Abstract
Autosomal dominant Hyper-IgE syndrome (AD-HIES) is a rare primary immunodeficiency characterized by eczema, recurrent skin and lung infections, elevated serum IgE, and various connective tissue, skeletal, and vascular abnormalities. Mutations in signal transducer and activator of transcription 3 (STAT3) have recently been found to account for most cases; however, the pathogenesis of the varied features remains poorly defined. A distinct syndrome, known as autosomal recessive HIES (AR-HIES) manifests as severe eczema, recurrent bacterial and viral skin infections, and sinopulmonary infections. As opposed to STAT3 deficient HIES, AR-HIES lacks the connective tissue and skeletal manifestations but has an increase in neurologic abnormalities. In this review, we discuss the clinical presentations, genetic etiologies, and immunologic abnormalities of these two syndromes. In addition, we discuss animal models of STAT3 deficiency that provide insight into the pathogenesis of HIES. Further understanding of how STAT3 results in the diverse manifestations of HIES will allow us to develop more specific therapies for HIES as well as for many of the manifestations, such as scoliosis, recurrent staphylococcal infections, and eczema, which are common in the general population.
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References
Davis SD, Schaller J, Wedgwood RJ 1966 Job's syndrome. Recurrent, “cold” staphylococcal abscesses. Lancet 1: 1013–1015
Buckley RH, Wray BB, Belmaker EZ 1972 Extreme hyperimmunoglobulinemia E and undue susceptibility to infection. Pediatrics 49: 59–70
Buckley RH 2001 The hyper IgE syndrome. Clin Rev Allergy Immunol 20: 139–154
Grimbacher B, Holland SM, Gallin JI, Greenberg F, Hill SC, Malech HL, Miller JA, O'Connell AC, Puck JM 1999 Hyper-IgE syndrome with recurrent infections—an autosomal dominant multisystem disorder. N Engl J Med 340: 692–702
Holland SM, DeLeo FR, Elloumi HZ, Hsu AP, Uzel G, Brodsky N, Freeman AF, Demidowich A, Davis J, Turner ML, Anderson VL, Darnell DN, Welch PA, Kuhns DB, Frucht DM, Malech HL, Gallin JI, Kobayashi SD, Whiteny AR, Voyich JM, Musser JM, Woellner C, Schaffer AA, Puck JM, Grimbacher B 2007 STAT3 mutations in they hyper-IgE syndrome. N Engl J Med 357: 1608–1619
Jiao H, Toth B, Fransson I, Rakoczi E, Balogh I, Magyarics Z, Derfalvi B, Csorba G, Szaflarska A, Megarbane A, Akatcherian C, Dbaibo G, Rajnavolgyi E, Hammarstrom L, Kere J, Lefranc G, Marodi L 2008 Novel and recurrent STAT3 mutations in hyper-IgE syndrome patients from different ethnic groups. Mol Immunol 46: 202–206
Minegishi Y, Saito M, Tsuchiya S 2007 Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome. Nature 448: 1058–1062
Renner ED, Ryalaarsdam S, Anover-Sombke S, Rack AL, Reichenbach J, Carey JC, Zhu Q, Jansson AF, Barboza J, Schimke LF, Leppert MF, Getz MM, Seger RA, Hill HR, Belohradsky BH, Torgerson TR, Ochs HD 2008 Novel signal transducer and activator of transcription 3 (STAT3) mutations, reduced T(H)17 cell numbers, and STAT3 phosphorylation in hyper-IgE syndrome. J Allergy Clin Immunol 122: 181–187
Renner ED, Puck JM, Holland SM, Schmitt M, Weiss M, Frosch M, Bergmann M, Davis J, Belohradsky BH, Grimbacher B 2004 Autosomal recessive hyperimmunoglobulin E syndrome: a distinct disease entity. J Pediatr 144: 93–99
Chamlin SL, McCalmont TH, Cunningham BB, Esterly NB, Lai CH, Mallory SB, Mancini AJ, Tamburro J, Frieden IJ 2002 Cutaneous manifestations of hyper-IgE syndrome in infants and children. J Pediatr 141: 572–575
Eberting CL, Davis J, Puck JM, Holland SM 2004 Dermatitis and the newborn rash of hyper-IgE syndrome. Arch Dermatol 140: 1119–1125
