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From the Townsend Letter
July 2019

New Understanding of Autoimmunity Development Through T Helper Cell Regulation, Part 2
by Debby Hamilton, MD, MPH
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Part one also online

Page 1, 2

Resveratrol
Resveratrol is a well-known polyphenol. It is best known for its presence in red wine, presumably leading to its benefits. In a manner similar to curcumin, resveratrol has an impact on many cellular pathways. Its anti-inflammatory effects appear to be from its negative impact on NFkB. By inhibiting NFkB, it causes a decrease in TNF-alpha and a subsequent decrease in IL-23, leading to decreased levels of autoimmune stimulating Th17.14 Part of the mechanism of TNF-alpha is to cause a T-cell proliferation, which is inhibited by resveratrol.14
     
Another mechanism for decreasing NFkB is through the activation of SIRT-1. Resveratrol activates SIRT-1 which deacetylates NFkB.15 Sirtuin 1 (Sirt-1) is a longevity gene related to multiple diseases associated with aging. Its mechanism of action is through a NAD+ dependent protein deacetylase which is how it inactivates NFkB.16 Sirt-1 also has a role as a master metabolic regulator. Resveratrol by increasing SIRT-1 has an anti-aging effect as well as an anti-inflammatory and anti-oxidative stress response.16
     
Autoimmune disease through activation of Th17 can be stimulated by dysbiosis. Therefore, restoring the microbiome can decrease inflammation, driving an increase in Th17 and a decrease in immune tolerance. In a mouse model of colonic inflammation, resveratrol led to a restoration of the bacterial microbiota in the intestine with a concomitant increase in the short chain fatty acid butyrate.17 This was accompanied by a decrease in Th17 cells and an increase in Treg cells.17 Because of its multiple mechanisms, resveratrol appears to be a good anti-inflammatory and anti-autoimmune supplement.

Quercetin
Quercetin is a flavonoid compound found in many fruits and vegetables. Flavonoids are part of the group of polyphenols that are used in integrative medicine for their antioxidant and anti-inflammatory properties. Quercetin is most well-known for its influence of decreasing histamine levels and IL-4 and IL-5 and therefore allergies.18 It appears to also have a role in autoimmune regulation. It decreases the release of the pro-inflammatory cytokines, IL-6 and IL-1 through inhibition of MAPK signaling.19 A decrease in these pro-inflammatory cytokines leads to a suppression in Th17 and subsequently IL-17 production.20
     
TransferFactorAnother mode of action for quercetin is inhibition of the protein kinase called mTOR (mammalian target of rapamycin). The function of mTOR as a serine/threonine kinase regulates cell growth, cell proliferation and survival, protein synthesis, transcription of proteins and autophagy.21 A new role of mTOR appears to be regulation of T-cell homeostasis.22 There are two different mTOR subunits that together can promote Th1, Th2, and Th17 differentiation.22 When quercetin inhibits both mTOR forms, it decreases Th17 and induces Treg development.20,22 Quercetin helps promote immune tolerance in this way and decreases the tendency towards autoimmunity.

EGCG
Epigallocatechin-3-gallate (EGCG) is a green tea polyphenol with well-known antioxidant and anti-inflammatory effects. It also plays a role in modulation of T helper cell differentiation. EGCG inhibits T helper cell differentiation into Th1 and Th17 cells through impacting their respective signaling transducers and transcription factors.23 It also has a role in increasing Treg cells.24,25 Some of the mechanisms are by decreasing Th-17 associated pro-inflammatory cytokines including IL-1β, IL-6, IL-17A, and TNF-α expressions.25 To do this, EGCG can down regulate the transcription factors STAT3 and mTOR.23 These results suggest that EGCG may improve T-cell-mediated autoimmune diseases .

Probiotics
Autoimmune disease triggered by elevated Th17 is often from dysbiosis or an imbalanced microbiome in the intestine. Severe imbalance with elevated Th17 and its cytokine IL-17 can lead to chronic intestinal inflammation promoting the development of inflammatory bowel disease (IBD).26,27 Probiotics have an anti-inflammatory effect in the intestine through immunomodulation and suppression of Th17 cell elevation.26 Probiotics impact the immune system through several mechanisms including signaling through the Toll-like receptor family.26 Several studies have shown the effectiveness of probiotics in preventing and treating IBD (ulcerative colitis, and Crohn's disease).27 In addition to decreasing Th17 cells, probiotics along with prebiotics increase Treg cells and therefore immune tolerance.28 With the majority of people now without a normal microbiome, it makes sense as a preventative measure to supplement with probiotics.

Vitamin D
Vitamin D appears to have a role in autoimmune disease. VDR or the vitamin D receptor is present on lymphocytes leading to one mechanism of interaction with the immune system.29 VDR contains many polymorphisms that lead to a difference in risk for vitamin D deficiency. Autoimmune diseases appear to be correlated with vitamin D levels where patients have an increased risk and increased severity of disease with lower vitamin D levels.29
     
How vitamin D influences autoimmune disease has been researched in several autoimmune diseases. It appears to influence two of the mechanisms of autoimmune development. It can inhibit the differentiation and increasing levels of Th17.30 Through this influence on Th17, vitamin D helped decrease symptom severity in children with asthma.30 Multiple studies have shown vitamin D to have a role in supporting Treg cells.31,32 The higher the vitamin D level, the higher the level of Treg cells leading to improved immune tolerance.

Vitamin A
Vitamin A, like vitamin D, appears to play a role in autoimmunity by modulating the balance of Th17 and Treg cells. Patients with SLE who had lower levels of vitamin A in the blood had higher levels of Th17 cells.33 Retinoic acid is the metabolite of vitamin A that is the key regulator in modulating this balance.33,34 Retinoic acid in the presence of TGF-B promotes the conversion of naïve T cells intoTreg cells.35 It also inhibits IL-6 from driving the naïve T cells into the development of the pro-inflammatory Th17 cells.34 Overall the retinoic acid can lead to different differentiation by being an important regulator of TGF-B.34

BDNF EssentialsSummary
With the increasing rates of autoimmune disease, it is important for practitioners to understand the underlying immune mechanisms. Research has consistently shown autoimmune disease to be associated with immune dysregulation. This dysregulation leads to an elevation of Th17 and Th2 with a decrease in Th1 and Treg cells, which creates a cycle of chronic inflammation and infection, perpetuating autoimmune disease. With the understanding of the immune mechanisms underlying this imbalance, we can use our tools in integrative medicine to break this inflammatory cycle.

Page 1, 2

Part one also online

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