Autoimmune myocarditis is a major cause of sudden death in children and young adults. Although widely thought to be of infectious etiology, in the majority of cases the cause of disease is unknown. We have discovered that expression of the human HLA class II molecule, HLA-DQ8, in nonobese diabetic mice that lack endogenous murine class II genes results in the spontaneous development of autoimmune myocarditis. Disease was characterized by premature death due to heart failure, destructive lymphocytic infiltrates in the myocardium, and circulating IgG autantibodies against cardiac myosin heavy chain, similar to human myocarditis. Analysis of CD4 T cell clones isolated directly from the heart lesions reveals that, in contrast to the autoantibodies that cross-react with skeletal and cardiac myosin, the CD4 T cells recognize only cardiac myosin, consistent with the cardiac-specificity of this autoimmune disease process. These clones produce large amounts of interferon-gamma, but not IL-4, consistent with a pathogenic Th1 phenotype.
The specific aims of this project are: 1) to use the T cell clones a functional probes to identify the epitopes of the myosin 3rotein that are reponsible for the loss of self-tolerance to cardiac myocytes, 2) to identify the primary cellular mediators involved in the pathogenesis of disease and to use congenic strains to determine whether type 1 diabetes and autoimmune myocarditis are controlled by common 'autoimmunity genes', 3) to investigate whether myocarditis in humans is an organ-specific autoimmune disease associated with HLA-DQ8 and whether it can be detected with a combination of HLA typing and immunological testing. These translational studies will involve a collaboration between the PI and Dr. Kenneth Baughman, Director of the Advanced Heart Disease Division at Brigham and Women's Hospital and a leader in the field of myocarditis. The results of these studies could open a new window into the etiology of human myocarditis and lead to improved methods to diagnose and treat this serious disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL077554-03
Application #
7074056
Study Section
Immunological Sciences Study Section (IMS)
Program Officer
Massicot-Fisher, Judith
Project Start
2004-07-15
Project End
2008-05-31
Budget Start
2006-06-01
Budget End
2007-05-31
Support Year
3
Fiscal Year
2006
Total Cost
$466,702
Indirect Cost
Name
Joslin Diabetes Center
Department
Type
DUNS #
071723084
City
Boston
State
MA
Country
United States
Zip Code
02215
Sousa, Giovane R; Pober, David; Galderisi, Alfonso et al. (2018) Glycemic Control, Cardiac Autoimmunity, and Long-Term Risk of Cardiovascular Disease in Type 1 Diabetes Mellitus: A DCCT/EDIC Cohort-Based Study. Circulation :
Lipes, Myra A; Galderisi, Alfonso (2015) Cardiac autoimmunity as a novel biomarker, mediator, and therapeutic target of heart disease in type 1 diabetes. Curr Diab Rep 15:30
Gottumukkala, Raju V S R K; Lv, HuiJuan; Cornivelli, Lizbeth et al. (2012) Myocardial infarction triggers chronic cardiac autoimmunity in type 1 diabetes. Sci Transl Med 4:138ra80
Lv, HuiJuan; Lipes, Myra A (2012) Role of impaired central tolerance to ?-myosin in inflammatory heart disease. Trends Cardiovasc Med 22:113-7
Lv, Huijuan; Havari, Evis; Pinto, Sheena et al. (2011) Impaired thymic tolerance to ýý-myosin directs autoimmunity to the heart in mice and humans. J Clin Invest 121:1561-73
Stewart, Garrick C; Lopez-Molina, Javier; Gottumukkala, Raju V S R K et al. (2011) Myocardial parvovirus B19 persistence: lack of association with clinicopathologic phenotype in adults with heart failure. Circ Heart Fail 4:71-8