Autoimmunizing mechanisms in thymoma and thymus

Annals of the New York Academy of Sciences

Volumn 1132, Issue , 2008, Pages 163-173

  Willcox, Nick ^a   Leite, Maria Isabel ^a   Kadota, Yoshihisa ^a,f   Jones, Margaret ^b   Meager, Anthony ^c   Subrahmanyam, Peddasomayajula ^d   Dasgupta, Bhaskar ^d   Morgan, B Paul ^e   Vincent, Angela ^a  

^a UNIVERSITY OF OXFORD   (United Kingdom)

^b UNIVERSITY OF OXFORD   (United Kingdom)

^c NATIONAL INSTITUTE FOR BIOLOGICAL STANDARDS AND CONTROL   (United Kingdom)

^d BASILDON HOSPITAL   (United Kingdom)

^e CARDIFF UNIVERSITY   (United Kingdom)

^f OSAKA UNIVERSITY GRADUATE SCHOOL OF MEDICINE   (Japan)

Author keywords

Acetylcholine receptor; AIRE; Autoantibody; Autoimmune polyendocrine syndrome 1 (APS1 or APECED); Autoimmunization; Complement; Germinal center; Immunopathology; Myasthenia gravis; Self tolerance; Thymic deletion; Thymic hyperplasia; Thymoma; Thymus

Indexed keywords

ALPHA INTERFERON; AUTOANTIBODY; CHOLINERGIC RECEPTOR; COMPLEMENT; COMPLEMENT COMPONENT C3B; CORTICOSTEROID;

ANTIBODY SPECIFICITY; ANTIBODY TITER; AUTOIMMUNE POLYENDOCRINOPATHY CANDIDIASIS ECTODERMAL DYSTROPHY; AUTOIMMUNITY; B LYMPHOCYTE; CELL TYPE; CONFERENCE PAPER; GERMINAL CENTER; HELPER CELL; HUMAN; IMMUNOLOGICAL TOLERANCE; IMMUNOPATHOLOGY; MICROENVIRONMENT; MYASTHENIA GRAVIS; NONHUMAN; PROTEIN EXPRESSION; THYMECTOMY; THYMOCYTE; THYMOMA; THYMUS; THYMUS HYPERPLASIA; UPREGULATION;

MYOIDA;

EID: 45249108484     PISSN: 00778923     EISSN: 17496632     Source Type: Book Series    
DOI: 10.1196/annals.1405.021     Document Type: Conference Paper

References (71)

