Clues to immune tolerance: The monogenic autoimmune syndromes

Annals of the New York Academy of Sciences

Volumn 1214, Issue 1, 2010, Pages 138-155

  Waterfield, Michael ^a,b   Anderson, Mark S ^a  

^a UNIVERSITY OF CALIFORNIA   (United States)

^b UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

ALPS; APS1; Autoimmunity; Immune tolerance; IPEX; Regulatory T cells

Indexed keywords

TRANSCRIPTION FACTOR FOXP3;

ARTICLE; AUTOIMMUNE DISEASE; AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME; AUTOIMMUNE POLYGLANDULAR SYNDROME 1; ENTEROPATHY; ENVIRONMENTAL FACTOR; HEREDITY; HUMAN; IMMUNODYSREGULATION POLYENDOCRINOPATHY ENTEROPATHY X LINKED SYNDROME; IMMUNOLOGICAL TOLERANCE; NONHUMAN; PATHOGENESIS; POLYENDOCRINOPATHY; REGULATORY T LYMPHOCYTE; X CHROMOSOME LINKED DISORDER;

EID: 78650357758     PISSN: 00778923     EISSN: 17496632     Source Type: Book Series    
DOI: 10.1111/j.1749-6632.2010.05818.x     Document Type: Article

References (154)

1. Zenewicz, L., C. Abraham, R. Flavell & J. Cho 2010. Unraveling the genetics of autoimmunity. Cell. 140: 791-797.
2. Gregersen, P. & L. Olsson 2009. Recent advances in the genetics of autoimmune disease. Annu. Rev. Immunol. 27: 363-391.
3. Husebye, E., J. Perheentupa, R. Rautemaa & O. Kämpe 2009. Clinical manifestations and management of patients with autoimmune polyendocrine syndrome type I. J. Intern. Med. 265: 514-529.
4. Perheentupa, J. 2006. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. J. Clin. Endocrinol. Metab. 91: 2843-2850.
5. Rautemaa, R., J. Hietanen, S. Niissalo, et al 2007. Oral and oesophageal squamous cell carcinoma-a complication or component of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED, APS-I). Oral Oncol. 43: 607-613.
6. Gylling, M. et al 2003. The hypoparathyroidism of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy protective effect of male sex. J. Clin. Endocrinol. Metab. 88: 4602-4608.
7. Ahonen, P., S. Myllarniemi I. Sipila, et al 1990. Clinical variation of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) in a series of 68 patients. N Engl. J. Med. 322: 1829-1836.
8. Myllärniemi, S. & J. Perheentupa 1978. Oral findings in the autoimmune polyendocrinopathy-candidosis syndrome (APECS) and other forms of hypoparathyroidism. Oral Surg. Oral Med. Oral Pathol. 45: 721-729.
9. Wolff, A. et al 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.
10. Rosatelli, M. et al 1998. A common mutation in Sardinian autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy patients. Hum. Genet. 103: 428-434.
11. Zlotogora, J. & M. Shapiro 1992. Polyglandular autoimmune syndrome type I among Iranian Jews. J. Med. Genet. 29: 824-826.
12. Consortium, F.-G.A. 1997. An autoimmune disease, APECED, caused by mutations in a novel gene featuring two PHD-type zinc-finger domains. Nat. Genet. 17: 399-403.
13. Nagamine, K. et al 1997. Positional cloning of the APECED gene. Nat. Genet. 17: 393-398.
14. Mathis, D., Benoist & C. Aire 2009. Annu. Rev. Immunol. 27: 287-312.
15. Scott, H. et al 1998. Common mutations in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy patients of different origins. Mol. Endocrinol. 12: 1112-1119.
16. Gylling, M. et al 2000. ss-Cell autoantibodies, human leukocyte antigen II alleles, and type 1 diabetes in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. J. Clin. Endocrinol. Metab. 85: 4434-4440.
17. Halonen, M. et al 2002. AIRE mutations and human leukocyte antigen genotypes as determinants of the autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy phenotype. J. Clin. Endocrinol. Metab. 87: 2568-2574.
