Cardiac Myosin and the TH1/TH2 Paradigm in Autoimmune Myocarditis
2001; Elsevier BV; Volume: 159; Issue: 1 Linguagem: Inglês
10.1016/s0002-9440(10)61665-3
ISSN1525-2191
Autores Tópico(s)Inflammatory Myopathies and Dermatomyositis
ResumoMyocarditis and dilated cardiomyopathy may represent acute and chronic stages of a progressive organ-specific autoimmune disease of the myocardium.1Caforio ALP Goldman JH Haven AJ Baig KM McKenna WJ Evidence for autoimmunity to myosin and other heart-specific autoantigens in patients with dilated cardiomyopathy and their relatives.Int J Cardiol. 1996; 54: 157-163Abstract Full Text PDF PubMed Scopus (83) Google Scholar, 2Brown CA O'Connell JB Myocarditis and idiopathic dilated cardiomyopathy.Am J Med. 1995; 99: 309-314Abstract Full Text PDF PubMed Scopus (84) Google Scholar, 3Felker GM Hu W Hare JM Hruban RH Baughman KI Kasper EK The spectrum of dilated cardiomyopathy. The Johns Hopkins experience with 1,278 patients.Medicine. 1999; 78: 270-283Crossref PubMed Scopus (205) Google Scholar Myocarditis is an inflammatory disease of the heart that is characterized by a cellular infiltrate in the myocardium, and dilated cardiomyopathy is a chronic heart muscle disease characterized by ventricular hypertrophy.1Caforio ALP Goldman JH Haven AJ Baig KM McKenna WJ Evidence for autoimmunity to myosin and other heart-specific autoantigens in patients with dilated cardiomyopathy and their relatives.Int J Cardiol. 1996; 54: 157-163Abstract Full Text PDF PubMed Scopus (83) Google Scholar, 2Brown CA O'Connell JB Myocarditis and idiopathic dilated cardiomyopathy.Am J Med. 1995; 99: 309-314Abstract Full Text PDF PubMed Scopus (84) Google Scholar, 3Felker GM Hu W Hare JM Hruban RH Baughman KI Kasper EK The spectrum of dilated cardiomyopathy. The Johns Hopkins experience with 1,278 patients.Medicine. 1999; 78: 270-283Crossref PubMed Scopus (205) Google Scholar, 4Towbin JA Bowles KR Bowles NE Etiologies of cardiomyopathy and heart failure.Nat Med. 1999; 5: 766-767Crossref Scopus (83) Google Scholar Dilated cardiomyopathy is a primary cause of severe heart failure with subsequent transplantation or death within several years after diagnosis.1Caforio ALP Goldman JH Haven AJ Baig KM McKenna WJ Evidence for autoimmunity to myosin and other heart-specific autoantigens in patients with dilated cardiomyopathy and their relatives.Int J Cardiol. 1996; 54: 157-163Abstract Full Text PDF PubMed Scopus (83) Google Scholar, 5Fuster V Gersh BJ Giuliani ER Tajik AJ Brandenburg AO Frye RL The natural history of idiopathic dilated cardiomyopathy.Am J Cardiol. 1981; 47: 525-531Abstract Full Text PDF PubMed Scopus (814) Google Scholar The direct result of cellular infiltration of the myocardium is necrosis and loss of myocytes leading to the development of contractile dysfunction and ventricular dilatation. The loss of myocytes and formation of scar tissue in the myocardium would lead to loss of contractile function and ventricular enlargement. In a small percentage of individuals, loss of myocyte function and development of dilated cardiomyopathy can result from mutations in or viral proteolytic digestion of dystrophin or dystrophin-associated glycoproteins that lead to cytoskeletal disruption and loss of overall contractile function in the heart.4Towbin JA Bowles KR Bowles NE Etiologies of cardiomyopathy and heart failure.Nat Med. 1999; 5: 766-767Crossref Scopus (83) Google Scholar, 6Badorff C Lee GH Lamphear BJ Martone ME Campbell KP Rhoads RE Knowlton KU Enteroviral protease 2A cleaves dystrophin: evidence of cytoskeletal disruption in an acquired cardiomyopathy.Nat Med. 1999; 5: 320-326Crossref PubMed Scopus (472) Google Scholar, 7Badorff C Berkely N Mehrotra S Talhouk JW Rhoads RE Knowlton KU Enteroviral protease 