Clinical and serologic parallels to APS-I in patients with thymomas and autoantigen transcripts in their tumors

Journal of Immunology

Volumn 193, Issue 8, 2014, Pages 3880-3890

  Wolff, Anette S B ^a   Kärner, Jaanika ^b   Owe, Jone F ^a,c   Oftedal, Bergithe E V ^a   Gilhus, Nils Erik ^a,c   Erichsen, Martina M ^c   Kämpe, Olle ^d   Meager, Anthony ^e   Peterson, Pärt ^b   Kisand, Kai ^b   Willcox, Nick ^f   Husebye, Eystein S ^a,c  

^a UNIVERSITY OF BERGEN   (Norway)

^b UNIVERSITY OF TARTU   (Estonia)

^c HAUKELAND UNIVERSITY HOSPITAL   (Norway)

^d KAROLINSKA UNIVERSITY HOSPITAL   (Sweden)

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

^f UNIVERSITY OF OXFORD   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

AUTOANTIBODY; AUTOANTIGEN; AUTOIMMUNE REGULATOR PROTEIN; INTERFERON; INTERLEUKIN 17; INTERLEUKIN DERIVATIVE; INTERLEUKIN-22; TRANSCRIPTION FACTOR;

ADRENAL INSUFFICIENCY; ADULT; AGED; AIRE GENE; ARTICLE; ASPLENIA; AUTOIMMUNE POLYENDOCRINOPATHY CANDIDIASIS ECTODERMAL DYSTROPHY; CLINICAL FEATURE; CONTROLLED STUDY; FEMALE; GENE MUTATION; GENETIC TRANSCRIPTION; HUMAN; HUMAN TISSUE; MAJOR CLINICAL STUDY; MALE; MUCOCUTANEOUS CANDIDIASIS; MYASTHENIA GRAVIS; THYMOMA; BLOOD; GENETICS; HETEROTAXY SYNDROME; HYPOPARATHYROIDISM; IMMUNOLOGY; MIDDLE AGED; POLYENDOCRINOPATHY;

ADRENAL INSUFFICIENCY; ADULT; AUTOANTIBODIES; AUTOANTIGENS; CANDIDIASIS, CHRONIC MUCOCUTANEOUS; FEMALE; HETEROTAXY SYNDROME; HUMANS; HYPOPARATHYROIDISM; INTERFERON TYPE I; INTERLEUKIN-17; INTERLEUKINS; MALE; MIDDLE AGED; MYASTHENIA GRAVIS; POLYENDOCRINOPATHIES, AUTOIMMUNE; THYMOMA; THYMUS NEOPLASMS; TRANSCRIPTION FACTORS;

EID: 84907481828     PISSN: 00221767     EISSN: 15506606     Source Type: Journal    
DOI: 10.4049/jimmunol.1401068     Document Type: Article

References (67)