18. Cetani, F. et al 2001. A novel mutation of the autoimmune regulator gene in an Italian kindred with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, acting in a dominant fashion and strongly cosegregating with hypothyroid autoimmune thyroiditis. J. Clin. Endocrinol. Metab. 86: 4747-4752.
19. Cervato, S. et al 2009. Evaluation of the AIRE gene mutations in a cohort of Italian patients with autoimmune-polyendocrinopathy-candidiasis-ectodermal-dystrophy (APECED) and in their relatives. Clin. Endocrinol. 70: 421-428.
20. Anderson, M.S. et al 2002. Projection of an immunological self shadow within the thymus by the aire protein. Science 298: 1395-1401.
21. Ramsey, C. et al 2002. Aire deficient mice develop multiple features of APECED phenotype and show altered immune response. Hum. Mol. Genet. 11: 397-409.
22. Derbinski, J., A. Schulte, B. Kyewski & L. Klein 2001. Promiscuous gene expression in medullary thymic epithelial cells mirrors the peripheral self. Nat. Immunol. 2: 1032-1039.
23. Kishimoto, H. & J. Sprent 1997. Negative selection in the thymus includes semimature T cells. J. Exp. Med. 185: 263-271.
24. Derbinski, J. & B. Kyewski 2005. Linking signalling pathways, thymic stroma integrity and autoimmunity. Trends Immunol. 26: 503-506.
25. DeVoss, J. et al 2006. Spontaneous autoimmunity prevented by thymic expression of a single self-antigen. J. Exp. Med. 203: 2727-2735.
26. Gavanescu, I., B. Kessler H. Ploegh, et al 2007. Loss of Aire-dependent thymic expression of a peripheral tissue antigen renders it a target of autoimmunity. Proc. Natl. Acad. Sci. USA 104: 4583-4587.
27. Shum, A.K. et al 2009. Identification of an autoantigen demonstrates a link between interstitial lung disease and a defect in central tolerance. Sci. Transl. Med. 1: 9ra20-29ra20.
28. Liston, A., S. Lesage J. Wilson, et al 2003. Aire regulates negative selection of organ-specific T cells. Nat. Immunol. 4: 350-354.
29. Kogawa, K. 2002. Expression of AIRE gene in peripheral monocyte/dendritic cell lineage. Immunol. Lett. 80: 195-198.
30. Gardner, J.M. et al 2008. Deletional tolerance mediated by extrathymic Aire-expressing cells. Science 321: 843-847.
31. Lee, J.W. et al 2007. Peripheral antigen display by lymph node stroma promotes T cell tolerance to intestinal self. Nat. Immunol. 8: 181-190.
32. Poliani, P.L. et al 2010. Human peripheral lymphoid tissues contain autoimmune regulator-expressing dendritic cells. Am. J. Pathol. 176: 1104-1112.
33. Bjorses, P. et al 1999. Localization of the APECED protein in distinct nuclear structures. Hum. Mol. Genet. 8: 259-266.
34. Koh, A.S. et al 2008. Aire employs a histone-binding module to mediate immunological tolerance, linking chromatin regulation with organ-specific autoimmunity. Proc. Natl. Acad. Sci. USA 105: 15878-15883.
35. Kumar, P.G. et al 2001. The autoimmune regulator (AIRE) is a DNA-binding protein. J. Biol. Chem. 276: 41357-41364.
36. Org, T. et al 2008. The autoimmune regulator PHD finger binds to non-methylated histone H3K4 to activate gene expression. EMBO Rep. 9: 370-376.
37. Bottomley, M.J. et al 2001. The SAND domain structure defines a novel DNA-binding fold in transcriptional regulation. Nat. Struct. Biol. 8: 626-633.
38. Derbinski, J. et al 2005. Promiscuous gene expression in thymic epithelial cells is regulated at multiple levels. J. Exp. Med. 202: 33-45.
39. Johnnidis, J.B. et al 2005. Chromosomal clustering of genes controlled by the aire transcription factor. Proc. Natl. Acad. Sci. USA 102: 7233-7238.
