Impaired thymic tolerance to α-myosin directs autoimmunity to the heart in mice and humans

Journal of Clinical Investigation

Volumn 121, Issue 4, 2011, Pages 1561-1573

  Lv, HuiJuan ^a,b,c   Havari, Evis ^a   Pinto, Sheena ^d   Gottumukkala, Raju V S R K ^a,b,c   Cornivelli, Lizbeth ^a   Raddassi, Khadir ^b,c   Matsui, Takashi ^c,e   Rosenzweig, Anthony ^c,e   Bronson, Roderick T ^c   Smith, Ross ^a   Fletcher, Anne L ^c,f   Turley, Shannon J ^c,f   Wucherpfennig, Kai ^c,f   Kyewski, Bruno ^d   Lipes, Myra A ^a,b,c  

^a JOSLIN DIABETES CENTER   (United States)

^b BRIGHAM AND WOMEN S HOSPITAL   (United States)

^c HARVARD MEDICAL SCHOOL   (United States)

^d GERMAN CANCER RESEARCH CENTER DKFZ   (Germany)

^e BETH ISRAEL DEACONESS MEDICAL CENTER   (United States)

^f DANA FARBER CANCER INSTITUTE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

MYOSIN HEAVY CHAIN ALPHA;

ANIMAL CELL; ARTICLE; AUTOIMMUNITY; BLOOD ANALYSIS; CD4+ T LYMPHOCYTE; CELL ISOLATION; CONTROLLED STUDY; FEMALE; HUMAN; HUMAN CELL; HUMORAL IMMUNITY; IMMUNE RESPONSE; INFANT; LYMPHOID ORGAN; MALE; MOLECULAR MECHANICS; MOUSE; MYOCARDITIS; NONHUMAN; PRIORITY JOURNAL; PROTEIN EXPRESSION; THYMUS;

ANIMALS; AUTOANTIGENS; AUTOIMMUNITY; BASE SEQUENCE; CARDIAC MYOSINS; CD4-POSITIVE T-LYMPHOCYTES; DISEASE MODELS, ANIMAL; DNA PRIMERS; FEMALE; HLA-DQ ANTIGENS; HUMANS; IMMUNE TOLERANCE; INFANT; INFANT, NEWBORN; MALE; MICE; MICE, INBRED C57BL; MICE, INBRED NOD; MICE, KNOCKOUT; MICE, TRANSGENIC; MYOCARDITIS; MYOCARDIUM; MYOSIN HEAVY CHAINS; THYMUS GLAND; VENTRICULAR MYOSINS;

EID: 79953309886     PISSN: 00219738     EISSN: 15588238     Source Type: Journal    
DOI: 10.1172/JCI44583     Document Type: Article

References (68)