1. Finnish-German APECED Consortium. 1997. An autoimmune disease, APECED, caused by mutations in a novel gene featuring two PHD-type zincfinger domains. Nat. Genet. 17: 399-403.
2. Nagamine, K., P. Peterson, H. S. Scott, J. Kudoh, S. Minoshima, M. Heino, K. J. Krohn, M. D. Lalioti, P. E. Mullis, S. E. Antonarakis, et al. 1997. Positional cloning of the APECED gene. Nat. Genet. 17: 393-398.
3. Anderson, M. S., E. S. Venanzi, L. Klein, Z. Chen, S. P. Berzins, S. J. Turley, H. von Boehmer, R. Bronson, A. Dierich, C. Benoist, and D. Mathis. 2002. Projection of an immunological self shadow within the thymus by the aire protein. Science 298: 1395-1401.
4. Husebye, E. S., J. Perheentupa, R. Rautemaa, and O. Kämpe. 2009. Clinical manifestations and management of patients with autoimmune polyendocrine syndrome type I. J. Intern. Med. 265: 514-529.
5. Perheentupa, J. 2006. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. J. Clin. Endocrinol. Metab. 91: 2843-2850.
6. Alimohammadi, M., P. Björklund, A. Hallgren, N. Pöntynen, G. Szinnai, N. Shikama, M. P. Keller, O. Ekwall, S. A. Kinkel, E. S. Husebye, et al. 2008. Autoimmune polyendocrine syndrome type 1 and NALP5, a parathyroid autoantigen. N. Engl. J. Med. 358: 1018-1028.
7. Söderbergh, A., A. G. Myhre, O. Ekwall, G. Gebre-Medhin, H. Hedstrand, E. Landgren, A. Miettinen, P. Eskelin, M. Halonen, T. Tuomi, et al. 2004. Prevalence and clinical associations of 10 defined autoantibodies in autoimmune polyendocrine syndrome type I. J. Clin. Endocrinol. Metab. 89: 557-562.
8. Söderbergh, A., F. Rorsman, M. Halonen, O. Ekwall, P. Björses, O. Kämpe, and E. S. Husebye. 2000. Autoantibodies against aromatic L-amino acid decarboxylase identifies a subgroup of patients with Addison's disease. J. Clin. Endocrinol. Metab. 85: 460-463.
9. Winqvist, O., G. Gebre-Medhin, J. Gustafsson, E. M. Ritzén, O. Lundkvist, F. A. Karlsson, and O. Kämpe. 1995. Identification of the main gonadal autoantigens in patients with adrenal insufficiency and associated ovarian failure. J. Clin. Endocrinol. Metab. 80: 1717-1723.
10. Winqvist, O., F. A. Karlsson, and O. Kämpe. 1992. 21-Hydroxylase, a major autoantigen in idiopathic Addison's disease. Lancet 339: 1559-1562.
11. Meager, A., K. Visvalingam, P. Peterson, K. Möll, A. Murumägi, K. Krohn, P. Eskelin, J. Perheentupa, E. Husebye, Y. Kadota, and N. Willcox. 2006. Antiinterferon autoantibodies in autoimmune polyendocrinopathy syndrome type 1. PLoS Med. 3: e289.
12. Meloni, A., M. Furcas, F. Cetani, C. Marcocci, A. Falorni, R. Perniola, M. Pura, A. S. Bøe Wolff, E. S. Husebye, D. Lilic, et al. 2008. Autoantibodies against type I interferons as an additional diagnostic criterion for autoimmune polyendocrine syndrome type I. J. Clin. Endocrinol. Metab. 93: 4389-4397.
13. Oftedal,B. E., A. S. BoeWolff, E. Bratland, O. Kämpe, J. Perheentupa, A. G.Myhre, A. Meager, R. Purushothaman, S. Ten, and E. S. Husebye. 2008. Radioimmunoassay for autoantibodies against interferon omega; its use in the diagnosis of autoimmune polyendocrine syndrome type I. Clin. Immunol. 129: 163-169.
14. Kisand, K., A. S. Bøe Wolff, K. T. Podkrajsek, L. Tserel, M. Link, K. V. Kisand, E. Ersvaer, J. Perheentupa, M. M. Erichsen, N. Bratanic, et al. 2010. Chronic mucocutaneous candidiasis in APECED or thymoma patients correlates with autoimmunity to Th17-associated cytokines. J. Exp. Med. 207: 299-308.
15. Puel, A., R. Dö ffinger, A. Natividad, M. Chrabieh, G. Barcenas-Morales, C. Picard, A. Cobat, M. Ouachée-Chardin, A. Toulon, J. Bustamante, et al. 2010. Autoantibodies against IL-17A, IL-17F, and IL-22 in patients with chronic mucocutaneous candidiasis and autoimmune polyendocrine syndrome type I. J. Exp. Med. 207: 291-297.
16. Aarli, J. A., K. Stefansson, L. S. Marton, and R. L. Wollmann. 1990. Patients with myasthenia gravis and thymoma have in their sera IgG autoantibodies against titin. Clin. Exp. Immunol. 82: 284-288.
