Molecular Mechanisms of Lymphocyte Interactions in Autoimmunity

Yale University, New Haven CT

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Abstract

DESCRIPTION (provided by applicant): The immune system evolved to ignore self proteins in favor of defending the host against foreign pathogens. However, the frequency of autoimmune disease demonstrates that these mechanisms are not foolproof. Much like immunity to foreign pathogens, the induction of autoimmune responses requires the collaboration of several cell types. These collaborations of lymphocytes in the induction of lupus autoimmunity will be the focus of the present study. Works from previous cycles of this grant were historically the first to identify the important role of B lymphocyes in presenting autoantigens and in the development of epitope spreading. In part, these early studies from our laboratory provided a rationale for B cell directed immunotherapies (anti-CD20;Rituxan) in the treatment of autoimmune syndromes. In studies designed to understand the mechanisms of B cell therapeutics, work presented here demonstrates that autoantigen specific B cells are the first to capture and present self peptide in the first 4 days of initiating autoimmunity. Thereafter, B cell APC function declines and other APC subsets, DCs and macrophages, acquire self antigen and can perpetuate T cell autoimmunity. This mechanism provides one explanation for how autoimmunity can focus responses, via BCR, at a specific group of self proteins among the milieu of intracellular proteins. Subsequently, other professional APCs may then amplify the autoimmune T cell response. This project will examine the mechanisms of how B cells capture self antigens, transfer self antigen to other APCs, and break T cell tolerance in vivo. We will determine the subsets of professional APCs capable of receiving antigen from B cells and the roles of other cell surface proteins in this process. These mechanisms will be examined both by conventional immunoassays in vitro as well as by novel confocal and intravital microscopy in vivo. Finally, we will examine the mechanisms of antigen trafficking between B cells and other APCs from SLE patient populations and normal human controls. These studies intend to provide insights into the mechanisms that may be critical in B cell directed immunotherapies in human autoimmmune disease.