1. Lipshultz SE, et al. The incidence of pediatric cardiomyopathy in two regions of the United States. N Engl J Med. 2003;348(17):1647-1655. (Pubitemid 36459470)
2. Nugent AW, et al. The epidemiology of childhood cardiomyopathy in Australia. N Engl J Med. 2003;348(17):1639-1646. (Pubitemid 36459469)
3. Rose NR, Baughman KL. Myocarditis and dilated cardiomyopathy. In: Rose NR, Mackay IR, eds. The Autoimmune Diseases. Boston, Massachusetts, USA: Academic Press; 2006:875-888.
4. Strauss A, Lock JE. Pediatric cardiomyopathy - a long way to go. N Engl J Med. 2003;348(17):1703-1705. (Pubitemid 36459477)
5. Neu N, Rose NR, Beisel KW, Herskowitz A, Gurri-Glass G, Craig SW. Cardiac myosin induces myocarditis in genetically predisposed mice. J Immunol. 1987;139(11):3630-3636. (Pubitemid 18013633)
6. Smith SC, Allen PM. Myosin-induced acute myocarditis is a T cell-mediated disease. J Immunol. 1991;147(7):2141-2147.
7. Elliott JF, et al. Autoimmune cardiomyopathy and heart block develop spontaneously in HLA-DQ8 transgenic IAbeta knockout NOD mice. Proc Natl Acad Sci U S A. 2003;100(23):13447-13452. (Pubitemid 37444762)
8. Taylor JA, Havari E, McInerney MF, Bronson R, Wucherpfennig KW, Lipes MA. A spontaneous model for autoimmune myocarditis using the human MHC molecule HLA-DQ8. J Immunol. 2004;172(4):2651-2658. (Pubitemid 38182417)
9. Lappe JM, Pelfrey CM, Tang WH. Recent insights into the role of autoimmunity in idiopathic dilated cardiomyopathy. J Card Fail. 2008;14(6):521-530. (Pubitemid 352043841)
10. Neu 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(8):2488-2492. (Pubitemid 17051821)
11. Horwitz MS, La Cava A, Fine C, Rodriguez E, Ilic A, Sarvetnick N. Pancreatic expression of interferon-gamma protects mice from lethal coxsackievirus B3 infection and subsequent myocarditis. Nat Med. 2000;6(6):693-697. (Pubitemid 30398795)
12. Weiss A, Leinwand LA. The mammalian myosin heavy chain gene family. Annu Rev Cell Dev Biol. 1996;12:417-439. (Pubitemid 26422720)
13. Donermeyer DL, Beisel KW, Allen PM, Smith SC. Myocarditis-inducing epitope of myosin binds constitutively and stably to I-Ak on antigen-presenting cells in the heart. J Exp Med. 1995;182(5):1291-1300.
14. Pummerer CL, et al. Identification of cardiac myosin peptides capable of inducing autoimmune myocarditis in BALB/c mice. J Clin Invest. 1996;97(9):2057-2062.
15. Rose NR. Viral damage or 'molecular mimicry'-placing the blame in myocarditis. Nat Med. 2000;6(6):631-632. (Pubitemid 30398782)
16. Stewart GC, et al. Myocardial parvovirus B19 persistence: lack of association with clinicopathologic phenotype in adults with heart failure. Circ Heart Fail. 2011;4(1):71-78.
17. Frustaci A, Russo MA, Chimenti C. Randomized study on the efficacy of immunosuppressive therapy in patients with virus-negative inflammatory cardiomyopathy: the TIMIC study. Eur Heart J. 2009; 30(16):1995-2002.
18. Kyewski B, Klein L. A central role for central tolerance. Annu Rev Immunol. 2006;24:571-606.
19. Krenz M, et al. Analysis of myosin heavy chain functionality in the heart. J Biol Chem. 2003;278(19):17466-17474. (Pubitemid 36799633)
20. Giger JM, Haddad F, Qin AX, Baldwin KM. In vivo regulation of the beta-myosin heavy chain gene in soleus muscle of suspended and weight-bearing rats. Am J Physiol Cell Physiol. 2000;278(6):C1153-C1161.
21. Miyata S, Minobe W, Bristow MR, Leinwand LA. Myosin heavy chain isoform expression in the failing and nonfailing human heart. Circ Res. 2000;86(4):386-390. (Pubitemid 30141756)
22. Kurabayashi M, Tsuchimochi H, Komuro I, Takaku F, Yazaki Y. Molecular cloning and characterization of human cardiac alpha- and beta-form myosin heavy chain complementary DNA clones. Regulation of expression during development and pressure overload in human atrium. J Clin Invest. 1988;82(2):524-531.
23. Yang M, Charlton B, Gautam AM. Development of insulitis and diabetes in B cell-deficient NOD mice. J Autoimmun. 1997;10(3):257-260. (Pubitemid 27286532)
24. Hayward SL, Bautista-Lopez N, Suzuki K, Atrazhev A, Dickie P, Elliott JF. CD4 T cells play major effector role and CD8 T cells initiating role in spontaneous autoimmune myocarditis of HLA-DQ8 transgenic IAb knockout nonobese diabetic mice. J Immunol. 2006;176(12):7715-7725. (Pubitemid 43849072)
