IgA rheumatoid factor (RF) is perhaps the most abundant and widely distributed IgA autoantibody in humans, occurring in a wide variety of clinical conditions. Although often associated with the occurrence of IgM RF, considerable evidence has raised the possibility that the production of IgA RF is independently regulated. We therefore propose to delineate mechanisms underlying the expression of IgA autoantibodies in human disease using IgA RF as a model system. Specifically, we plan to determine the relationship of the site(s) of RF production to the isotype of RF expressed in rheumatoid arthritis, a disease in which both IgA RF and IgM RF are produced, and diseases in which only IgA RF is expressed, namely mesangial IgA nephropathy and Henoch-Schonlein purpura. Various body fluids, both non-mucosal and mucosal in origin, will be examined including serum, synovial fluid, saliva, tears, and intestinal secretions. Potential sites of production will be further assessed by histological and cell culture studies of cells and tissues representing both systemic sites (e.g., peripheral blood, synovial fluid, and bone marrow lymphocytes) and mucosal sites (e.g., salivary gland and intestinal gland and intestinal biopsies). Possible mechanisms involved in the induction of IgA RF production will be investigated by analysis of serum, secretions (saliva and tears), and the in vitro products of peripheral blood lymphocytes from normal individuals and patients from the various disease groups subsequent to secondary parenteral or oral immunization. Changes in the levels of IgA RF, IgM RF, and IgG, IgA, and IgM antibody specific for the immunizing antigen will be evaluated. In addition, the role of T cells in regulating IgA RF as compared to IgM RF production will be considered. We will also attempt to identify possible genetic factors associated with the expression of IgA RF by examining idiotypic relationships among IgA rheumatoid factors produced in different diseases and between IgA and IgM rheumatoid factors where present in the same disease and by determining the VH and VL gene groups involved in the production of IgA RF using IgA RF-producing hybridomas and transformed cell lines.
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