title: Consequences of unlocking the cardiac myosin molecule in human myocarditis and cardiomyopathies.
abstract: Myocarditis, often initiated by viral infection, may progress to autoimmune inflammatory heart disease, dilated cardiomyopathy and heart failure. Although cardiac myosin is a dominant autoantigen in animal models of myocarditis and is released from the heart during viral myocarditis, the characterization, role and significance of anti-cardiac myosin autoantibodies is poorly defined. In our study, we define the human cardiac myosin epitopes in human myocarditis and cardiomyopathies and establish a mechanism to explain how anti-cardiac myosin autoantibodies may contribute to heart disease. We show that autoantibodies to cardiac myosin in sera from myocarditis and dilated cardiomyopathies in humans targeted primarily epitopes in the S2 hinge region of cardiac myosin. In addition, anti-cardiac myosin antibodies in sera or purified IgG from myocarditis and cardiomyopathy targeted the beta-adrenergic receptor and induced antibody-mediated cAMP-dependent protein kinase A (PKA) cell signaling activity in heart cells. Antibody-mediated PKA activity in sera was abrogated by absorption with anti-human IgG. Antibody-mediated cell signaling of PKA was blocked by antigen-specific inhibition by human cardiac myosin or the beta-adrenergic receptor but not the alpha adrenergic receptor or bovine serum albumin. Propranolol, a beta blocker and inhibitor of the beta-adrenergic receptor pathway also blocked the antibody-mediated signaling of the beta-adrenergic receptor and PKA. The data suggest that IgG antibody against human cardiac myosin reacts with the beta-adrenergic receptor and triggers PKA signaling in heart cells. In summary, we have identified a new class of crossreactive autoantibodies against human cardiac myosin and the beta-adrenergic receptor in the heart. In addition, we have defined disease specific peptide epitopes in the human cardiac myosin rod S2 region in human myocarditis and cardiomyopathy as well as a mechanistic role of autoantibody in the pathogenesis of disease.
authors.affiliation: Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
authors.forename: Adita
authors.initials: A
authors.lastname: Mascaro-Blanco
authors.forename: Kathy
authors.initials: K
authors.lastname: Alvarez
authors.forename: Xichun
authors.initials: X
authors.lastname: Yu
authors.forename: JoAnn
authors.initials: J
authors.lastname: Lindenfeld
authors.forename: Leann
authors.initials: L
authors.lastname: Olansky
authors.forename: Timothy
authors.initials: T
authors.lastname: Lyons
authors.forename: David
authors.initials: D
authors.lastname: Duvall
authors.forename: Janet S
authors.initials: JS
authors.lastname: Heuser
authors.forename: Albina
authors.initials: A
authors.lastname: Gosmanova
authors.forename: Carl J
authors.initials: CJ
authors.lastname: Rubenstein
authors.forename: Leslie T
authors.initials: LT
authors.lastname: Cooper
authors.forename: David C
authors.initials: DC
authors.lastname: Kem
authors.forename: Madeleine W
authors.initials: MW
authors.lastname: Cunningham
mesh_terms: D058672:Adrenergic beta-2 Receptor Antagonists; D000595:Amino Acid Sequence; D001323:Autoantibodies / Q000097:blood / Q000276:immunology*; D024722:Cardiac Myosins / Q000276:immunology*; D009202:Cardiomyopathies / Q000276:immunology* / Q000378:metabolism; D002311:Cardiomyopathy, Dilated / Q000276:immunology / Q000378:metabolism; D003429:Cross Reactions; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000939:Epitopes; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D008969:Molecular Sequence Data; D009205:Myocarditis / Q000276:immunology* / Q000378:metabolism; D011433:Propranolol / Q000494:pharmacology; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism
chemical_list: D058672:Adrenergic beta-2 Receptor Antagonists; D001323:Autoantibodies; D000939:Epitopes; D007074:Immunoglobulin G; D018343:Receptors, Adrenergic, beta-2; D011433:Propranolol; D017868:Cyclic AMP-Dependent Protein Kinases; D024722:Cardiac Myosins
references.citation: Am J Cardiovasc Pathol. 1987 Jan;1(1):3-14
references.pmid: 3455232
references.citation: J Exp Med. 1995 Mar 1;181(3):1123-31
references.pmid: 7869033
references.citation: J Immunol. 1991 Oct 1;147(7):2141-7
references.pmid: 1918949
references.citation: Circulation. 1992 May;85(5):1734-42
references.pmid: 1533350
references.citation: Ernst Schering Res Found Workshop. 2006;(55):169-93
references.pmid: 16329663