25. Jones WK, Sanchez A, Robbins J. Murine pulmonary myocardium: developmental analysis of cardiac gene expression. Dev Dyn. 1994;200(2):117-128. (Pubitemid 24190001)
26. Arif S, et al. Autoreactive T cell responses show proinflammatory polarization in diabetes but a regulatory phenotype in health. J Clin Invest. 2004;113(3):451-463. (Pubitemid 38544189)
27. Jaeckel E, Lipes MA, Von Boehmer H. Recessive tolerance to preproinsulin 2 reduces but does not abolish type 1 diabetes. Nat Immunol. 2004;5(10):1028-1035. (Pubitemid 41057722)
28. Derbinski J, et al. Promiscuous gene expression in thymic epithelial cells is regulated at multiple levels. J Exp Med. 2005;202(1):33-45. (Pubitemid 41002908)
29. Mahdavi V, Chambers AP, Nadal-Ginard B. Cardiac alpha- and beta-myosin heavy chain genes are organized in tandem. Proc Natl Acad Sci U S A. 1984;81(9):2626-2630.
30. Gardner JM, et al. Deletional tolerance mediated by extrathymic Aire-expressing cells. Science. 2008;321(5890):843-847.
31. Lee JW, et al. Peripheral antigen display by lymph node stroma promotes T cell tolerance to intestinal self. Nat Immunol. 2007;8(2):181-190.
32. Nichols LA, Chen Y, Colella TA, Bennett CL, Clausen BE, Engelhard VH. Deletional self-tolerance to a melanocyte/melanoma antigen derived from tyrosinase is mediated by a radio-resistant cell in peripheral and mesenteric lymph nodes. J Immunol. 2007;179(2):993-1003.
33. Fletcher AL, et al. Lymph node fibroblastic reticular cells directly present peripheral tissue antigen under steady-state and inflammatory conditions. J Exp Med. 2010;207(4):689-697.
34. Cohen JN, et al. Lymph node-resident lymphatic endothelial cells mediate peripheral tolerance via Aire-independent direct antigen presentation. J Exp Med. 2010;207(4):681-688.
35. Guerau-de-Arellano M, Martinic M, Benoist C, Mathis D. Neonatal tolerance revisited: a perinatal window for Aire control of autoimmunity. J Exp Med. 2009;206(6):1245-1252.
36. Witherden D, van Oers N, Waltzinger C, Weiss A, Benoist C, Mathis D. Tetracycline-controllable selection of CD4(+) T cells: half-life and survival signals in the absence of major histocompatibility complex class II molecules. J Exp Med. 2000;191(2):355-364. (Pubitemid 30060924)
37. Gotter J, Brors B, Hergenhahn M, Kyewski B. Medullary epithelial cells of the human thymus express a highly diverse selection of tissue-specific genes colocalized in chromosomal clusters. J Exp Med. 2004;199(2):155-166. (Pubitemid 38139246)
38. Haddad F, Bodell PW, Qin AX, Giger JM, Baldwin KM. Role of antisense RNA in coordinating cardiac myosin heavy chain gene switching. J Biol Chem. 2003;278(39):37132-37138. (Pubitemid 37175227)
39. Taneja V, et al. Spontaneous myocarditis mimicking human disease occurs in the presence of an appropriate MHC and non-MHC background in transgenic mice. J Mol Cell Cardiol. 2007;42(6):1054-1064. (Pubitemid 46829194)
40. Lompre AM, et al. Species- and age-dependent changes in the relative amounts of cardiac myosin isoenzymes in mammals. Dev Biol. 1981;84(2):286-290. (Pubitemid 11036284)
41. Pugliese A, et al. The insulin gene is transcribed in the human thymus and transcription levels correlated with allelic variation at the INS VNTR-IDDM2 susceptibility locus for type 1 diabetes. Nat Genet. 1997;15(3):293-297. (Pubitemid 27098726)
42. Vafiadis P, et al. Insulin expression in human thymus is modulated by INS VNTR alleles at the IDDM2 locus. Nat Genet. 1997;15(3):289-292. (Pubitemid 27098725)
43. Giraud M, et al. An IRF8-binding promoter variant and AIRE control CHRNA1 promiscuous expression in thymus. Nature. 2007;448(7156):934-937. (Pubitemid 47312776)
44. Liston A, et al. Gene dosage-limiting role of Aire in thymic expression, clonal deletion, and organ-specific autoimmunity. J Exp Med. 2004;200(8):1015-1026. (Pubitemid 39431126)
45. Liston A, Lesage S, Gray DH, Boyd RL, Goodnow CC. Genetic lesions in T-cell tolerance and thresholds for autoimmunity. Immunol Rev. 2005;204:87-101. (Pubitemid 40460495)
46. Hart DN, Fabre JW. Demonstration and characterization of Ia-positive dendritic cells in the interstitial connective tissues of rat heart and other tissues, but not brain. J Exp Med. 1981;154(2):347-361. (Pubitemid 11044167)
