|
|
Background The hyper-IgE syndrome (or Job's syndrome) is a rare disorder of immunity and connective tissue characterized by dermatitis, boils, cyst-forming pneumonias, elevated serum IgE levels, retained primary dentition, and bone abnormalities. Inheritance is autosomal dominant; sporadic cases are also found.
Methods We collected longitudinal clinical data on patients with the hyper-IgE syndrome and their families and assayed the levels of cytokines secreted by stimulated leukocytes and the gene expression in resting and stimulated cells. These data implicated the signal transducer and activator of transcription 3 gene (STAT3) as a candidate gene, which we then sequenced.
Results We found increased levels of proinflammatory gene transcripts in unstimulated peripheral-blood neutrophils and mononuclear cells from patients with the hyper-IgE syndrome, as compared with levels in control cells. In vitro cultures of mononuclear cells from patients that were stimulated with lipopolysaccharide, with or without interferon-
Conclusions Mutations in STAT3 underlie sporadic and dominant forms of the hyper-IgE syndrome, an immunodeficiency syndrome involving increased innate immune response, recurrent infections, and complex somatic features.
, 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.
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.
Related Letters:
STAT3 Mutation in the Original Patient with Job's Syndrome
Renner E. D., Torgerson T. R., Rylaarsdam S., Añover-Sombke S., Golob K., LaFlam T., Zhu Q., Ochs H. D.
Extract |
Full Text |
PDF
N Engl J Med 2007;
357:1667-1668, Oct 18, 2007.
Correspondence
This article has been cited by other articles:
HOME | SUBSCRIBE | SEARCH | CURRENT ISSUE | PAST ISSUES | COLLECTIONS | PRIVACY | HELP | beta.nejm.org Comments and questions? Please contact us. The New England Journal of Medicine is owned, published, and copyrighted © 2008 Massachusetts Medical Society. All rights reserved. |
Previous
