Steven M. Holland, M.D., Frank R. DeLeo, Ph.D., Houda Z. Elloumi, Ph.D., Amy P. Hsu, B.A., Gulbu Uzel, M.D., Nina Brodsky, B.S., Alexandra F. Freeman, M.D., Andrew Demidowich, B.A., Joie Davis, A.P.R.N., Maria L. Turner, M.D., Victoria L. Anderson, C.R.N.P., Dirk N. Darnell, M.A., Pamela A. Welch, B.S.N., Douglas B. Kuhns, Ph.D., David M. Frucht, M.D., Harry L. Malech, M.D., John I. Gallin, M.D., Scott D. Kobayashi, Ph.D., Adeline R. Whitney, B.A., Jovanka M. Voyich, Ph.D., James M. Musser, M.D., Ph.D., Cristina Woellner, M.Sc., Alejandro A. Schäffer, Ph.D., Jennifer M. Puck, M.D., and Bodo Grimbacher, M.D.
Background The hyper-IgE syndrome (or Job's syndrome) is a raredisorder of immunity and connective tissue characterized bydermatitis, boils, cyst-forming pneumonias, elevated serum IgElevels, retained primary dentition, and bone abnormalities.Inheritance is autosomal dominant; sporadic cases are also found.
Methods We collected longitudinal clinical data on patientswith the hyper-IgE syndrome and their families and assayed thelevels of cytokines secreted by stimulated leukocytes and thegene expression in resting and stimulated cells. These dataimplicated the signal transducer and activator of transcription3 gene (STAT3) as a candidate gene, which we then sequenced.
Results We found increased levels of proinflammatory gene transcriptsin unstimulated peripheral-blood neutrophils and mononuclearcells from patients with the hyper-IgE syndrome, as comparedwith levels in control cells. In vitro cultures of mononuclearcells from patients that were stimulated with lipopolysaccharide,with or without interferon-, had higher tumor necrosis factor levels than did identically treated cells from unaffected persons(P=0.003). In contrast, the cells from patients with the hyper-IgEsyndrome generated lower levels of monocyte chemoattractantprotein 1 in response to the presence of interleukin-6 (P=0.03),suggesting a defect in interleukin-6 signaling through its downstreammediators, one of which is STAT3. We identified missense mutationsand single-codon in-frame deletions in STAT3 in 50 familialand sporadic cases of the hyper-IgE syndrome. Eighteen discretemutations, five of which were hot spots, were predicted to directlyaffect the DNA-binding and SRC homology 2 (SH2) domains.
Conclusions Mutations in STAT3 underlie sporadic and dominantforms of the hyper-IgE syndrome, an immunodeficiency syndromeinvolving increased innate immune response, recurrent infections,and complex somatic features.
Source Information
From the National Institute of Allergy and Infectious Diseases, Bethesda, MD (S.M.H., H.Z.E., A.P.H., G.U., N.B., A.F.F., A.D., V.L.A., D.N.D., P.A.W., H.L.M., J.I.G.), and Hamilton, MT (F.R.D., S.D.K., A.R.W., J.M.V., J.M.M.); the National Human Genome Research Institute (J.D.), the National Cancer Institute (M.L.T.), and the National Center for Biotechnology Information (A.A.S.) — all in Bethesda, MD; Science Applications International Corporation–Frederick, National Cancer Institute at Frederick, Frederick, MD (D.B.K.); the Center for Drug Evaluation and Research, Food and Drug Administration, Rockville, MD (D.M.F.); Royal Free Hospital and University College London, London (C.W., B.G.); and the University of California at San Francisco, San Francisco (J.M.P.). Drs. Puck and Grimbacher contributed equally to this article. This article (10.1056/NEJMoa073687) was published at www.nejm.org on September 19, 2007.
Address reprint requests to Dr. Holland at the National Institute of Allergy and Infectious Diseases, National Institutes of Health, CRC B3-4141 MSC 1684, Bethesda, MD 20892, or at smh{at}nih.gov.
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, had higher tumor necrosis factor 
levels than did identically treated cells from unaffected persons (P=0.003). In contrast, the cells from patients with the hyper-IgE syndrome generated lower levels of monocyte chemoattractant protein 1 in response to the presence of interleukin-6 (P=0.03), suggesting a defect in interleukin-6 signaling through its downstream mediators, one of which is STAT3. We identified missense mutations and single-codon in-frame deletions in STAT3 in 50 familial and sporadic cases of the hyper-IgE syndrome. Eighteen discrete mutations, five of which were hot spots, were predicted to directly affect the DNA-binding and SRC homology 2 (SH2) domains. 
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