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GM-CSF Pathway Defects May Account for Reduced Neutrophil Chemotaxis in Atopic Dermatitis

ˆThe ‰journal of allergy and clinical immunology/Journal of allergy and clinical immunology/˜The œjournal of allergy and clinical immunology(2007)

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Abstract
RATIONALE: We have previously shown that despite high cutaneous colonization rates with Staph. aureus and local expression of neutrophil chemoattractants, atopic dermatitis (AD) subjects' biopsies are neutropenic and this cannot be explained by defects in blood neutrophil chemokine receptor or integrin expression. METHODS: To understand the molecular basis for the neutrophil defect, gene expression profiles of unstimulated purified peripheral blood neutrophils (90-99% purity) from 5 AD subjects and 4 nonatopic controls (NA) were generated using Human Whole Genome (55,000 genes) CodeLink Bioarrays and analyzed with Codelink and SAM software packages. Genes with false discovery rate q<0.1 and ±;1.5 fold change (FC) were considered significantly up- or down-regulated. To evaluate the relative chemotactic responsiveness of whole blood neutrophils from AD vs NA, we measured CD11b up-regulation (10 min) and CD62L-shedding (5 min) by FACS following stimulation with CXCL8 (1000 ng/ml). RESULTS: Comparative analysis of gene expression showed that 325 genes were down-regulated in AD neutrophils including eight genes belonging to the GM-CSF pathway - beta-chain of the GM-CSF receptor (-1.94FC), STAT5b (-1.57FC), JAK3 (-2.10FC), phosphatidylinositol-4-phosphate-5-kinase-1alpha (-1.99FC), SP1 (-1.52FC), ELF4 (-1.69FC), vav1 (-1.56FC) and vav3 (-2.25FC). CXCL8-induced CD11b up-regulation and CD62L-shedding in AD compared to NA neutrophils were significantly reduced (6% and 24% of NA, respectively, p<0.05). CONCLUSIONS: Neutrophils from AD subjects have decreased responsiveness to the chemoattractant CXCL8. We hypothesize from our array data that this might be explained by defects in the GM-CSF pathway, as GM-CSF is known to be an important priming stimulus for chemotactic responses in neutrophils.
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Adaptive Immunity Regulation
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