George Lynn Cross Research Professor
Ph.D.: 1973, University of Tennessee Center for the Health Sciences at Memphis
Pre-OUHSC: Oklahoma Medical Research Foundation
Research Interests: Molecular mimicry, Autoimmunity and Infection
Teaching: Microbial Pathogenesis and Immunology, Host-Parasite Interactions; Bacterial Pathogenesis; Medical and Dental Microbiology
Email: Madeleine-Cunningham@ouhsc.edu Dr. Cunningham's CV
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.
Current Laboratory Personnel:
Kathleen Alvarez, Research Assistant
Adda Blanco, Research Assistant
Carol Cox, Ph.D., Assistant Professor of Research
Glory Dunlap, Lab Technician
Erica Edwards, Graduate Student
Jennifer Myers, Graduate Student
Taken from over 100 peer-reviewed articles:
Krisher, K.and M.W. Cunningham. 1985. Myosin: A link between heart and group A streptococci. Science 227:413-415.
Cunningham, M.W. and R.A. Swerlick. 1986. Polyspecificity of monoclonal antibodies against group A streptococci and myosin. J. Exp. Med.164:998-1012.
Cunningham, M.W., J.M. McCormack, L.R. Talaber, J.B. Harley, E.M. Ayoub, R.M. Muneer, L.T. Chun, and D.V. Reddy. 1988. Human monoclonal antibodies reactive with antigens of the group A streptococcus and human heart. J. Immunol. 141:2760-766.
McCormack, J.M. and M.W. Cunningham. 1988. Recombinant interleukin-2 enhancement of antibody production by human-human hybridomas. Cell. Immunol. 115:325-333.
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: 2677-2683.
Fenderson, P.G., V.A. Fischetti, and M.W. Cunningham. 1989. Tropomyosin shares immunologic epitopes with group A streptococcal M proteins. J. Immunol. 142:2475-2481.
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 streptococcal M protein, enteroviruses, and human cardiac myosin.Proc.Natl.Acad.Sci.USA 89:1320-1324.
McCormack, J.M., C.A. Crossley, E.M. Ayoub, J.B. Harley, and M.W. Cunningham. 1993. Post-streptococcal anti-myosin antibody marker associated with systemic lupus erythematosus and Sjogren's syndrome. J.Infec.Dis. 168:915-921.
Huber, S.A., A. Moraska, and M.W. Cunningham. 1994. Alterations in major histocompatibility complex association of myocarditis induced by coxsackievirus B3 mutants selected with anti-group A streptococcal monoclonal antibodies. Proc. Natl. Acad. Sci USA. 91: 5543-5547.
Shikhman, A.R., and M.W. Cunningham. 1994. Immunological mimicry between N-acetyl-B-D-glucosamine and cytokeratin peptides: Evidence for a microbially-driven anti-keratin response. J. Immunol.152:4375-4387.
Shikhman, A.R., N.S. Greenspan, and M.W. Cunningham. 1994. Cytokeratin peptide SFGSGFGGGY mimics N-acetyl-B-d-glucosamine in reaction with antibodies and lectins, and induces in vivo anti-carbohydrate response. J. Immunol. 153: 5593-5606.
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 coxsackieviral myocarditis.J.Immunol.156:3528-3534.
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.Immun.65: 3913-3923.
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.
Shikhman, A. R. and M. W. Cunningham. 1997. Trick or treat: toward peptide mimic vaccines. Nature Biotechnology 15: 512-513.
Adderson, E. E., A. R. Shikhman, K. E. Ward, and M.W. Cunningham. 1998. Molecular analysis of polyreactive monoclonal antibodies from rheumatic carditis: Human anti-N-acetyl-glucosamine/anti-myosin antibody V region genes. J. Immunol. 161: 2020-2031.
Cunningham, M.W., H.C. Meissner, and D.Y.M. Leung.1999. Anti-human cardiac myosin autoantibodies in Kawasaki syndrome. J. Immunol. 163: 1060-1065.
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.
Malkiel, S, L. Liao, M.W. Cunningham, and B. Diamond. 2000. T-cell-dependent antibody response to the dominant epitope of streptococcal polysaccharide, N-acetyl-glucosamine, is cross-reactive with cardiac myosin.Infect. Immun. 68: 5803-5808.
Quinn, A., V. Fischetti, S. Kosanke, S. M. Factor, and M. Cunningham. 2001. Induction of autoimmune valvular heart disease by recombinant streptococcal M protein. Infec. Immun. 69: 4072-4078.