Freeman A, Kleiner D, Nadiminti H, Davis J, Quezado M, Anderson V, Puck JM, Holland SM 2007 Causes of death in hyper IgE syndrome. J Allergy Clin Immunol 119: 1234–1240
Freeman AF, Davis J, Anderson VL, Barson W, Darnell DN, Puck JM, Holland SM 2006 Pneumocystis jiroveci infection in patients with hyper-immunoglobulin E syndrome. Pediatrics 118: e1271–e1275
Hutto JO, Bryan CS, Greene FL, White CJ, Gallin JL 1988 Cryptococcosis of the colon resembling Crohn's disease in a patient with the hyperimmunoglobulinemia E syndrome. Gastroenterology 94: 808–812
Jacobs DH, Macher AM, Handler R, Bennett JE, Collen MJ, Gallin JI 1984 Esophageal cryptococcosis in a patient with the hyperimmunoglobulin E-recurrent infection (Job's) syndrome. Gastroenterology 87: 201–203
Freeman AF, Collura-Burke CJ, Patronas NJ, Ilcus LS, Darnell D, Davis J, Puck JM, Holland SM 2007 Brain abnormalities in patients with hyperimmunoglobulin E syndrome. Pediatrics 119: e1121–e1125
Hoger PH, Boltshauser E, Hitzig WH 1985 Craniosynostosis in hyper-IgE syndrome. Eur J Pediatr 144: 414–417
Smithwick EM, Finelt M, Pahwa S, Good RA, Naspitz CK, Mendes NF, Kopersztyk S, Spira TJ, Nahmias AJ 1978 Cranial synostosis in job's syndrome. Lancet 1: 826
O'Connell AC, Puck JM, Grimbacher B, Facchetti F, Majorana A, Gallin JI, Malech HL, Holland SM 2000 Delayed eruption of permanent teeth in hyperimmunoglobulinemia E recurrent infection syndrome. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 89: 177–185
Domingo DL, Freeman AF, Davis J, Puck JM, Tianxia W, Holland SM, Hart TC 2008 Novel intraoral phenotypes in hyper immunoglobulin E syndrome. Oral Dis 14: 73–81
Alomar-Melero E, Martin TD, Janelle GM, Peng YG 2008 An unusual giant right coronary artery aneurysm resembles an intracardiac mass. Anesth Analg 107: 1161–1162
Ling JC, Freeman AF, Gharib AM, Arai AE, Lederman RJ, Rosing DR, Holland SM 2007 Coronary artery aneurysms in patients with hyper IgE recurrent infection syndrome. Clin Immunol 122: 255–258
Young TY, Jerome D, Gupta S 2007 Hyperimmunoglobulinemia E syndrome associated with coronary artery aneurysms: deficiency of central memory CD4+ T cells and expansion of effector memory CD4+ T cells. Ann Allergy Asthma Immunol 98: 389–392
Leonard GD, Posadas E, Herrmann PC, Anderson VL, Jaffe ES, Holland SM, Wilson WH 2004 Non-Hodgkin's lymphoma in Job's syndrome: a case report and review of the literature. Leuk Lymphoma 45: 2521–2525
Gorin LJ, Jeha SC, Sullivan MP, Rosenblatt HM, Shearer WT 1989 Burkitt's lymphoma developing in a 7 year old body with hyper IgE syndrome. J Allergy Clin Immunol 83: 5–10
Oztop I, Demirkan B, Tarhan O, Kayahan H, Yilmaz U, Kargi A, Alakavuklar M 2004 The development of a pulmonary adenocarcinoma in a patient with Job's syndrome. Tumori 90: 132–135
Speckmann C, Enders A, Woellner C 2008 Reduced memory B cells in patients with hyper IgE syndrome. Clin Immunol 129: 448–454
de Beaucoudrey L, Puel A, Filipe-Santos O, Cobat A, Ghandil P, Chrabieh M, Feinberg J, von Bernuth H, Samarina A, Jannière L, Fieschi C, Stéphan JL, Boileau C, Lyonnet S, Jondeau G, Cormier-Daire V, Le Merrer M, Hoarau C, Lebranchu Y, Lortholary O, Chandesris MO, Tron F, Gambineri E, Bianchi L, Rodriguez-Gallego C, Zitnik SE, Vasconcelos J, Guedes M, Vitor AB, Marodi L, Chapel H, Reid B, Roifman C, Nadal D, Reichenbach J, Caragol I, Garty BZ, Dogu F, Camcioglu Y, Gülle S, Sanal O, Fischer A, Abel L, Stockinger B, Picard C, Casanova JL 2008 Mutations in STAT3 and IL12RB1 impair the development of human IL-17 producing T cells. J Exp Med 205: 1543–1550
Ma CS, Chew GY, Simpson N, Priyadarshi A, Wong M, Grimbacher B, Fulcher DA, Tangye SG, Cook MC 2008 Deficiency of Th17 cells in hyper IgE syndrome due to mutations in STAT3. J Exp Med 205: 1551–1557
