The Ying and Yang of STAT3 in Human Disease

Journal of Clinical Immunology

Volumn 35, Issue 7, 2015, Pages 615-623

  Vogel, Tiphanie P ^a   Milner, Joshua D ^b   Cooper, Megan A ^a  

^a WASHINGTON UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES   (United States)

Author keywords

gain of function; Hyper IgE syndrome; Job syndrome; monogenic autoimmunity; STAT3

Indexed keywords

ANTIBIOTIC AGENT; IMMUNOGLOBULIN; STAT3 PROTEIN;

ANTIBIOTIC PROPHYLAXIS; AUTOSOMAL DOMINANT DISORDER; BONE MARROW TRANSPLANTATION; CLINICAL FEATURE; GAIN OF FUNCTION MUTATION; GERMLINE MUTATION; HUMAN; HYPER IGE SYNDROME; IMMUNE DEFICIENCY; IMMUNOTHERAPY; LOSS OF FUNCTION MUTATION; MURINE MODEL; NONHUMAN; PRIORITY JOURNAL; REVIEW; SOMATIC MUTATION; ADULT STEM CELL; ANIMAL; AUTOIMMUNE DISEASE; DISEASE MODEL; GENETICS; HEMATOLOGIC DISEASE; METABOLISM; MUTATION; PHOSPHORYLATION; PHYSIOLOGY;

ADULT STEM CELLS; ANIMALS; AUTOIMMUNE DISEASES; DISEASE MODELS, ANIMAL; HEMATOLOGIC NEOPLASMS; HUMANS; JOB SYNDROME; MUTATION; PHOSPHORYLATION; STAT3 TRANSCRIPTION FACTOR;

EID: 84946485705     PISSN: 02719142     EISSN: 15732592     Source Type: Journal    
DOI: 10.1007/s10875-015-0187-8     Document Type: Review

References (103)

