Myocardial infarction triggers chronic cardiac autoimmunity in type 1 diabetes.
Patients with type 1 diabetes (T1D) suffer excessive morbidity and mortality after 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 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 autoantibody production, and T helper type 1 effector cell responses against cardiac (α-)myosin. PIA was prevented by inducing tolerance to α-myosin, demonstrating that immune responses to cardiac myosin are essential 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 nondiabetic patients with myocarditis, which 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.
Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA.
Raju V S R K
RV
Gottumukkala
HuiJuan
H
Lv
Lizbeth
L
Cornivelli
Amy J
AJ
Wagers
Raymond Y
RY
Kwong
Roderick
R
Bronson
Garrick C
GC
Stewart
P Christian
PC
Schulze
William
W
Chutkow
Howard A
HA
Wolpert
Richard T
RT
Lee
Myra A
MA
Lipes
D000818:Animals; D001323:Autoantibodies / Q000276:immunology; D015551:Autoimmunity / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D051379:Mice; D009203:Myocardial Infarction / Q000276:immunology*; D009206:Myocardium / Q000276:immunology*
D001323:Autoantibodies