Dr. Cunningham's laboratory has been highly focused on the investigation of  molecular mimicry, autoimmunity and infection in inflammatory heart disease  for the past 20 years. The models of autoimmunity and infection that we have  chosen to investigate include rheumatic carditis, a sequela of group A streptococcal pharyngitis, and myocarditis, a complication that can follow coxsackieviral  infections. Rheumatic carditis affects the heart valves, while myocarditis results  in the destruction of the myocardium. In both diseases molecular mimicry may  be an important mechanism by which infections lead to presentation of crossreactive  antigens and breakdown of self tolerance. In rheumatic carditis, the autoimmune  mechanisms are due to molecular mimicry between group A streptococcal antigens  and cardiac myosin. Our goal has been to study the molecular and immunological  basis of antibody and T cell crossreactivity between group A streptococcal M  protein and myosin, and to study the role of these immune crossreactivity mechanisms  in the pathogenesis of rheumatic heart disease and myocarditis. Heart crossreactive  monoclonal antibodies and T cells have identified the streptococcal M protein,  cardiac myosin and coxsackieviral capsid proteins as antigens that participate  in molecular mimicry in rheumatic fever as well as inflammatory heart disease.  Under investigation are the following: human mAbs from acute rheumatic fever  patients, nucleotide sequences of mAb VH and VL regions genes from disease,  cytotoxic monoclonal antibodies which react with extracellular matrix of heart  or endothelial cells, mimicry between the group A carbohydrate N-acetyl-glucosamine  and peptides, and crossreactive T cell clones. We have indentified pathogenic  epitopes of steptococcal M protein and cardiac myosin in animal models of heart disease and have  identified epitopes recognized in human diseases such as rheumatic carditis,  myocarditis, diabetic cardiomyopathy and Kawasaki syndrome. We have a strong interest in peptide therapeutics  to prevent disease, and our work has identified epitopes which are detrimental  to M protein vaccines. Production of transgenic mice expressing human immunoglobulin  VH and VL genes as well as other immune system related genes for development  of transgenic models of autoimmune heart disease is in progress. A second focus of the laboratory is on the study of autoimmunity and behavior which is manifest in diseases such as Sydenham’s chorea following group A streptococcal infection. Our study identified antibody mediated neuronal cell signaling as the basis for the choreic movement disorder. Other related movement and psychiatric disorders such as obsessive compulsive disorder, Tourette’s Syndrome and Tics are under investigation for subsets that may be related to streptococcal infection and/or to autoantibodies which signal in the brain.

Teaching:  Host-Parasite Interactions; Bacterial Pathogenesis; Medical and Dental Microbiology.

Recent Books Edited:Effects of Microbes on the Immune System/Lippincott  Williams and Wilkens; Molecular Mimicry, Microbes and Autoimmunity/ASM Press; Autoimmunity, and Infection/Autoimmunity/2006/Taylor and Francis.

Email:  madeleine-cunningham@ouhsc.edu

Selected Publications:

Krisher, K. and M.W. Cunningham. l985. Myosin:A link between heart and group A streptococci. Science 227: 413.

