MARKER B LYMPHOCYTES IN INFLAMMATORY BOWEL DISEASE PATHOGENESIS

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Marker antibodies have been recognized in inflammatory bowel diseases, most notably in the immunogenetic relationship of pANCA to ulcerative colitis. Since antibodies reflect the B cell response to active antigenic challenge, the antigens driving these marker B cell responses are likely to include ones responsible for the underlying pathogenic mucosal inflammation. Thus, whether or not the antibodies are themselves pathogenic, identification of these marker antibodies is a potentially powerful strategy in the search for candidate target antigens in these diseases. This renewal application focuses on progress during the past grant period, indicating that Crohn's disease and Campylobacter jejuni enterocolitis are associated with a distinct and high-titer antibody response defined by its clonal restriction (VH3-15 gene), and specificity for a discrete set of antigens expressed on the human erythrocyte and Campylobacter jejuni. This finding suggests that a common immunopathogenic pathway, manifested by antigenic activation of this B cell population, is shared by these diseases. At the least, the antigen(s) and its cognate response may provide a discrete and analytically useful component of the disease- associated immune response. Moreover, in view of the role of H. pylori in peptic ulcer disease, a simple but provocative hypothesis is that this shared pathway is the immune response to Campylobacter or related bacteria. The aims of the renewal application are to isolate and monoclonally express these marker antibodies by phage display technology (Aim 1). Conventional and recombinant antibodies will then be used to identify the cognate Campylobacter and erythrocyte antigens by biochemical and recombinant approaches (Aims 2 and 3). These aims will be completed in collaboration with Dr. Targan, and provide the structural information and analytic tools needed to evaluate three predictions regarding the role of these antigens in disease-related immune response. First, relevant antigens should be present in affected mucosa (tested in Aims 2 and 3). Second, an antigen-specific T cell response should be present in these mucosal sites. In collaboration with Dr. Kronenberg and Targan, antigen- reactive B and T cell populations will be therefore characterized for their local abundance, differentiative state, and pattern of effector activity (Aim 4). Third, familial studies in collaboration with Dr. Rotter will test whether these responses are immunogenetic traits related to disease susceptibility.