2A directly cleaves dystrophin and is inhibited by a dystrophin-based substrate analogue.J Biol Chem. 2000; 275: 11191-11197Crossref PubMed Scopus (75) Google Scholar, 8Lee GH Badorff C Knowlton KU Dissociation of sarcoglycans and the dystrophin carboxyl terminus from the sarcolemma in enteroviral cardiomyopathy.Circ Res. 2000; 87: 489-495Crossref PubMed Scopus (30) Google Scholar However, the most common cause of myocarditis is viral infection. An exhaustive list of myocarditis-inducing agents including microbial pathogens and toxins is provided by Brown and O'Connell2Brown CA O'Connell JB Myocarditis and idiopathic dilated cardiomyopathy.Am J Med. 1995; 99: 309-314Abstract Full Text PDF PubMed Scopus (84) Google Scholar in a review of myocarditis and dilated cardiomyopathy. Among the most common viral causes of human myocarditis are coxsackieviruses.2Brown CA O'Connell JB Myocarditis and idiopathic dilated cardiomyopathy.Am J Med. 1995; 99: 309-314Abstract Full Text PDF PubMed Scopus (84) Google Scholar, 9Woodruff JF Viral myocarditis—a review.Am J Pathol. 1980; 101: 425-466PubMed Google Scholar, 10Martino TA Liu P Sole MJ Viral infection and the pathogenesis of dilated cardiomyopathy.Circ Res. 1994; 74: 182-188Crossref PubMed Scopus (199) Google Scholar, 11Baboonian C Davies MJ Booth JC McKenna WJ Coxsackie B viruses and human heart disease.Curr Top Microbiol Immunol. 1997; 223: 31-52PubMed Google Scholar Mouse models of coxsackievirus-induced myocarditis were studied by Woodruff and colleagues12Wong CY Woodruff JJ Woodruff JF Generation of cytotoxic T lymphocytes during coxsackievirus B-3 infection.: II. Characterization of effector cells and demonstration of cytotoxicity against viral-infected myofibers.J Immunol. 1977; 118: 1165-1169PubMed Google Scholar, 13Wong CY Woodruff JF Woodruff JJ Generation of cytotoxic lymphocytes in the pathogenesis of coxsackievirus B3 heart disease.J Immunol. 1977; 118: 1159-1174PubMed Google Scholar, 14Huber SA Job LP Woodruff JF Lysis of infected myofibers by coxsackievirus B3 immune lymphocytes.Am J Pathol. 1980; 98: 681-694PubMed Google Scholar who demonstrated that lymphocytes from mouse models of myocarditis could destroy cardiomyocytes in culture. Gauntt and colleagues15Gauntt C Tracy S Chapman N Wood H Kolbeck P Karaganis A Winfrey C Cunningham M Coxsackievirus-induced chronic myocarditis in murine models.Eur Heart J. 1995; 16: S56-S58Crossref PubMed Google Scholar also investigated the role of virulent myocarditic versus nonvirulent amyocarditic coxsackieviruses in mouse models of myocarditis. In their studies, there appeared to be several stages of disease in their mouse model. The first early stage of viral replication and cell lysis in the heart showed no evidence of heart failure or cellular inflammation, however, with the onset of specific immune responses, cellular infiltration of the myocardium was observed in susceptible mice. The cellular infiltrates in the myocardium were minimal to severe and led to the loss of myocytes by necrosis. The development of dilated cardiomyopathy is thought to represent the third and more chronic stage of heart disease that develops after the cellular inflammation.16Reyes MP Ho KL Smith F Woodruff JF A mouse model of dilated type cardiomyopathy due to coxsackie B3 heart disease.J Infect Dis. 1981; 144: 232-236Crossref PubMed Scopus (46) Google Scholar It would follow that once the damage has been done to the cardiomyocyte function either by elimination of large numbers of myocytes because of inflammation, necrosis, and scarring or by disruption of the cytoskeleton so that the myocyte is dysfunctional, then anti-inflammatory therapy would not be effective. Anti-inflammatory therapies would only be efficacious during the time of