Gene dosage-limiting role of Aire in thymic expression, clonal deletion, and organ-specific autoimmunity

Journal of Experimental Medicine

Volumn 200, Issue 8, 2004, Pages 1015-1026

  Liston, Adrian ^a   Gray, Daniel H D ^b   Lesage, Sylvie ^a,c   Fletcher, Anne L ^b   Wilson, Judith ^a   Webster, Kylie E ^d   Scott, Hamish S ^d   Boyd, Richard L ^b   Peltonen, Leena ^e   Goodnow, Christopher C ^a  

^a Biology and Environment   (Australia)

^b MONASH UNIVERSITY   (Australia)

^c CENTRE HOSPITALIER DE L UNIVERSITÉ DE MONTRÉAL   (Canada)

^d WALTER AND ELIZA HALL INSTITUTE OF MEDICAL RESEARCH   (Australia)

^e UNIVERSITY OF HELSINKI   (Finland)

Author keywords

Autoimmune diseases; Clonal deletion; Diabetes mellitus type I; Immune tolerance; Thymus

Indexed keywords

AUTOIMMUNE REGULATOR PROTEIN; CD4 ANTIGEN; INSULIN; PROTEIN DERIVATIVE; T LYMPHOCYTE RECEPTOR; THYROGLOBULIN; UNCLASSIFIED DRUG;

ANTIBODY SPECIFICITY; ARTICLE; AUTOIMMUNE DISEASE; AUTOIMMUNE POLYENDOCRINOPATHY CANDIDIASIS ECTODERMAL DYSTROPHY; AUTOIMMUNITY; DIABETES MELLITUS; DISEASE COURSE; GENE DOSAGE; GENE INACTIVATION; GENE MUTATION; HETEROZYGOTE; HOMOZYGOTE; IMMUNOLOGICAL TOLERANCE; MOUSE; NONHUMAN; PANCREAS ISLET; PRIORITY JOURNAL; PROTEIN DEFICIENCY; PROTEIN DEPLETION; PROTEIN EXPRESSION; QUANTITATIVE TRAIT LOCUS; SENSITIVITY ANALYSIS; T LYMPHOCYTE; TESTIS; THYMUS; TRANSGENE; TRANSGENIC MOUSE;

ANIMALS; AUTOIMMUNITY; CLONAL DELETION; GENE DOSAGE; GENE EXPRESSION; IMMUNE TOLERANCE; INSULIN; MICE; MICE, TRANSGENIC; ORGAN SPECIFICITY; POLYENDOCRINOPATHIES, AUTOIMMUNE; PROMOTER REGIONS (GENETICS); RECEPTORS, ANTIGEN, T-CELL; THYMUS GLAND; THYROID GLAND; TRANSCRIPTION FACTORS;

EID: 7244227646     PISSN: 00221007     EISSN: None     Source Type: Journal    
DOI: 10.1084/jem.20040581     Document Type: Article

References (51)