1. Zhong Z, Wen Z, Darnell Jr JE. Stat3: a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6. Science. 1994;264(5155):95–8.
2. Levy DE, Darnell Jr JE. Stats: transcriptional control and biological impact. Nat Rev Mol Cell Biol. 2002;3(9):651–62.
3. Holland SM et al. STAT3 mutations in the hyper-IgE syndrome. N Engl J Med. 2007;357(16):1608–19.
4. Minegishi Y et al. Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome. Nature. 2007;448(7157):1058–62.
5. Koskela HL et al. Somatic STAT3 mutations in large granular lymphocytic leukemia. N Engl J Med. 2012;366(20):1905–13.
6. Flanagan SE et al. Activating germline mutations in STAT3 cause early-onset multi-organ autoimmune disease. Nat Genet. 2014;46(8):812–4.
7. Milner JD et al. Early-onset lymphoproliferation and autoimmunity caused by germline STAT3 gain-of-function mutations. Blood. 2015;125(4):591–9.
8. Haapaniemi EM et al. Autoimmunity, hypogammaglobulinemia, lymphoproliferation, and mycobacterial disease in patients with activating mutations in STAT3. Blood. 2015;125(4):639–48.
9. O’Shea JJ, Holland SM, Staudt LM. JAKs and STATs in immunity, immunodeficiency, and cancer. N Engl J Med. 2013;368(2):161–70.
10. Mogensen TH. STAT3 and the Hyper-IgE syndrome: clinical presentation, genetic origin, pathogenesis, novel findings and remaining uncertainties. JAKSTAT. 2013;2(2), e23435.
11. UniProt C. UniProt: a hub for protein information. Nucleic Acids Res. 2015;43(Database issue):D204–12.
12. Ng IH et al. Selective STAT3-alpha or -beta expression reveals spliceform-specific phosphorylation kinetics, nuclear retention and distinct gene expression outcomes. Biochem J. 2012;447(1):125–36.
13. Shao H, Quintero AJ, Tweardy DJ. Identification and characterization of cis elements in the STAT3 gene regulating STAT3 alpha and STAT3 beta messenger RNA splicing. Blood. 2001;98(13):3853–6.
14. Dewilde S et al. Of alphas and betas: distinct and overlapping functions of STAT3 isoforms. Front Biosci. 2008;13:6501–14.
15. Maritano D et al. The STAT3 isoforms alpha and beta have unique and specific functions. Nat Immunol. 2004;5(4):401–9.
16. Chakraborty A, Tweardy DJ. Granulocyte colony-stimulating factor activates a 72-kDa isoform of STAT3 in human neutrophils. J Leukoc Biol. 1998;64(5):675–80.
17. Hevehan DL, Miller WM, Papoutsakis ET. Differential expression and phosphorylation of distinct STAT3 proteins during granulocytic differentiation. Blood. 2002;99(5):1627–37.
18. Villarino AV et al. Mechanisms of Jak/STAT signaling in immunity and disease. J Immunol. 2015;194(1):21–7.
19. Casanova JL, Holland SM, Notarangelo LD. Inborn errors of human JAKs and STATs. Immunity. 2012;36(4):515–28.
20. Wake, M.S. and C.J. Watson. STAT3 the oncogene - still eluding therapy? FEBS J. 2015;282(14):2600–11.
21. Yang J, Stark GR. Roles of unphosphorylated STATs in signaling. Cell Res. 2008;18(4):443–51.
22. Decker T, Kovarik P. Serine phosphorylation of STATs. Oncogene. 2000;19(21):2628–37.
23. Carow B, Rottenberg ME. SOCS3, a major regulator of infection and inflammation. Front Immunol. 2014;5:58.
24. Wegrzyn J et al. Function of mitochondrial Stat3 in cellular respiration. Science. 2009;323(5915):793–7.
25. Camporeale A, Poli V. IL-6, IL-17 and STAT3: a holy trinity in auto-immunity? Front Biosci (Landmark Ed). 2012;17:2306–26.
26. Takeda K et al. Targeted disruption of the mouse Stat3 gene leads to early embryonic lethality. Proc Natl Acad Sci U S A. 1997;94(8):3801–4.
27. Tangye SG, Cook MC, Fulcher DA. Insights into the role of STAT3 in human lymphocyte differentiation as revealed by the hyper-IgE syndrome. J Immunol. 2009;182(1):21–8.
28. Kane A et al. STAT3 is a central regulator of lymphocyte differentiation and function. Curr Opin Immunol. 2014;28:49–57.
29. Fornek JL et al. Critical role for Stat3 in T-dependent terminal differentiation of IgG B cells. Blood. 2006;107(3):1085–91.