Levy DE, Loomis CA 2007 STAT3 signaling and the hyper IgE syndrome. N Engl J Med 357: 1655–1658
Murray PJ 2007 The JAK-STAT signaling pathway: input and output integration. J Immunol 178: 2623–2629
Yeganeh M, Henneke P, Rezaei N, Ehl S, Thiel D, Matamoros N, Pietrogrande C, Espanol T, Litzman J, Franco JL, Sanal O, Kilic SS, Breborowicz A, Plebani A, Renner E, Rothenfusser S, Hawn TR, Woellner C, Grimbacher B 2008 Toll-like receptor stimulation induces higher TNF-a secretion in peripheral blood mononuclear cells from patients with hyper IgE syndrome. Int Arch Allergy Immunol 146: 190–194
Takeda K, Clausen BE, Kaisho T, Tsujimura T, Terada N, Forster I, Akira S 1999 Enhanced Th1 activity and development of chronic enterocolitis in mice devoid of Stat3 in macrophages and neutrophils. Immunity 10: 39–49
Chou WC, Levy DE, Lee CK 2006 STAT3 positively regulates an early step in B cell development. Blood 108: 3005–3011
Harris TJ, Grosso JF, Yen HR, Xin H, Kortylewski M, Albesiano E, Hipkiss EL, Getnet D, Goldberg MV, Maris CH, Housseau F, Yu H, Pardoll DM, Drake CG 2007 An in vivo requirement for STAT3 signaling in Th17 Development and Th17 dependant autoimmunity. J Immunol 179: 4313–4317
Milner JD, Brenchley JM, Laurence A, Freeman AF, Hill BJ, Elias KM, Kanno Y, Spalding C, Elloumi HZ, Paulson ML, Davis J, Hsu A, Asher AI, O'Shea J, Holland SM, Paul WE, Douek DC 2008 Impaired Th17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome. Nature 452: 773–776
Dong C 2008 Th17 cells in development: an updated view of their molecular identity and genetic programming. Nat Rev Immunol 8: 337–348
Aujla SJ, Chan YR, Zheng M, Fei M, Askew DJ, Pociask DA, Reinhart TA, McAllister F, Edeal J, Gaus K, Husain S, Kreindler JL, Dubin PJ, Pilewski JM, Myerburn MM, Mason CA, Iwakura Y, Kolls JK 2008 IL-22 medicates mucosal host defense against gram-negative bacterial pneumonia. Nat Med 14: 275–281
Huang W, Na L, Fidel PL, Schwarzenberger P 2004 Requirement of interleukin-17A for systemic anti-Candida albicans host defense in mice. J Infect Dis 190: 624–631
Wolk K, Kunz S, Witte E, Friedrich M, Asadullah K, Sabat R 2004 IL-22 increases the innate immunity of tissues. Immunity 21: 241–254
Ong PY, Ohtake T, Brandt C 2002 Endogenous antimicrobial peptides and skin infections in atopic dermatitis. N Engl J Med 347: 1151–1160
Kao CY, Chen Y, Thai P, Wachi S, Kim C, Tam L, Wu R 2004 IL-17 markedly up-regulates beta-defensin-2 expression in human airway epithelium via JAK and NF-kB signaling pathways. J Immunol 173: 3482–3491
Ozaki K, Spolski R, Feng CG, Qi CF, Cheng J, Sher A, Morse HC 3rd, Liu C, Schwartzberg PL, Leonard WJ 2002 A critical role for IL-21 in regulating immunoglobulin production. Science 298: 1630–1634
Avery DT, Ma CS, Bryant VL, Santner-Nanan B, Nanan R, Wong M, Fulcher DA, Cook MC, Tangye SG 2008 STAT3 is required for IL-21 induced secretion of IgE from human naïve B cells. Blood 112: 1784–1793
Takeda K, Noguchi K, Shi W, Tanaka T, Matsumoto M, Yoshida N, Kishimoto T, Akira S 1997 Targeted disruption of the mouse Stat3 gene leads to early embryonic lethality. Proc Natl Acad Sci U S A 94: 3801–3804
Hokuto I, Ikegami M, Yoshida M, Takeda K, Akira S, Perl AK, Hull WM, Wert SE, Whitsett JA 2004 Stat-3 is required for pulmonary homeostasis during hyperoxia. J Clin Invest 113: 28–37
Zhang Z, Welte T, Troiano N, Maher SE, Fu XY, Bothwell AL 2005 Osteoporosis with increased osteoclastogenesis in hematopoietic cell-specific STAT3-deficient mice. Biochem Biophys Res Commun 328: 800–807
Datta HK, Ng WF, Walker JA, Tuck SP, Varanasi SS 2008 The cell biology of bone metabolism. J Clin Pathol 61: 577–587