1. Ohashi, P.S., S. Oehen, K. Buerki, H. Pircher, C.T. Ohashi, B. Odermatt, B. Malissen, R.M. Zinkernagel, and H. Hengartner. 1991. Ablation of "tolerance" and induction of diabetes by virus infection in viral antigen transgenic mice. Cell. 65:305-317.
2. + T cells undergoing peripheral deletion in response to cross-presentation of self-antigen. J. Exp. Med. 194:707-717.
3. Lambolez, F., K. Jooss, F. Vasseur, and A. Sarukhan. 2002. Tolerance induction to self antigens by peripheral dendritic cells. Eur. J. Immunol. 32:2588-2597.
4. Greenwald, R.J., V.A. Boussiotis, R.B. Lorsbach, A.K. Abbas, and A.H. Sharpe. 2001. CTLA-4 regulates induction of anergy in vivo. Immunity. 14:145-155.
5. Shevach, E. 2002. CD4+CD25+ suppressor T cells: more questions than answers. Nat. Rev. Immunol. 2:389-400.
6. Le Douarin, N., C. Corbel, A. Bandeira, V. Thomas-Vaslin, Y. Modigliani, A. Coutinho, and J. Salaun. 1996. Evidence for a thymus-dependent form of tolerance that is not based on elimination or anergy of reactive T cells. Immunol. Rev. 149:35-53.
7. Fritz, R.B., and M.L. Zhao. 1996. Thymic expression of myelin basic protein (MBP). Activation of MBP-specific T cells by thymic cells in the absence of exogenous MBP. J. Immunol. 157:5249-5253.
8. Kojima, K., M. Reindl, H. Lassmann, H. Wekerle, and C. Linington. 1997. The thymus and self-tolerance: co-existence of encephalitogenic S100 beta-specific T cells and their nominal autoantigen in the normal adult rat thymus. Int. Immunol. 9:897-904.
9. Kirchner, T., S. Tzartos, F. Hoppe, B. Schalke, H. Wekerle, and H.K. Muller-Hermelink. 1988. Pathogenesis of myasthenia gravis. Acetylcholine receptor-related antigenic determinants in tumor-free thymuses and thymic epithelial tumors. Am. J. Pathol. 130:268-280.
10. Egwuagu, C.E., P. Charukamnoetkanok, and I. Gery. 1997. Thymic expression of autoantigens correlates with resistance to autoimmune disease. J. Immunol. 159:3109-3112.
11. Martens, H., B. Goxe, and V. Geenen. 1996. The thymic repertoire of neuroendocrine self-antigens: physiological implications in T-cell life and death. Immunol. Today. 17:312-317.
12. Hanahan, D. 1998. Peripheral-antigen-expressing cells in thymic medulla: factors in self-tolerance and autoimmunity. Curr. Opin. Immunol. 10:656-662.
13. Heath, V.L., N.C. Moore, S.M. Parnell, and D.W. Mason. 1998. Intrathymic expression of genes involved in organ specific autoimmune disease. J. Autoimmun. 11:309-318.
14. Werdelin, O., U. Cordes, and T. Jensen. 1998. Aberrant expression of tissue-specific proteins in the thymus: a hypothesis for the development of central tolerance. Scand. J. Immunol. 47:95-100.
15. Sospedra, M., X. Ferrer-Francesch, O. Dominguez, M. Juan, M. Foz-Sala, and R. Pujol-Borrell. 1998. Transcription of a broad range of self-antigens in human thymus suggests a role for central mechanisms in tolerance toward peripheral antigens. J. Immunol. 161:5918-5929.
16. Klein, L., M. Klugmann, K.A. Nave, V.K. Tuohy, and B. Kyewski. 2000. Shaping of the autoreactive T-cell repertoire by a splice variant of self protein expressed in thymic epithelial cells. Nat. Med. 6:56-61.
17. Anderson, A.C., L.B. Nicholson, K.L. Legge, V. Turchin, H. Zaghouani, and V.K. Kuchroo. 2000. High frequency of autoreactive myelin proteolipid protein-specific T cells in the periphery of naive mice: mechanisms of selection of the self-reactive repertoire. J. Exp. Med. 191:761-770.
18. Vafiadis, P., S.T. Bennett, J.A. Todd, J. Nadeau, R. Grabs, C.G. Goodyer, S. Wickramasinghe, E. Colle, and C. Polychronakos. 1997. Insulin expression in human thymus is modulated by INS VNTR alleles at the IDDM2 locus. Nat. Genet. 15:289-292.
