Role of Splenic Macrophages in the Initiation of Tolerance to Apoptotic Cell Associate Antigens

Abstract

Systemic Autoimmune disease occurs due to the breakdown of tolerance to self-antigens caused in part by impaired clearance of apoptotic cells. The spleen is a primary site for generation of the tolerogenic response to selfantigens in the periphery. The marginal zone (MZ), which contains the specialized macrophage (MΦs) populations: Marginal Zone Macrophages (MZMs) and Metallophilic Marginal zone Macrophages (MMMs), as well as B cells and dendritic cells (DCs) play a requisite role in capture of apoptotic cells and the initiation of tolerance to associated self antigens. Moreover, defective MZ cellular architecture may lead to increased auto-reactivity that exacerbates autoimmune like disease progression. MZMs are specialized to recognize and capture apoptotic cells and promote peripheral tolerance to apoptotic cells and associated antigens. However, the mechanism by which MZMs enforce this tolerance is not known. Thus, the overall goal of our project is to fill the lapse in the scientific knowledge and understanding of the mechanism(s) by which the splenic stromal MΦs drive immune tolerance to apoptotic cell associated antigens.