inflammatory onset. In fact, immunosuppressive therapy was not effective in the Myocarditis Trial.2Brown CA O'Connell JB Myocarditis and idiopathic dilated cardiomyopathy.Am J Med. 1995; 99: 309-314Abstract Full Text PDF PubMed Scopus (84) Google Scholar By the time myocarditis symptoms present, many cases may have already advanced to a stage in which necrosis and scarring have already led to ventricular dilatation and contractile dysfunction. For comparison, in rheumatic carditis, the valve is insidiously and permanently damaged by autoimmune attack after streptococcal pharyngitis. In rheumatic carditis, valve injury may not be evident until a heart murmur is perceived that reflects the scarred valve. In myocarditis, the end-stage of disease may represent a physical, structural defect as a result of autoimmune-mediated damage during the inflammatory stage of the disease. Although infectious pathogens, including viruses,17Huber SA Gauntt CJ Sakkinen P Enteroviruses and myocarditis: viral pathogenesis through replication, cytokine induction, and immunopathogenicity.Adv Virus Res. 1998; 51: 35-80Crossref PubMed Google Scholar group A streptococci,18Cunningham MW Pathogenesis of group A streptococcal infections.Clin Microbiol Rev. 2000; 13: 470-511Crossref PubMed Scopus (1801) Google Scholar or chlamydia,19Bachmaier K Neu N de la Maza L Pal S Hessel A Penninger JM Chlamydia infections and heart disease linked through antigenic mimicry.Science. 1999; 283: 1335-1339Crossref PubMed Scopus (366) Google Scholar are important etiological agents of inflammatory heart disease, immune and specifically autoimmune mechanisms are the major effectors of pathogenic injury.2Brown CA O'Connell JB Myocarditis and idiopathic dilated cardiomyopathy.Am J Med. 1995; 99: 309-314Abstract Full Text PDF PubMed Scopus (84) Google Scholar The autoantigen most often associated with both myocarditis and rheumatic carditis is cardiac myosin.18Cunningham MW Pathogenesis of group A streptococcal infections.Clin Microbiol Rev. 2000; 13: 470-511Crossref PubMed Scopus (1801) Google Scholar, 20Cunningham MW Hall NK Krisher KK Spanier AM A study of monoclonal antibodies against streptococci and myosin.J Immunol. 1985; 136: 293-298Google Scholar, 21Cunningham MW Swerlick RA Polyspecificity of antistreptococcal murine monoclonal antibodies and their implications in autoimmunity.J Exp Med. 1986; 164: 998-1012Crossref PubMed Scopus (86) Google Scholar, 22Cunningham MW Antone SM Smart M Liu R Kosanke S Molecular analysis of human cardiac myosin-cross-reactive B- and T-cell epitopes of the group A streptococcal M5 protein.Infect Immun. 1997; 65: 3913-3923Crossref PubMed Google Scholar, 23Neu N Rose NR Beisel KW Herskowitz A Gurri-Glass G Craig SW Cardiac myosin induces myocarditis in genetically predisposed mice.J Immunol. 1987; 139: 3630-3636PubMed Google Scholar, 24Kodama M Matsumoto Y Fujiwara M Massani M Izumi T Shibota A A novel experimental model of giant cell myocarditis induced in rats by immunization with cardiac myosin fraction.Clin Immunol Immunopathol. 1991; 57: 250-262Crossref Scopus (306) Google Scholar, 25Neu N Beisel KW Traystman MD Rose NR Craig SW Autoantibodies specific for the cardiac myosin isoform are found in mice susceptible to coxsackievirus B3 induced myocarditis.J Immunol. 1987; 138: 2488-2492PubMed Google Scholar, 26Donermeyer DL Beisel KW Allen PM Smith SC Myocarditis-inducing epitope of myosin binds constitutively and stably to I-A K on antigen presenting cells in the heart.J Exp Med. 1995; 182: 1291-1300Crossref PubMed Scopus (108) Google Scholar, 27Smith SC Allen PM Myosin-induced acute myocarditis is a T cell mediated disease.J Immunol. 