19. Pugliese, A., M. Zeller, A. Fernandez Jr., L.J. Zalcberg, R.J. Bartlett, C. Ricordi, M. Pietropaolo, G.S. Eisenbarth, S.T. Bennett, and D.D. Patel. 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.
20. 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.
21. The Finnish-German APECED Consortium. 1997. An autoimmune disease, APECED, caused by mutations in a novel gene featuring two PHD-type zinc-finger domains. Nat. Genet. 17:399-403.
22. Betterle, C., N.A. Greggio, and M. Volpato. 1998. Clinical review 93: autoimmune polyglandular syndrome type 1. J. Clin. Endocrinol. Metab. 83:1049-1055.
23. Heino, M., P. Peterson, J. Kudoh, K. Nagamine, A. Lagerstedt, V. Ovod, A. Ranki, I. Rantala, M. Nieminen, J. Tuukkanen, et al. 1999. Autoimmune regulator is expressed in the cells regulating immune tolerance in thymus medulla. Biochem. Biophys. Res. Commun. 257:821-825.
24. Heino, M., P. Peterson, N. Sillanpaa, S. Guerin, L. Wu, G. Anderson, H.S. Scott, S.E. Antonarakis, J. Kudoh, N. Shimizu, et al. 2000. RNA and protein expression of the murine autoimmune regulator gene (Aire) in normal, RelB-deficient and in NOD mouse. Eur. J. Immunol. 30:1884-1893.
25. Pitkanen, J., V. Doucas, T. Sternsdorf, T. Nakajima, S. Aratani, K. Jensen, H. Will, P. Vahamurto, J. Ollila, M. Vihinen, et al. 2000. The autoimmune regulator protein has transcriptional transacrivating properties and interacts with the common coactivator CREB-binding protein. J. Biol. Chem. 275:16802-16809.
26. Bjorses, P., M. Halonen, J.J. Palvimo, M. Kolmer, J. Aaltonen, P. Ellonen, J. Perheentupa, I. Ulmanen, and L. Peltonen. 2000. Mutations in the AIRE gene: effects on subcellular location and transactivation function of the autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy protein. Am. J. Hum. Genet. 66:378-392.
27. Ramsey, C., O. Winqvist, L. Puhakka, M. Halonen, A. Moro, O. Kampe, P. Eskelin, M. Pelto-Huikko, and L. Peltonen. 2002. Aire deficient mice develop multiple features of APECED phenotype and show altered immune response. Hum. Mol. Genet. 11:397-409.
28. Bjorses, P., M. Pelto-Huikko, J. Kaukonen, J. Aaltonen, L. Peltonen, and I. Ulmanen. 1999. Localization of the APECED protein in distinct nuclear structures. Hum. Mol. Genet. 8:259-266.
29. Anderson, M.S., E.S. Venanzi, L. Klein, Z. Chen, S. 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.
30. Liston, A., S. Lesage, J. Wilson, L. Peltonen, and C.C. Goodnow. 2003. Aire regulates negative selection of organspecific T cells. Nat. Immunol. 4:350-354.
31. + T cells. J. Exp. Med. 179:1539-1549.
32. Akkaraju, S., W.Y. Ho, D. Leong, K. Canaan, M.M. Davis, and C.C. Goodnow. 1997. A range of CD4 T cell tolerance: partial inactivation to organ-specific antigen allows nondestructive thyroiditis or insulitis. Immunity. 7:255-271.
33. Akkaraju, S., K. Canaan, and C.C. Goodnow. 1997. Self-reactive B cells are not eliminated or inactivated by autoantigen expressed on thyroid epithelial cells. J. Exp. Med. 186:2005-2012.
34. Hartley, S.B., J. Crosbie, R. Brink, A.B. Kantor, A. Basten, and C.C. Goodnow. 1991. Elimination from peripheral lymphoid tissues of self-reactive B lymphocytes recognizing membrane-bound antigens. Nature. 353:765-769.
35. Bowen, K.M., L. Andrus, and K.J. Lafferty. 1980. Successful allotransplantation of mouse pancreatic islets to nonimmunosuppressed recipients. Diabetes. 29:98-104.
