Two aspects of peripheral immune tolerance : systemic and mucosal tolerance mechanisms

Abstract

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT REQUEST OF AUTHOR.] Autoimmune diseases are a significant cause of human morbidity and mortality. The defects in immune system that lead to the pathogenesis of autoimmune disease have not been entirely characterized. Autoimmunity develops when there is a dysregulation of the immune tolerance mechanisms leading to persistence of autoreactive T cells. The importance of tolerance in immune system is evidenced by the myriad of autoimmune diseases that develop in various models of autoimmunity in mice and humans. The role of systemic immune tolerance is to prevent the immune reaction against organs and tissues while the role of the gut immune tolerance is to prevent immune reactions against commensal bacteria and food antigens in addition to self antigens. How these effects are brought about is a topic of intense research. Current debate exists as to the location and the mechanisms of systemic peripheral tolerance. Using a defined tolerogenic approach, we examined the site and nature of APC - autoreactive T cell interaction during induction of peripheral immune tolerance. Fc receptor-deficient (FcR-/-) mice were induced for experimental allergic encephalomyelitis (EAE), with a myelin oligodendrocyte glycoprotein (MOG) 35-55 peptide and when the disease became apparent the mice were given FcR+/+ APCs and treated with Ig-MOG, a tolerogenic Ig expressing MOG peptide. Under this regimen the mice were able to reverse their EAE only when given FcR+/+ APCs that can present Ig-MOG and carry out T cell tolerance. Employing the Fc receptor-deficient (FcR-/-) mice and the Ig-MOG 35-55 based antigen delivery system, we examined the T cell APC interactions and the effects of such interactions on T cell function and behavior. The results indicate that tolerance occurs in a time dependent fashion when both the T cells and APCs have accumulated in the peripheral lymph nodes. 2-Photon microscopy revealed that tolerized T cells exhibit organ-specific changes in motility, pattern of migration and trafficking. Moreover, such a tolerance takes place due to a Th2 bias in the lymph node. Regarding the immune tolerance in the gut, which is a very effective and important process; studies on localization of the site and the mechanism of tolerance in the gut are still in development. Research points to dendritic cells in the gut as being the main modulators of gut immunity and tolerance. Recent reports indicate those lamina propria DCs are also capable of sampling gut luminal contents by extending their dendrites while some reports point toward the site of antigen presentation to be the mesenteric LN. In this account, we sought to examine the location and mechanism of oral antigen presentation using the Ig-chimera as the antigen delivery system. Here we demonstrate that Ig-MOG given orally is able to suppress both MOG and CNS homogenate induced disease in B6 mice. In addition, this modulation of EAE by oral Ig-MOG is peptide specific as evidenced by lack of suppression seen with control Ig-chimera, Ig-W. Even though agg Ig-chimeras have been documented to produce IL-10 from the APC, IL-10 was partially uninvolved in this system as IL-10-/- mice were also able to ameliorate the disease upon oral Ig-MOG treatment. The resolution of the disease was independent of Treg expansion and correlated with the suppression of pro-inflammatory cytokines like IFN and IL-17. The CD4 T cells of the lamina propria expressed less of the activation molecules hinting toward lamina propria as the putative site of induction of tolerance. Indeed APCs from lamina propria failed to induce proliferation and cytokine production when co-incubated with splenic CD4 T cells. Thus non-free antigen administered orally leads to induction of oral tolerance by the lamina propria APC.