RESEARCH SUPPORT, NON-U.S. GOV'T
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Reduced expression of chemoattractant receptors by polymorphonuclear leukocytes in Hyper IgE Syndrome patients.

Hyper IgE Syndrome (HIES) is a rare genetic disorder, characterized by elevated serum IgE levels and reduced inflammatory responses to bacterial infections. This leads to dermatitis, recurrent lung infections and "cold abscesses". Recently, progress was made in HIES research, when mutations in STAT3 were found in the autosomal dominant form of HIES, and impaired responses of T helper 17 cells were reported. However, the causes for reduced inflammatory responses in these patients were not fully elucidated. In view of studies that indicated that polymorphonuclear leukocytes (PMN) of HIES patients are defective in their chemotactic properties, we asked if the PMN of these patients have reduced expression of receptors for chemoattractants. To analyze this possibility, we focused on fMLP and ELR(+)-CXC chemokines - which are essential for mounting acute inflammatory responses - and determined the coding sequences and expression levels of their corresponding receptors: FPR (for fMLP) as well as CXCR1 and CXCR2 (the receptors for ELR(+)-CXC chemokines). The analyses of these receptors in HIES patients indicated that their coding sequences were intact and normal. However, the percentages of PMN that expressed FPR, CXCR1 and CXCR2 were significantly lower in HIES patients. In addition, lower expression levels per cell were denoted for CXCR1 in PMN of the patients. A cumulative score that was calculated for the three chemoattractant receptors together indicated that in some of the patients there were prominent reductions, of up to approximately 50% in the overall expression of the receptors (indicated by % positive cells and mean expression levels per cell). In addition, we asked whether deregulation of PMN activities in HIES may result from binding of IgE to corresponding receptors on HIES PMN. Our findings indicate that this is probably not the case, because similarly to normal PMN, the cells of HIES patients did not express notable levels of the IgE receptors FcvarepsilonRI and FcvarepsilonRII. Together, these results provide novel information on the expression of key determinants in PMN migration in HIES, suggesting that a defect in the expression of chemoattractant receptors may lead to impaired chemotaxis found in HIES patients, and to decreased inflammatory responses.

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