1. Tzartos, S.J., T. Barkas, M.T. Cung, et al. 1998. Anatomy of the antigenic structure of a large membrane autoantigen, the muscle-type nicotinic acetylcholine receptor. Immunol. Rev. 163 : 89 120.
2. Vincent A. 2002. Unravelling the pathogenesis of myasthenia gravis. Nat. Rev. Immunol. 2 : 797 804.
3. Schluep M., N. Willcox, A. Vincent, et al. 1987. Acetyl-choline receptors in human thymic myoid cells in situ: an immunohistological study. Ann. Neurol. 22 : 212 222.
4. Wakkach, A., T. Guyon, C. Bruand, et al. 1996. Expression of acetylcholine receptor genes in human thymic epithelial cells: implications for myasthenia gravis. J. Immunol. 157 : 3752 3760.
5. Andreetta, F., F. Baggi, C. Antozzi, et al. 1997. Acetylcholine receptor alpha-subunit isoforms are differentially expressed in thymuses from myasthenic patients. Am. J. Pathol. 150 : 341 348.
6. MacLennan, C.A., D. Beeson, N. Willcox, et al. 1998. Muscle nicotinic acetylcholine receptor mRNA expression in hyperplastic and neoplastic myasthenia gravis thymus. Ann. N.Y. Acad. Sci. 841 : 407 410.
7. Taubert, R., J. Schwendemann & B. Kyewski. 2007. Highly variable expression of tissue-restricted self-antigens in human thymus: implications for self-tolerance and autoimmunity. Eur. J. Immunol. 37 : 838 848.
8. Giraud, M., R. Taubert, C. Vandiedonck, et al. 2007. An IRF8-binding promoter variant and AIRE control CHRNA1 promiscuous expression in thymus. Nature 448 : 934 937.
9. Giraud, M., C. Vandiedorck & H.-J. Garchon. 2008. Genetic factors in autoimmune myasthenia gravis. Ann. N.Y. Acad. Sci. Myasthenia Gravis and Related Disorders: 11th International Conference. In Press.
10. Kyewski, B. & L. Klein. 2006. A central role for central tolerance. Annu. Rev. Immunol. 24 : 571 606.
11. Matsuo, H., A.-P. Batocchi, S. Hawke, et al. 1995. Peptide-selected T cell lines from myasthenia gravis patients and controls recognize epitopes that are not processed from whole acetylcholine receptor. J. Immunol. 155 : 3683 3692.
12. Nagvekar, N., L. Corlett, L.W. Jacobson, et al. 1999. Scanning a DRB3*0101 (DR52a)-restricted AChR epitope cross-presented by DR3. J. Immunol. 162 : 4079 4087.
13. Diethelm-Okita, B., G.B. Wells, A. Kuryatov, et al. 1998. Response of CD4+ T cells from myasthenic patients and healthy subjects of biosynthetic and synthetic sequences of the nicotinic acetylcholine receptor. J. Autoimmun. 11 : 191 203.
14. Nakano, S. & A.G. Engel. 1993. Myasthenia gravis: quantitative immunocytochemical analysis of inflammatory cells and detection of complement membrane attack complex at the end-plate in 30 patients. Neurology 43 : 1167 1172.
15. Castleman, B & E.H. Norris. 1949. The pathology of the thymus in myasthenia gravis: a study of 35 cases. Medicine 28 : 27 58.
16. Roxanis, I., K. Micklem & N. Willcox. 2001. True epithelial hyperplasia in the thymus of early-onset myasthenia gravis patients: implications for immunopathogenesis. J. Neuroimmunol. 112 : 163 173.
17. Bofill, M., G. Janossy, N. Willcox, et al. 1985. Microenvironments in the normal thymus and the thymus in myasthenia gravis. Am. J. Pathol. 119 : 462 473.
18. Roxanis, I., K. Micklem, J. McConville, et al. 2002. Thymic myoid cells and germinal center formation in myasthenia gravis; possible roles in pathogenesis. J. Neuroimmunol. 125 : 185 197.
19. Shiono, H., I. Roxanis, W. Zhang, et al. 2003. Scenarios for autoimmunization of T and B cells in myasthenia gravis. Ann. N.Y. Acad Sci. 998 : 237 256.
20. Willcox, N., M. Schluep, M.A. Ritter, et al. 1987. Myasthenic and nonmyasthenic thymoma. An expansion of a minor cortical epithelial cell subset? Am. J. Pathol. 127 : 447 460.
21. Aarli, J.A., K. Stefansson, L.S. Marton, et al. 1990. Patients with myasthenia gravis and thymoma have in their sera IgG autoantibodies against titin. Clin. Exp. Immunol. 82 : 284 288.
22. Mygland, Å., O.B. Tysnes, R. Matre, et al. 1992. Ryanodine receptor autoantibodies in myasthenia gravis patients with a thymoma. Ann. Neurol. 32 : 589 591.
23. Kadota, Y., M. Okumura, S. Miyoshi, et al. 2000. Altered T cell development in human thymoma is related to impairment of MHC class II transactivator expression induced by interferon-gamma (IFN-gamma). Clin. Exp. Immunol. 121 : 59 68.
