Until recently, the role of B-lymphocytes in the pathogenesis of autoimmune mediated diabetes has been largely overlooked. The 80% incidence of diabetes in NOD mice is virtually eliminated however when the mice are made B-lymphocyte deficient by knocking out their immunoglobulin mu chain. This protection is mediated at least in part by the loss of B-lymphocyte antigen presenting function. This project explores how the antigen presentation and possibly cytokine production by B-lymphocytes contributes to diabetes in NOD mice. By adoptive transfer of cells from NOD and 6 congenic NOD strains into NOD.Igmu/null mice, we will explore how at least 9 Idd genes influence B-lymphocyte control of islet autoimmunity, including the induction of insulinitis, autoantibody production, cellular immune responses to autoantigens, and progression to hyperglycemia. Age-dependence of diabetogenic B-lymphocyte function in NOD mice will be examined. We will partition the marginal zone and non-marginal zone (primarily follicular) B-lymphocytes from spleens of the NOD and congenic mice to directly examine their roles in diabetes. Microarray and flow cytometry will be used to characterized the cell populations that do or do not confer diabetes to the NOD.Igmu/null recipients. Our second specific aim is to examine the functions of B-lymphocytes that promote diabetes. We will examine both before and after they have been placed in NOD.Igmu/null recipients. The ability of diabetogenic and non- diabetogenic B-lymphocytes and subsets to take up, process, and present two autoantigens, insulin and GAD65, to T-lymphocyte clones will be compared. Antigen specific and non-antigen specific, complement- mediated antigen uptake by surface immunoglobulin and CD21 will be assessed as a possible cause of differing antigen presenting capacity. Cytokine production by B-lymphocytes has recently been suggested to control T-lymphocyte functions, including their ability to mature into Th1 or Th2 pathways. We will therefore examine the cytokine production profiles of splenic B-lymphocytes from NOD and NOD congenic donors before and after they are adoptively transferred into NOD.mu/null recipients. Understanding B-lymphocytes control of autoimmunity should provide new avenues toward diabetes, diagnosis, prevention, and treatment.
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