Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) and IPEX-related disorders: An evolving web of heritable autoimmune diseases

Current Opinion in Pediatrics

Volumn 25, Issue 6, 2013, Pages 708-714

  Verbsky, James W ^a   Chatila, Talal A ^b  

^a MEDICAL COLLEGE OF WISCONSIN   (United States)

^b BOSTON CHILDREN S HOSPITAL   (United States)

Author keywords

autoimmunity; CD25; FOXP3; ITCH; STAT1; STAT5; T regulatory cells; tolerance

Indexed keywords

INTERLEUKIN 2; INTERLEUKIN 2 RECEPTOR ALPHA; SOMATOMEDIN BINDING PROTEIN 3; STAT1 PROTEIN; STAT5 PROTEIN; STAT5B PROTEIN; TRANSCRIPTION FACTOR FOXP3;

AUTOIMMUNITY; CD8+ T LYMPHOCYTE; CELLULAR IMMUNITY; GAIN OF FUNCTION MUTATION; GENETIC DISORDER; HUMAN; IMMUNE DYSREGULATION; IMMUNOLOGICAL TOLERANCE; IMMUNOPATHOGENESIS; IMMUNOPATHOLOGY; INFECTIOUS COMPLICATION; IPEX SYNDROME; LOSS OF FUNCTION MUTATION; MICROFLORA; MUCOCUTANEOUS CANDIDIASIS; PHENOTYPE; PRIORITY JOURNAL; REGULATORY T LYMPHOCYTE; REVIEW;

AUTOANTIBODIES; AUTOIMMUNITY; DIARRHEA; FEMALE; FORKHEAD TRANSCRIPTION FACTORS; GENETIC DISEASES, X-LINKED; GENETIC PREDISPOSITION TO DISEASE; HUMANS; IMMUNOLOGIC DEFICIENCY SYNDROMES; INTERLEUKIN-2 RECEPTOR ALPHA SUBUNIT; INTESTINAL DISEASES; MALE; MUTATION; POLYENDOCRINOPATHIES, AUTOIMMUNE; REPRESSOR PROTEINS; STAT5 TRANSCRIPTION FACTOR; T-LYMPHOCYTES, REGULATORY; UBIQUITIN-PROTEIN LIGASES;

EID: 84888115370     PISSN: 10408703     EISSN: 1531698X     Source Type: Journal    
DOI: 10.1097/MOP.0000000000000029     Document Type: Review

References (96)