1991; 147: 2141-2147PubMed Google Scholar In 1985, myosin was identified as an autoantigen involved in cross-reactivity between the group A streptococcus and heart.28Krisher K Cunningham MW Myosin: a link between streptococci and heart.Science. 1985; 227: 413-415Crossref PubMed Scopus (156) Google Scholar Since this time, evidence has supported the molecular mimicry hypothesis that streptococcal M protein and the group A carbohydrate both induce anti-myosin responses that attack the heart.22Cunningham MW Antone SM Smart M Liu R Kosanke S Molecular analysis of human cardiac myosin-cross-reactive B- and T-cell epitopes of the group A streptococcal M5 protein.Infect Immun. 1997; 65: 3913-3923Crossref PubMed Google Scholar, 29Adderson EE Shikhman AR Ward KE Cunningham MW Molecular analysis of polyreactive monoclonal antibodies from rheumatic carditis: human anti-N-acetyl-glucosamine/anti-myosin antibody V region genes.J Immunol. 1998; 161: 2020-2031PubMed Google Scholar, 30Galvin JE Hemric ME Ward K Cunningham MW Cytotoxic monoclonal antibody from rheumatic carditis reacts with human endothelium: implications in rheumatic heart disease.J Clin Invest. 2000; 106: 217-224Crossref PubMed Scopus (183) Google Scholar, 31Quinn A Kosanke S Fischetti VA Factor SM Cunningham MW Induction of autoimmune valvular heart disease by recombinant streptococcal M protein.Infect Immun. 2001; 69: 4072-4078Crossref PubMed Scopus (115) Google Scholar, 32Shikhman AR Greenspan NS Cunningham MW A subset of mouse monoclonal antibodies cross-reactive with cytoskeletal proteins and group A streptococcal M proteins recognizes N-acetyl-beta-d-glucosamine.J Immunol. 1993; 151: 3902-3913PubMed Google Scholar, 33Malkiel S Liao L Cunningham MW Diamond B T-cell-dependent antibody response to the dominant epitope of streptococcal polysaccharide, N-acetyl-glucosamine, is cross-reactive with cardiac myosin.Infect Immun. 2000; 68: 5803-5808Crossref PubMed Scopus (43) Google Scholar In fact, immunological mimicry was demonstrated between streptococcal M protein and myocarditic coxsackieviruses and was linked to cytotoxic antibody against heart cells as well as T lymphocyte responses.32Shikhman AR Greenspan NS Cunningham MW A subset of mouse monoclonal antibodies cross-reactive with cytoskeletal proteins and group A streptococcal M proteins recognizes N-acetyl-beta-d-glucosamine.J Immunol. 1993; 151: 3902-3913PubMed Google Scholar, 34Cunningham MW Antone SM Gulizia JM McManus BM Fischetti VA Gauntt CJ Cytotoxic and viral neutralizing antibodies crossreact with streptococcal M protein, enteroviruses, and human cardiac myosin.Proc Natl Acad Sci USA. 1992; 89: 1320-1324Crossref PubMed Scopus (137) Google Scholar, 35Huber SA Moraska A Cunningham M Alterations in major histocompatibility complex association of myocarditis induced by coxsackievirus B3 mutants selected with monoclonal antibodies to group A streptococci.Proc Natl Acad Sci USA. 1994; 91: 5543-5547Crossref PubMed Scopus (31) Google Scholar, 36Huber S Polgar J Moraska A Cunningham M Schwimmbeck P Schultheiss P T lymphocyte responses in CVB3-induced murine myocarditis.Scand J Infect Dis. 1993; 88: S67-S78Google Scholar Interestingly, a myocarditic peptide of streptococcal M protein that mimics cardiac myosin tolerized and protected MRL/++ mice against autoimmune myocarditis after coxsackieviral infection.37Huber SA Cunningham MW Streptococcal M protein peptide with similarity to myosin induces CD4+ T cell-dependent myocarditis in MRL/++ mice and induces partial tolerance against coxsakieviral myocarditis.J Immunol. 