<\/a>Reconciling Th1\/Th2 Discrepancies<\/span><\/h3>\nYou\u2019ve probably heard about the Th1 and Th2 response. To rewind, the Th1\/Th2 theory is one attempt at understanding immune regulation, and Th1 and Th2 cells are its key players.<\/p>\n
This theory dates back to studies on mouse immune cells in the 80s. However, it is still considered controversial and it\u2019s not without limitations and discrepancies [R<\/a>].<\/p>\nAccording to the Th1\/Th2 theory [R<\/a>]:<\/p>\n\n- Th1 cells<\/strong> drive the so-called type-1 pathway<\/em> (\u201ccellular immunity\u201d). They are thought to be involved in fighting viruses and other pathogens that enter cells, getting rid of cancerous cells, and triggering delayed-type hypersensitivity (DTH) skin reactions.<\/li>\n
- Th2 cells<\/strong> drive the type-2 pathway<\/em> (\u201chumoral immunity\u201d). They are hypothesized to increase antibody production and fight invaders that are outside cells. They may be involved in tolerance of organ transplants (xenografts) and of the fetus during pregnancy<\/li>\n<\/ul>\n
But the human immune system is incredibly complex. We have many other types of immune cells that are orchestrated by various factors — from our encounter with microbes, to our health status, genetics, mood, and more.<\/p>\n
That\u2019s where Th17 cells<\/strong> come in. These cells were identified only recently and scientists think they can fill the missing gaps and explain some inconsistencies with the Th1\/Th2 theory [R<\/a>].<\/p>\nFor example, Th17 cells are implicated in several human diseases and their cytokines are linked to inflammation and tissue damage [R<\/a>].<\/p>\nIn turned out that about a third of the progenitors — T helper cells — develop into Th17 cells, a third into Th1, and a third into Th2 cells [R<\/a>].<\/p>\nHowever, Th17 science is new and the findings so far have been inconclusive. Let\u2019s take a look at how much we know about this newly-discovered immune pattern.<\/p>\n
<\/a>Overview<\/span><\/h3>\nT helper cells start off as \u201cnaive\u201d T cells and can turn into Th1<\/a>, Th2<\/a>, or Th17 cells.<\/p>\nA naive T cell can either become an inflammatory Th17 cell or an anti-inflammatory Treg cell. According to some researchers, the goal in inflammation is to convert more Th17 cells to Treg<\/a> cells [R<\/a>].<\/p>\nCytokines or the lack of them influence which cell the naive helper cell will convert into. The two necessary cytokines are TGFb<\/a> and IL-6<\/a>, which we\u2019ve spoken about [R<\/a>].<\/p>\nScientists claim that IL-6 (some say IL-21<\/a>) is what ultimately determines if it turns into an inflammatory or anti-inflammatory cell. IL-23<\/a> is a cytokine that may determine if these Th17 will cause disease, though more research is needed [R<\/a>].<\/p>\nIL-1\u03b2<\/a> can also increase the production of Th17 cells [R<\/a>].Th17 cells produce the cytokine IL-17, as well as TNF<\/a> and others [R<\/a>].<\/p>\n<\/a>Link to Kynurenine<\/span><\/h3>\nKynurenine is a metabolite of the amino acid tryptophan, used by the body while producing niacin. Recently, this pathway has been linked with everything from inflammation to immune imbalances and brain disorders [R<\/a>].<\/p>\nStudies are still trying to decipher its impact on disease and whether it can be a therapeutic target [R<\/a>].<\/p>\nScientists think that IL-17 increases kynurenine (so does cortisol, IL-1<\/a>, TNF, and IFNy\/Th1 dominance) [R<\/a>].<\/p>\nLimited data linked IL-17 to IBS<\/a> [R<\/a>]. However, the effects of increasing this pathway are mixed. Some animal studies suggest that it increases oxidative stress<\/a> and may be associated with low mood [R<\/a>].<\/p>\nKynurenine can turn into kynurenic acid or quinolinic acid. Kynurenic acid blocks NMDA, AMPA, glutamate<\/a> and nicotinic receptors, all of which are important for learning and memory.<\/p>\nThus, some scientists hypothesize that kynurenic acid can reduce intelligence [R<\/a>]. On the other hand, inhibiting Kynurenic acid seems to result in cognitive enhancement in mice [R<\/a>]. Although intriguing, human data are needed.<\/p>\n![\"\"](\"https:\/\/selfhacked.com\/blog\/app\/uploads\/2019\/11\/Screenshot-2019-11-27-14.48.52-480x304.png\")
