Inflammatory bowel disease (IBD) is characterized by extensive inflammation and immune destruction of the intestine without an obvious inciting agent. There is evidence that a major component of the pathology in these diseases is poorly regulated activation of several immune effector mechanisms. Regulation of lymphocyte function in the intestine differs from that of other lymphoid organs including peripheral blood, spleen and tonsil.
The aim of this proposal is to characterize and understand the mechanisms responsible for the altered immunoreactivity of gut lymphocytes in IBD compared to immune responses of normal gut lymphocytes. The hypothesis is that the immunoglobulin dysregulation seen in IBD results from altered cytokine secretion which leads to production of different Ig isotypes and subclasses. Previous work has characterized normal lamina propria mononuclear cells with respect to a) the expression of cell surface activation antigens; b) the frequency of spontaneous immunoglobulin secreting for various immunoglobulin classes; and c) the level of spontaneous immunoglobulin secretion by intestinal mononuclear cells. The results of these studies have provided a detailed characterization of the state of activation of normal intestinal B cells. Data from several laboratories suggest that these normal characteristics will be substantially altered in IBD. We now propose to provide a similarly detailed characterization of the physiology of B cells from ulcerative colitis and Crohn's disease lamina propria and a comparison of B cells from IBD and normal lamina propria. These studies are directed at better understanding the immunoregulatory factors involved in the enhanced spontaneous secretion of various antibody classes in normal intestine and its dysregulation in IBD, thereby providing a basis for the study, understanding and control of IBD. We will combine techniques of cell biology (cytokine production), molecular biology (mRNA content, in situ hybridization, Ig VH region usage) and immunology (B and T cell activation and the effects of cytokines on intestinal antibody secretion) to determine the state of activation of intestinal mononuclear cells and the mediators involved in altered Ig secretion seen in IBD. These findings will provide data on the mechanism of the immune abnormalities in IBD, and will have relevance to normal host defense in the intestine and may provide rationales for therapeutic modulation of inflammatory bowel diseases in which marked abnormalities of B and T cell physiology have been demonstrated.
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