1. Chatila TA, Blaeser F, Ho N, et al. JM2, encoding a fork head-related protein, is mutated in X-linked autoimmunity-allergic disregulation syndrome. J Clin Invest 2000; 106:R75-81.
2. Wildin RS, Ramsdell F, Peake J, et al. X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nat Genet 2001; 27:18-20.
3. Bennett CL, Christie J, Ramsdell F, et al. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet 2001; 27:20-21.
4. Wildin RS, Smyk-Pearson S, Filipovich AH. Clinical and molecular features of the immunodysregulation, polyendocrinopathy, enteropathy, X linked (IPEX) syndrome. J Med Genet 2002; 39:537-545.
5. Torgerson TR, Ochs HD. Immune dysregulation, polyendocrinopathy, enteropathy, X-linked: forkhead box protein 3 mutations and lack of regulatory T cells. J Allergy Clin Immunol 2007; 120:744-750; quiz 751-752.
6. Barzaghi F, Passerini L, Bacchetta R. Immune dysregulation, polyendocrinopathy, enteropathy, x-linked syndrome: a paradigm of immunodeficiency with autoimmunity. Front Immunol 2012; 3:211.
7. Nieves DS, Phipps RP, Pollock SJ, et al. Dermatologic and immunologic findings in the immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome. Arch Dermatol 2004; 140:466-472.
8. Josefowicz SZ, Lu LF, Rudensky AY. Regulatory T cells: mechanisms of differentiation and function. Annu Rev Immunol 2012; 30:531-564.
9. Benoist C, Mathis D. Treg cells, life history, and diversity. Cold Spring Harb Perspect Biol 2012; 4:a007021.
10. Lio CW, Hsieh CS. Becoming self-aware: the thymic education of regulatory T cells. Curr Opin Immunol 2011; 23:213-219.
11. Hsieh CS, Liang Y, Tyznik AJ, et al. Recognition of the peripheral self by naturally arising CD25 CD4 T cell receptors. Immunity 2004; 21:267-277.
12. Hsieh CS, Zheng Y, Liang Y, et al. An intersection between the self-reactive regulatory and nonregulatory T cell receptor repertoires. Nat Immunol 2006;7:401-410.
13. Haribhai D, Williams JB, Jia S, et al. A requisite role for induced regulatory T cells in tolerance based on expanding antigen receptor diversity. Immunity;2011;35:109-122.
14. Bilate AM, Lafaille JJ. Induced CD4Foxp3 regulatory T cells in immune tolerance. Annu Rev Immunol 2012; 30:733-758.
15. Atarashi K, Tanoue T, Shima T, et al. Induction of colonic regulatory T cells by indigenous Clostridium species. Science 2011; 331:337-341.
16. Lathrop SK, Bloom SM, Rao SM, et al. Peripheral education of the immune system by colonic commensal microbiota. Nature 2011; 478: 250-254.
17. Zhou X, Bailey-Bucktrout SL, Jeker LT, et al. Instability of the transcription factor Foxp3 leads to the generation of pathogenic memory T cells in vivo. Nat Immunol 2009; 10:1000-1007.
18. Paust S, Lu L, McCarty N, Cantor H. Engagement of B7 on effector T cells by regulatory T cells prevents autoimmune disease. Proc Natl Acad Sci U S A,2004;101:10398-10403.
19. Read S, Malmstrom V, Powrie F.Cytotoxic T lymphocyte-associated antigen. 4 plays an essential role in the function of CD25()CD4() regulatory cells that control intestinal inflammation. J Exp Med,2000;192:295-302
20. Asseman C, Mauze S, Leach MW, et al. An essential role for interleukin 10 in the function of regulatory T cells that inhibit intestinal inflammation. J Exp Med 1999 190:995-1004.
21. Nakamura K, Kitani A, Strober W. Cell contact-dependent immunosuppression by CD4()CD25() regulatory T cells is mediated by cell surface-bound transforming growth factor beta. J Exp Med 2001; 194:629-644.
22. Green EA, Gorelik L, McGregor CM, et al. CD4CD25 T regulatory cells control antiislet CD8 T cells through TGF-beta-TGF-beta receptor interactions in type 1 diabetes. Proc Natl Acad Sci U S A 2003; 100:10878-10883.
23. Grossman WJ, Verbsky JW, Barchet W, et al. Human T regulatory cells can use the perforin pathway to cause autologous target cell death. Immunity ,2004;21;589-601.
24. Shevach EM. Mechanisms of foxp3 T regulatory cell-mediated suppression. Immunity 2009; 30:636-645.
25. Vignali DA, Collison LW, Workman CJ. How regulatory T cells work. Nat Rev Immunol 2008; 8:523-532.