1996; 156: 3528-3534PubMed Google Scholar Nevertheless, it is debated as to whether or not mimicry between coxsackieviruses and cardiac myosin plays a role in the pathogenesis of myocarditis.38Rose NR Viral damage or 'molecular mimicry'—placing the blame in myocarditis.Nat Med. 2000; 6: 631-632Crossref PubMed Scopus (81) Google Scholar, 39Horwitz MS La Cava A Fine C Rodriguez E Illic A Pancreatic expression of interferon-gamma protects mice from lethal coxsackievirus B3 infection and subsequent myocarditis.Nat Med. 2000; 6: 693-697Crossref PubMed Scopus (144) Google Scholar There is strong evidence that cardiac myosin is a dominant autoantigen in autoimmune myocarditis23Neu N Rose NR Beisel KW Herskowitz A Gurri-Glass G Craig SW Cardiac myosin induces myocarditis in genetically predisposed mice.J Immunol. 1987; 139: 3630-3636PubMed Google Scholar and viral-induced myocarditis.25Neu N Beisel KW Traystman MD Rose NR Craig SW Autoantibodies specific for the cardiac myosin isoform are found in mice susceptible to coxsackievirus B3 induced myocarditis.J Immunol. 1987; 138: 2488-2492PubMed Google Scholar Cardiac myosin-induced myocarditis histologically resembles the viral-induced disease. Investigators have demonstrated that myosin-induced myocarditis can be adoptively transferred by CD4+ T lymphocytes.27Smith SC Allen PM Myosin-induced acute myocarditis is a T cell mediated disease.J Immunol. 1991; 147: 2141-2147PubMed Google Scholar Although CD4+ lymphocytes can transfer disease, it has been shown that autoimmune myocarditis can occur in mice lacking CD4 or CD8 molecules,40Penninger JM Neu N Timms E Wallace VA Koh D-R Kishihara K Plummer C Mak TW Induction of experimental autoimmune myocarditis in mice lacking CD4 or CD8 molecules.J Exp Med. 1993; 178: 1837-1842Crossref PubMed Scopus (59) Google Scholar and that myocardial infiltrates consisted of T cells that were double-negative T cells with αβTCR. In addition to T cells, passive administration of anti-myosin monoclonal antibody was found to induce myocarditis in DBA/2 but not BALB/c mice because of the presence of myosin or a myosin-like protein in the extracellular matrix of DBA/2 mice.41Liao L Sindhwani R Rojkind M Factor S Leinwand L Diamond B Antibody-mediated autoimmune myocarditis depends on genetically determined target organ sensitivity.J Exp Med. 1995; 187: 1123-1131Crossref Scopus (134) Google Scholar Gauntt and colleagues42Gauntt C Arizpe H Higdon A Bowers D Rozek M Crawley R Molecular mimicry, anti-coxsackievirus B2 neutralizing monoclonal antibodies and myocarditis.J Immunol. 1995; 154: 2983-2995PubMed Google Scholar, 43Gauntt CJ Arizpe HM Higdon AL Rozek MM Crawley R Cunningham MW Anti-coxsackievirus B3 neutralizing antibodies with pathological potential.Eur Heart J. 1991; 12: 124-129Crossref PubMed Google Scholar, 44Gauntt CJ Higdon AL Arizpe HM Tamayo MR Crawley R Henkel RD Pereira ME Tracy SM Cunningham MW Epitopes shared between coxsackievirus B3 (CVB3) and normal heart tissue contribute to CVB3-induced murine myocarditis.Clin Immunol Immunopathol. 1993; 68: 129-134Crossref PubMed Scopus (47) Google Scholar investigated the relationship between coxsackievirus and myosin and suggested that molecular mimicry between myosin and coxsackieviruses may play a role in myocarditis. Anti-coxsackieviral-neutralizing antibody produced myocardial inflammation in mice.42Gauntt C Arizpe H Higdon A Bowers D Rozek M Crawley R Molecular mimicry, anti-coxsackievirus B2 neutralizing monoclonal antibodies and myocarditis.J Immunol. 1995; 154: 2983-2995PubMed Google Scholar Therefore, both antibody and T cells may contribute to the pathogenesis of inflammatory myocardial lesions. Susceptibility to anti-myosin antibody-induced myocarditis was dependent on the strain of mice. For example, different pathogenic mechanisms have been reported in DBA/2 (antibody-mediated disease) and BALB/c (T-cell-mediated) mouse strains.41Liao L Sindhwani R Rojkind M Factor S Leinwand L Diamond B Antibody-mediated autoimmune myocarditis depends on genetically determined target organ sensitivity.J Exp Med. 1995; 187: 1123-1131Crossref Scopus (134) Google Scholar, 45Huber SA Lodge PA Coxsackievirus B-3 myocarditis: identification of different pathogenic mechanisms in DBA/2 and BALB/c mice.Am J Pathol. 