Okada S, Nakamura M, Katoh H, Miyao T, Shimazaki T, Ishii K, Yamane J, Yoshimura A, Iwamoto Y, Toyama Y, Okano H 2006 Conditional ablation of Stat3 or Socs3 discloses a dual role for reactive astrocytes after spinal cord injury. Nat Med 12: 829–834
Hilfiker-Kleiner D, Hilfiker A, Fuchs M, Kaminski K, Schaefer A, Schieffer B, Hillmer A, Schmiedl A, Ding Z, Podewski E, Podewski E, Poli V, Schneider MD, Schulz R, Park JK, Wollert KC, Drexler H 2004 Signal transducer and activator of transcription 3 is required for myocardial capillary growth, control of interstitial matrix deposition and heart protection from ischemic injury. Circ Res 95: 187–195
Scarabelli TM, Townsend PA, Chen Scarabelli C, Yuan Z, McCauley RB, Di Rezze J, Patel D, Putt J, Allebban Z, Abboud J, Chilukuri K, Gardin J, Saravolatz L, Knight RA, Latchman DS, Stephanou A 2008 Amino acid supplementation differentially modulates STAT1 and STAT3 activation in the myocardium exposed to ischemia/reperfusion injury. Am J Cardiol 101: 63E–68E
Olive M, Mellad JA, Beltran LE, Ma M, Cimato T, Noguchi AC, San H, Childs R, Kovacic JC, Boehm M 2008 p21Cip1 modulates arterial wound repair through the stromal cell-derived factor-1/CXCR4 axis in mice. J Clin Invest 118: 2050–2061
Sano S, Itami S, Takeda K, Tarutani M, Yamaguchi Y, Miura H, Yoshikawa K, Akira S, Takeda J 1999 Keratinocyte-specific ablation of Stat3 exhibits impaired skin remodeling, but does not affect skin morphogenesis. EMBO J 18: 4657–4668
Kimata H 1995 High dose intravenous gammaglobulin treatment for hyperimmunoglobulinemia E syndrome. J Allergy Clin Immunol 95: 771–774
Wakim M, Alazard M, Yajima A, Speights D, Saxon A, Stiehm ER 1998 High dose intravenous immunoglobulin in atopic dermatitis and hyper-IgE syndrome. Ann Allergy Asthma Immunol 81: 153–158
Donabedian H, Alling DW, Gallin JI 1982 Levamisole is inferior to placebo in the hyperimmunoglobulin E recurrent infection (Job's) syndrome. N Engl J Med 307: 290–292
King CL, Gallin JI, Malech HL, Abramson SL, Nutman TB 1989 Regulation of immunoglobulin production in hyperimmunoglobulin E recurrent infection syndrome by IFN-gamma. Proc Natl Acad Sci U S A 86: 10085–10089
Thompson RA, Kumararatne DS 1989 Hyper-IgE syndrome and H2 receptor blockade. Lancet 2: 630
Etzioni A, Shehadeh N, Brecher A, Yorman S, Pollack S 1997 Cyclosporin A in hyperimmunoglobulin E syndrome. Ann Allergy Asthma Immunol 78: 413–414
Gennery AR, Flood TJ, Abinun M, Cant AJ 2000 Bone marrow transplantation does not correct the hyper-IgE syndrome. Bone Marrow Transplant 25: 1303–1305
Minegishi Y, Saito M, Morio T, Watanabe K, Agematsu K, Tsuchiya S, Takada H, Hara T, Kawamaura N, Ariga T, Kaneko H, Kondo N, Tsuge I, Yachie A, Sakiyama Y, Iwata T, Bessho F, Ohishi T, Joh K, Imai K, Kogawa K, Shinohara M, Fujieda M, Wakiguchi H, Pasic S, Abinun M, Ochs HD, Renner ED, Jansson A, Belohradsky BH, Metin A, Shimizu N, Mizutani S, Miyawaki T, Nonoyama S, Karasuyama H 2006 Human tyrosine kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired immunity. Immunity 25: 745–755
Woellner C, Schaffer AA, Puck JM, Renner ED, Knebel C, Holland SM, Plebani A, Grimbacher B 2007 The hyper IgE syndrome and mutations in Tyk2. Immunity 26: 535
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This research was supported by the National Institute of Allergy and Infectious Diseases. This project has been funded, in part, with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E.
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Freeman, A., Holland, S. Clinical Manifestations, Etiology, and Pathogenesis of the Hyper-IgE Syndromes. Pediatr Res 65, 32–37 (2009). https://doi.org/10.1203/PDR.0b013e31819dc8c5
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DOI: https://doi.org/10.1203/PDR.0b013e31819dc8c5
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