30. Cui W et al. An interleukin-21-interleukin-10-STAT3 pathway is critical for functional maturation of memory CD8+ T cells. Immunity. 2011;35(5):792–805.
31. Takeda K et al. Enhanced Th1 activity and development of chronic enterocolitis in mice devoid of Stat3 in macrophages and neutrophils. Immunity. 1999;10(1):39–49.
32. Gotthardt D et al. Loss of STAT3 in murine NK cells enhances NK cell-dependent tumor surveillance. Blood. 2014;124(15):2370–9.
33. Davis SD, Schaller J, Wedgwood RJ. Job’s Syndrome. Recurrent, “cold”, staphylococcal abscesses. Lancet. 1966;1(7445):1013–5.
34. Buckley RH, Wray BB, Belmaker EZ. Extreme hyperimmunoglobulinemia E and undue susceptibility to infection. Pediatrics. 1972;49(1):59–70.
35. Grimbacher B et al. Hyper-IgE syndrome with recurrent infections--an autosomal dominant multisystem disorder. N Engl J Med. 1999;340(9):692–702.
36. Chandesris MO et al. Autosomal dominant STAT3 deficiency and hyper-IgE syndrome: molecular, cellular, and clinical features from a French national survey. Medicine (Baltimore). 2012;91(4):e1–19.
37. Jiao H et al. Novel and recurrent STAT3 mutations in hyper-IgE syndrome patients from different ethnic groups. Mol Immunol. 2008;46(1):202–6.
38. Schimke LF et al. Diagnostic approach to the hyper-IgE syndromes: immunologic and clinical key findings to differentiate hyper-IgE syndromes from atopic dermatitis. J Allergy Clin Immunol. 2010;126(3):611–7.
39. Woellner C et al. Mutations in STAT3 and diagnostic guidelines for hyper-IgE syndrome. J Allergy Clin Immunol. 2010;125(2):424–32.
40. Siegel AM et al. A critical role for STAT3 transcription factor signaling in the development and maintenance of human T cell memory. Immunity. 2011;35(5):806–18.
41. Chandesris MO et al. Frequent and widespread vascular abnormalities in human signal transducer and activator of transcription 3 deficiency. Circ Cardiovasc Genet. 2012;5(1):25–34.
42. Wallet N et al. Diffuse large B-cell lymphoma in hyperimmunoglobulinemia E syndrome. Clin Lymphoma Myeloma. 2007;7(6):425–7.
43. Sowerwine KJ, Holland SM, Freeman AF. Hyper-IgE syndrome update. Ann N Y Acad Sci. 2012;1250:25–32.
44. Siegel AM et al. Diminished allergic disease in patients with STAT3 mutations reveals a role for STAT3 signaling in mast cell degranulation. J Allergy Clin Immunol. 2013;132(6):1388–96.
45. Wolach O et al. Variable clinical expressivity of STAT3 mutation in hyperimmunoglobulin E syndrome: genetic and clinical studies of six patients. J Clin Immunol. 2014;34(2):163–70.
46. Grimbacher B et al. Genetic linkage of hyper-IgE syndrome to chromosome 4. Am J Hum Genet. 1999;65(3):735–44.
47. Milner JD et al. Impaired T(H)17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome. Nature. 2008;452(7188):773–6.
48. Ma CS et al. Deficiency of Th17 cells in hyper IgE syndrome due to mutations in STAT3. J Exp Med. 2008;205(7):1551–7.
49. de Beaucoudrey L et al. Mutations in STAT3 and IL12RB1 impair the development of human IL-17-producing T cells. J Exp Med. 2008;205(7):1543–50.
50. Burkett PR, Meyer Zu Horste G, Kuchroo VK. Pouring fuel on the fire: Th17 cells, the environment, and autoimmunity. J Clin Invest. 2015;125(6):2211–9.
51. Hsu AP et al. Intermediate phenotypes in patients with autosomal dominant hyper-IgE syndrome caused by somatic mosaicism. J Allergy Clin Immunol. 2013;131(6):1586–93.
52. Avery DT et al. B cell-intrinsic signaling through IL-21 receptor and STAT3 is required for establishing long-lived antibody responses in humans. J Exp Med. 2010;207(1):155–71.
53. Meyer-Bahlburg A et al. Heterozygous signal transducer and activator of transcription 3 mutations in hyper-IgE syndrome result in altered B-cell maturation. J Allergy Clin Immunol. 2012;129(2):559–62.