1986; 122: 284-291PubMed Google Scholar Susceptibility may be related to genetic factors including target organ sensitivity or influences such as infection and polarizing TH1/TH2 cytokines. Antibodies against myosin were elevated after coxsackieviral infection of susceptible mouse strains.25Neu N Beisel KW Traystman MD Rose NR Craig SW Autoantibodies specific for the cardiac myosin isoform are found in mice susceptible to coxsackievirus B3 induced myocarditis.J Immunol. 1987; 138: 2488-2492PubMed Google Scholar In rheumatic carditis, infection plays a major role as well as anti-myosin antibody46Cunningham MW McCormack JM Talaber LR Harley JB Ayoub EM Muneer RS Chun LT Reddy DV Human monoclonal antibodies reactive with antigens of the group A Streptococcus and human heart.J Immunol. 1988; 141: 2760-2766PubMed Google Scholar, 47Cunningham MW McCormack JM Fenderson PG Ho MK Beachey EH Dale JB Human and murine antibodies cross-reactive with streptococcal M protein and myosin recognize the sequence GLN-LYS-SER-LYS-GLN in M protein.J Immunol. 1989; 143: 2677-2683PubMed Google Scholar that has been shown to be cytotoxic for heart cells in culture and to recognize cell surface cross-reactive antigen laminin on the valve and myocyte cell surface.29Adderson EE Shikhman AR Ward KE Cunningham MW Molecular analysis of polyreactive monoclonal antibodies from rheumatic carditis: human anti-N-acetyl-glucosamine/anti-myosin antibody V region genes.J Immunol. 1998; 161: 2020-2031PubMed Google Scholar, 30Galvin JE Hemric ME Ward K Cunningham MW Cytotoxic monoclonal antibody from rheumatic carditis reacts with human endothelium: implications in rheumatic heart disease.J Clin Invest. 2000; 106: 217-224Crossref PubMed Scopus (183) Google Scholar In rheumatic carditis, antibodies deposit in myocardium as well as valvular endothelium30Galvin JE Hemric ME Ward K Cunningham MW Cytotoxic monoclonal antibody from rheumatic carditis reacts with human endothelium: implications in rheumatic heart disease.J Clin Invest. 2000; 106: 217-224Crossref PubMed Scopus (183) Google Scholar, 48Kaplan MH Bolande R Ratika L Blair J Presence of bound immunoglobulins and complement in the myocardium in acute rheumatic fever.N Engl J Med. 1964; 271: 637-645Crossref PubMed Scopus (99) Google Scholar, 49Gulizia JM Cunningham MW McManus BM Immunoreactivity of anti-streptococcal monoclonal antibodies to human heart valves. Evidence for multiple cross-reactive epitopes.Am J Pathol. 1991; 138: 285-301PubMed Google Scholar and T cells infiltrate the valve.50Guilherme L Cunha-Neto E Coelho V Snitcowsky R Pomerantzeff PMA Assis RV Pedra F Neumann J Goldberg A Patarroyo ME Pileggi F Kalil J Human heart-filtrating T cell clones from rheumatic heart disease patients recognize both streptococcal and cardiac proteins.Circulation. 1995; 92: 415-420Crossref PubMed Scopus (161) Google Scholar There have been a number of studies that have demonstrated anti-cardiac myosin or anti-heart antibodies in acute and chronic myocarditis51Lauer B Padberg K Schultheiss HP Strauer BE Autoantibodies against human ventricular myosin in sera of patients with acute and chronic myocarditis.J Am Coll Cardiol. 1994; 23: 146-153Abstract Full Text PDF PubMed Scopus (80) Google Scholar, 52Neumann DA Burek CL Baughman KL Rose NR Herskowitz A Circulating heart reactive antibodies in patients with myocarditis or cardiomyopathy.J Am Coll Cardiol. 