The main focus of Dr. Lipe's laboratory is to understand the immunological basis of type 1 diabetes (T1D) and its associated cardiovascular disease (CVD) complications, an area they have pioneered. They examine disease mechanisms at molecular and cellular levels in both mouse models and patients with T1D. Major questions include what initiates the loss of self-tolerance to islet beta cells or cardiomyocytes; what are the effector mechanisms and how to prevent this immune attack; and how major histocompatibility complex (MHC) molecules function in conferring susceptibility to autoimmunity.
Starting with the unexpected discovery that humanized HLA-DQ8+NOD mice develop premature death from autoimmune myocarditis (inflammation of heart muscle), they showed that myocarditis is caused by α-myosin heavy chain (MyHC)-specific CD4+ T cells that escape thymic negative selection. They further showed that immune responses to α-MyHC are essential for the development of myocarditis, proving that α-MyHC is a primary autoantigen in this disease process. Current studies are focused on identifying the disease-triggering epitope(s) within the α-MyHC protein, with a view to developing therapeutic blockers to prevent or arrest autoimmune heart disease in T1D.
In another set of translational studies, their group showed that the same alterations in immune function that confers risk for T1D contributes to the development of myocarditis following myocardial infarction (MI), which is the leading cause of death in T1D. They first showed that experimental MI triggers a chronic post-infarction autoimmune syndrome in NOD mice, characterized by destructive myocardial lymphocytic infiltrates, poor infarct healing, and the development of autoantibody and T cell responses against cardiac antigens. They further showed that induction of tolerance to a-MyHC eliminated the anti-cardiac immune targeting and the development post-infarct autoimmunity, demonstrating that this disease process is antigen-driven and preventable.
Extending these findings to patients with T1D, they developed a panel of sensitive and specific assays for cardiac autoantibody detection and demonstrated positivity in the majority of post-MI T1D patients. They further identified shared autoantibody expression signatures between post-MI T1D patients and acute myocarditis patients without T1D or MI, and have confirmed the presence of myocarditis in T1D patients with these expression signatures using non-invasive cardiac magnetic resonance imaging techniques. The laboratory is currently testing the hypothesis that clinically unrecognized cardiac autoimmunity contributes to poor CVD outcomes in large T1D populations, including the longitudinal DCCT/EDIC cohort, with the ultimate goal of improving the diagnosis and treatment of diabetic heart disease.