Tolerance in Polyclonal and Oligoclonal Immune Systems

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DESCRIPTION (provided by applicant): Allelic and isotypic (haplotype) exclusion establishes that each B cell expresses only one immunoglobulin heavy and light chain pair and, consequently, exhibits a single specificity. Nevertheless, B cells expressing either two heavy or two light chains (haplotype-included) exist in healthy individuals and wild-type mice at a frequency estimated to be approximately 2-10% of the B cell population. Analyses of immunoglobulin transgenic mice have demonstrated that autoreactive B cells can sometimes bypass mechanisms of central tolerance by co-expressing non-autoreactive antigen receptors. These haplotype-included cells co-express autoreactive and non-autoreactive antigen receptors and are found in the mature B cell population. Because the majority of primary immunoglobulin gene rearrangements encode autoreactive specificities, we propose that wild-type haplotype-included B cells have higher chances of being autoreactive than haplotype-included (single Ab-expressing) B cells. The goal of this proposal is to understand the nature and regulation of haplotype-included B cells in mice and to determine if these cells are associated with autoimmunity. To accomplish this we outline three Specific Aims that will characterize dual immunoglobulin light chain- expressing B cells in mice with a wild-type antibody repertoire, determine whether these B cells contribute to the autoimmune process of autoimmune-prone mice, and understand how haplotype- included B cells are physiologically regulated. Haplotype-included autoreactive B cells will be evaluated both in vitro and in vivo using various mouse models and a variety of techniques that include the generation and characterization of B cell hybridomas and the use of cell adoptive transfer. Because autoimmunity is a significant health issue that has multiple, as of yet, poorly understood etiological bases, a molecular and cellular analysis of haplotype-included B lymphocytes is warranted. In particular, we predict haplotype-included B cells to be unique in that the autoantibody they express have the potential to exhibit a high avidity interaction with autoantigen and produce antibodies that simultaneously bind foreign as well as self-antigens. Project Narrative: Systemic autoimmune diseases such as lupus erythematosus and rheumatoid arthritis are complex disorders caused by defects in B and other blood cell types and that continue to cause significant morbidity and mortality. Although significant knowledge on these conditions has been achieved, substantial work remains to be done to fully understand the etiology and pathogenesis of these diseases. Some B cells in autoimmunity secrete autoantibodies that bind to molecules produced by the organism. It is still vastly unclear why these cells are generated and why they are activated to secrete autoantibodies. Our studies aim at characterizing a small population of B cells in mice that express two types of antibodies to determine whether these cells are progenitors of autoantibody-secreting cells and pathogenic players of autoimmunity.