Th17 versus Treg balance: a unifying hypothesis about IBD?

[Guest guest]

It is becoming evident that inflammatory bowel disease may be the result of an imbalance between Th17 cells and T regulatory (Treg cells). Th17 cells are pro-inflammatory, and their name orginates from the fact that they produce interleukin-17 (IL-17), a pro-inflammatory cytokine. The production of Th17 cells is stimulated by interleukin-23 (IL-23), among many other factors. Tregs are anti-inflammatory and suppress inflammation, in part by production of interleukin-10 (IL-10). As discussed in the latest newsletter, many of the genes involved in inflammatory bowel disease are now being found to be associated with either Th17 cell or Treg development and activity.

The latest paper on this is from Abraham and Cho (2009) ... just published in the journal Inflammatory Bowel Diseases, and not yet listed in Pubmed:

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Inflamm. Bowel Dis. 27 Feb [Epub ahead of print] (2009)

Interleukin-23/Th17 pathways and inflammatory bowel disease.

Clara Abraham, MD *, Judy Cho, MD

Department of Medicine, Digestive Diseases, Yale University, New Haven, Connecticut email: Clara Abraham (clara.abraham@...)

Keywords

inflammatory bowel disease • inflammation • autoimmunity • IL-23 • Th17 cells

Abstract

The IL-23/Th17 pathway has recently been identified to play a critical role in a number of chronic inflammatory diseases including inflammatory bowel disease (IBD). The identification in IBD patients of associations in IL23R and regions that include other genes in the IL-23/Th17 pathway has highlighted the importance of proper IL-23/Th17 pathway regulation in intestinal immune homeostasis. IL-23 plays a role in CD4+ Th17 lineage cells, characterized by IL-17 secretion and the expression of the transcription factor retinoic acid-related orphan receptor (ROR)gammat, and in other immune and nonimmune cells. The balance between effector T cell subsets, such as Th17 cells, and CD4+ T regulatory subsets is finely regulated; dysregulation of this balance can lead to inflammation and autoimmunity. As such, the IL-23/Th17 pathway contributes to immune responses that play a role in defenses to microbial infection, as well as in the intestinal inflammation observed in both animal models of colitis and human IBD.

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As I already mentioned, this model of IBD [an imbalance between Tregs and Th17 cells] is consistent with the recent genetic studies. It also begins to explain the 'hygeine hypothesis', namely that the eradication of parasitic worms in Western societies has shifted the balance between Th17 and Tregs. Helminths tend to shift the immune system towards anti-inflammatory Tregs, away from pro-inflammatory Th17 cells (see my recent message # 108314 in the archives). Absence of parastic worms in the gastrointestinal tract results in lack of suppression of Th17 cells, and hence a predisposition towards inflammation.

Can this model account for some of the other environmental risk factors for IBD? One of the most peculiar environmental factors affecting susceptibility to ulcerative colitis (and PSC) is lack of smoking. I havn't found a satisfactory explanation for this until the Th17 versus Treg balance hypothesis came along. It turns out that one of the regulators of the balance between Tregs and Th17 cells is the aryl hydrocarbon receptor, see:

Ho PP, Steinman L 2008 The aryl hydrocarbon receptor: a regulator of Th17 and Treg cell development in disease. Cell Res. 18: 605-608.

As described in the latter article, some compounds that bind to the aryl hydrocarbon receptor shift the balance towards Tregs, while others shift the balance towards Th17 cells. It has been shown that the aryl hydrocarbon receptor is activated by cigarette smoking (references provided on request), but it is not yet known whether cigarette smoking shifts the balance towards Tregs or towards Th17 cells in the gastrointestinal tract. It will be interesting to see if in ulcerative colitis and PSC, it shifts the balance towards Tregs?

One of the main dietary factors regulating the balance between Th17 cells and Tregs is vitamin A (specifically the vitamin A derivative, retinoic acid):

Kim CH 2008 Regulation of FoxP3 regulatory T cells and Th17 cells by retinoids. Clin. Dev. Immunol. 2008: 416910.

Th17 cells are suppressed by retinoic acid, while Tregs are stimulated by retinoic acid. This would account for the observation that vitamin A deficiency causes diarrhea, and might begin to account for the observation that certain retinoic acid analogues used to treat acne, such as accutane/isotretinoin, have been implicated as triggers of IBD:

Reddy D, Siegel CA, Sands BE, Kane S 2006 Possible association between isotretinoin and inflammatory bowel disease. Am. J. Gastroenterol. 101: 1569-1573.

The story is clearly incomplete, but I'll try to keep you posted when new developments occur.

Dave

(father of (23); PSC 07/03; UC 08/03)