references.citation: Heart. 1997 Jan;77(1):62-7
references.pmid: 9038697
references.citation: J Biol Chem. 1984 Sep 25;259(18):11226-30
references.pmid: 6147352
references.citation: Hum Pathol. 1987 Jun;18(6):619-24
references.pmid: 3297992
references.citation: Clin Immunol Immunopathol. 1993 Aug;68(2):118-23
references.pmid: 7689424
references.citation: Nat Med. 2003 Jul;9(7):914-20
references.pmid: 12819778
references.citation: J Immunol. 2006 Dec 1;177(11):8234-40
references.pmid: 17114501
references.citation: J Immunol. 1987 Dec 1;139(11):3630-6
references.pmid: 3680946
references.citation: J Exp Med. 2006 Aug 7;203(8):2009-19
references.pmid: 16880257
references.citation: J Clin Invest. 1993 Dec;92(6):2877-82
references.pmid: 7504694
references.citation: Nature. 1970 Aug 15;227(5259):680-5
references.pmid: 5432063
references.citation: Clin Immunol Immunopathol. 1990 Nov;57(2):250-62
references.pmid: 2208806
references.citation: Clin Exp Immunol. 1982 Jun;48(3):533-45
references.pmid: 6288291
references.citation: Eur J Heart Fail. 2002 Aug;4(4):411-7
references.pmid: 12167378
references.citation: J Immunol. 1997 Dec 1;159(11):5422-30
references.pmid: 9548482
references.citation: J Am Coll Cardiol. 2000 Jan;35(1):11-8
references.pmid: 10636253
references.citation: Nat Med. 1999 Mar;5(3):266-7
references.pmid: 10086375
references.citation: Semin Immunol. 1998 Feb;10(1):5-13
references.pmid: 9529651
references.citation: Nature. 2002 Jan 10;415(6868):206-12
references.pmid: 11805844
references.citation: Immunogenetics. 1999 Feb;49(2):79-85
references.pmid: 9887344
references.citation: Autoimmunity. 2001;34(3):211-5
references.pmid: 11908780
references.citation: Am J Pathol. 2002 Jan;160(1):297-306
references.pmid: 11786423
references.citation: J Immunol. 2005 Jan 1;174(1):261-9
references.pmid: 15611248
references.citation: Am J Cardiol. 1983 Nov 1;52(8):1072-8
references.pmid: 6356861
references.citation: J Clin Invest. 2004 May;113(10):1379-82
references.pmid: 15146232
references.citation: J Immunol. 1988 Oct 15;141(8):2760-6
references.pmid: 3049816
references.citation: J Am Coll Cardiol. 1990 Nov;16(6):839-46
references.pmid: 2229805
references.citation: J Exp Med. 1986 Oct 1;164(4):998-1012
references.pmid: 3531385
references.citation: Arch Pathol Lab Med. 1989 Dec;113(12):1357-62
references.pmid: 2480099
references.citation: Am J Pathol. 1980 Mar;98(3):681-94
references.pmid: 6244737
references.citation: N Engl J Med. 1997 Jun 26;336(26):1860-6
references.pmid: 9197214
references.citation: N Engl J Med. 2003 Oct 16;349(16):1526-33
references.pmid: 14561795
references.citation: Autoimmunity. 2001;34(3):199-204
references.pmid: 11908778
references.citation: Am J Med. 1995 Sep;99(3):309-14
references.pmid: 7653492
references.citation: Herz. 2000 May;25(3):291-8
references.pmid: 10904855
references.citation: Am J Pathol. 2004 Dec;165(6):1883-94
references.pmid: 15579433
references.citation: J Immunol. 2004 Mar 1;172(5):3225-34
references.pmid: 14978130
references.citation: Eur Heart J. 1997 Feb;18(2):270-5
references.pmid: 9043844
references.citation: J Immunol. 1999 Jul 15;163(2):1060-5
references.pmid: 10395705
references.citation: Am Heart J. 1993 Dec;126(6):1385-92
references.pmid: 7504393
references.citation: Circ Res. 1994 Aug;75(2):278-84
references.pmid: 8033341
references.citation: Clin Microbiol Rev. 2000 Jul;13(3):470-511
references.pmid: 10885988
references.citation: Medicine (Baltimore). 1999 Jul;78(4):270-83
references.pmid: 10424207
references.citation: Circ Res. 1995 Jan;76(1):64-72
references.pmid: 8001279
references.citation: Am J Physiol. 1988 Oct;255(4 Pt 2):H960-4
references.pmid: 2845818
references.citation: J Immunol. 1992 Jun 15;148(12):3806-13
references.pmid: 1602130
references.citation: J Clin Invest. 2004 May;113(10):1419-29
references.pmid: 15146239
references.citation: Proc Natl Acad Sci U S A. 1992 Feb 15;89(4):1320-4
references.pmid: 1311095
references.citation: Genomics. 1990 Oct;8(2):194-206
references.pmid: 2249844
references.citation: J Immunol. 1989 Oct 15;143(8):2677-83
references.pmid: 2677144
references.citation: Int J Cardiol. 1996 May;54(2):157-63
references.pmid: 8803680
references.citation: Circ Res. 2000 Feb 18;86(3):281-5
references.pmid: 10679479
references.citation: Am J Pathol. 1980 Nov;101(2):425-84
references.pmid: 6254364
references.citation: Ernst Schering Res Found Workshop. 2006;(55):141-54
references.pmid: 16331858
references.citation: J Clin Invest. 2000 Jul;106(2):217-24
references.pmid: 10903337