for ANS dysfunction in ME/CFS. And some of these approaches (e.g. taking regular cold showers) could produce an exacerbation of ME/CFS symptoms. So, if you want to try some of these approaches, please take medical advice first. Self-help measures aimed at improving parasympathetic activity (vagal tone) • Deep diaphragm breathing (belly breathing) – Deep, slow breathing increases the sensitivity of the nerves that activate the parasympathetic nervous system (PNS). Breath deep so that your belly rises and falls, keeping your in and out breaths the same length, aiming for about 5-6 breaths per minute (there is a video on this below).• Mindfulness/Meditation (Black et al. 2015) – activates the PNS.• Gentle aerobic exercise (Yoga/Tai Chi/ swimming) (Chang et al. 2008) – Not only does this stimulate the PNS, it also encourages deep breathing.• Humming or singing – stimulates the muscles at the back of the throat to activate the Vagus nerve. Even more reason to sing in the shower or the car or hum your favourite tune!• Supporting a healthy gut (diet) – The presence of healthy gut bacteria has been claimed to create a positive feedback loop through the Vagus nerve, increasing its tone. Probiotics, animal protein and essential fats (omega 3 and 6 – found in oily fish, avocados, olive oil, nuts) have all been claimed to decrease an overactive sympathetic nervous system (SNS) and stimulate the Vagus nerve. Also, ensuring your diet is sufficient in Bvitamins, Calcium, Magnesium and Zinc, to support nerve function is said to Cutting down on or eliminating caffeine and alcohol is also important as they both stimulate the SNS.• Muscle Relaxation – By actively relaxing your muscles, through ‘progressive muscle relaxation’ techniques or with a warm bath, helps stimulate the PNS by switching off the SNS. Relaxed muscles send messages to the brain, telling it that nothing is alerting the body to a threat, so it can relax.• Massage and Acupuncture – Certain pressure points in the feet, neck and ears are believed to manually stimulate the Vagus nerve (da Silva et al. 2014) and create a sense of relaxation.• Cold – Counterintuitively, taking a cold shower, splashing cold water on your face, drinking cold water, or being in a cool environment, are thought to stimulate your Vagus nerve and PNS.• Sunlight – Being out in the sunlight produces a chemical called Alpha-MSH, which activates the Vagus nerve (Ottani et al. 2010) and PNS.• Laughter! – Stimulates the Vagus nerve, is also believed to be good for cognitive function and it releases endorphins (the ‘feel-good’ hormones).Here are some videos on Vagus nerve/ parasympathetic system stimulation: And here are some gentle Yoga videos: References (click to open)ReferencesBeaumont, A., Burton, A.R., Lemon, J., Bennett, B., Lloyd, A. and Vollmer-Conna, U. (2012) Reduced Cardiac Vagal Modulation Impacts on Cognitive Performance in Chronic Fatigue Syndrome, PLoS ONE, 7 (11). Black, D.S., O’Reilley, G.A., Olmstead, R., Breen, E.C. and Irwin, M.R. (2015) Mindfulness meditation and improvement in sleep quality and daytime impairment among older adults with sleep disturbances: a randomized clinical trial, JAMA International Medicine, 175, 4: 494-501. Boneva, R.S., Decker, M.J., Maloney, E.M., Lin, J.M., Jones, J.F., Helgason, H., Heim, C., Rye, D. and Reeves, W.C. (2007) Higher heart rate and reduced heart rate variability persist during sleep in chronic fatigue syndrome: a population-based study, Autonomic Neuroscience, 137 (1-2): 94-101. Chang, R.Y., Koo, M., Yu, Z.R., Kan, C.B., Chu, I.T., Hsu, C.T. and Chen, C.Y. (2008) The effect of t'ai chi exercise on autonomic nervous function of patients with coronary artery disease. Journal of Alternative and Complimentary Medicine, 14, 9. Clancy, J.A., Mary, D.A., Witte, K., Greenwood, J.P. and Deuchars, J.B. (2014) Non-invasive Vagus Nerve Stimulation in Healthy Humans Reduces Sympathetic Nerve Activity, Brain Stimulation. Cvejic, E., Sandler, C.X., Keech, A., Barry, B.K., Lloyd, A.R. and Vollmer-Conna, U. (2017) Autonomic nervous system