Menu Close

J Clin Invest

J Clin Invest. distributed cardiac myosin autoantibody signatures between post-MI T1D patients and nondiabetic patients with myocarditis C that were absent in post-MI type 2 diabetic patients – and confirmed the presence of myocarditis in MGC34923 T1D by cardiac magnetic resonance imaging techniques. These data provide experimental and clinical evidence for a distinct post-MI autoimmune syndrome in T1D. Our findings suggest that PIA may contribute to worsened post-MI E6130 outcomes in T1D, and spotlight a role for antigen-specific immunointervention to selectively block this pathway. INTRODUCTION Over past decades, new knowledge about basic mechanisms underlying the pathogenesis of cardiovascular disease (CVD) has led to aggressive pharmacological and interventional therapies, resulting in a major decline in mortality from myocardial infarction (MI) in the general population (1). Despite this progress, CVD accounts for 65C70% of deaths in individuals with type 1 diabetes (T1D) (2, 3) and incurs a ~13-fold increase in age-adjusted mortality rates in T1D patients compared to the nondiabetic populace (3). This extra mortality has shown essentially no improvement over the past 30 years, despite improved outcomes from other diabetes complications, in particular, renal failure (4) which has long been considered the primary driver of CVD mortality in T1D (5). While chronic hyperglycemia has been established as a key mediator of CVD risk in T1D (6), the mechanisms accounting for the excessive post-MI mortality are poorly comprehended. Although numerous factors related to diabetes have been implicated, none have been unique to T1D (2). Type 1 diabetes is an autoimmune disorder caused by T lymphocyte-mediated destruction of the pancreatic cells (insulitis). Once established, insulitis can be detected indirectly by screening serum for autoantibodies to islet antigens. The -cell specificity of this autoimmune attack has been attributed to specific alleles of major histocompatibility complex (MHC) class II, most notably HLA-DQ8 (hereafter, DQ8). However, non-MHC genes that are associated with more broad spectrum defects in immunological tolerance are also required and are thought to underlie the clustering of other autoimmune disorders in individuals with T1D (7). Environmental factors are also crucial E6130 for the development of T1D, and it has been assumed that in genetically susceptible individuals, an inflammatory trigger C presumably, an infection or other cause of -cell injury C is required for disease expression. Inflammation plays a crucial role in the early stages of E6130 tissue repair following MI (8, 9). After acute MI, signals are generated that trigger the influx of neutrophils, macrophages and dendritic cells into the infarct zone (10, 11), along with the release of proinflammatory cytokines such as tumor necrosis factor- (TNF-), interleukin (IL)-1 and IL-6 (9). While these innate immune responses are crucial for repairing the damaged heart, these same cytokines and signals from necrotic cells are known to be particularly potent maturation factors for dendritic cells, transforming them into highly immunogenic antigen-presenting cells capable of activating adaptive immune responses (12, 13). However, there has been substantial debate about whether endogenous (danger) signals generated by tissue damage can by themselves C in the absence of adjuvant or microbial stimuli C fully activate adaptive immune responses (14, 15). It has been postulated that in tissue injury settings, the released self-antigens should not be recognized as foreign because high-avidity T cells specific for these self-antigens would normally have been deleted during thymic unfavorable selection, a major barrier against autoimmunity. We as well as others have shown that.