54. Deenick EK et al. Naive and memory human B cells have distinct requirements for STAT3 activation to differentiate into antibody-secreting plasma cells. J Exp Med. 2013;210(12):2739–53.
55. Ma CS et al. Functional STAT3 deficiency compromises the generation of human T follicular helper cells. Blood. 2012;119(17):3997–4008.
56. Ives ML et al. Signal transducer and activator of transcription 3 (STAT3) mutations underlying autosomal dominant hyper-IgE syndrome impair human CD8(+) T-cell memory formation and function. J Allergy Clin Immunol. 2013;132(2):400–11.
57. Wilson RP et al. STAT3 is a critical cell-intrinsic regulator of human unconventional T cell numbers and function. J Exp Med. 2015;212(6):855–64.
58. Saito M et al. Defective IL-10 signaling in hyper-IgE syndrome results in impaired generation of tolerogenic dendritic cells and induced regulatory T cells. J Exp Med. 2011;208(2):235–49.
59. Steward-Tharp SM et al. A mouse model of HIES reveals pro- and anti-inflammatory functions of STAT3. Blood. 2014;123(19):2978–87.
60. Zhang LY et al. Clinical features, STAT3 gene mutations and Th17 cell analysis in nine children with hyper-IgE syndrome in mainland China. Scand J Immunol. 2013;78(3):258–65.
61. Sundin M et al. Novel STAT3 mutation causing hyper-IgE syndrome: studies of the clinical course and immunopathology. J Clin Immunol. 2014;34(4):469–77.
62. Mogensen TH, Jakobsen MA, Larsen CS. Identification of a novel STAT3 mutation in a patient with hyper-IgE syndrome. Scand J Infect Dis. 2013;45(3):235–8.
63. Saikia B et al. Hyper-IgE syndrome with a novel STAT3 mutation-a single center study from India. Asian Pac J Allergy Immunol. 2014;32(4):321–7.
64. Renner ED et al. Novel signal transducer and activator of transcription 3 (STAT3) mutations, reduced T(H)17 cell numbers, and variably defective STAT3 phosphorylation in hyper-IgE syndrome. J Allergy Clin Immunol. 2008;122(1):181–7.
65. Yong PF et al. An update on the hyper-IgE syndromes. Arthritis Res Ther. 2012;14(6):228.
66. Goussetis E et al. Successful long-term immunologic reconstitution by allogeneic hematopoietic stem cell transplantation cures patients with autosomal dominant hyper-IgE syndrome. J Allergy Clin Immunol. 2010;126(2):392–4.
67. Nester TA et al. Effects of allogeneic peripheral stem cell transplantation in a patient with job syndrome of hyperimmunoglobulinemia E and recurrent infections. Am J Med. 1998;105(2):162–4.
68. Gennery AR et al. Bone marrow transplantation does not correct the hyper IgE syndrome. Bone Marrow Transplant. 2000;25(12):1303–5.
69. Patel NC et al. Successful haploidentical donor hematopoietic stem cell transplant and restoration of STAT3 function in an adolescent with autosomal dominant Hyper-IgE syndrome. J Clin Immunol. 2015;35(5):479–85.
70. Jerez A et al. STAT3 mutations unify the pathogenesis of chronic lymphoproliferative disorders of NK cells and T-cell large granular lymphocyte leukemia. Blood. 2012;120(15):3048–57.
71. Rajala HL et al. Uncovering the pathogenesis of large granular lymphocytic leukemia-novel STAT3 and STAT5b mutations. Ann Med. 2014;46(3):114–22.
72. Pilati C et al. Somatic mutations activating STAT3 in human inflammatory hepatocellular adenomas. J Exp Med. 2011;208(7):1359–66.
73. Jerez A et al. STAT3 mutations indicate the presence of subclinical T-cell clones in a subset of aplastic anemia and myelodysplastic syndrome patients. Blood. 2013;122(14):2453–9.
74. Verbsky JW, Chatila TA. Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) and IPEX-related disorders: an evolving web of heritable autoimmune diseases. Curr Opin Pediatr. 2013;25(6):708–14.
75. Oliveira JB, Fleisher T. Autoimmune lymphoproliferative syndrome. Curr Opin Allergy Clin Immunol. 2004;4(6):497–503.
76. Kimura A, Kishimoto T. IL-6: regulator of Treg/Th17 balance. Eur J Immunol. 2010;40(7):1830–5.
77. Chaudhry A et al. CD4+ regulatory T cells control TH17 responses in a Stat3-dependent manner. Science. 2009;326(5955):986–91.