17. Marx, A., N. Willcox, M. I. Leite, W. Y. Chuang, B. Schalke, W. Nix, and P. Ströbel. 2010. Thymoma and paraneoplastic myasthenia gravis. Autoimmunity 43: 413-427.
18. Skeie, G. O., J. A. Aarli, and N. E. Gilhus. 2006. Titin and ryanodine receptor antibodies in myasthenia gravis. Acta Neurol. Scand. Suppl. 183: 19-23.
19. Vrolix, K., J. Fraussen, P. C. Molenaar, M. Losen, V. Somers, P. Stinissen, M. H. De Baets, and P. Martínez-Martínez. 2010. The auto-antigen repertoire in myasthenia gravis. Autoimmunity 43: 380-400.
20. Beekman, R., J. B. Kuks, and H. J. Oosterhuis. 1997. Myasthenia gravis: diagnosis and follow-up of 100 consecutive patients. J. Neurol. 244: 112-118.
21. Gaman, A., G. Gaman, and A. Bold. 2009. Acquired aplastic anemia: correlation between etiology, pathophysiology, bone marrow histology and prognosis factors. Rom. J. Morphol. Embryol. 50: 669-674.
22. Oosterhuis, H. J., T. E. Feltkamp, A. L. van Rossum, P. M. van den Berg-Loonen, and L. E. Nijenhuis. 1976. HL-A antigens, autoantibody production, and associated diseases in thymoma patients, with and without myasthenia gravis. Ann. N. Y. Acad. Sci. 274: 468-474.
23. Souadjian, J. V., P. Enriquez, M. N. Silverstein, and J. M. Pépin. 1974. The spectrum of diseases associated with thymoma. Coincidence or syndrome? Arch. Intern. Med. 134: 374-379.
24. Hapnes, L., N. Willcox, B. E. Oftedal, J. F. Owe, N. E. Gilhus, A. Meager, E. S. Husebye, and A. S. Wolff. 2012. Radioligand-binding assay reveals distinct autoantibody preferences for type I interferons in APS I and myasthenia gravis subgroups. J. Clin. Immunol. 32: 230-237.
25. Meager, A., M. Wadhwa, P. Dilger, C. Bird, R. Thorpe, J. Newsom-Davis, and N. Willcox. 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.
26. Kärner, J., A. Meager, M. Laan, J. Maslovskaja, M. Pihlap, A. Remm, E. Juronen, A. S. Wolff, E. S. Husebye, K. T. Podkrajšek, et al. 2013. Anticytokine autoantibodies suggest pathogenetic links with autoimmune regulator deficiency in humans and mice. Clin. Exp. Immunol. 171: 263-272.
27. Cheng, M. H., U. Fan, N. Grewal, M. Barnes, A. Mehta, S. Taylor, E. S. Husebye, E. J. Murphy, and M. S. Anderson. 2010. Acquired autoimmune polyglandular syndrome, thymoma, and an AIRE defect. N. Engl. J. Med. 362: 764-766.
28. Scherbaum, W. A., F. Schumm, B. Maisch, C. Müller, A. Fateh-Moghadam, S. H. Flüchter, F. J. Seif, G. F. Bottazzo, and P. A. Berg. 1983. Myasthenia gravis: overlap with 'polyendocrine' autoimmunity. Klin. Wochenschr. 61: 509-515.
29. Seker, M., H. I. Gozu, B. B. Oven Ustaalioglu, B. Sonmez, F. Y. Erkal, M. Kocak, N. O. Barisik, E. Orbay, M. Sargin, H. Sargin, et al. 2009. Myasthenia gravis and autoimmune Addison disease in a patient with thymoma. Clin. Lung Cancer 10: 367-370.
30. Qiao, J., G. Zhou, Y. Ding, D. Zhu, and H. Fang. 2011. Multiple paraneoplastic syndromes: myasthenia gravis, vitiligo, alopecia areata, and oral lichen planus associated with thymoma. J. Neurol. Sci. 308: 177-179.
31. Scarpino, S., A. Di Napoli, A. Stoppacciaro, M. Antonelli, E. Pilozzi, R. Chiarle, G. Palestro, M. Marino, F. Facciolo, E. A. Rendina, et al. 2007. Expression of autoimmune regulator gene (AIRE) and T regulatory cells in human thymomas. Clin. Exp. Immunol. 149: 504-512.
32. Ströbel, P., A. Murumägi, R. Klein, M. Luster, M. Lahti, K. Krohn, B. Schalke, W. Nix, R. Gold, P. Rieckmann, 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.
33. Kisand, K., D. Lilic, J. L. Casanova, P. Peterson, A. Meager, and N. Willcox. 2011. Mucocutaneous candidiasis and autoimmunity against cytokines in APECED and thymoma patients: clinical and pathogenetic implications. Eur. J. Immunol. 41: 1517-1527.
34. Willcox, N., M. Schluep, M. A. Ritter, H. J. Schuurman, J. Newsom-Davis, and B. Christensson. 1987. Myasthenic and nonmyasthenic thymoma. An expansion of a minor cortical epithelial cell subset? Am. J. Pathol. 127: 447-460.
