Activation and Regulation of Rheumatoid Factor B cells

Yale University, New Haven CT

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Abstract

DESCRIPTION (provided by investigator): Autoreactive B cells are the source of pathogenic autoantibodies and are critical APCs for the stimulation of autoreactive T cells. Hence, it is fundamentally important to understand how these B cells develop, are regulated in normal animals, and escape self-tolerance during autoimmunity. This has been the major long-term focus of our lab. Immunoglobulin transgenic (Ig-Tg) mouse systems have been invaluable in efforts to address these questions. To understand the regulation of anti-IgG autoantibodies (Rheumatoid Factors, RF), we have created an Ig-Tg model called AM14. AM14 recognizes only IgG2a of the a allotype (IgG2a"a") and not of IgG2a"b". Thus we have used allotype congenic mice to control the presence or absence of the autoAg. B cells appear clonally ignorant in normal AM14 Tg mice. However, AM14 RF B cells are induced over time to become AFC's only when the Tgs are crossed onto autoimmune-prone backgrounds that have the autoAg. Thus, AM14 is a model system in which the loss of tolerance to a relevant autoAg can be readily observed and studied. In addition we have found unexpectedly that somatic hypermutation and selection are occurring in unusual populations of B cells proliferating and differentiating outside of germinal centers, at the outer PALS area. A major limitation in the study of spontaneous autoimmunity is the stochastic onset of autoimmunity; the timing and nature of autoantibodies can vary widely even among littermates of the same inbred strain. Recently we have discovered a method to circumvent these problems in the AM14 system: we found that the appearance of AM14 Id+ B cells in the peripheral blood of autoimmune-prone H-only Tg mice indicates the recent onset of proliferation and differentiation-i.e. autoimmunity-in the spleens of these mice. Serially tracking cohorts of H Tg mice reveals when these cells appear in the PBL for the first time and thus, the onset of autoimmunity. From this point, the mice can be analyzed, treated, or followed to study the further evolution of disease. Here we propose to use this system to: 1) Determine the factors-environmental and genetic-that are required for the onset and early propagation of disease (expansion of autoreactive RF B cells); 2) Define the cascade of events that leads from an initial nidus proliferating autoreactive B cells to chronic, ongoing disease; 3) Determine the identities, at the phenotypic and molecular level, of the unique B lineage cells that that have escaped peripheral tolerance.