78. Cohen AC et al. Cutting edge: decreased accumulation and regulatory function of CD4+ CD25(high) T cells in human STAT5b deficiency. J Immunol. 2006;177(5):2770–4.
79. Komatsu N et al. Pathogenic conversion of Foxp3+ T cells into TH17 cells in autoimmune arthritis. Nat Med. 2014;20(1):62–8.
80. Gagliani N et al. Th17 cells transdifferentiate into regulatory T cells during resolution of inflammation. Nature. 2015;523(7559):221–5.
81. Tsoi LC et al. Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity. Nat Genet. 2012;44(12):1341–8.
82. Danoy P et al. Association of variants at 1q32 and STAT3 with ankylosing spondylitis suggests genetic overlap with Crohn’s disease. PLoS Genet. 2010;6(12), e1001195.
83. Seddighzadeh M et al. Variants within STAT genes reveal association with anticitrullinated protein antibody-negative rheumatoid arthritis in 2 European populations. J Rheumatol. 2012;39(8):1509–16.
84. Barrett JC et al. Genome-wide association defines more than 30 distinct susceptibility loci for Crohn’s disease. Nat Genet. 2008;40(8):955–62.
85. Frampton JE. Tocilizumab: a review of its use in the treatment of juvenile idiopathic arthritis. Paediatr Drugs. 2013;15(6):515–31.
86. van Vollenhoven RF et al. Tofacitinib or adalimumab versus placebo in rheumatoid arthritis. N Engl J Med. 2012;367(6):508–19.
87. Lee EB et al. Tofacitinib versus methotrexate in rheumatoid arthritis. N Engl J Med. 2014;370(25):2377–86.
88. Dupuis S et al. Impairment of mycobacterial but not viral immunity by a germline human STAT1 mutation. Science. 2001;293(5528):300–3.
89. Dupuis S et al. Impaired response to interferon-alpha/beta and lethal viral disease in human STAT1 deficiency. Nat Genet. 2003;33(3):388–91.
90. Averbuch D et al. The clinical spectrum of patients with deficiency of signal transducer and activator of transcription-1. Pediatr Infect Dis J. 2011;30(4):352–5.
91. van de Veerdonk FL et al. STAT1 mutations in autosomal dominant chronic mucocutaneous candidiasis. N Engl J Med. 2011;365(1):54–61.
92. Liu L et al. Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis. J Exp Med. 2011;208(8):1635–48.
93. Hambleton S et al. STAT2 deficiency and susceptibility to viral illness in humans. Proc Natl Acad Sci U S A. 2013;110(8):3053–8.
94. Kofoed EM et al. Growth hormone insensitivity associated with a STAT5b mutation. N Engl J Med. 2003;349(12):1139–47.
95. Yildiz M et al. Activating STAT6 mutations in follicular lymphoma. Blood. 2015;125(4):668–79.
96. McDonald DR. TH17 deficiency in human disease. J Allergy Clin Immunol. 2012;129(6):1429–35.
97. He J et al. STAT3 mutations correlated with hyper-IgE syndrome lead to blockage of IL-6/STAT3 signalling pathway. J Biosci. 2012;37(2):243–57.
98. Uzel G et al. Dominant gain-of-function STAT1 mutations in FOXP3 wild-type immune dysregulation-polyendocrinopathy-enteropathy-X-linked-like syndrome. J Allergy Clin Immunol. 2013;131(6):1611–23.
99. Kristensen T et al. Clinical relevance of sensitive and quantitative STAT3 mutation analysis using next-generation sequencing in T-cell large granular lymphocytic leukemia. J Mol Diagn. 2014;16(4):382–92.
100. Ohgami RS et al. STAT3 mutations are frequent in CD30+ T-cell lymphomas and T-cell large granular lymphocytic leukemia. Leukemia. 2013;27(11):2244–7.
101. Miyazaki K et al. An adolescent with marked hyperimmuno-globulinemia E showing minimal change nephrotic syndrome and a STAT3 gene mutation. Clin Nephrol. 2011;75(4):369–73.
102. Giacomelli M et al. SH2-domain mutations in STAT3 in hyper-IgE syndrome patients result in impairment of IL-10 function. Eur J Immunol. 2011;41(10):3075–84.
103. Al Khatib S et al. Defects along the T(H)17 differentiation pathway underlie genetically distinct forms of the hyper IgE syndrome. J Allergy Clin Immunol. 2009;124(2):342–8.