1990; 16: 839-846Abstract Full Text PDF PubMed Scopus (163) Google Scholar, 53Maisch B Drude L Hengstenberg C Herzum M Hufnagel G Kochsiek K Schmaltz A Schonian U Schwab MD Are antisarcolemmal (ASAs) and antimyolemmal antibodies (AMLAs) "natural" antibodies?.Basic Res Cardiol. 1991; 86: 101-114PubMed Google Scholar, 54Neumann DA Rose NR Ansari AA Herskowitz AH Induction of multiple heart autoantibodies in mice with coxsackievirus B3- and cardiac myosin-induced autoimmune myocarditis.J Immunol. 1993; 152: 343-350Google Scholar and soluble interleukin-2 levels were correlated with disease severity and cardiac autoantibodies.55Limas CJ Goldenberg IF Limas C Soluble interleukin-2 levels in patients with dilated cardiomyopathy. Correlation with disease severity and cardiac autoantibodies.Circulation. 1995; 91: 631-634Crossref PubMed Google Scholar Thus, in inflammatory heart diseases, myocarditis and rheumatic carditis, both antibody and T cells are implicated in the disease. Using rodent models, the role of cardiac myosin as an autoantigen in the pathogenesis of autoimmune myocarditis has been well established23Neu N Rose NR Beisel KW Herskowitz A Gurri-Glass G Craig SW Cardiac myosin induces myocarditis in genetically predisposed mice.J Immunol. 1987; 139: 3630-3636PubMed Google Scholar, 24Kodama M Matsumoto Y Fujiwara M Massani M Izumi T Shibota A A novel experimental model of giant cell myocarditis induced in rats by immunization with cardiac myosin fraction.Clin Immunol Immunopathol. 1991; 57: 250-262Crossref Scopus (306) Google Scholar, 26Donermeyer DL Beisel KW Allen PM Smith SC Myocarditis-inducing epitope of myosin binds constitutively and stably to I-A K on antigen presenting cells in the heart.J Exp Med. 1995; 182: 1291-1300Crossref PubMed Scopus (108) Google Scholar, 27Smith SC Allen PM Myosin-induced acute myocarditis is a T cell mediated disease.J Immunol. 1991; 147: 2141-2147PubMed Google Scholar, 56Pummarer CL Luze K Grassl G Bachmaier K Offner F Lenz DM Zamborelli TJ Penninger JM Neu N Identification of cardiac myosin peptides capable of inducing autoimmune myocarditis in BALB/c mice.J Clin Invest. 1996; 97: 2057-2062Crossref PubMed Scopus (162) Google Scholar, 57Inomata T Hanawa T Mihanishi E Yajima S Nakayama T Maita M Kodama T Izumi A Shibata A Abo T Localization of porcine cardiac myosin epitopes that induce experimental autoimmune myocarditis.Circ Res. 1995; 76: 726-733PubMed Google Scholar, 58Wegmann KW Zhao W Griffin AC Hickey WF Identification of myocarditogenic peptides derived from cardiac myosin capable of inducing experimental allergic myocarditis in the Lewis rat.J Immunol. 1994; 153: 892-900PubMed Google Scholar. Myocarditis can be induced by cardiac myosin in A/J mice,23Neu N Rose NR Beisel KW Herskowitz A Gurri-Glass G Craig SW Cardiac myosin induces myocarditis in genetically predisposed mice.J Immunol. 1987; 139: 3630-3636PubMed Google Scholar, 27Smith SC Allen PM Myosin-induced acute myocarditis is a T cell mediated disease.J Immunol. 1991; 147: 2141-2147PubMed Google Scholar BALB/c mice,56Pummarer CL Luze K Grassl G Bachmaier K Offner F Lenz DM Zamborelli TJ Penninger JM Neu N Identification of cardiac myosin peptides capable of inducing autoimmune myocarditis in BALB/c mice.J Clin Invest. 1996; 97: 2057-2062Crossref PubMed Scopus (162) Google Scholar, 59Liao L Sindhwani R Leinwand L Diamond B Factor S Cardiac α-myosin heavy chains differ in their induction of myocarditis: identification of pathogenic epitopes.J Clin Invest. 1993; 92: 2877-2882Crossref PubMed Scopus (48) Google Scholar and in Lewis rats.24Kodama M Matsumoto Y Fujiwara M Massani M Izumi T Shibota A A novel experimental model of giant cell myocarditis induced in rats by immunization with cardiac myosin fraction.Clin Immunol Immunopathol. 