40. Derbinski, J., S. Pinto S. Rosch, et al 2008. Promiscuous gene expression patterns in single medullary thymic epithelial cells argue for a stochastic mechanism. Proc. Natl. Acad. Sci. USA 105: 657-662.
41. Villasenor, J., W. Besse C. Benoist, et al 2008. Ectopic expression of peripheral-tissue antigens in the thymic epithelium: probabilistic, monoallelic, misinitiated. Proc. Natl. Acad. Sci. USA 105: 15854-15859.
42. Abramson, J., M. Giraud C. Benoist, et al 2010. Aire's partners in the molecular control of immunological tolerance. Cell. 140: 123-135.
43. Rando, O. & H. Chang 2009. Genome-wide views of chromatin structure. Annu. Rev. Biochem. 78: 245-271.
44. Org, T. et al 2009. AIRE activated tissue specific genes have histone modifications associated with inactive chromatin. Hum. Mol. Genet. 18: 4699-4710.
45. Liiv, I. et al. 2008. DNA-PK contributes to the phosphorylation of AIRE: importance in transcriptional activity. Biochim. Biophys. Acta. 1783: 74-83.
46. Oven, I. et al 2007. AIRE recruits P-TEFb for transcriptional elongation of target genes in medullary thymic epithelial cells. Mol. Cell Biol. 27: 8815-8823.
47. Pitkanen, J. et al 2005. Cooperative activation of transcription by autoimmune regulator AIRE and CBP. Biochem. Biophys. Res. Commun. 333: 944-953.
48. Nitiss, J. 2009. DNA topoisomerase II and its growing repertoire of biological functions. Nat. Rev. Cancer. 9: 327-337.
49. Meloni, A. 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.
50. Zhang, L. et al 2007. A robust immunoassay for anti-interferon autoantibodies that is highly specific for patients with autoimmune polyglandular syndrome type 1. Clin. Immunol. 125: 131-137.
51. Kisand, K. et al 2010. Chronic mucocutaneous candidiasis in APECED or thymoma patients correlates with autoimmunity to Th17-associated cytokines. J. Exp. Med. 207: 299-308.
52. Puel, A. 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.
53. Alimohammadi, M. et al 2008. Autoimmune polyendocrine syndrome type 1 and NALP5, a parathyroid autoantigen. N. Engl. J. Med. 358: 1018-1028.
54. Husebye, E. et al 1997. Autoantibodies against aromatic L-amino acid decarboxylase in autoimmune polyendocrine syndrome type I. J. Clin. Endocrinol. Metab. 82: 147-150.
55. Soderbergh, A. et al 2004. Prevalence and clinical associations of 10 defined autoantibodies in autoimmune polyendocrine syndrome type I. J. Clin. Endocrinol. Metab. 89: 544-547.
56. Pugliese, A. 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.
57. Vafiadis, P. et al 1997. Insulin expression in human thymus is modulated by INS VNTR alleles at the IDDM2 locus. Nat. Genet. 15: 289-292.
58. Giraud, M. et al 2007. An IRF8-binding promoter variant and AIRE control CHRNA1 promiscuous expression in thymus. Nature 448: 934-937.
59. Cheng, M. et al 2010. Acquired autoimmune polyglandular syndrome, thymoma, and an AIRE defect. N. Engl. J. Med. 362: 764-766.
60. Ochs, H., E. Gambineri & T. Torgerson 2007. IPEX, FOXP3 and regulatory T-cells: a model for autoimmunity. Immunol. Res. 38: 112-121.
61. Torgerson, T. & H. Ochs 2007. Immune dysregulation, polyendocrinopathy, enteropathy, X-linked: forkhead box protein 3 mutations and lack of regulatory T cells. J. Allergy Clin. Immunol. 120: 744-750.
62. Powell, B., N. Buist & P. Stenzel 1982. An X-linked syndrome of diarrhea, polyendocrinopathy, and fatal infection in infancy. J. Pediatr. 100: 731-737.
63. Battaglia, M. et al 2006. Rapamycin promotes expansion of functional CD4+ CD25+ FOXP3+ regulatory T cells of both healthy subjects and type 1 diabetic patients. J. Immunol. 177: 8338-8847.
