Antineutrophil cytoplasmic antibodies with a perinuclear immunofluorescent pattern (pANCA) are a marker for a subtype of ulcerative colitis (UC) and may be important in disease pathogenesis. Our goal in this project, entitled """"""""Ulcerative Colitis Specific pANCA: Role in Disease Pathogenesis"""""""" is to characterize the role of pANCA and related antigens in the pathogenesis of UC. Previous investigations, performed as part of the now discontinued USPHS grant DK43026, have shown that the presence or absence of ANCA in patient sera divide the UC population into two groups. In UC, the presence of pANCA may be a marker of a clinically and genetically specific immunoregulatory abnormality, manifested by a distinct type of mucosal inflammation that differs from the mucosal inflammation of UC patients not expressing this marker. We described very recently that B- cells in the involved and uninvolved mucosa are """"""""spontaneously"""""""" producing pANCA in 60% of UC patients, but not in normal patients, those with diverticulitis, or active or inactive Crohn's disease (CD). The overabundance of clones of pANCA-secreting B-cell in some UC mucosa may be due to participation in a disease-related mucosal immune response that differs from the response in mucosa devoid of pANCA B-cell clones. We hypothesize that this difference relates to a genetically determined response of host T-cells to the pANCA reactive antigen(s), generating a proinflammatory mucosal response. Recently, studies have localized the UC pANCA antigen to the nuclear membrane/heterochromatin of polymorphonuclear leukocytes (PMN), distinguishing the UC pANCA from all other known pANCA antigens. Furthermore, we have been successful in isolating a human UC specific ANCA rFab monoclonal antibody from a cDNA library obtained from the mucosa of a patient expressing UC specific pANCA in his serum. These advances provide a basis for protocols designed to identify and clone the nuclear associated antigens with the project by Dr. Kronenberg; determine whether there is cross-reactivity with mucosal antigens and/or lumenal bacteria with the project by Dr. Braun; determine the diversity and nature of the mucosal B-cell response with the project by Dr. Braun; and, determine the class, origin and functions of pANCA/antigen-specific T- cells with the project by Dr. Kronenberg, and eventually their role in the perturbation of normal intestinal function.
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