Myocarditis and rheumatic carditis are sequelae of viral or bacterial infections, respectively, and occur in humans and animal models following viral infection, group A streptococcal infection, or immunization with cardiac myosin(CM). Myocarditis may be a precursor of dilated cardiomyopathy and heart failure. The pathogenesis of these diseases may have a common denominator related in part to molecular mimicry between the infectious pathogen and the host autoantigen CM or to immune responses against CM released from cardiomyocytes during infection. Although CM can induce myocarditis and valvulitis in animals, the role of CM in the molecular pathogenesis of disease in humans is not well defined. The goal of the proposed work is to define the autoimmune response to human CM in humans and in CM-induced animal models of myocarditis to understand how an intracellular molecule such as myosin can act through immunological mimicry of exogenous foreign antigens or endogenous self antigens to cause disease. We will investigate links between innate and adaptive immunity to CM and use animal models to provide clues for studies in humans. We will test the hypothesis that autoimmune carditis may arise due to the influence of molecular mimicry, which may lead to the involvement of other heart proteins/antigens through innate immunity, mimicry or epitope spreading.
In aims 1 and 2, we plan to evaluate a group of myocarditis patients longitudinally where we can determine immunological parameters of recovery and disease which may be important in understanding and developing individualized treatment plans in the future. In order to decipher pathogenic reactivity in patients we plan: 1)To produce human monoclonal antibodies from selected patients with myocarditis and cardiomyopathy to determine mimicry and the role of antibody in the pathogenesis of myocarditis and cardiomyopathy;2)To evaluate human T cell responses and to produce T cell clones to CM epitopes using synthetic peptides of human CM in carditis and cardiomyopathy and correlate epitopes with disease;3) To determine the ability of CM to act as an endogenous ligand and stimulate innate immunity 4) To investigate our previously established Lewis rat CM peptide-induced model of severe myocarditis for parameters of inflammatory heart disease including the role of molecular mimicry, cytokines, regulatory T cells, Th17 cells and antibody in the induction of and protection against myocarditis. Our work will provide a better understanding of pathogenic and protective immune mechanisms in animal models of myocarditis and cardiomyopathy and their relationship to human disease.

Public Health Relevance

Myocarditis and cardiomyopathy are a cause of heart failure and forty-five percent of all heart transplantations. Myocarditis may begin with a flu-like viral illness or other complications affecting the heart and eventually may develop into cardiomyopathy with heart enlargement, loss of function of the heart muscle, and cardiac arrythmias. Underlying autoimmune mechanisms that contribute to the disease are not well established in humans. Studies proposed will contribute to our understanding of the immunologic basis of the disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL056267-14
Application #
8473087
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Schwartz, Lisa
Project Start
1997-08-01
Project End
2014-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
14
Fiscal Year
2013
Total Cost
$515,955
Indirect Cost
$145,887
Name
University of Oklahoma Health Sciences Center
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
878648294
City
Oklahoma City
State
OK
Country
United States
Zip Code
73117
Myers, Jennifer M; Cooper, Leslie T; Kem, David C et al. (2016) Cardiac myosin-Th17 responses promote heart failure in human myocarditis. JCI Insight 1:
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Liles, Campbell; Li, Hongliang; Veitla, Vineet et al. (2015) AT2R autoantibodies block angiotensin II and AT1R autoantibody-induced vasoconstriction. Hypertension 66:830-5
Li, Hongliang; Kem, David C; Zhang, Ling et al. (2015) Novel retro-inverso peptide inhibitor reverses angiotensin receptor autoantibody-induced hypertension in the rabbit. Hypertension 65:793-9
Li, Hongliang; Yu, Xichun; Cicala, Maria Verena et al. (2015) Prevalence of angiotensin II type 1 receptor (AT1R)-activating autoantibodies in primary aldosteronism. J Am Soc Hypertens 9:15-20
Li, Hongliang; Zhang, Ling; Huang, Bing et al. (2015) A peptidomimetic inhibitor suppresses the inducibility of β1-adrenergic autoantibody-mediated cardiac arrhythmias in the rabbit. J Interv Card Electrophysiol 44:205-12
Galloway, Allison; Li, Hongliang; Vanderlinde-Wood, Megan et al. (2015) Activating autoantibodies to the β1/2-adrenergic and M2 muscarinic receptors associate with atrial tachyarrhythmias in patients with hyperthyroidism. Endocrine 49:457-63
Kem, David C; Li, Hongliang; Velarde-Miranda, Carolina et al. (2014) Autoimmune mechanisms activating the angiotensin AT1 receptor in 'primary' aldosteronism. J Clin Endocrinol Metab 99:1790-7
Cunningham, Madeleine W (2014) Rheumatic fever revisited. Nat Rev Cardiol 11:123
Li, Hongliang; Scherlag, Benjamin J; Kem, David C et al. (2014) Inducible cardiac arrhythmias caused by enhanced *1-adrenergic autoantibody expression in the rabbit. Am J Physiol Heart Circ Physiol 306:H422-8

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