64. Rao, A. et al 2007. Successful bone marrow transplantation for IPEX syndrome after reduced-intensity conditioning. Blood 109: 383-385.
65. Brunkow, M. et al. 2001. Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat. Genet. 27: 68-73.
66. Bennett, C. et al 2001. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat. Genet. 27: 20-21.
67. Wildin, R. et al 2001. X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nat. Genet. 27: 18-20.
68. Lu, L. & A. Rudensky 2009. Molecular orchestration of differentiation and function of regulatory T cells. Genes Dev. 23: 1270-1282.
69. Wing, K. & S. Sakaguchi 2009. Regulatory T cells exert checks and balances on self tolerance and autoimmunity. Nat. Immunol. 11: 7-13.
70. Sakaguchi, S., N. Sakaguchi & M. Asano 1995. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J. Immunol. 155: 1151.
71. Fontenot, J., M. Gavin & A. Rudensky 2003. Foxp3 programs the development and function of CD4+ CD25+ regulatory T cells. Nat. Immunol. 4: 330-336.
72. Hori, S., T. Nomura & S. Sakaguchi 2003. Control of regulatory T cell development by the transcription factor Foxp3. Science 299: 1057-1061.
73. Fontenot, J. et al 2005. Regulatory T cell lineage specification by the forkhead transcription factor foxp3. Immunity 22: 329-341.
74. Kim, J.M., J.P. Rasmussen & A.Y. Rudensky 2007. Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice. Nat. Immunol. 8: 191-197.
75. Williams, L. & A. Rudensky 2007. Maintenance of the Foxp3-dependent developmental program in mature regulatory T cells requires continued expression of Foxp3. Nat. Immunol. 8: 277-284.
76. Gavin, M. et al 2007. Foxp3-dependent programme of regulatory T-cell differentiation. Nature 445: 771-775.
77. Rubtsov, Y. et al 2008. Regulatory T cell-derived interleukin-10 limits inflammation at environmental interfaces. Immunity 28: 546-558.
78. Wing, K. et al 2008. CTLA-4 control over Foxp3+ regulatory T cell function. Science 322: 271-275.
79. Hsieh, C. et al 2004. Recognition of the peripheral self by naturally arising CD25+ CD4+ T cell receptors. Immunity 21: 267-277.
80. Nishikawa, H. et al 2005. Definition of target antigens for naturally occurring CD4+ CD25+ regulatory T cells. J. Exp. Med. 201: 681-686.
81. Kim, H. & W. Leonard 2007. CREB/ATF-dependent T cell receptor-induced FoxP3 gene expression: a role for DNA methylation. J. Exp. Med. 204: 1543-1551.
82. Mantel, P. et al. 2006. Molecular mechanisms underlying FOXP3 induction in human T cells. J. Immunol. 176: 3593-3602.
83. Schmidt-Supprian, M. 2004. Differential dependence of CD4+ CD25+ regulatory and natural killer-like T cells on signals leading to NF-κB activation. Proc. Natl. Acad. Sci. USA 101: 4566-4571.
84. Zheng, Y. et al 2010. Role of conserved non-coding DNA elements in the Foxp3 gene in regulatory T-cell fate. Nature 463: 808-812.
85. Fontenot, J., J. Rasmussen, M. Gavin & A. Rudensky 2005. A function for interleukin 2 in Foxp3-expressing regulatory T cells. Nat. Immunol. 6: 1142-1151.
86. Willerford, D. et al 1995. Interleukin-2 receptor alpha chain regulates the size and content of the peripheral lymphoid compartment. Immunity 3: 521-530.
87. Caudy, A., S. Reddy T. Chatila, et al 2007. CD25 deficiency causes an immune dysregulation, polyendocrinopathy, enteropathy, X-linked-like syndrome, and defective IL-10 expression from CD4 lymphocytes. J. Allergy Clin. Immunol. 119: 482-487.
88. Sharfe, N., H. Dadi, M. Shahar & C. Roifman 1997. Human immune disorder arising from mutation of the chain of the interleukin-2 receptor. Proc. Natl. Acad. Sci. USA 94: 3168-3171.