<\/p>\n
<\/a>Other Pathways<\/span><\/h3>\nInterleukin 17 acts antagonistically with TNF<\/a> and IL-1<\/a> [R<\/a>] (antagonism is the opposite of synergy).<\/p>\nIn some studies, IL-17 was associated with allergic responses. Researchers found that it induces the production of other inflammatory compounds (such as IL-6<\/a>, IL-1\u03b2, TGF<\/a>-\u03b2, TNF, IL-8<\/a>, MCP-1<\/a>, and PGE2) that is thought to lead to negative events like airway narrowing in people with asthma [R<\/a>].<\/p>\nTh17 cells seem to have a circadian rhythm<\/a>. The amount of Th17 cells changes during the day-night cycle. Animal studies suggest that the production of Th17 is higher at midnight than at noon [R<\/a>].<\/p>\nScience reminds us that Th17 and IL-17 aren\u2019t just \u201cbad,\u201d though.<\/p>\n
Based mostly on animal findings, Th17 appears to have a protective role in combating fungi [R<\/a>] and some bacterial infections (\u201cextracellular\u201d) [R<\/a>], along with Tregs<\/a> [R<\/a>].<\/p>\nResearchers are investigating whether Th17 may have anticancer properties, but studies are still in the early phases. Other scientists speak of the \u201ccancer and autoimmune trade-off,\u201d but this theory is still filled with inconsistencies, leaving us with more questions than answers [R<\/a>].<\/p>\nAdditionally, Th17 cells appear to be resistant to the suppressive effects of Tregs [R<\/a>, R<\/a>].<\/p>\nStudies in animal models of MS<\/a> suggest that Th1 cells are important in initiating acute attacks, while Th17 cells are hypothesized to be more important in mediating the progression of this disease. This hasn\u2019t been confirmed in humans, but one study found higher IL-17 expression in chronic versus acute MS<\/a> lesions [R<\/a>].<\/p>\nLimited data suggest that in people with food allergies (classical type), IL-17 production was impaired, but not in healthy people. The study found IL-17 was a potential biomarker for tolerance to food antigens. Large-scale studies are needed [R<\/a>].<\/p>\nA normal range of IL-17A has yet to be defined. One study proposed levels of 0.89 pg\/ml. In people with mild sleep<\/a> apnea, levels are 1.02 pg\/ml, in moderate sleep apnea 1.18 pg\/ml, and in severe sleep apnea 1.62 pg\/ml. (all median values). More research is needed [R<\/a>].<\/p>\n<\/a>Gender Differences<\/strong><\/span><\/h3>\nStudies suggest that women are more susceptible than men to autoimmune conditions, including Multiple Sclerosis<\/a> (female to male ratio of 2:1), Rheumatoid Arthritis (2:1), Systemic Lupus Erythematosus (9:1), Sjogren\u2019s syndrome (9:1), and Hashimoto\u2019s thyroiditis (9:1) [R<\/a>].<\/p>\nThe higher female prevalence of these diseases may be related to the fact that women might develop more robust immune responses than men [R<\/a>].<\/p>\nLimited studies have suggested that men are more prone to Th17<\/a> and Th2 dominance<\/a>, while women are thought to be more prone to Th1 dominance<\/a>. However, there\u2019s no hard evidence to back this up (R<\/a>, R<\/a>).<\/p>\nFor example, one study found that women have higher levels of Th1<\/a> cells, IgM, and CD4+<\/sup> cell counts, and show stronger immune response responses to vaccinations. Other studies had mixed findings [R<\/a>].<\/p>\nAdditionally, studies indicate that pregnancy is a Th2 state. Scientists think that lower Th1 activity is part of the adaptive physiological response that women go through in pregnancy (R<\/a>).<\/p>\nThis is said to prevent the mother\u2019s antibodies from mounting an attack against the fetus. It\u2019s also thought to explain why women are more prone to infections during pregnancy. Many women with rheumatoid arthritis — typically seen as a Th1 disease — experience relapses after pregnancy (R<\/a>).<\/p>\nOn the other hand, male sex hormones or androgens may increase PPAR alpha<\/a>, which causes inhibition of Th1 dominance<\/a> in animals. At the same time, men tend to have lower PPAR gamma<\/a>, which is hypothesized to lead to Th17 dominance (R<\/a>).