Origin of Rare Immune Disorder Traced to Mutations

BETHESDA, Md., Sept. 20 -- The etiology of the rare immune system disorder hyper-IgE syndrome, or Job's syndrome, tracks to mutations in a gene involved in signal transduction and transcription activation, investigators here reported.

Patients with the syndrome had multiple mutations in STAT3 and evidence of a defect in the interleukin-6 signaling pathway, which is mediated partly by STAT3, Steven M. Holland, M.D., of the National Institute of Allergy and Infectious Diseases, and colleagues, reported online ahead of publication in the Oct. 18 issue of The New England Journal of Medicine.

"The newly recognized genetic cause of the hyper-IgE syndrome-STAT3 mutation-affects complex, compartmentalized somatic and immune regulation," the authors concluded. "The discovery of this genetic cause opens new doors to understanding organ-specific infection, inflammation, and therapy."

The hyper-IgE syndrome has multiple, disparate manifestations that include dermatitis, boils, cyst-forming pneumonias, elevated serum IgE levels, retained primary dentition, and bone abnormalities. The syndrome arises from autosomal dominant inheritance, but sporadic cases also occur.

Various immunity-related and cytogenetic clues spurred investigations that failed to uncover an etiologic culprit, and microarray analysis yielded inconsistent findings, said the investigators.

Against that background, an NIAID-led research team initiated a comprehensive effort to phenotype affected individuals in a large cohort and to assay gene expression and in vitro cytokine production to identify relevant pathways to hyper-IgE syndrome etiology.

The study involved 50 patients and 48 family members, and control DNA samples were obtained from 148 unaffected individuals.

As compared with the control group, patients had:

• Increased levels of proinflammatory gene transcripts in unstimulated peripheral-blood neutrophils and mononuclear cells.
• Significantly higher levels of tumor necrosis factor-? in stimulated mononuclear cells (P=0.003).
• Significantly lower levels of monocyte chemoattractant protein 1 in the presence of IL-6 (P=0.03).

Investigators identified missense mutations and single-codon in-frame deletions in STAT3 in the 50 patients with hyper-IgE syndrome. Gene-expression analysis revealed 18 discrete mutations predicted to have direct effects on DNA-binding domains and Src 2 homology domains, the latter of which are protein modules found in proteins involved in signal transduction. The mutations included five DNA hot spots, sites where mutations occur frequently.

"STAT3 mutation is the predominant cause of sporadic and familial hyper-IgE syndrome, although other genomic loci may also be involved," the authors concluded.