ENDOGENOUS GLUCOCORTICOIDS PROTECT FROM HELICOBACTER-INDUCED AUTOIMMUNE GASTRITIS

Gastric cancer is the 4th leading cause of cancer deaths worldwide. Helicobacter pylori infection is the primary risk factor for gastric cancer. In the United States, gastric cancer rates have been declining for several decades, likely due to reduced H. pylori infection rates. However, over the last 20 years, there has been a significant increase in the incidence of gastric cancer among young Caucasian women. This rise in cases is distinct because these patients typically present with autoimmune gastritis (AIG) and lack active H. pylori infections. H. pylori infection is linked to the increased risk of a host of autoimmune diseases, but the mechanisms controlling AIG development in these patients remain unknown. In this study, we investigated how the anti-inflammatory hormones glucocorticoids control the gastric inflammatory response to H. felis infection. Glucocorticoids were depleted systemically by bilateral adrenalectomy (ADX). Loss of glucocorticoids significantly increased gastric CD4+ T cell infiltration and Ifng production in response to H. felis infection compared to adrenal-intact felis-infected controls. Moreover, ADX mice exhibited a significant reduction of regulatory T cells. Importantly, the increased inflammation induced by ADX led to H. felis eradication by 2 months post-challenge while intact mice remained colonized. Despite eradicating H. felis, inflammation persisted in ADX mice for up to 1 year post-challenge, and ADX mice developed dysplasia. Next, serum was screened for self-reactive antibodies to investigate potential mechanisms driving the persistent gastric inflammation. Both adrenal-intact and ADX felis-challenged female mice exhibited self-reactive IgM antibodies in their sera, but self-reactive IgG was only detected in ADX mice, suggesting that self-reactive T cells facilitated antibody class switching. Together, these data suggest that glucocorticoids limit the intensity of the gastric inflammatory response to Helicobacter infection, allowing bacterial persistence but protecting from the development of autoimmunity. Moreover, our results suggest that endocrine disruption may increase the risk of AIG development.