<\/p>\nTo some extent, researchers believe that Th1 and Th17 \u201ccompete\u201d with each other, but this is also uncertain. Some studies indicate that IL-2<\/a> produced by Th1 cells activates STAT5, which competes with STAT3<\/a> (thought to be produced in Th17 dominance) (R<\/a>).<\/p>\nIn line with this, the castration of male mice enhances Th1 autoimmunity and lowers Th2<\/a> cytokine production. We can\u2019t extrapolate these findings to humans [R<\/a>].<\/p>\nAll in all, more human research on these gender-related mechanisms is needed<\/strong>.<\/p>\n<\/a>Diseases Associated With Increased Th17<\/strong><\/span><\/h3>\nThe majority of studies covered in this section deal with associations only, which means that a cause-and-effect relationship hasn\u2019t been established.<\/strong><\/p>\nFor example, just because autoimmune diseases have been linked with increased Th17 activity doesn\u2019t mean that and autoimmunity is caused by Th17 dominance. Data are lacking to make such claims.<\/p>\n
Also, even if a study did find that Th17 activity contributes to autoimmune diseases, Th17 cells are highly unlikely to be the only causative factor. Complex autoimmune disorders always involve multiple possible factors – including biochemistry, environment, health status, and genetics – that may vary from one person to another.<\/p>\n
Additionally, some of the studies listed below rely on animal experiments, which can\u2019t be applied to humans.<\/strong> More research is needed before we understand how Th17 cells affect health in humans.<\/p>\n\n- Several Autoimmune diseases: Hashimoto’s [R<\/a>], Grave’s [R<\/a>], Multiple Sclerosis [R<\/a>], Lupus\/SLE [R<\/a>], Uveitis [R<\/a>], Type 1 diabetes [R<\/a>], Systemic Sclerosis [R<\/a>], Autoimmune myocarditis [R<\/a>], Vitiligo [R<\/a>]<\/li>\n
- Heart disease [R<\/a>, R<\/a>] (IL-17) – contradictory [R<\/a>]<\/li>\n
- IBS<\/a> [R<\/a>] – some cases<\/li>\n
- Rheumatoid arthritis [R<\/a>, R<\/a>]<\/li>\n
- Hashimoto\u2019s [R<\/a>], Graves [R<\/a>]<\/li>\n
- Multiple Sclerosis<\/a> [R<\/a>]<\/li>\n
- Asthma [R<\/a>], Airway inflammation [R<\/a>]<\/li>\n
- IBD [R<\/a>]: Crohn’s [R<\/a>], Colitis [R<\/a>]<\/li>\n
- Sleep apnea [R<\/a>, R<\/a>]<\/li>\n
- Skin: Acne Lesions [R<\/a>], Psoriasis [R<\/a>], Eczema[R<\/a>]<\/li>\n
- Some cancers (extremely limited data) [R<\/a>]<\/li>\n
- Fibromyalgia [R<\/a>] – increased IL-17A<\/li>\n
- Osteoporosis in menopausal women [R<\/a>, R<\/a>]<\/li>\n
- Depression [R<\/a>] (IL17<\/a> and TGFbeta1) [R<\/a>]<\/li>\n
- Periodontal Disease [R<\/a>]<\/li>\n
- Lyme arthritis. Lyme or B. burgdorferi seems to increase IL-6, IL-1b<\/a>, IL-23, and TGFb, which increases Th17 immunity and may trigger Lyme arthritis [R<\/a>].<\/li>\n
- Stroke damage (IL-17) [R<\/a>]<\/li>\n<\/ul>\n
Th17 overactivity is hypothesized to lead to infertility in women because the Th17 response makes the immune system attack sperm [R<\/a>].<\/p>\nOn the other hand, Estradiol<\/a> (E2) inhibits Th17 cell responses, so that sperm is not attacked during ovulation. Some scientists say this sheds light on the connection between fungal infections (which increase Th17) and female infertility, but proper data are lacking to back up this whole Th17-infertility theory [R<\/a>].<\/p>\nTh17 is lower in chronic fatigue syndrome. A cause-and-effect relationship hasn\u2019t been established [R<\/a>].<\/p>\n
According to the Th1\/Th2 theory [R<\/a>]:<\/p>\n But the human immune system is incredibly complex. We have many other types of immune cells that are orchestrated by various factors — from our encounter with microbes, to our health status, genetics, mood, and more.<\/p>\n That\u2019s where Th17 cells<\/strong> come in. These cells were identified only recently and scientists think they can fill the missing gaps and explain some inconsistencies with the Th1\/Th2 theory [R<\/a>].<\/p>\n For example, Th17 cells are implicated in several human diseases and their cytokines are linked to inflammation and tissue damage [R<\/a>].<\/p>\n In turned out that about a third of the progenitors — T helper cells — develop into Th17 cells, a third into Th1, and a third into Th2 cells [R<\/a>].<\/p>\n However, Th17 science is new and the findings so far have been inconclusive. Let\u2019s take a look at how much we know about this newly-discovered immune pattern.