35. Wolff, A. S., M. M. Erichsen, A. Meager, N. F. Magitta, A. G. Myhre, J. Bollerslev, K. J. Fougner, K. Lima, P. M. Knappskog, and E. S. Husebye. 2007. Autoimmune polyendocrine syndrome type 1 in Norway: phenotypic variation, autoantibodies, and novel mutations in the autoimmune regulator gene. J. Clin. Endocrinol. Metab. 92: 595-603.
36. Masunaga, A., I. Sugawara, H. Nakamura, T. Yoshitake, and S. Itoyama. 1997. Cytokeratin expression in normal human thymus at different ages. Pathol. Int. 47: 842-847.
37. Shezen, E., E. Okon, H. Ben-Hur, and O. Abramsky. 1995. Cytokeratin expression in human thymus: immunohistochemical mapping. Cell Tissue Res. 279: 221-231.
38. Willcox, N., M. I. Leite, Y. Kadota, M. Jones, A. Meager, P. Subrahmanyam, B. Dasgupta, B. P. Morgan, and A. Vincent. 2008. Autoimmunizing mechanisms in thymoma and thymus. Ann. N. Y. Acad. Sci. 1132: 163-173.
39. Boonen, A., R. Rennenberg, and S. van der Linden. 2000. Thymoma-associated systemic lupus erythematosus, exacerbating after thymectomy. A case report and review of the literature. Rheumatology (Oxford) 39: 1044-1046.
40. Klein, R., A. Marx, P. Ströbel, B. Schalke, W. Nix, and N. Willcox. 2013. Autoimmune associations and autoantibody screening show focused recognition in patient subgroups with generalized myasthenia gravis. Hum. Immunol. 74: 1184-1193.
41. Erichsen, M. M., K. Løvås, B. Skinningsrud, A. B. Wolff, D. E. Undlien, J. Svartberg, K. J. Fougner, T. J. Berg, J. Bollerslev, B. Mella, et al. 2009. Clinical, immunological, and genetic features of autoimmune primary adrenal insufficiency: observations from a Norwegian registry. J. Clin. Endocrinol. Metab. 94: 4882-4890.
42. Lima, K., T. G. Abrahamsen, A. B. Wolff, E. Husebye, M. Alimohammadi, O. Kämpe, and I. Følling. 2011. Hypoparathyroidism and autoimmunity in the 22q11.2 deletion syndrome. Eur. J. Endocrinol. 165: 345-352.
43. De Ravin, S. S., E. W. Cowen, K. A. Zarember, N. L. Whiting-Theobald, D. B. Kuhns, N. G. Sandler, D. C. Douek, S. Pittaluga, P. L. Poliani, Y. N. Lee, et al. 2010. Hypomorphic Rag mutations can cause destructive midline granulomatous disease. Blood 116: 1263-1271.
44. Chen, K., W. Wu, D. Mathew, Y. Zhang, S. K. Browne, L. B. Rosen, M. P. McManus, M. A. Pulsipher, M. Yandell, J. F. Bohnsack, L. B. Jorde, L. D. Notarangelo, and J. E. Walter. 2014. Autoimmunity due to RAG deficiency and estimated disease incidence in RAG1/2 mutations. J. Allergy Clin. Immunol. 133:880-882 e810.
45. Bratland, E., B. Skinningsrud, D. E. Undlien, E. Mozes, and E. S. Husebye. 2009. T cell responses to steroid cytochrome P450 21-hydroxylase in patients with autoimmune primary adrenal insufficiency. J. Clin. Endocrinol. Metab. 94: 5117-5124.
46. Hedstrand, H., O. Ekwall, J. Haavik, E. Landgren, C. Betterle, J. Perheentupa, J. Gustafsson, E. Husebye, F. Rorsman, and O. Kämpe. 2000. Identification of tyrosine hydroxylase as an autoantigen in autoimmune polyendocrine syndrome type I. Biochem. Biophys. Res. Commun. 267: 456-461.
47. Guerau-de-Arellano, M., M. Martinic, C. Benoist, and D. Mathis. 2009. Neonatal tolerance revisited: a perinatal window for Aire control of autoimmunity. J. Exp. Med. 206: 1245-1252.
48. Gardner, J. M., J. J. Devoss, R. S. Friedman, D. J. Wong, Y. X. Tan, X. Zhou, K. P. Johannes, M. A. Su, H. Y. Chang, M. F. Krummel, and M. S. Anderson. 2008. Deletional tolerance mediated by extrathymic Aire-expressing cells. Science 321: 843-847.
49. Gardner, J. M., T. C. Metzger, E. J. McMahon, B. B. Au-Yeung, A. K. Krawisz, W. Lu, J. D. Price, K. P. Johannes, A. T. Satpathy, K. M. Murphy, et al. 2013. Extrathymic Aire-expressing cells are a distinct bone marrow-derived population that induce functional inactivation of CD4+ T cells. Immunity 39: 560-572.
50. Kekäläinen, E., A. Miettinen, and T. P. Arstila. 2007. Does the deficiency of Aire in mice really resemble human APECED? Nat. Rev. Immunol. 7: 1.