47. Smith 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 U S A. 1992;89(19):9131-9135.
48. Steinman RM, Hawiger D, Nussenzweig MC. Tolerogenic dendritic cells. Annu Rev Immunol. 2003;21:685-711. (Pubitemid 37174545)
49. Ono M, Shimizu J, Miyachi Y, Sakaguchi S. Control of autoimmune myocarditis and multiorgan inflammation by glucocorticoid-induced TNF receptor family-related protein(high), Foxp3-expressing CD25+ and CD25- regulatory T cells. J Immunol. 2006;176(8):4748-4756.
50. Aschenbrenner K, et al. Selection of Foxp3+ regulatory T cells specific for self antigen expressed and presented by Aire+ medullary thymic epithelial cells. Nat Immunol. 2007;8(4):351-358. (Pubitemid 46745410)
51. Bensinger SJ, Bandeira A, Jordan MS, Caton AJ, Laufer TM. Major histocompatibility complex class II-positive cortical epithelium mediates the selection of CD4(+)25(+) immunoregulatory T cells. J Exp Med. 2001;194(4):427-438. (Pubitemid 32835039)
52. Derbinski J, Kyewski B. How thymic antigen presenting cells sample the body's self-antigens. Curr Opin Immunol. 2010;22(5):592-600.
53. Bonasio R, Scimone ML, Schaerli P, Grabie N, Lichtman AH, von Andrian UH. Clonal deletion of thymocytes by circulating dendritic cells homing to the thymus. Nat Immunol. 2006;7(10):1092-1100. (Pubitemid 44420654)
54. Grabie N, et al. IL-12 is required for differentiation of pathogenic CD8+ T cell effectors that cause myocarditis. J Clin Invest. 2003;111(5):671-680. (Pubitemid 36278585)
55. Allen S, et al. Promiscuous thymic expression of an autoantigen gene does not result in negative selection of pathogenic T cells. J Immunol. 2005;175(9):5759-5764. (Pubitemid 41508059)
56. Huseby ES, Sather B, Huseby PG, Goverman J. Age-dependent T cell tolerance and autoimmunity to myelin basic protein. Immunity. 2001;14(4):471-481. (Pubitemid 32441599)
57. Elahi AW, Vijayakumar AN, Lichstein E, Mokhtarian F. Interplay of antibody and T cell responses in acute myocardial infarction. J Lab Clin Med. 2001;138(2):112-118. (Pubitemid 32696275)
58. Trudeau JD, Dutz JP, Arany E, Hill DJ, Fieldus WE, Finegood DT. Neonatal beta-cell apoptosis: a trigger for autoimmune diabetes? Diabetes. 2000;49(1):1-7.
59. Turley S, Poirot L, Hattori M, Benoist C, Mathis D. Physiological {beta} cell death triggers priming of self-reactive T cells by dendritic cells in a type-1 diabetes model. J Exp Med. 2003;198(10):1527-1537. (Pubitemid 37467167)
60. Webb GD, Smallhorn JF, Therrien J, Redington AN. Congenital heart disease. In: Zipes DP, Libby P, Bonow RO, Braunwald E, eds. Braunwald's Heart Disease. Philadelphia, Pennsylvania, USA: Elsevier Saunders; 2005:1489-1552.
61. Andrews RE, Fenton MJ, Ridout DA, Burch M. Newonset heart failure due to heart muscle disease in childhood: a prospective study in the United kingdom and Ireland. Circulation. 2008;117(1):79-84. (Pubitemid 350291184)
62. Lee K, Wucherpfennig K, Wiley D. Structure of a human insulin peptide-HLA-DQ8 complex and susceptibility to type 1 diabetes. Nat Immunol. 2001;2(6):501-507.
63. Suri A, Walters JJ, Gross ML, Unanue ER. Natural peptides selected by diabetogenic DQ8 and murine I-A molecules show common sequence specificity. J Clin Invest. 2005;115(8):2268-2276. (Pubitemid 41135930)
64. Yu B, Gauthier L, Hausmann DH, Wucherpfennig KW. Binding of conserved islet peptides by human and murine MHC class II molecules associated with susceptibility to type I diabetes. Eur J Immunol. 2000;30(9):2497-2506.
65. Baughman KL. Diagnosis of myocarditis: death of Dallas criteria. Circulation. 2006;113(4):593-595.
66. Abraham WT, et al. Coordinate changes in Myosin heavy chain isoform gene expression are selectively associated with alterations in dilated cardiomyopathy phenotype. Mol Med. 2002;8(11):750-760. (Pubitemid 36337501)
67. van Rooij E, Sutherland LB, Qi X, Richardson JA, Hill J, Olson EN. Control of stress-dependent cardiac growth and gene expression by a microRNA. Science. 2007;316(5824):575-579. (Pubitemid 46683138)
68. Havari E, et al. Expression of the B7.1 costimulatory molecule on pancreatic beta cells abrogates the requirement for CD4 T cells in the development of type 1 diabetes. J Immunol. 2004;173(2):787-796. (Pubitemid 38924253)