Hyper-IgE Heterogeneity Unmasked: A Bad Apple (STAT3) Identified

The hyper-IgE syndrome (sometimes known as the Job or hyperimmunoglobulinemia E-staphylococcal abscess syndrome) is characterized by papules, pustules, and patchy eczema beginning during the first few months of life. Other characteristics include deep, noninflamed staphylococcal skin infections (cold abscesses); sino-pulmonary infections; candidal infections; osteopenia and bone fracture at an early age; impaired resorption of the primary teeth; and coarse facial features. Newborns with the syndrome frequently have papules that evolve into crusted pustules. The laboratory findings include markedly increased levels of serum IgE and impaired neutrophil chemotaxis. The most common form of the disorder has autosomal dominant inheritance; although the gene has not been identified, it has been localized to chromosome 4q21. Researchers have had better luck identifying the tyrosine kinase 2 gene as the cause of some cases of autosomal recessive hyper-IgE.

Minegishi and colleagues studied sporadic cases of hyper-IgE: In 8 of 15 unrelated patients with unaffected parents, they found mutations in the DNA region of STAT3, a Signal Transducer and Activator of Transcription gene. This mutation was found on human chromosome 17q21 — a different location than that implicated in the more common autosomal dominant form.

Patients with recessive hyper-IgE had defects in signaling pathways for interleukin (IL)-6, IL-10, IL-12, IL-23, and type I interferon, suggesting the presence of a defective molecule and implying a role for STATs of the Janus kinase (JAK) family. Molecular studies identified mutations in the DNA-binding region of the well-characterized transcription factor STAT3 gene. Introducing mutant STAT3 into normal cells interfered with normal STAT3 function; the interference is probably related to impaired heterodimers of normal and abnormal STAT3.

Holland and colleagues extend these observations. They studied a larger group of patients from 35 families of diverse ethnicity in the U.S. and U.K. They found that mutations were also common in the SH2 (SRC homology 2) region, as well as in the DNA-binding domain. They conclude that STAT3 mutations underlie both sporadic and dominant forms of the hyper-IgE syndrome. An accompanying editorial gives a broad and useful overview of STAT3 and the JAK signaling pathway and enumerates the roles of STAT proteins in the physiology of several lymphokines and hormones, including prolactin and growth hormone.