Mertens, N. M. J., J. E. Galvin, E. E. Adderson, and M. W. Cunningham. 2001. Molecular analysis of crossreactive anti-streptococcal/anti-myosin mouse monoclonal antibodies. Mol. Immunol. 37: 901-913.
Roberts, S., T. Dunn. D. Jankelow, C. Duran, S. Kosanke and M.W. Cunningham. 2001. Immune mechanisms in rheumatic valvulitis: focus on valvular endothelium. J. Infect. Dis. 183: 507-511.
Cunningham, M. W. 2001. Cardiac myosin and the TH1/TH2 paradigm in autoimmune myocarditis. Amer. J. Pathol. 159:5-12.
Galvin, J. E., M. E. Hemric, S. D. Kosanke, S. M. Factor, A. Quinn, and M. W. Cunningham. 2002. Multiple epitopes of cardiac myosin induce autoimmune myocarditis and valvulitis in Lewis rats. Amer. J. Pathol. 160: 297-306.
Kirvan, C. A., S. E. Swedo, J. S. Heuser, and M. W. Cunningham. 2003. Mimicry and autoantibody-mediated neuronal cell signaling in Sydenham's chorea. Nature Medicine 9: 914-920.
Li,Y., J.S. Heuser, S.D. Kosanke, M Hemric, and M.W, Cunningham. 2004. Cryptic epitope identified in rat and human cardiac myosin S2 region induces myocarditis in Lewis rat. J. Immunol. 172: 3225-3234.
Li, Y, J. S. Heuser, S. D. Kosanke, M. Hemric, and M.W. Cunningham. 2005. Protection against experimental autoimmune myocarditis is mediated by interleukin-10-producing T cells that are controlled by dendritic cells. Amer J Pathol. 167: 5-15.
Ellis, N.M. J., Y. Li, W. Hildebrand, V.A. Fischetti, and M.W. Cunningham.2005. T cell mimicry and epitope specificity of crossreactive T cell clones from rheumatic heart disease. J. Immunol.175: 5448-5456.
Fae, K., 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.
C. A. Kirvan, S. E. Swedo, L. A. Snider, M. W. Cunningham. 2006. Antibody-mediated neuronal cell signaling in behavior and movement disorders. J. Neuroimmunol. 179: 173-179.
Li, Y. J.S. Heuser, S. D. Kosanke, and M.W. Cunningham. 2006. Mimicry and antibody-mediated cell signaling in autoimmune myocarditis. J. Immunol. 177: 8234-8240.
Cunningham, M.W. 2006. Editorial. T reg cells: sentinels against autoimmune heart disease. Circ. Res. 99: 1024-1026.
Cooper, L. T., R. Virmani, N.M. Chapman, A. Frustaci, R. J. Rodeheffer, M.W. Cunningham, D. M. McNamara. 2006. National institutes of health-sponsored workshop on inflammation and immunity in dilated cardiomyopathy. Mayo Clin Proc. 81(2): 199-204.
Blank, M., L. Marini, G. Spina, J. Kalil, S. Jacobsen, H.J. Thiesen, M.W. Cunningham, L. Guilherme, Y. Shoenfeld. 2006. Overlapping Humoral Autoimmunity links Rheumatic Fever and the Antiphospholipid Syndrome. Rheumatology. 45: 833-41.
Kirvan, C.A., C. J. Cox, S. E. Swedo, and M.W. Cunningham. 2007. Tubulin is a neuronal target of autoantibodies in Sydenham's chorea. J. Immunol. 178: 7412-7421.
McNamara, C., A.S. Zinkernagel, P. Macheboeuf, M. W. Cunningham, V. Nizet, O. Ghosh. 2008. Coiled-coil irregularities and instabilities in group A streptococcal M1 are required for virulence functions. Science 319: 1405-1408.
Mascaro-Blanco, A., K. Alvarez, X. Yu, J. Lindenfeld, L. Olansky, T. Lyons, D. Duvall, J. S. Heuser, A. Gosamanova, C. J. Rubenstein, L. T. Cooper, D.C. Kem, and M. W. Cunningham. 2008. Consequences of unlocking the cardiac myosin molecule in human myocarditis and cardiomyopathies. Autoimmunity41:442-53.
Zhang, P., C.J. Cox, K.M. Alvarez, and M.W. Cunningham. 2009. Cutting Edge: Cardiac myosin activates innate immune responses through TLRs. J Immunol.183: 27-31
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.