EXCEED THE SPACE PROVIDED. Rheumatic fever is a sequela of group A streptococcal infection primarily in children. Manifestations of the disease include carditis, arthritis and chorea. Our hypothesis is that autoimmune mechanisms due to molecular mimicry between the group A streptococcus and human tissues are responsible for the disease. Our data support this hypothesis. We have identified host and streptococcal antigens which react with anti-strep/heart antibodies and T cells, and we have identified streptococcal and human cardiac myosin epitopes which produce carditis and valvulitis in animal models of disease. Despite our progress, we do not know how these crossreactive autoantibodies function in the pathogenesis of acute rheumatic fever(ARF) or the exact nature and antigenic specificities of the T cells in rheumatic carditis. Therefore, the goal and objectives propose to answer questions about the potential role of antibody in disease and to investigate the nature of the T cells which are crossreactive and appear to be responsible for valvulitis. The objectives are 1) to produce a panel of cytotoxic/crossreactive monoclonal antibodies (mAbs) from humans and transgenic mice and passively transfer IgM and IgG mAbs to test for tissue deposition in vivo; 2) to determine the nucleotide sequences of crossreactive antibody V, D, and J region genes; 3) to produce transgenic mice containing the VDJ genes(H &L) of human and mouse crossreactive and/or cytotoxic mAbs; 4) to investigate the Lewis rat model of valvulitis by producing and characterizing T cell clones from rats immunized with rM6 protein and cardiac myosin and in passive transfer experiments determine if these T cells produce disease; 5) to compare valves immunohistochemically from rheumatic carditis and Lewis rat valvulitis to identify similarities. These studies will attempt to define the steps in the pathogenesis of rheumatic carditis and will continue to support the growing body of evidence that infectious agents play a role inthe development of autoimmunity inman. $ R37 PERFORMANCE SITE ========================================Section End===========================================

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37HL035280-19
Application #
6876704
Study Section
Special Emphasis Panel (NSS)
Program Officer
Massicot-Fisher, Judith
Project Start
1989-08-01
Project End
2009-02-28
Budget Start
2005-03-01
Budget End
2006-02-28
Support Year
19
Fiscal Year
2005
Total Cost
$366,250
Indirect Cost
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
Cunningham, M W; Cox, C J (2016) Autoimmunity against dopamine receptors in neuropsychiatric and movement disorders: a review of Sydenham chorea and beyond. Acta Physiol (Oxf) 216:90-100
Garcia, Alan F; Yamaga, Karen M; Shafer, Leigh Anne et al. (2016) Cardiac Myosin Epitopes Recognized by Autoantibody in Acute and Convalescent Rheumatic Fever. Pediatr Infect Dis J 35:1021-6
Carapetis, Jonathan R; Beaton, Andrea; Cunningham, Madeleine W et al. (2016) Acute rheumatic fever and rheumatic heart disease. Nat Rev Dis Primers 2:15084
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:
Gorton, Davina; Sikder, Suchandan; Williams, Natasha L et al. (2016) Repeat exposure to group A streptococcal M protein exacerbates cardiac damage in a rat model of rheumatic heart disease. Autoimmunity 49:563-570
Li, Hongliang; Zhang, Ling; Huang, Bing et al. (2015) A peptidomimetic inhibitor suppresses the inducibility of ?1-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 ?1/2-adrenergic and M2 muscarinic receptors associate with atrial tachyarrhythmias in patients with hyperthyroidism. Endocrine 49:457-63
Singer, Harvey S; Mascaro-Blanco, Adda; Alvarez, Kathy et al. (2015) Neuronal antibody biomarkers for Sydenham's chorea identify a new group of children with chronic recurrent episodic acute exacerbations of tic and obsessive compulsive symptoms following a streptococcal infection. PLoS One 10:e0120499
Lotan, Dafna; Benhar, Itai; Alvarez, Kathy et al. (2014) Behavioral and neural effects of intra-striatal infusion of anti-streptococcal antibodies in rats. Brain Behav Immun 38:249-62
Kirvan, Christine A; Galvin, Jeffrey E; Hilt, Silvia et al. (2014) Identification of streptococcal m-protein cardiopathogenic epitopes in experimental autoimmune valvulitis. J Cardiovasc Transl Res 7:172-81

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