26. Deaglio S, Dwyer KM, Gao W, et al. Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J Exp Med 2007; 204:1257-1265.
27. Mellor AL, Chandler P, Baban B, et al. Specific subsets of murine dendritic cells acquire potent T cell regulatory functions following CTLA4-mediated induction of indoleamine 2,3 dioxygenase. Int Immunol 2004; 16:1391-1401.
28. Glocker EO, Kotlarz D, Klein C, et al. IL-10 and IL-10 receptor defects in humans. Ann N Y Acad Sci 2011; 1246:102-107.
29. Verbsky JW, Grossman WJ. Hemophagocytic lymphohistiocytosis: diagnosis, pathophysiology, treatment, and future perspectives. Ann Med 2006; 38:20-31.
30. Caudy AA, Reddy ST, Chatila T, et al. CD25 deficiency causes an immune dysregulation, polyendocrinopathy, enteropathy, X-linked-like syndrome, and defective IL-10 expression from CD4 lymphocytes. J Allergy Clin Immunol.2007;119:482-487.
31. Verbsky JW, Chatila TA. T-regulatory cells in primary immune deficiencies. Curr Opin Allergy Clin Immunol 2011; 11:539-544.
32. Li B, Samanta A, Song X, et al. FOXP3 is a homo-oligomer and a component of a supramolecular regulatory complex disabled in the human XLAAD/IPEX autoimmune disease. Int Immunol 2007; 19:825-835.
33. Chatila TA, Williams CB. Foxp3: shades of tolerance. Immunity 2012;36:693-694
34. Ono M, Yaguchi H, Ohkura N, et al. Foxp3 controls regulatory T-cell function by interacting with AML1/Runx1. Nature 2007; 446:685-689.
35. WuY, BordeM, Heissmeyer V, et al. FOXP3 controls regulatory T cell function through cooperation with NFAT. Cell 2006; 126:375-387.
36. d'Hennezel E, Bin Dhuban K, Torgerson T, Piccirillo CA. The immunogenetics of immune dysregulation, polyendocrinopathy, enteropathy, X linked (IPEX) syndrome. J Med Genet 2012; 49:291-302.
37. Torgerson TR, Linane A, Moes N, et al. Severe food allergy as a variant of IPEX syndrome caused by a deletion in a noncoding region of the FOXP3 gene. Gastroenterology 2007; 132:1705-1717.
38. Yong PL, Russo P, Sullivan KE. Use of sirolimus in IPEX and IPEX-like children. J Clin Immunol 2008; 28:581-587.
39. De Benedetti F, Insalaco A, Diamanti A, et al. Mechanistic associations of a mild phenotype of immunodysregulation, polyendocrinopathy, enteropathy, x-linked syndrome. Clin Gastroenterol Hepatol 2006; 4:653-659.
40. Lin W, Truong N, Grossman WJ, et al. Allergic dysregulation and hyperimmunoglobulinemia E in Foxp3 mutant mice. J Allergy Clin Immunol 2005;116:1106-1115.
41. Clark LB, Appleby MW, Brunkow ME, et al. Cellular and molecular characterization of the scurfy mouse mutant. J Immunol 1999; 162:2546-2554.
42. Blair PJ, Bultman SJ, Haas JC, et al. CD4CD8-T cells are the effector cells in disease pathogenesis in the scurfy (sf) mouse. J Immunol 1994; 153:3764-3774.
43. Lyon MF, Peters J, Glenister PH, et al. The scurfy mouse mutant has previously unrecognized hematological abnormalities and resembles Wiskott-Aldrich syndrome. Proc Natl Acad Sci U S A 1990; 87:2433-2437.
44. Godfrey VL, Wilkinson JE, Russell LB. X-linked lymphoreticular disease in the scurfy (sf) mutant mouse. Am J Pathol 1991; 138:1379-1387.
45. Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4CD25 regulatory T cells. Nat Immunol 2003; 4:330-336.
46. Lin W, Truong N, Grossman WJ, et al. Allergic dysregulation and hyper immunoglobulinemia E in Foxp3 mutant mice. J Allergy Clin Immunol 2005;116:1106-1115.
47. Chinen T, Volchkov PY, Chervonsky AV, Rudensky AY. A critical role for regulatory T cell-mediated control of inflammation in the absence of commensal microbiota. J Exp Med 2010; 207:2323-2330.
48. Rivas MN, Koh YT, Chen A, et al. MyD88 is critically involved in immune tolerance breakdown at environmental interfaces of Foxp3-deficient mice. J Clin Invest 2012; 122:1933-1947.
49. Sharfe N, Dadi HK, Shahar M, Roifman CM. Human immune disorder arising from mutation of the alpha chain of the interleukin-2 receptor. Proc Natl Acad Sci U S A 1997; 94:3168-3171.