<\/p>\n T helper cells start off as \u201cnaive\u201d T cells and can turn into Th1<\/a>, Th2<\/a>, or Th17 cells.<\/p>\n A naive T cell can either become an inflammatory Th17 cell or an anti-inflammatory Treg cell. According to some researchers, the goal in inflammation is to convert more Th17 cells to Treg<\/a> cells [R<\/a>].<\/p>\n Cytokines or the lack of them influence which cell the naive helper cell will convert into. The two necessary cytokines are TGFb<\/a> and IL-6<\/a>, which we\u2019ve spoken about [R<\/a>].<\/p>\n Scientists claim that IL-6 (some say IL-21<\/a>) is what ultimately determines if it turns into an inflammatory or anti-inflammatory cell. IL-23<\/a> is a cytokine that may determine if these Th17 will cause disease, though more research is needed [R<\/a>].<\/p>\n IL-1\u03b2<\/a> can also increase the production of Th17 cells [R<\/a>].Th17 cells produce the cytokine IL-17, as well as TNF<\/a> and others [R<\/a>].<\/p>\n Kynurenine is a metabolite of the amino acid tryptophan, used by the body while producing niacin. Recently, this pathway has been linked with everything from inflammation to immune imbalances and brain disorders [R<\/a>].<\/p>\n Studies are still trying to decipher its impact on disease and whether it can be a therapeutic target [R<\/a>].<\/p>\n Scientists think that IL-17 increases kynurenine (so does cortisol, IL-1<\/a>, TNF, and IFNy\/Th1 dominance) [R<\/a>].<\/p>\n Limited data linked IL-17 to IBS<\/a> [R<\/a>]. However, the effects of increasing this pathway are mixed. Some animal studies suggest that it increases oxidative stress<\/a> and may be associated with low mood [R<\/a>].<\/p>\n Kynurenine can turn into kynurenic acid or quinolinic acid. Kynurenic acid blocks NMDA, AMPA, glutamate<\/a> and nicotinic receptors, all of which are important for learning and memory.<\/p>\n Thus, some scientists hypothesize that kynurenic acid can reduce intelligence [R<\/a>]. On the other hand, inhibiting Kynurenic acid seems to result in cognitive enhancement in mice [R<\/a>]. Although intriguing, human data are needed.<\/p>\n Interleukin 17 acts antagonistically with TNF<\/a> and IL-1<\/a> [R<\/a>] (antagonism is the opposite of synergy).<\/p>\n In some studies, IL-17 was associated with allergic responses. Researchers found that it induces the production of other inflammatory compounds (such as IL-6<\/a>, IL-1\u03b2, TGF<\/a>-\u03b2, TNF, IL-8<\/a>, MCP-1<\/a>, and PGE2) that is thought to lead to negative events like airway narrowing in people with asthma [R<\/a>].<\/p>\n Th17 cells seem to have a circadian rhythm<\/a>. The amount of Th17 cells changes during the day-night cycle. Animal studies suggest that the production of Th17 is higher at midnight than at noon [R<\/a>].<\/p>\n Science reminds us that Th17 and IL-17 aren\u2019t just \u201cbad,\u201d though.<\/p>\n Based mostly on animal findings, Th17 appears to have a protective role in combating fungi [R<\/a>] and some bacterial infections (\u201cextracellular\u201d) [R<\/a>], along with Tregs<\/a> [R<\/a>].<\/p>\n Researchers are investigating whether Th17 may have anticancer properties, but studies are still in the early phases. Other scientists speak of the \u201ccancer and autoimmune trade-off,\u201d but this theory is still filled with inconsistencies, leaving us with more questions than answers [R<\/a>].<\/p>\n Additionally, Th17 cells appear to be resistant to the suppressive effects of Tregs [R<\/a>, R<\/a>].<\/p>\n Studies in animal models of MS<\/a> suggest that Th1 cells are important in initiating acute attacks, while Th17 cells are hypothesized to be more important in mediating the progression of this disease. This hasn\u2019t been confirmed in humans, but one study found higher IL-17 expression in chronic versus acute MS<\/a> lesions [R<\/a>].<\/p>\n Limited data suggest that in people with food allergies (classical type), IL-17 production was impaired, but not in healthy people. The study found IL-17 was a potential biomarker for tolerance to food antigens. Large-scale studies are needed [R<\/a>].