51. Ströbel, P., A. Rosenwald, N. Beyersdorf, T. Kerkau, O. Elert, A. Murumägi, N. Sillanpää, P. Peterson, V. Hummel, P. Rieckmann, et al. 2004. Selective loss of regulatory T cells in thymomas. Ann. Neurol. 56: 901-904.
52. Wang, X., M. Laan, R. Bichele, K. Kisand, H. S. Scott, and P. Peterson. 2012. Post-Aire maturation of thymic medullary epithelial cells involves selective expression of keratinocyte-specific autoantigens. Front. Immunol. 3: 19.
53. Kekäläinen, E., H. Tuovinen, J. Joensuu, M. Gylling, R. Franssila, N. Pöntynen, K. Talvensaari, J. Perheentupa, A. Miettinen, and T. P. Arstila. 2007. A defect of regulatory T cells in patients with autoimmune polyendocrinopathy-candidiasisectodermal dystrophy. J. Immunol. 178: 1208-1215.
54. Laakso, S. M., T. T. Laurinolli, L. H. Rossi, A. Lehtoviita, H. Sairanen, J. Perheentupa, E. Kekäläinen, and T. P. Arstila. 2010. Regulatory T cell defect in APECED patients is associated with loss of naive FOXP3(+) precursors and impaired activated population. J. Autoimmun. 35: 351-357.
55. Ryan, K. R., C. A. Lawson, A. R. Lorenzi, P. D. Arkwright, J. D. Isaacs, and D. Lilic. 2005. CD4+CD25+ T-regulatory cells are decreased in patients with autoimmune polyendocrinopathy candidiasis ectodermal dystrophy. J. Allergy Clin. Immunol. 116: 1158-1159.
56. Wolff, A. S., B. E. Oftedal, K. Kisand, E. Ersvaer, K. Lima, and E. S. Husebye. 2010. Flow cytometry study of blood cell subtypes reflects autoimmune and inflammatory processes in autoimmune polyendocrine syndrome type I. Scand. J. Immunol. 71: 459-467.
57. Kyewski, B., and L. Klein. 2006. A central role for central tolerance. Annu. Rev. Immunol. 24: 571-606.
58. Inoue, M., P. Starostik, A. Zettl, P. Ströbel, S. Schwarz, F. Scaravilli, K. Henry, N. Willcox, H. K. Müller-Hermelink, and A. Marx. 2003. Correlating genetic aberrations with World Health Organization-defined histology and stage across the spectrum of thymomas. Cancer Res. 63: 3708-3715.
59. Derbinski, J., and B. Kyewski. 2010. How thymic antigen presenting cells sample the body's self-antigens. Curr. Opin. Immunol. 22: 592-600.
60. Taubert, R., J. Schwendemann, and B. Kyewski. 2007. Highly variable expression of tissue-restricted self-antigens in human thymus: implications for selftolerance and autoimmunity. Eur. J. Immunol. 37: 838-848.
61. Giraud, M., R. Taubert, C. Vandiedonck, X. Ke, M. Lévi-Strauss, F. Pagani, F. E. Baralle, B. Eymard, C. Tranchant, P. Gajdos, et al. 2007. An IRF8-binding promoter variant and AIRE control CHRNA1 promiscuous expression in thymus. Nature 448: 934-937.
62. Maclennan, C. A., A. Vincent, A. Marx, N. Willcox, N. E. Gilhus, J. Newsom- Davis, and D. Beeson. 2008. Preferential expression of AChR epsilon-subunit in thymomas from patients with myasthenia gravis. J. Neuroimmunol. 201-202: 28-32.
63. Li, B., J. Li, C. S. Hsieh, L. P. Hale, Y. J. Li, B. H. Devlin, and M. L. Markert. 2009. Characterization of cultured thymus tissue used for transplantation with emphasis on promiscuous expression of thyroid tissue-specific genes. Immunol. Res. 44: 71-83.
64. Pazirandeh, A., Y. Xue, I. Rafter, J. Sjovall, M. Jondal, and S. Okret. 1999. Paracrine glucocorticoid activity produced by mouse thymic epithelial cells. FASEB J. 13: 893-901.
65. Wolff, A. S., A. K. Sarkadi, L. Maródi, J. Kärner, E. Orlova, B. E. Oftedal, K. Kisand, E. Oláh, A. Meloni, A. G. Myhre, et al. 2013. Anti-cytokine autoantibodies preceding onset of autoimmune polyendocrine syndrome type I features in early childhood. J. Clin. Immunol. 33: 1341-1348.
66. Arstila, T. P., and H. Jarva. 2013. Human APECED; a Sick Thymus Syndrome? Front. Immunol. 4: 313.
67. Scherbaum, W. A., and P. A. Berg. 1982. Development of adrenocortical failure in non-Addisonian patients with antibodies to adrenal cortex. A clinical followup study. Clin. Endocrinol. (Oxf.) 16: 345-352.