function, activity patterns, and sleep after physical or cognitive challenge in people with chronic fatigue syndrome, Journal of Psychosomatic Research, 103, 91-94. Da Silva, M.A. and Dorsher, P.T. (2014) Neuroanatomic and clinical correspondences: acupuncture and vagus nerve stimulation. Journal of Alternative and Complimentary Medicine, 20, 4: 233-240. Fisher, J.P., Young, C.N. and Fadel, P.J. (2010) Central Sympathetic Overactivity: Maladies and Mechanisms, Autonomic Neuroscience, 148 (1-2): 5-15. Hillebrand, S., Gast, K., Mutsert, R., Swenne, C., Jukema, W., Middledrop, S., Rosendaal, F. and Dekkers, O. (2013) Heart rate variability and first cardiovascular event in populations without known cardiovascular disease: meta-analysis and dose–response meta-regression, EP Europace, 14 (1): 742749. Johnson, C. (2014) System Reset: New Way to Reduce Fight or Flight Response Found, HealthRising. Available: Johnson, C. (2017) Chronic Fatigue Syndrome Studies link Autonomic Nervous System Problems to the Brain, HelathRising Available: Lacerda, E.M., Nacul, L., Pheby, D., Shepherd, C. and Spencer, P. (2010) Exploring the feasibility of establishing a disease-specific post-mortem tissue bank in the UK: a case study in ME/CFS, British Medical Journals, 63 (11). Martinez, M., Mora, T., Vargas, A., Fuentes-Iniestra, M., Martinez-Kavin, M., (2014) Sympathetic nervous system dysfunction in fibromyalgia, chronic fatigue syndrome, irritable bowel syndrome, and interstitial cystitis: a review of case-control studies, Journal of Clinical Rheumatology, 20, 3: 14650. Mason, H., Vandoni, M., deBarbieri, G., Codrons, E., Ugargol, V. and Bernardi, L. (2013). Cardiovascular and Respiratory Effect of Yogic Slow Breathing in the Yoga Beginner: What is the Best Approach? Evidence-Based Complementary and Alternative Medicine. Meeus, M., Goubert, D., Backer, F.D., Struyf, F., Hermans, L., Coppieters, I., Wandele, I.D., Silva, H.D. and Calders, P. (2013) Heart rate variability in patients with fibromyalgia and patients with chronic fatigue syndrome: A systematic review, Seminars in Arthritis and Rheumatism, 43, 2; 279-287. Miller, A.H., Jones, J.F., Drake, D.F., Tian, H., Unger, E. and Pagnoni, G. (2014) Decreased Basal Ganglia Activation in Subjects with Chronic Fatigue Syndrome: Association with Symptoms of Fatigue, PLoS One, 9 (5). Nick Earl (2017) Relaxation 101- How to activate the Parasympathetic Nervous System. HealthVibed, Available: Orjatsalo, M., Alakuijala, A. and Pertinen, M. (2017) Autonomic Nervous System Functioning Related to Nocturnal Sleep in Patients with Chronic Fatigue Syndrome Compared to Tired Controls, Journal of Clinical Sleep Medicine. Ottani, A., Giuliani, D., Galantucci, M., Spaccapelo, L., Novelino, E., Grieco, P., Jochem, J. and Guarini, S. (2010). Melanocortins counteract inflammatory and apoptotic responses to prolonged myocardial ischemia/reperfusion through a vagus nerve-mediated mechanism, European Journal of Pharmacology, 637, 1-3: 124-130. Papaioannou, V., Pneumatikos, I. and Maglaveras, N. (2013) Association of heart rate variability and inflammatory response in patients with cardiovascular diseases: current strengths and limitations, Frontiers in Physiology, 4: 174. Robinson, L.J., Durham, J., MacLachlan, L. and Newton, J.L. (2015) Autonomic function in chronic fatigue syndrome with and without painful temporomandibular disorder, Fatigue: Biomedicine, Health and Behaviour, 3, 4. SelfHacked (2015) 32 Ways to Stimulate your Vagus Nerve (and Symptoms of Vagal Dysfunction) SelfHacked Available: Tanaka, M., Tajima, S., Mizuno, K., Ishii, A., Konishi, Y., Mike, Y. and Watanabe, Y. (2015) Frontier studies on fatigue, autonomic nerve dysfunction, and sleep-rhythm disorder, The Journal of Physiological Science, 65, 6; 483-498. back to top of article to click to close                                                                                                                                           click to closeback to top of article




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