Defective interleukin-12/interferon-gamma pathway in patients with hyperimmunoglobulinemia E syndrome.

OBJECTIVE: Patients with the hyperimmunoglobulinemia E (hyper-IgE) syndrome are reported to have defective production of interferon gamma (IFN-gamma). Because IFN-gamma is a major activator of polymorphonuclear leukocytes (PMNs), this could result in defective PMN chemotaxis and markedly elevated IgE levels because of the unopposed action of interleukin (IL)-4. IL-12, an important enhancer of IFN-gamma production, also suppresses IgE production. This study assessed the IL-12/IFN-gamma pathway in patients with hyper-IgE syndrome. METHODS: Production of IL-12 and IFN-gamma by mononuclear cells from 10 patients with hyper-IgE syndrome in response to a number of stimuli was determined, as well as the effect of IL-12 on IFN-gamma release and cell proliferation. RESULTS: IL-12 and IFN-gamma production by the patients' cells was similar to that of control subjects independent of the stimulus used, except for Staphylococcus aureus, with which cells of patients with hyper-IgE syndrome released markedly less IFN-gamma (19.8%; P <.002). The ability of recombinant IL-12 to enhance IFN-gamma release from patients' cells in response to all stimuli was, however, significantly lower than with control cells (12% to 51%; P <.03). CONCLUSION: The lymphocytes of patients with hyper-IgE syndrome have an impaired response to IL-12, resulting in decreased IFN-gamma production, which may be of key importance in the pathogenesis of the immune abnormalities of hyper-IgE syndrome.

Intracellular and extracellular cytokine production by human mixed mononuclear cells in response to group B streptococci.

Group B streptococci (GBS) are a major cause of severe infection in newborns, pregnant females, and other immunocompromised hosts. Infection often includes septicemia, shock, pneumonia, and respiratory failure. In previous studies, we have reported that GBS induce marked production of tumor necrosis factor alpha (TNF-alpha) by human mononuclear cells. The present study was designed to measure the production of TNF-alpha as well as additional cytokines, including interleukin 1beta (IL-1beta), IL-6, IL-8, IL-12, and gamma interferon (IFN-gamma) but also to determine from what cells and at what time point during incubation with GBS that these cytokines are produced. Mixed mononuclear cells were incubated with heat-killed GBS, media alone, or 1 microg of Escherichia coli lipopolysaccharide (LPS). Brefeldin A was added to each sample prior to staining, which prevented the export of cytokines by the Golgi apparatus. The cells were then stained with the appropriate conjugated antibodies and analyzed by using a flow cytometer. Results indicate that intracellular cytokines appear, in almost all cases, simultaneous to or before secreted proteins are detected. In contrast to the response to LPS, where TNF-alpha, IL-1beta, IL-6, and IL-8 appear almost simultaneously, the human monocyte response to GBS results in the production of TNF-alpha but delayed appearance of IL-1beta, IL-6, and IL-8. The lymphocyte response to GBS was also strikingly different from that to LPS in that both secreted IFN-gamma and IL-12 was detected, while LPS failed to induce production of these critical cytokines. This suggests an important role for TNF-alpha, IFN-gamma, and IL-12 in GBS pathogenesis and/or immunity.

The face of Job.

We evaluated facial features in 9 patients from 7 kindreds with Job syndrome. Consistent features included prominent forehead with deep-set eyes, increased width of the nose, a full lower lip, and thickening of the nose and ears. The mean alar width (Z score = +3.9) and outer canthal distance (Z score = +2.2) were significantly increased. A recognizable face of Job syndrome exists.