<\/p>\n A normal range of IL-17A has yet to be defined. One study proposed levels of 0.89 pg\/ml. In people with mild sleep<\/a> apnea, levels are 1.02 pg\/ml, in moderate sleep apnea 1.18 pg\/ml, and in severe sleep apnea 1.62 pg\/ml. (all median values). More research is needed [R<\/a>].<\/p>\n Studies suggest that women are more susceptible than men to autoimmune conditions, including Multiple Sclerosis<\/a> (female to male ratio of 2:1), Rheumatoid Arthritis (2:1), Systemic Lupus Erythematosus (9:1), Sjogren\u2019s syndrome (9:1), and Hashimoto\u2019s thyroiditis (9:1) [R<\/a>].<\/p>\n The higher female prevalence of these diseases may be related to the fact that women might develop more robust immune responses than men [R<\/a>].<\/p>\n Limited studies have suggested that men are more prone to Th17<\/a> and Th2 dominance<\/a>, while women are thought to be more prone to Th1 dominance<\/a>. However, there\u2019s no hard evidence to back this up (R<\/a>, R<\/a>).<\/p>\n For example, one study found that women have higher levels of Th1<\/a> cells, IgM, and CD4+<\/sup> cell counts, and show stronger immune response responses to vaccinations. Other studies had mixed findings [R<\/a>].<\/p>\n Additionally, studies indicate that pregnancy is a Th2 state. Scientists think that lower Th1 activity is part of the adaptive physiological response that women go through in pregnancy (R<\/a>).<\/p>\n This is said to prevent the mother\u2019s antibodies from mounting an attack against the fetus. It\u2019s also thought to explain why women are more prone to infections during pregnancy. Many women with rheumatoid arthritis — typically seen as a Th1 disease — experience relapses after pregnancy (R<\/a>).<\/p>\n On the other hand, male sex hormones or androgens may increase PPAR alpha<\/a>, which causes inhibition of Th1 dominance<\/a> in animals. At the same time, men tend to have lower PPAR gamma<\/a>, which is hypothesized to lead to Th17 dominance (R<\/a>).<\/p>\n To some extent, researchers believe that Th1 and Th17 \u201ccompete\u201d with each other, but this is also uncertain. Some studies indicate that IL-2<\/a> produced by Th1 cells activates STAT5, which competes with STAT3<\/a> (thought to be produced in Th17 dominance) (R<\/a>).<\/p>\n In line with this, the castration of male mice enhances Th1 autoimmunity and lowers Th2<\/a> cytokine production. We can\u2019t extrapolate these findings to humans [R<\/a>].<\/p>\n All in all, more human research on these gender-related mechanisms is needed<\/strong>.<\/p>\n The majority of studies covered in this section deal with associations only, which means that a cause-and-effect relationship hasn\u2019t been established.<\/strong><\/p>\n For example, just because autoimmune diseases have been linked with increased Th17 activity doesn\u2019t mean that and autoimmunity is caused by Th17 dominance. Data are lacking to make such claims.<\/p>\n Also, even if a study did find that Th17 activity contributes to autoimmune diseases, Th17 cells are highly unlikely to be the only causative factor. Complex autoimmune disorders always involve multiple possible factors – including biochemistry, environment, health status, and genetics – that may vary from one person to another.<\/p>\n Additionally, some of the studies listed below rely on animal experiments, which can\u2019t be applied to humans.<\/strong> More research is needed before we understand how Th17 cells affect health in humans.<\/p>\n Th17 overactivity is hypothesized to lead to infertility in women because the Th17 response makes the immune system attack sperm [R<\/a>].<\/p>\n On the other hand, Estradiol<\/a> (E2) inhibits Th17 cell responses, so that sperm is not attacked during ovulation. Some scientists say this sheds light on the connection between fungal infections (which increase Th17) and female infertility, but proper data are lacking to back up this whole Th17-infertility theory [R<\/a>].<\/p>\n Th17 is lower in chronic fatigue syndrome. A cause-and-effect relationship hasn\u2019t been established [R<\/a>].<\/p>\n\n
<\/a>Overview<\/span><\/h3>\n
<\/a>Link to Kynurenine<\/span><\/h3>\n
<\/p>\n<\/a>Other Pathways<\/span><\/h3>\n
<\/a>Gender Differences<\/strong><\/span><\/h3>\n
<\/a>Diseases Associated With Increased Th17<\/strong><\/span><\/h3>\n
\n