Increased Incidence of Inflammatory Bowel Disease: The Price of the Decline of Infectious Burden?

Hélène Feillet; Jean-François Bach

Disclosures

Curr Opin Gastroenterol. 2004;20(6) 

In This Article

Multiple Mechanisms

Several mechanisms have been proposed to explain the protective role of infections on immune disorders. Most of the evidence supporting these various hypotheses is derived from the study of animal models of autoimmune and allergic diseases.

Two main sets of mechanisms have been proposed that involve competition or suppression. Competition between anti-infectious immune responses and other responses, whether they are directed to allergens, autoantigens, or specific bacteria (as may be the case in IBD) may be considered at several levels: (1) competition for antigen processing by phagocytic cells; (2) competition for binding of antigen peptides to MHC molecules; and (3) competition for cytokines essential for lymphocyte differentiation and homeostasis.

In the latter case, one may hypothesize that lymphoid cells proliferating in response to pathogens compete with homeostatic signals, notably MHC-self peptide recognition and cytokines including IL-7. This possibility has been recently reported for mycobacteria in the NOD mice where it has been shown that complete Freund's adjuvant inhibits the proliferation of unrelated T cells.[32**] It is tempting to discuss this observation in the context of the report by Stockinger that T-cell proliferation in response to colitis and related antigens can inhibit the development of colitis in SCID mice reconstituted with CD45RBhi T cells, presumably through competition for homeostatic signals.[33]

Suppressor mechanisms essentially involve suppressor cytokines such as IL-10 and TGF-β, two cytokines known to play a central role in the mode of action of regulatory T cells, particularly in the experimental colitis models.[9,34] These cytokines can be produced by T cells through a mechanism of bystander suppression: regulatory T cells stimulated by infectious agents produce IL-10 or TGF-β, whose suppressor effect extends to other immune responses such as autoimmune and allergic responses.[35] The production of the two cytokines can also be induced by stimulation of toll-like receptors, the probable explanation of diabetes protection observed in NOD mice after treatment with various TLR agonists.[36,37] This latter hypothesis would fit with the loss of the lactobacilli IBD protective effect noted in TLR9-/- mice.[19**] Two recent observations bring some support to the possible TLR involvement in the protective effect of infections on immune disorders in humans. A significant correlation was observed between a polymorphism of the TLR2 gene and the propensity of developing asthma in children raised on animal farms, an environment previously shown to confer some protection from atopy.[38**] Moreover, schistosome-infected children show altered cytokine production in response to TLR2 and TLR4 agonists, suggesting that the helminth infection modulates TLR responses.[39]

Other mechanisms could be considered, involving various receptors and ligands as has been described for a measles virus protein[40] and the Hepatitis A virus (HAV) receptor. It has been shown that atopic diseases are more common in subjects previously exposed to HAV.[41] Recently, the possibility has emerged that HAV may act by direct action on Th2 cells, which express the HAV receptor. This latter observation derives from the positional cloning of the asthma predisposing gene on human chromosome 5 through a complex approach using congenic mice.[42] Interestingly, the propensity of developing atopy among HAV-seropositive subjects is linked to the HAV gene polymorphism.[43*]

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