89. Liu, Y. et al 2008. A critical function for TGF- signaling in the development of natural CD4+ CD25 +Foxp3+ regulatory T cells. Nat. Immunol. 9: 632-640.
90. Salomon, B. et al 2000. B7/CD28 costimulation is essential for the homeostasis of the CD4+ CD25 +immunoregulatory T cells that control autoimmune diabetes. Immunity 12: 431-440.
91. Curotto de Lafaille, M. & J. Lafaille 2009. Natural and adaptive foxp3+ regulatory T cells: more of the same or a division of labor. Immunity 30: 626-635.
92. Apostolou, I. & H. von Boehmer 2004. In vivo instruction of suppressor commitment in naive T cells. J. Exp. Med. 199: 1401-1408.
93. Curotto de Lafaille, M. 2004. CD25-T cells generate CD25+ Foxp3+ regulatory T cells by peripheral expansion. J. Immunol. 173: 7259-7268.
94. Coombes, J. et al 2007. A functionally specialized population of mucosal CD103 +DCs induces Foxp3+ regulatory T cells via a TGF-beta and retinoic acid-dependent mechanism. J. Exp. Med. 204: 1757-1764.
95. Sun, C. et al 2007. Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 T reg cells via retinoic acid. J. Exp. Med. 204: 1775-1785.
96. Wu, Y. et al 2006. FOXP3 controls regulatory T cell function through cooperation with NFAT. Cell. 126: 375-387.
97. Chaudhry, A. et al 2009. CD4+ regulatory T cells control TH17 responses in a Stat3-dependent manner. Science 326: 986-991.
98. Ono, M. et al. 2007. Foxp3 controls regulatory T-cell function by interacting with AML1/Runx1. Nature 446: 685-689.
99. Zheng, Y., A. Chaudhry & A. Kas 2009. Regulatory T-cell suppressor program co-opts transcription factor IRF4 to control TH2 responses. Nature 458: 351-356.
100. Zhou, L. et al 2008. TGF-beta-induced Foxp3 inhibits TH17 cell differentiation by antagonizing RORgammat function. Nature 453: 236-240.
101. Marson, A. et al 2007. Foxp3 occupancy and regulation of key target genes during T-cell stimulation. Nature 445: 931-935.
102. Zheng, Y. et al 2007. Genome-wide analysis of Foxp3 target genes in developing and mature regulatory T cells. Nature 445: 936-940.
103. Gavin, M., S. Clarke & E. Negrou 2001. Homeostasis and anergy of CD4+ CD25+ suppressor T cells in vivo. Nat. Immunol. 3: 33-41.
104. McHugh, R. et al 2002. CD4+ CD25+ immunoregulatory T cells: gene expression analysis reveals a functional role for the glucocorticoid-induced TNF receptor. Immunity 16: 311-323.
105. Gavin, M. et al 2006. Single-cell analysis of normal and FOXP3-mutant human T cells: FOXP3 expression without regulatory T cell development. Proc. Natl. Acad. Sci. USA 103: 6659-6664.
106. Walker, M. et al 2003. Induction of FoxP3 and acquisition of T regulatory activity by stimulated human CD4 CD25-T cells. J. Clin. Invest. 112: 1437-1443.
107. Tran, D., H. Ramsey & E. Shevach 2007. Induction of FOXP3 expression in naive human CD4+ FOXP3 T cells by T-cell receptor stimulation is transforming growth factor-β dependent but does not confer a regulatory phenotype. Blood 110: 2983-2990.
108. Walker, M., Carson B. Nepom, et al 2005. De novo generation of antigen-specific CD4+ CD25 +regulatory T cells from human CD4+ CD25-cells. Proc. Natl. Acad. Sci. USA 102: 4103-4108.
109. Miyara, M. et al 2009. Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor. Immunity 30: 899-911.
110. Sakaguchi, S., M. Miyara, C. Costantino & D. Hafler 2010. FOXP3+ regulatory T cells in the human immune system. Nat. Rev. Immunol. 10: 490-500.