24. Souadjian. J.V., P. Enriquez, M.N. Silverstein, et al. 1974. The spectrum of diseases associated with thymoma. Coincidence or syndrome? Arch. Intern. Med. 134 : 374 379.
25. Willcox, N. 1993. Myasthenia gravis. Curr. Opin. Immunol. 5 : 910 917.
26. Romi F, L. Bo, G.O. Skeie, et al. 2002. Titin and ryanodine receptor epitopes are expressed in cortical thymoma along with costimulatory molecules. J. Neuroimmunol. 128 : 82 89.
27. Meager, A., M. Wadhwa, P. Dilger, et al. 2003. Anti-cytokine autoantibodies in autoimmunity: preponderance of neutralizing autoantibodies against interferon-alpha, interferon-omega and interleukin-12 in patients with thymoma and/or myasthenia gravis. Clin. Exp. Immunol. 132 : 128 136.
28. Buckley, C., J. Newsom-Davis, N. Willcox, et al. 2001. Do titin and cytokine anti-bodies in MG patients predict thymoma or thymoma recurrence? Neurology 57 : 1579 1582.
29. Shiono, H., Y.-L. Wong, I. Matthews, et al. 2003. Spontaneous production of anti-IFN-α and anti-IL-12 autoantibodies by thymoma cells from myasthenia gravis patients suggests autoimmunization in the tumor. Internat. Immunol. 15 : 903 913.
30. Ronnblom, L., M.L. Eloranta & G.V. Alm. 2006. The type I interferon system in systemic lupus erythematosus. Arthritis Rheum. 54 : 408 420.
31. Pascual, V., L. Farkas & J. Banchereau. 2006. Systemic lupus erythematosus: all roads lead to type I interferons. Curr. Opin. Immunol. 18 : 676 682.
32. Bauer, J.W., E.C. Baechler, M. Petri, et al. 2006. Elevated serum levels of interferon-regulated chemokines are biomarkers for active human systemic lupus erythematosus. PLoS Med. 2006 Dec 19 3 : e491.
33. Foulis, A.K., M.A. Farquharson & A. Meager. 1987. Immunoreactive alpha-interferon in insulin-secreting beta cells in type 1 diabetes mellitus. Lancet 2 : 1423 1427.
34. Ma-Krupa, W., M.S. Jeon, S. Spoerl, et al. 2004. Activation of arterial wall dendritic cells and breakdown of self-tolerance in giant cell arteritis. J. Exp. Med. 199 : 173 183.
35. Meager, A., K. Visvalingam, P. Peterson, et al. 2006. Anti-interferon autoantibodies in autoimmune polyendocrinopathy syndrome type 1. PLoS Med. Jun 13 3 : e289 (pp 1 13).
36. Perheentupa, J. 2006. Autoimmune polyendocrinopathy-candidiasis- ectodermal dystrophy. J. Clin. Endocrinol. Metab. 91 : 2843 2850.
37. Zhang, W., J.-L. Liu, A. Meager, et al. 2003. Autoantibodies to IL-12 in myasthenia gravis patients with thymoma; effects on the IFN-γ responses of healthy CD4+ T cells. J. Neuroimmunol. 139 : 102 108.
38. Nagafuchi S., K. Umene, F. Yamanaka, et al. 2007. Recurrent herpes simplex virus infection in a patient with auto-immune polyendocrino-pathy- candidiasis-ectodermal dystrophy associated with L29P and IVS9-1G>C compound heterozygous autoimmune regulator gene mutations. J. Intern. Med. 261 : 605 610.
39. Weigert M. & M. Potter. 1977. Antibody variable region genetics; summary and abstracts of the homogeneous immunoglobulin workshop. Immunogenetics 4 : 401 435.
40. Flohr, F., S. Schneider-Schaulies, O. Haller, et al. 1999. The central interactive region of human MxA GTPase is involved in GTPase activation and interaction with viral target structures. FEBS Lett. 463 : 24 28.
41. Ströbel, P., A. Murumagi, R. Klein, et al. 2007. Deficiency of the autoimmune regulator AIRE in thymomas is insufficient to elicit autoimmune polyendocrinopathy syndrome type 1 (APS-1). J. Pathol. 211 : 563 571.
42. Scarpino S., A. Di Napoli, A. Stoppacciaro, et al. 2007. Expression of autoimmune regulator gene (AIRE) and T regulatory cells in human thymomas. Clin Exp Immunol. 149 : 504 512.
43. Anderson, M.S., E.S. Venanzi, L. Klein, et al. 2002. Projection of an immunological self shadow within the thymus by the aire protein. Science 298 : 1395 1401.
44. Derbinski, J., J. Gabler, B. Brors, et al. 2005. Promiscuous gene expression in thymic epithelial cells is regulated at multiple levels. J. Exp. Med. 202, 33 45.
45. Mathis D & C Benoist. 2007. A decade of AIRE. Nat. Revs. Immunol. 7 : 645 650.
46. Hoch W., J. McConville, S. Helms, et al. 2001. Auto-antibodies to the receptor tyrosine kinase MuSK in patients with myasthenia gravis without acetylcholine receptor antibodies. Nat. Med. 7 : 365 368.
47. Leite MI, P. Strobel, M. Jones, et al. 2005. Fewer thymic changes in MuSK antibody-positive than in MuSK antibody-negative MG. Ann. Neurol. 57 : 444 448.