1991; 57: 250-262Crossref Scopus (306) Google Scholar, 58Wegmann KW Zhao W Griffin AC Hickey WF Identification of myocarditogenic peptides derived from cardiac myosin capable of inducing experimental allergic myocarditis in the Lewis rat.J Immunol. 1994; 153: 892-900PubMed Google Scholar However, C57BL/6 mice are resistant to myosin-induced myocarditis. Induction of coxsackievirus-induced myocarditis is seen in a similar group of mouse strains including A/J and A.SW,25Neu N Beisel KW Traystman MD Rose NR Craig SW Autoantibodies specific for the cardiac myosin isoform are found in mice susceptible to coxsackievirus B3 induced myocarditis.J Immunol. 1987; 138: 2488-2492PubMed Google Scholar, 60Wolfgram LJ Beisel KW Herskowitz A Rose NR Variations in the susceptibility to coxsackievirus B3-induced myocarditis among different strains of mice.J Immunol. 1986; 136: 1846-1852PubMed Google Scholar C3H,15Gauntt C Tracy S Chapman N Wood H Kolbeck P Karaganis A Winfrey C Cunningham M Coxsackievirus-induced chronic myocarditis in murine models.Eur Heart J. 1995; 16: S56-S58Crossref PubMed Google Scholar and BALB/c and DBA/2.45Huber SA Lodge PA Coxsackievirus B-3 myocarditis: identification of different pathogenic mechanisms in DBA/2 and BALB/c mice.Am J Pathol. 1986; 122: 284-291PubMed Google Scholar BALB/c mice that have disruption of the gene for the negative immunoregulatory receptor PD-1 develop dilated cardiomyopathy with diffuse deposition of IgG throughout the heart and on the surface of cardiomyocytes. Autoantibodies in the disease model reacted with an unidentified 33-kd heart-specific protein.61Nishimura H Okazaki T Tanaka Y Nakatani K Hara M Matsumori A Sasayama S Mizoguchi AH Minato N Honjo T Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice.Science. 2001; 291: 319-322Crossref PubMed Scopus (1474) Google Scholar Exposure of cardiac myosin in the heart may be an important event leading to the onset of disease in the susceptible host.62McManus BM Chow LH Wilson JE Anderson DR Gulizia JM Gauntt CJ Klingel KE Beisel KW Kandolf R Direct myocardial injury by enterovirus: a central role in the evolution of murine myocarditis.Clin Immunol Immunopathol. 1993; 68: 159-169Crossref PubMed Scopus (141) Google Scholar Evidence has shown that in normal myocardium myosin-class II major histocompatibility antigen complexes are present before the induction of autoimmune myocarditis.63Smith SC Allen PM Expression of myosin-class II major histocompatibility complexes in the normal myocardium occurs before induction of autoimmune myocarditis.Proc Natl Acad Sci USA. 1992; 89: 9131-9135Crossref PubMed Scopus (107) Google Scholar Induction of myocarditis is seen only with cardiac myosin and not skeletal myosin23Neu N Rose NR Beisel KW Herskowitz A Gurri-Glass G Craig SW Cardiac myosin induces myocarditis in genetically predisposed mice.J Immunol. 1987; 139: 3630-3636PubMed Google Scholar or other α-helical coiled-coil proteins such as tropomyosin (Galvin and Cunningham, unpublished data). Streptococcal M protein mimics cardiac myosin sequences or epitopes and immunization with the M protein or peptides leads to myocardial and valvular inflammatory heart lesions in BALB/c mice and Lewis rats.22Cunningham MW Antone SM Smart M Liu R Kosanke S Molecular analysis of human cardiac myosin-cross-reactive B- and T-cell epitopes of the group A streptococcal M5 protein.Infect Immun. 1997; 65: 3913-3923Crossref PubMed Google Scholar, 31Quinn A Kosanke S Fischetti VA Factor SM Cunningham MW Induction of autoimmune valvular heart disease by recombinant streptococcal M protein.Infect Immun. 2001; 69: 4072-4078Crossref PubMed Scopus (115) Google Scholar Therefore, it would seem that the α-helical structure is not the critical factor in breaking self tolerance, but that
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