111. Allan, S., Song-Zhao G. Abraham, et al 2008. Inducible reprogramming of human T cells into Treg cells by a conditionally active form of FOXP3. Eur. J. Immunol. 38: 3282-3289.
112. Hoffmann, P. et al 2009. Loss of FOXP3 expression in natural human CD4+ CD25 +regulatory T cells upon repetitive in vitro stimulation. Eur. J. Immunol. 39: 1088-1097.
113. Kleinewietfeld, M. et al 2009. CD49d provides access to" untouched" human Foxp3+ Treg free of contaminating effector cells. Blood 113: 827-836.
114. Liu, W. et al 2006. CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells. J. Exp. Med. 203: 1701-1711.
115. Nadig, S. et al 2010. In vivo prevention of transplant arteriosclerosis by ex vivo-expanded human regulatory T cells. Nat. Med. 16: 809-813.
116. Ehrenstein, M. et al 2004. Compromised function of regulatory T cells in rheumatoid arthritis and reversal by anti-TNF alpha therapy. J. Exp. Med. 200: 277-285.
117. Esensten, J., D. Wofsy & J. Bluestone 2009. Regulatory T cells as therapeutic targets in rheumatoid arthritis. Nat. Rev. Rheumatol. 5: 560-565.
118. Valencia, X. et al 2006. TNF downmodulates the function of human CD4+ CD25hi T-regulatory cells. Blood 108: 253-261.
119. Brusko, T. et al 2007. No alterations in the frequency of FOXP3+ regulatory T-cells in type 1 diabetes. Diabetes 56: 604-612.
120. Kukreja, A. et al 2002. Multiple immuno-regulatory defects in type-1 diabetes. J. Clin. Invest. 109: 131-140.
121. Lindley, S. 2005. Defective suppressor function in CD4+ CD25+ T-cells from patients with type 1 diabetes. Diabetes 54: 92-99.
122. Putnam, A., F. Vendrame, F. Dotta & P. Gottlieb 2005. CD4+ CD25high regulatory T cells in human autoimmune diabetes. J. Autoimmun. 24: 55-62.
123. Sneller, M. 1992. A novel lymphoproliferative/autoimmune syndrome resembling murine lpr/gld disease. J. Clin. Invest. 90: 334-341.
124. Teachey, D., A. Seif & S. Grupp 2009. Advances in the management and understanding of autoimmune lymphoproliferative syndrome (ALPS). Br. J. Haematol. 148: 205-216.
125. Worth, A., A. Thrasher & H. Gaspar 2006. Autoimmune lymphoproliferative syndrome: molecular basis of disease and clinical phenotype. Br. J. Haematol. 133: 124-140.
126. Straus, S. et al 2001. The development of lymphomas in families with autoimmune lymphoproliferative syndrome with germline Fas mutations and defective lymphocyte apoptosis. Blood 98: 194-200.
127. Dimopoulou, M. et al 2007. Successful treatment of autoimmune lymphoproliferative syndrome and refractory autoimmune thrombocytopenic purpura with a reduced intensity conditioning stem cell transplantation followed by donor lymphocyte infusion. Bone Marrow Transplant. 40: 605-606.
128. Takahashi, T. et al 1994. Generalized lymphoproliferative disease in mice, caused by a point mutation in the Fas ligand. Cell. 76: 969-976.
129. Watanabe-Fukunaga, R. et al. 1992. Lymphoproliferation disorder in mice explained by defects in Fas antigen that mediates apoptosis. Nature 356: 314-317.
130. Fisher, G. et al 1995. Dominant Interfering Fas Gene Mutations Impair Apoptosis in a Human Autoimmune Lymphoproliferative Syndrome. Cell. 81: 935-946.
131. Rieux-Laucat, F. et al 1995. Mutations in Fas associated with human lymphoproliferative syndrome and autoimmunity. Science 268: 1347-1349.
132. Wu, J. et al 1996. Fas ligand mutation in a patient with systemic lupus erythematosus and lymphoproliferative disease. J. Clin. Invest. 98: 1107-1113.
