Myocardial Infarction Triggers Chronic Cardiac Autoimmunity in Type 1 Diabetes

Abstract

Patients with type 1 diabetes (T1D) suffer excessive morbidity and mortality following myocardial infarction (MI) that is not fully explained by the metabolic effects of diabetes. Acute MI is known to trigger a profound innate inflammatory response with influx of mononuclear cells and production of proinflammatory cytokines that are crucial for cardiac repair. We hypothesized that these same pathways might exert ‘adjuvant effects’ and induce pathological responses in autoimmune-prone T1D hosts. Here we show that experimental MI in nonobese diabetic (NOD) mice - but not in control C57BL/6 mice - results in a severe post-infarction autoimmune (PIA) syndrome characterized by destructive lymphocytic infiltrates in the myocardium, infarct expansion, sustained cardiac IgG autoantibody production and Th1 effector cell responses against cardiac (α-)myosin. PIA was prevented by inducing tolerance to α-myosin, demonstrating that immune responses to cardiac myosin are required for this disease process. Extending these findings to humans, we developed a panel of immunoassays for cardiac autoantibody detection and found autoantibody positivity in 83% post-MI T1D patients. We further identified shared cardiac myosin autoantibody signatures between post-MI T1D patients and non-diabetic patients with myocarditis – that were absent in post-MI type 2 diabetic patients - and confirmed the presence of myocarditis in 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 outcomes in T1D, and highlight a role for antigen-specific immunointervention to selectively block this pathway.

Autoimmune Diabetes Inflames the Heart

“…T ese mice were perhaps a disappointment in that they did not spontaneously develop T1D, but surprisingly, humanized DQ8 NOD mice did develop fatal myocarditis. T us begins a tale of bench to bedside that now culminates with the current report by Gottumukkala et al (1).…”

“…In a series of translational experiments, Gottumukkala et al (1) then showed that post-MI patients with T1D, but not T2D, expressed multiple autoantibodies directed against cardiac proteins (Fig. 1).…”

Type 1 diabetes

“…Patients with type 1 diabetes have less favourable outcomes than non-diabetic patients after an acute coronary event, 110 a finding that might be explained by a recent report that, after myocardial infarction, patients with type 1 diabetes express antibodies to cardiac proteins, whereas patients with type 2 diabetes do not. 111 The risk for microvascular complications, including retinopathy, nephropathy, and neuropathy, decreases with intensive insulin therapy. Over the past 5 years, several large clinical trials have advanced the prediction and prevention of microvascular complications (table 1).…”

Positive and negative selection of the T cell repertoire: what thymocytes see (and don't see)

“…First, very low expression levels of particular self antigens in human mTECs correlate with a high frequency of cognate, auto-reactive T cells and/or autoantibodies in the case of the myosin heavy chain 6 93, 94 , an autoantigen in autoimmune myocarditis, or GAD65 95 and ZnT8, both targets in type 1 diabetes (B.K., S. Pinto, R. Mallone, unpublished observations). Genetic polymorphisms in regulatory regions of some autoantigens, which exert subtle effects on the expression level of self antigens in mTECs but not peripheral tissues correlate with susceptibility to organ-specific auto-immunity as shown for insulin and type 1 diabetes 96-98 , the alpha-chain of the acetylcholine receptor and myasthenia gravis 99 and the thyroid stimulating hormone receptor and Graves’ disease 100 .…”