50. Roifman CM. Human IL-2 receptor alpha chain deficiency. Pediatr Res 2000;48:6-11.
51. Goudy K, Aydin D, Barzaghi F, et al. Human IL2RA null mutation mediates immunodeficiency with lymphoproliferation and autoimmunity. Clin Immunol.2013;146:248-261.
52. Asano M, Toda M, Sakaguchi N, Sakaguchi S. Autoimmune disease as a consequence of developmental abnormality of a T cell subpopulation. J Exp Med 1996; 184:387-396.
53. Sakaguchi S, Sakaguchi N, Asano M, et al. 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 1995; 155:1151-1164.
54. Setoguchi R, Hori S, Takahashi T, Sakaguchi S. Homeostatic maintenance of natural Foxp3() CD25() CD4() regulatory T cells by interleukin (IL)-2 and induction of autoimmune disease by IL-2 neutralization. J Exp Med 2005;201:723-735.
55. Fontenot JD, Rasmussen JP, Gavin MA, Rudensky AY. A function for interleukin. 2 in Foxp3-expressing regulatory T cells. Nat Immunol,2005;6:1142- 1151
56. de la Rosa M, Rutz S, Dorninger H, Scheffold A. Interleukin-2 is essential for CD4CD25 regulatory T cell function. Eur J Immunol 2004; 34:2480-2488.
57. Furtado GC, Curotto de Lafaille MA, Kutchukhidze N, Lafaille JJ. Interleukin 2 signaling is required for CD4() regulatory T cell function. J Exp Med 2002;196:851-857.
58. Barron L, Dooms H, Hoyer KK, et al. Cutting edge: mechanisms of IL-2-dependent maintenance of functional regulatory T cells. J Immunol 2010;185:6426-6430.
59. Pandiyan P, Zheng L, Ishihara S, et al. CD4CD25Foxp3 regulatory T cells induce cytokine deprivation-mediated apoptosis of effector CD4 T cells. Nat Immunol 2007; 8:1353-1362.
60. Davidson TS, DiPaolo RJ, Andersson J, Shevach EM. Cutting Edge: IL-2 is essential for TGF-beta-mediated induction of Foxp3 T regulatory cells. J Immunol 2007; 178:4022-4026.
61. Zheng SG, Wang J, Horwitz DA. Cutting edge: Foxp3CD4CD25 regulatory T cells induced by IL-2 and TGF-beta are resistant to Th17 conversion by IL-6. J Immunol 2008; 180:7112-7116.
62. Liao W, Lin JX, Leonard WJ. Interleukin-2 at the crossroads of effector responses, tolerance, and immunotherapy. Immunity 2013; 38:13-25.
63. Poltorak A, He X, Smirnova I, et al. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 1998; 282:2085-2088.
64. Liao W, Lin JX, Wang L, et al. Modulation of cytokine receptors by IL-2 broadly regulates differentiation into helper T cell lineages. Nat Immunol2011; 12:551-559.
65. Shi M, Lin TH, Appell KC, Berg LJ. Janus-kinase-3-dependent signals induce chromatin remodeling at the Ifng locus during T helper 1 cell differentiation. Immunity 2008; 28:763-773.
66. Liao W, Schones DE, Oh J, et al. Priming for T helper type 2 differentiation by interleukin 2-mediated induction of interleukin 4 receptor alpha-chain expression. Nat Immunol 2008; 9:1288-1296.
67. Laurence A, O'Shea JJ. T(H)-17 differentiation: of mice and men. Nat Immunol. 2007;8:903-905.
68. Amadi-Obi A, Yu CR, Liu X, et al. TH17 cells contribute to uveitis and scleritis and are expanded by IL-2 and inhibited by IL-27/STAT1. Nat Med 2007;13:711-718.
69. Ballesteros-Tato A, Leon B, Graf BA, et al. Interleukin-2 inhibits germinal center formation by limiting T follicular helper cell differentiation. Immunity. 2012;36:847-856.
70. Johnston RJ, Choi YS, Diamond JA, et al. STAT5 is a potent negative regulator of TFH cell differentiation. J Exp Med 2012; 209:243-250.
71. Pipkin ME, Sacks JA, Cruz-Guilloty F, et al. Interleukin-2 and inflammation induce distinct transcriptional programs that promote the differentiation of effector cytolytic T cells. Immunity 2010; 32:79-90.
72. Williams MA, Tyznik AJ, Bevan MJ. Interleukin-2 signals during priming are required for secondary expansion of CD8 memory T cells. Nature 2006;441:890-893.
73. Siegel JP, Sharon M, Smith PL, Leonard WJ. The IL-2 receptor beta chain (p70): role in mediating signals for LAK, NK, and proliferative activities. Science 1987; 238:75-78.
74. Mingari MC, Gerosa F, Carra G, et al. Human interleukin-2 promotes proliferation of activated B cells via surface receptors similar to those of activated T cells. Nature 1984; 312:641-643.