48. Leite, M.I., M. Jones, P. Ströbel, et al. 2007. Myasthenia gravis thymus: complement vulnerability of epithelial and myoid cells, complement attack on them, and correlations with autoantibody status. Am. J. Pathol. 171 : 893 905.
49. Engel, A.G., E.H. Lambert & F.M. Howard. 1977. Immune complexes (IgG and C3) at the motor end-plate in myasthenia gravis: ultrastructural and light microscopic localization and electrophysiologic correlations. Mayo Clin. Proc. 52 : 267 280.
50. Safar, D., C. Aimé, S. Cohen-Kaminsky, et al. 1991. Antibodies to thymic epithelial cells in myasthenia gravis. J. Neuroimmunol. 35 : 101 110.
51. Daveau, M., M. Benard, M. Scotte, et al. 2004. Expression of a functional C5a receptor in regenerating hepatocytes and its involvement in a proliferative signaling pathway in rat. J. Immunol. 173 : 3418 3424.
52. Cole, D.S. & B.P. Morgan. 2004. Beyond lysis: how complement influences cell fate. Clin. Sci. (Lond.) 104 : 455 466.
53. Dashiell S.M., H. Rus & C.L. Koski. 2000. Terminal complement complexes concomitantly stimulate proliferation and rescue of Schwann cells from apoptosis. Glia 30 : 187 198.
54. Wekerle, H. & U.P. Ketelsen. 1977. Intrathymic pathogenesis and dual genetic control of myasthenia gravis. Lancet 1 : 678 680.
55. Lauriola, L., F. Ranelletti, N. Maggiano, et al. 2005. Thymus changes in anti-MuSK-positive and -negative myasthenia gravis. Neurology 64 : 536 538.
56. Vincent, A., M.I. Leite, M.E. Farrugia, et al. 2008. Antibodies in myasthenia gravis without acetylcholine receptor antibodies. Ann. N.Y. Acad. Sci. Myasthenia Gravis and Related Disorders: 11th International Conference. In Press.
57. Aloisi F. & R. Pujol-Borrell. 2006. Lymphoid neogenesis in chronic inflammatory diseases. Nat. Rev. Immunol. 6 : 205 217.
58. Drayton D.L., S. Liao, R.H. Mounzer, et al. 2006. Lymphoid organ development: from ontogeny to neogenesis. Nat. Immunol. 7 : 344 353.
59. Vandiedonck, C., M. Giraud & H.-J. Garchon. 2005. Genetics of autoimmune myasthenia gravis: the multifaceted contribution of the HLA complex. J. Autoimmun. 25 : 6 11.
60. Vafiadis, P., S.T. Bennett, J.A. Todd, et al. 1997. Insulin expression in human thymus is modulated by INS VNTR alleles at the IDDM2 locus. Nat. Genet. 15 : 289 292.
61. Pugliese, A., M. Zeller, A. Fernandez, et al. 1997. 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. 15 : 293 297.
62. Yamanouchi, J., D. Rainbow, P. Serra, et al. 2007. Interleukin-2 gene variation impairs regulatory T cell function and causes autoimmunity. Nat. Genet. 39 : 329 337.
63. Vincent, A., N. Willcox, M. Hill, et al. 1999. Determinant spreading and immune responses to acetylcholine receptors in myasthenia gravis. Immunol. Revs. 164 : 157 168.
64. Spreadbury I., U. Kishore, D. Beeson, et al. 2005. Inhibition of acetylcholine receptor function by seronegative myasthenia gravis non-IgG factor correlates with desensitisation. J Neuroimmunol. 62 : 149 156.
65. Hill, M., D. Beeson, P. Moss, et al. 1999. Early-onset myasthenia gravis: a recurring T-cell epitope in the adult-specific acetylcholine receptor e subunit presented by the susceptibility allele HLA-DR52a. Ann. Neurol. 45 : 224 231.
66. Meraouna, A., G. Cizeron-Clairac, R. LePanse, et al. 2006. The chemokine CXCL13 is a key molecule in autoimmune myasthenia gravis. Blood 108 : 432 440.
67. Klaus, G.G., J.H. Humphrey, A. Kunkl, et al. 1980. The follicular dendritic cell: its role in antigen presentation in the generation of immunological memory. Immunol. Revs. 53 : 3 28.
68. MacLennan, I.C. 1994. Germinal centers. Annu. Rev. Immunol. 12 : 117 139.
69. Graus, Y.F., M.H. de Baets, P.W. Parren, et al. 1997. Human anti-nicotinic acetyl-choline receptor recombinant Fab fragments isolated from thymus-derived phage display libraries from myasthenia gravis patients reflect predominant specificities in serum and block the action of pathogenic serum antibodies. J. Immunol. 158 : 1919 1929.
70. Matthews, I., G.P. Sims, S. Ledwidge, et al. 2002. Antibodies to human acetylcholine receptor in parous women: evidence for immunization by fetal antigen. Lab. Invest. 82 : 1407 1417.
71. Sims, GP., H. Shiono, N. Willcox, et al. 2001. Somatic hypermutation and selection of B cells in thymic germinal centers responding to acetylcholine receptor in myasthenia gravis. J. Immunol. 167 : 1935 1944.