Genetic and environmental factors interact in the process by which the human immune system is killing the beta cells in insulin-dependent diabetes mellitus (IDDM). Environmental and non-HLA genetic factors modify IDDM risk and influence non-progression of islet immunity, age of IDDM onset, and immunologic manifestations mechanisms of IDDM development in individuals who share underlying markers of disease risk but differ in diabetes research with human genome and molecular biotechnology expertise in genome wide analysis of genes which contribute to IDDM, in highly sensitive analysis of proteins and peptides, and in DNA sequencing of high throughput and decreased cost. A coordinated multidisciplinary approach to study individuals at risk for IDDM is taken to relate genetic and pathogenetic markers, including T cell autoreactivity, islet cell antigen auto-antibodies, as well as regulating mechanisms of HLA expression and antigen presentation, with human beta cell function to determine what makes an individual develop clinical IDDM. The following projects interact in this program project: Project 1 will identify and characterize environmental and allele specific transcriptional control of HLA class II molecules (Gerald T. Nepom); Project 2 will examine the control of the GAD65 auto-antibody response and role of anti-GAD65 epitope affinity enhancement associated with overt IDDM (Ake Lernmark); Project 3 will examine the pathophysiological process causing hyperglycemia in immune marker positive phenotypic NIDDM patients (Jerry P. Palmer), and Project 4 will identify genetic and immunological factors which are associate with progression or non-progression to IDDM in marker positive non diabetic young adults (William A. Hagoplian). Project 1 will interact with Project 2 to assess functional consequences of antigen presentation and immune activation. Both Project 1 and 2 will utilize subjects in Project 3 and 4. The interaction between Projects 3 and 4 will be essential for the ascertainment of different IDDM marker positive phenotypes. The interactions between these projects are coordinated through a Gene Screen and Rapid Sequencing Biotechnology Core facility at the Department of Molecular Biotechnology (Leroy Hood) and the Virginia Mason Research Center (Patrick Concannon). These studies will determine genetic and immune factors which control progression to clinical IDDM and will identify novel approaches to prevention and cure of insulin dependent diabetes mellitus.