1. Cunningham, M.W., and R.A. Swerlick. 1986. Polyspecificity of monoclonal antibodies against group A streptococci and myosin. J. Exp. Med. 164: 998.
2. Cunningham, M.W., J.M. McCormack, P.G. Fenderson, M.K. Ho, E.H. Beachey, and J.B. Dale. 1989. Human and murine antibodies crossreactive with streptococcal M protein and myosin recognized the sequence GLN-LYS-SER-LYS-GLN in M protein.J. Immunol. 143: 2677.
3. Cunningham, M.W., S.M. Antone, J.M. Gulizia, B.M. McManus, V.A. Fischetti, and C.J. Gauntt. 1992. Cytotoxic and viral neutralizing antibodies crossreact with strptococcal M protein, enteroviruses, and human cardiac myosin. Proc. Natl. Acad. Sci. USA. 89: 1320-1324.
4. Huber, S.A., A. Moraska, and M.W. Cunningham. 1994. Alterations in major histo-compatability complex association of myocarditis induced by coxsackie virus B3 mutants selected with monoclonal antibodies to group A streptococci. Proc. Natl. Acad. Sci. USA 91:5543.
5. Skikhman, A.R. and M.W. Cunningham. 1994. Cytokeratin peptide SFGSGFGGGY mimics N-acetyl-beta-D-glucosamine and cytokeratin peptides. Evidence for a microbially driven anti-keratin antibody response. J. Immunol. 153:5593-5606.
6. Huber, S.A. and M.W. Cunningham. 1996. Streptococcal M protein peptide with similarity to myosin induces CD4+ T cell-dependent myocarditis in MRL/++ mice and induces partial tolerance against coxsackie viral myocarditis. J. Immunol. 156:3528.
7. Shikhman, A.R. and M.W. Cunningham. 1997. Trick or treat: toward peptide mimic vaccines. Nature Biotechnology 15:512-513.
8. Antone, S.M., E.E. Adderson, N.M.J. Mertens, and M.W. Cunningham. 1997. Molecular analysis of V gene sequences encoding cytotoxic anti-streptococcal/anti-myosin mAb 36.2.2 which recognizes the heart cell surface protein laminin. J. Immunol. 159:5422-5430
9. Cunningham, M.W., S.M. Antone, M. Smart, R. Liu and S. Kosanke. 1997. Molecular analysis of human cardiac myosin-cross-reactive B-and T-cell epitopes of the group A streptococcal M5 protein. Infect. Immunol. 65:3913-3923
10. Adderson, E.E., A.R. Shikhman, K.E. Ward and M.W. Cunningham. 1998. Molecular anlysis of polyreactive monoclonal antibodies from rheumatic carditis: human anti-N-acetyl glucosamine/anti-myosin antibody V region genes. J. Immunol. 161:2020-2031.
11. Cunningham, M.W., H.C. Meissner and D.Y.M. Leung. 1999. Anti-human cardiac myosin auto antibodies in Kawasaki syndrome. J. Immunol. 163:1060-1065.
12. Cunningham, M.W. 2000. Pathogenesis of group A streptococci. Clin. Micro. Rev. 13:470-511.
13. Galvin, J.E. M. E. Hemric, K. Ward and M.W. Cunningham. 2000. Cytotoxic monoclonal antibody from rheumatic carditis reacts with human endothelium: implications in rheumatic heart disease. J. Clin. Invest. 106: 217-224.
14. Roberts, S., T. Dunn. D. Jankelow, C. Duran, S. Kosanke and M.W. Cunningham. 2001. Immune mechanisms in rheumatic carditis: focus on valvular endothelium. J. Infect. Dis. 183: 507-511.
15. Mertens, N. M. J., J. E. Galvin, E. E. Adderson, and M.W. Cunningham. 2001. Molecular analysis of anti-streptococcal/anti-myosin mouse monoclonal antibodies. Mol. Immunol. 37:901-913.
16. Quinn, A., V. Fischetti, S. Kosanke, S. M. Factor, and M.W. Cunningham. 2001. Induction of autoimmune valvular heart disease by recombinant streptococcal M protein. Infect. Immun. 69: 4072-4078.
17. Cunningham, M.W. 2001. Cardiac myosin and the TH1/TH2 paradigm in autoimmune myocarditis. Amer. J. Path. 159: 5-12.
18. Galvin, J.E., M.E. Hemric, S. D. Kosanke, S.M. Factor, A. Quinn, and M.W. Cunningham. 2002. Induction of myocarditis and valvulitis in Lewis rats by different epitopes of cardiac myosin and its implications in rheumatic carditis. Amer J Path. 160: 297-306.
19. Kiryan, C.A., J.S. Heauser, and M.W. Cunningham. 2003. Mimicry and autoantibody-mediated neuronal cell signaling in Sydenham chorea. Nature Medicine 9: 914-920.
20. Li, J S Heause, S D Kosanke, M Hemric and M.W. Cunningham. 2004. Cryptic Epitope indentified in rat and human cardiac myosin S2 region induces myocarditis in the Lewis rat. J. Immunol. 142: 3225-3234.
21. Ellis, N. M. W Hildebrand, V.A. Fischetti and M. W. Cunningham. 2005. T Cell Mimicry and Epitope Specificity of Human T Cell Clones from Rheumatic Heart Disease. J Immunol 175: 5448-5456.
22. Fae, Kellwen, C.D. Diefenbach da Silva, S.E. Oshiro, A.C. Tanaka, P.M.A. Pomerantzeff, C. Douay, D. Charron, A. Toubert, M.W. Cunningham, J. Kalil, and L. Guilherme. 2006. Mimicry in recognition of cardiac myosin peptides by heart-intralesional T cell clones from rheumatic heart disease. J. Immunol. 176: 5662-5670.
23. Christine A. Kirvan, Susan E. Swedo, Lisa A. Snider, Madeleine W. Cunningham. 2006. Antibody-mediatedneuronal cell signaling in behavior and movement disorders. J. Neuroimmunol. (In Press)
24. Li, Y., J.S. Heuser, S. D. Kosanke, M.W. Cunningham. 2006. Mimicry and antibody-mediated cell signaling in autoimmune myocarditis. (J Immunol In Revision)

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