133. Jackson, C. et al 1999. Autoimmune lymphoproliferative syndrome with defective Fas: genotype influences penetrance. Am. J. Hum. Genet. 64: 1002-1014.
134. Kasahara, Y. 1998. Novel Fas (CD95/APO-1) mutations in infants with a lymphoproliferative disorder. Int. Immunol. 10: 195-202.
135. Le Deist, F. et al 1996. Clinical, immunological, and pathological consequences of Fas-deficient conditions. Lancet 348: 719-723.
136. Bettinardi, A. et al 1997. Missense mutations in the Fas gene resulting in autoimmune lymphoproliferative syndrome: a molecular and immunological analysis. Blood 89: 902-909.
137. Oliveira, J. et al 2007. NRAS mutation causes a human autoimmune lymphoproliferative syndrome. Proc. Natl. Acad. Sci. USA 104: 8953-8958.
138. Wang, J. et al 1999. Inherited human Caspase 10 mutations underlie defective lymphocyte and dendritic cell apoptosis in autoimmune lymphoproliferative syndrome type II. Cell. 98: 47-58.
139. Zhu, S. et al 2006. Genetic alterations in caspase-10 may be causative or protective in autoimmune lymphoproliferative syndrome. Hum. Genet. 119: 284-294.
140. Chun, H. et al. 2002. Pleiotropic defects in lymphocyte activation caused by caspase-8 mutations lead to human immunodeficiency. Nature 419: 395-399.
141. Oliveira, J. et al. 2010. Revised diagnostic criteria and classification for the autoimmune lymphoproliferative syndrome: report from the 2009 NIH International Workshop. Blood epub ahead of print June 10
142. Lenardo, M., J. Oliveira, L. Zheng & V. Rao 2010. ALPS-ten lessons from an International Workshop on a Genetic Disease of Apoptosis. Immunity 32: 291-295.
143. Holzelova, E. et al. 2004. Autoimmune lymphoproliferative syndrome with somatic Fas mutations. N. Engl. J. Med. 351: 1409.
144. Dowdell, K. et al 2010. Somatic FAS mutations are common in patients with genetically undefined autoimmune lymphoproliferative syndrome (ALPS). Blood 115: 5164-5169.
145. Bleesing, J., S. Straus & T. Fleisher 2000. Autoimmune lymphoproliferative syndrome. A human disorder of abnormal lymphocyte survival. Pediatr. Clin. North Am. 47: 1291-1310.
146. Seif, A., C. Manno, S. Grupp & D. Teachey 2008. Testing patients with Evans syndrome for the Autoimmune Lymphoproliferative Syndrome(ALPS): results of a large multinational clinical trial (ASPHO supplement). Pediatr. Blood Cancer 50: S22-S23.
147. Dianzani, U. 1997. Deficiency of the Fas apoptosis pathway without Fas gene mutations in pediatric patients with autoimmunity/lymphoproliferation. Blood 89: 2871-2879.
148. Snow, A. et al 2009. Restimulation-induced apoptosis of T cells is impaired in patients with X-linked lymphoproliferative disease caused by SAP deficiency. J. Clin. Invest. 119: 2976-2989.
149. Strasser, A., P. Jost & S. Nagata 2009. The many roles of FAS receptor signaling in the immune system. Immunity 30: 180-192.
150. Goodnow, C. 2007. Multistep pathogenesis of autoimmune disease. Cell. 130: 25-35.
151. Tang, Q. et al 2004. In vitro-expanded antigen-specific regulatory T cells suppress autoimmune diabetes. J. Exp. Med. 199: 1455-1465.
152. Brusko, T., A. Putnam & J. Bluestone 2008. Human regulatory T cells: role in autoimmune disease and therapeutic opportunities. Immunol. Rev. 223: 371-390.
153. Putnam, A. et al 2009. Expansion of human regulatory T-cells from patients with type 1 diabetes. Diabetes 58: 652-662.
154. Trzonkowski, P. et al 2009. First-in-man clinical results of the treatment of patients with graft versus host disease with human ex vivo expanded CD4+ CD25+ CD127-T regulatory cells. Clin. Immunol. 133: 22-26.