Autoimmune Mechanisms in the Progression of CVD in Type 1 Diabetes

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DESCRIPTION (provided by applicant): It is well established that patients with type 1 diabetes (T1D) suffer excessive morbidity and mortality following myocardial infarction (Ml). However, the underlying mechanisms are poorly understood and are not explained by classical risk factors. We have recently discovered that the experimental induction of Ml in nonobese diabetic (NOD) mice, a model of human T1D, triggers the development of a post-infarct autoimmunity (PIA) syndrome with the production of high-titer IgG autoantibodies and T cell reactivity against cardiac rnyosin as well as destructive lymphocytic infiltrates in the myocardium. PIA does not develop in similarly infarcted control C57BL/6 mice. Interestingly, our previous studies have shown that transgenic NOD mice expressing the T1 D-associated human MHC class II molecule, HLA-DQ8, also developed autoimmune heart disease that was similarly characterized by high-titer IgG cardiac myosin autoantibodies, T cell responses against cardiac myosin and lymphocytic infiltrates in the myocardium. These findings raise the likelihood that a subset of human 11D patients also develop PIA after acute Ml. The specific aims of this study are: 1) To determine whether PIA alters ventricular remodeling and worsens cardiac function and whether the presence of hyperglycemia interacts with PIA to disproportionately worsen cardiac outcome; 2) To identify the primary immunological effector mechanisms in PIA and assess whether susceptibility to PIA is controlled by diabetes-associated MHC class II genes; and 3) To define the mechanisms underlying the initiation of PIA. This project represents a continued collaborative effort between Dr. Myra Lipes, an immunologist who studies T1D and autoimmune heart disease and Dr. Richard Lee, a cardiologist with extensive expertise in experimental mouse Ml and cardiac remodeling . The results of these studies could open up a new window into the etiology of CVD complications in T1D and provide an important foundation for future clinical studies.