? Autoimmune diabetes in NOD mice is characterized by dysregulated B cell tolerance to islet autoantigens. This loss of tolerance to islet autoantigens is caused by aberrant negative selection of developing B cells. We recently demonstrated that a defect in immature B cell egress from the NOD bone marrow results in a lymphopenic transitional (TR) B compartment in the periphery and relaxes B cell selection into the splenic follicle. Phenotypic comparison of immature and TR NOD B cells with non-autoimmune counterparts revealed deficient expression of a developmental marker known as AA4.1 (a.k.a., CD93). This molecule is a type 1 glycosylated transmembrane protein and resembles the selectin-family of adhesion molecules. We determined that the NOD CD93 deficiency is caused by a primary sequence polymorphism in its first EGF-like domain. This variation causes an A.A. substitution from AsnrHis at position 264. Interestingly, the CD93 gene is located in the NOD Idd13 locus on chromosome 2. However, CD93 has not been previously considered as a candidate diabetes susceptibility gene. In this proposal we will test the following hypotheses: 1) CD93 regulates the efficiency of immature B cell egress from the bone marrow, 2) the NOD CD93 mutation causes a homeostatic change in TR B cell production favoring relaxed negative selection at the peripheral B cell tolerance checkpoint. Overall, the proposed studies will determine whether the NOD CD93 gene acts as a diabetes susceptibility gene by modulating the stringency of peripheral B cell selection in non-obese diabetic mice. Elucidation of the parameters governing the pathogenesis of autoimmune diabetes will permit identification of novel targets of immunomodulation for the prevention and cure of Type 1 Diabetes Mellitus. ? Narrative: ? Type 1 diabetes mellitus (T1DM) is an autoimmune disease affecting more than 1 million Americans. At the time of onset, the majority of individuals with T1DM are in the pediatric age groups. Despite exogenous insulin administration, the long-term complications of T1DM incur devastating human suffering and economic burden. ? ?
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