75. Leonard WJ, O'Shea JJ. Jaks and STATs: biological implications. Annu Rev Immunol 1998; 16:293-322.
76. Ihle JN. The Stat family in cytokine signaling. Curr Opin Cell Biol 2001;13:211-217.
77. Socolovsky M, Fallon AE, Wang S, et al. Fetal anemia and apoptosis of red cell progenitors in Stat5a-/-5b-/-mice: a direct role for Stat5 in Bcl-X(L) induction. Cell 1999; 98:181-191.
78. Cui Y, Riedlinger G, Miyoshi K, et al. Inactivation of Stat5 in mouse mammary epithelium during pregnancy reveals distinct functions in cell proliferation, survival, and differentiation. Mol Cell Biol 2004; 24:8037-8047.
79. Kofoed EM, Hwa V, Little B, et al. Growth hormone insensitivity associated with a STAT5b mutation. N Engl J Med 2003; 349:1139-1147.
80. Hwa V, Little B, Adiyaman P, et al. Severe growth hormone insensitivity resulting from total absence of signal transducer and activator of transcription.5b, J Clin Endocrinol Metab.2005;90:4260-4266
81. Vidarsdottir S, Walenkamp MJ, Pereira AM, et al. Clinical and biochemical characteristics of a male patient with a novel homozygous STAT5b mutation. J Clin Endocrinol Metab 2006; 91:3482-3485.
82. Walenkamp MJ, Vidarsdottir S, Pereira AM, et al. Growth hormone secretion and immunological function of a male patient with a homozygous STAT5b mutation. Eur J Endocrinol 2007; 156:155-165.
83. Bernasconi A, Marino R, Ribas A, et al. Characterization of immunodeficiency in a patient with growth hormone insensitivity secondary to a novel STAT5b gene mutation. Pediatrics 2006; 118:e1584-e1592.
84. Hwa V, Camacho-Hubner C, Little BM, et al. Growth hormone insensitivity and severe short stature in siblings: a novel mutation at the exon 13-intron 13 junction of the STAT5b gene. Horm Res 2007; 68:218-224.
85. Pugliese-Pires PN, Tonelli CA, Dora JM, et al. A novel STAT5B mutation causing GH insensitivity syndrome associated with hyperprolactinemia and immune dysfunction in two male siblings. Eur J Endocrinol 2010; 163:349-355.
86. Liu L, Okada S, Kong XF, et al. Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis. J Exp Med 2011; 208:1635-1648.
87. van de Veerdonk FL, Plantinga TS, Hoischen A, et al. STAT1 mutations in autosomal dominant chronic mucocutaneous candidiasis. N Engl J Med.2011;365:54-61.
88. Boisson-Dupuis S, Kong XF, Okada S, et al. Inborn errors of human STAT1: allelic heterogeneity governs the diversity of immunological and infectious phenotypes. Curr Opin Immunol 2012; 24:364-378.
89. Uzel G, Sampaio EP, Lawrence MG, et al. Dominant gain-of-function STAT1 mutations in FOXP3 wild-type immune dysregulation-polyendocrinopathyenteropathy- X-linked-like syndrome. J Allergy Clin Immunol 2013; 131:1611-1623; e1613
90. Lohr NJ, Molleston JP, Strauss KA, et al. Human ITCH E3 ubiquitin ligase deficiency causes syndromic multisystem autoimmune disease. Am J Hum Genet 2010; 86:447-453.
91. Perry WL, Hustad CM, Swing DA, et al. The itchy locus encodes a novel ubiquitin protein ligase that is disrupted in a18H mice. Nat Genet 1998;18:143-146.
92. Fang D, Elly C, Gao B, et al. Dysregulation of T lymphocyte function in itchy mice: a role for Itch in TH2 differentiation. Nat Immunol 2002;3:281-287.
93. Gao M, Labuda T, Xia Y, et al. Jun turnover is controlled through JNKdependent phosphorylation of the E3 ligase Itch. Science 2004; 306:271-275.
94. Fang D, Kerppola TK. Ubiquitin-mediated fluorescence complementation reveals that Jun ubiquitinated by Itch/AIP4 is localized to lysosomes. Proc Natl Acad Sci U S A 2004; 101:14782-14787.
95. Heissmeyer V, Macian F, Im SH, et al. Calcineurin imposes T cell unresponsiveness through targeted proteolysis of signaling proteins. Nat Immunol. 2004;5;255-265.
96. Venuprasad K, Huang H, Harada Y, et al. The E3 ubiquitin ligase Itch regulates expression of transcription factor Foxp3 and airway inflammation by enhancing the function of transcription factor TIEG1. Nat Immunol 2008; 9:245-253.