36. Goodnow, C.C., J. Crosbie, S. Adelstein, T.B. Lavoie, S.J. Smith-Gill, R.A. Brink, H. Pritchard-Briscoe, J.S. Wotherspoon, R.H. Loblay, K. Raphael, et al. 1988. Altered immunoglobulin expression and functional silencing of self-reactive B lymphocytes in transgenic mice. Nature. 334:676-682.
37. Smith-Gill, S.J., A.C. Wilson, M. Potter, E.M. Prager, R.J. Feldmann, and C.R. Mainhart. 1982. Mapping the antigenic epitope for a monoclonal antibody against lysozyme. J. Immunol. 128:314-322.
38. Zhang, M., M.S. Vacchio, B.P. Vistica, S. Lesage, C.E. Egwuagu, C.R. Yu, M.P. Gelderman, M.C. Kennedy, E.F. Wawrousek, and I. Gery. 2003. T cell tolerance to a neo-self antigen expressed by thymic epithelial cells: the soluble form is more effective than the membrane-bound form. J. Immunol. 170:3954-3962.
39. Gray, D.H., A.P. Chidgey, and R.L. Boyd. 2002. Analysis of thymic stromal cell populations using flow cytometry. J. Immunol. Methods. 260:15-28.
40. Lesage, S., S.B. Hartley, S. Akkaraju, J. Wilson, M. Townsend, and C.C. Goodnow. 2002. Failure to censor forbidden clone of CD4 T cells in autoimmune diabetes. J. Exp. Med. 196:1175-1188.
41. Van Parijs, L., D.A. Peterson, and A.K. Abbas. 1998. The Fas/Fas ligand pathway and Bcl-2 regulate T cell responses to model self and foreign antigens. Immunity. 8:265-274.
42. Derbinski, J., A. Schulte, B. Kyewski, and L. Klein. 2001. Promiscuous gene expression in medullary thymic epithelial cells mirrors the peripheral self. Nat. Immunol. 2:1032-1039.
43. Kojima, H., T. Nakamura, Y. Fujita, A. Kishi, M. Fujimiya, S. Yamada, M. Kudo, Y. Nishio, H. Maegawa, M. Haneda, et al. 2002. Combined expression of pancreatic duodenal homeobox 1 and islet factor 1 induces immature enterocytes to produce insulin. Diabetes. 51:1398-1408.
44. Perniola, R., A. Falorni, M.G. Clemente, F. Forini, E. Accogli, and G. Lobreglio. 2000. Organ-specific and non-organ-specific autoantibodies in children and young adults with autoimmune polyendocrinopathy-candidiasis- ectodermal dystrophy (APECED). Eur. J. Endocrinol. 143:497-503.
45. Chentoufi, A.A., and C. Polychronakos. 2002. Insulin expression levels in the thymus modulate insulin-specific autoreactive T-cell tolerance: the mechanism by which the IDDM2 locus may predispose to diabetes. Diabetes. 51:1383-1390.
46. Miyamoto, K., S. Miyake, M. Schachner, and T. Yamamura. 2003. Heterozygous null mutation of myelin P0 protein enhances susceptibility to autoimmune neuritis targeting P0 peptide. Eur. J. Immunol. 33:656-665.
47. Huseby, E.S., B. Sather, P.G. Huseby, and J. Goverman. 2001. Age-dependent T cell tolerance and autoimmunity to myelin basic protein. Immunity. 14:471-481.
48. Ahonen, P. 1985. Autoimmune polyendocrinopathy-candidosis-ectodermal dystrophy (APECED): autosomal recessive inheritance. Clin. Genet. 27:535-542.
49. Boe, A.S., P.M. Knappskog, A.G. Myhre, J.I. Sorheim, E.S. Husebye, A. Soderbergh, F. Rorsman, M. Halonen, O. Ekwall, P. Bjorses, and O. Kampe. 2002. Mutational analysis of the autoimmune regulator (AIRE) gene in sporadic autoimmune Addison's disease can reveal patients with unidentified autoimmune polyendocrine syndrome type I. Eur. J. Endocrinol. 146:519-522.
50. Buzi, F., R. Badolato, C. Mazza, S. Giliani, L.D. Notarangelo, G. Radetti, and A. Plebani. 2003. Autoimmune polyendocrinopathy-candidiasis- ectodermal dystrophy syndrome: time to review diagnostic criteria? J. Clin. Endocrinol. Metab. 88:3146-3148.
51. Sediva, A., D. Cihakova, and J. Lebl. 2002. Immunological findings in patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) and their family members: are heterozygotes subclinically affected? J. Pediatr. Endocrinol. Metab. 15:1491-1496.