Negative regulation of intestinal IgA by inflammatory cues in absence of infection.

Abstract

Abstract Pathogen-specific IgA elicited at mucosal site is associated with a better immune protection upon vaccination. Although some effective mucosal vaccines are available and approved, the majority of current vaccines are administered intramuscularly or subcutaneously and were developed irrespectively of a particular site of infection. Vaccine adjuvants are selected in their capacity to elicit a strong inflammatory response. However, few studies show the effectiveness of FDA-approved adjuvants to mucosal vaccines. Here, we unveil the role of inflammatory pathways in their negative regulation of IgA production in murine intestines. We are currently studying and identifying the molecular and cellular pathways involved in the production of protective IgA antibodies in the intestines in absence of particular inflammatory cues. Indeed, in absence of some inflammatory signals, we observed an increase of free IgAs and IgA-bound bacteria in the intestines of mice in steady state. IgA levels were normal in the serum and the concentration of IgG antibodies were also normal in both the intestines and serum suggesting a skewed toward IgAs restricted to the intestines. Furthermore, we could show that this IgA production is for the most part T-dependent and involves the formation of germinal centers localized in the Peyer’s Patches. We are now developing vaccine models to elicit potent IgA-mediated protection in the aim to use these finding at our advantage to promote pathogen-specific intestinal responses through new designs of mucosal vaccines. We believe that developing mucosal vaccines that elicit a protective immunity through natural routes of infection hold the promise to act better, faster and safer against worldwide pathogenic threat. RWJF Grant Project # 826399 Moderna Research Fellowship