Insulin-dependent Diabetes Mellitus (IDDM) represents a significant public health issue in that it affects a large number of children and exacts a heavy price in morbidity and mortality. Susceptibility to this disorder is inherited, but the genes involved remain poorly characterized. Our long-term goal is to elucidate the molecular basis of inherited primary immunological disorders. The focus of this proposal is to identify the genetic defect and the pathogenesis of X-linked Allergic Autoimmune Diabetes (XLAAD), an X-linked recessive immunological disorder characterized by neonatal IDDM and other autoimmune phenomena and associated with severe allergic inflammation. The hypothesis being tested is that this syndrome is a primary immunological disease resulting from a single gene defect that involves a regulator of T helper type 2 (Th2) differentiation. We propose to fine map and identify the gene defect in a cohort of affected pedigrees, and to elucidate the mechanism of skewed T helper subset 2 differentiation that we have noted in patients with this disorder. The proposed studies will provide critical insights into pathogenesis of IDDM and allergic inflammation in this group of patients and, more generally, in diseases of autoimmunity, atopy and immunodeficiency.