Aggregation of high-affinity receptors for immunoglobulin E (Fc⑀RI) on the surface of mast cells results in degranulation, a response that is potentiated by binding of stem cell factor (SCF) to its receptor Kit. We observed that one of the major initial signaling events associated with Fc⑀RI-mediated activation of human mast cells (HuMCs) is the rapid tyrosine phosphorylation of a protein of 25 to 30 kDa. The phosphorylation of this protein was also observed in response to SCF. This protein was identified as non-T-cell activation linker (NTAL), an adaptor molecule similar to linker for activated T cells (LAT). Unlike the Fc⑀RI response, SCF induced NTAL phosphorylation in the absence of detectable LAT phosphorylation. When SCF and antigen were added concurrently, there was a marked synergistic effect on NTAL phosphorylation, however, SCF did not enhance the phosphorylation of LAT induced by Fc⑀RI aggregation. Fc⑀RI-and SCF-mediated NTAL phosphorylation appear to be differentially regulated by Src kinases and/or Kit kinase, respectively. Diminution of NTAL expression by silencing RNA oligonucleotides in HuMCs resulted in a reduction of both Kit-and Fc⑀RI-mediated degranulation. NTAL, thus, appears to be an important link between the signaling pathways that are initiated by these receptors, culminating in mast cell degranulation. IntroductionMast cell activation leading to degranulation, arachidonic acid metabolism, and cytokine production is initiated following antigendependent aggregation of high-affinity receptors for immunoglobulin E (IgE) (Fc⑀RI) on the cell surface. 1 Stem cell factor (SCF), although primarily required for the growth, differentiation, and survival of mast cells by binding to Kit,2,3 potentiates secretory responses elicited via the Fc⑀RI. 4 Both Fc⑀RI and Kit responses follow tyrosine kinase activation and subsequent protein tyrosine phosphorylation. 5,6 Fc⑀RI possess no inherent tyrosine kinase activity thus require the recruitment of the Src family tyrosine kinase, Lyn, and the zeta-associated protein 70 (ZAP 70)-related tyrosine kinase, spleen tyrosine kinase (Syk), into the signaling complex, where, following receptor aggregation, they become sequentially activated. 7,8 Subsequent tyrosine phosphorylation of the  and ␥ chains of the Fc⑀RI, and of the transmembrane adaptor molecule linker for activated T cells (LAT), provides multiple docking sites for downstream Src homology 2 (SH2) domaincontaining signaling molecules. 9 These initial tyrosine-phosphorylation events appear to be crucial for subsequent Fc⑀RI-mediated degranulation to proceed.Unlike the Fc⑀RI, Kit does possess inherent tyrosine kinase activity. 10,11 Binding of SCF induces autophosphorylation of Kit with consequential binding of SH2 domain-containing signaling molecules to the Kit cytosolic domain. 12 In contrast to Fc⑀RI signaling, to date there is little evidence that LAT or similar transmembrane adaptor molecules become phosphorylated following Kit activation. Thus, despite, Kit's ability to potentiate Fc⑀RI-mediated ...
SummaryBackground Cysteinyl leukotrienes (CysLTs) play important roles in the pathogenesis of eosinophilic airway inflammation characterized by bronchoconstriction, mucus secretion and airway hyper-responsiveness via cysteinyl leukotriene receptor 1 (CysLTR1)-mediated mechanism. CysLTR1-selective antagonists have anti-bronchoconstrictive and antiinflammatory effects in asthma, particularly aspirin-intolerant asthma (AIA). Methods To investigate the association of CysLTR1 with AIA development, we identified three single nucleotide polymorphisms (SNPs), À 634C 4 T, À 475A 4 C, À 336A 4 G, in the 5
SummaryBackground Nasal polyps infiltrated with eosinophils are commonly found in chronic asthmatic patients, more frequently in those with aspirin-intolerant asthma (AIA) than aspirin-tolerant asthma (ATA). Some studies have suggested a contribution of superantigens derived from Staphylococcus sp to nasal polyposis and eosinophilia, but their relative importance in AIA and ATA subjects is unknown. Objective We investigated whether local production of specific IgE to staphylococcal enterotoxins A and B (SEA and SEB) and relationships with markers of eosinophilic inflammation differ in the nasal polyps of AIA and ATA subjects. Methods Fifteen AIA subjects with positive responses to lysine-aspirin bronchoprovocation and 15 ATA subjects underwent polypectomy. Immunoassays were used to quantify eosinophil cationic protein (ECP), IL-5, mast cell tryptase, soluble IL-2 recepters (sIL-2R), total IgE, and specific IgE for SEA and SEB. Results ECP levels in nasal polyp homogenates were higher in AIA subjects than in ATA subjects (Po0.02), with no significant differences in tryptase, IL-5 or sIL-2R. Total IgE, and specific IgE to both SEA and SEB, were detectable in some nasal polyps from both subject groups, but median levels were markedly higher in AIA subjects than in ATA subjects (P 5 0.04, 0.01, 0.05, respectively). Levels of specific IgE to SEA and SEB correlated significantly with levels of ECP and IL-5, but not those of tryptase or sIL-2R. Conclusion These findings suggest that staphylococcal superantigens may drive local eosinophilic inflammation in nasal polyp tissue, and that this is exacerbated in subjects with AIA.
SummaryBackground The immuno-pathological mechanism for occupational asthma induced by grain dust (GD) remains to be clarified. There have been few reports suggesting the involvement of neutrophils inducing bronchoconstriction after inhalation of GD. Objective To further understand the role of neutrophil in the pathogenesis of GD-induced asthma. Materials and methodsWe studied the phenotype of leucocytes of the bronchial mucosa in patients with GD-induced asthma. Bronchial biopsy specimens were obtained by fibreoptic bronchoscopy from six subjects with GD-induced asthma. Six allergic asthma patients sensitive to house dust mite were enrolled as controls. Bronchial biopsy specimens were examined by immunohistochemistry with a panel of monoclonal antibodies to tryptase-containing mast cell (AA1), activated eosinophil (EG2), pan T-lymphocyte (CD3) and neutrophil elastase (NE). Induced sputum was collected before and after the GD-bronchoprovocation test. The IL-8 level in the sputum was measured using ELISA. Results There was a significant increase in the number of AA1 þ and NE þ cells in bronchial mucosa of GD-induced asthma, compared with those of allergic asthma (P ¼ 0.01, P ¼ 0.01, respectively). No significant differences were observed in the number of EG2 þ and CD3 þ cells (P ¼ 0.13, P ¼ 0.15, respectively). IL-8 was abundant in the sputum of all GD-induced asthma patients and significantly increased after the bronchial challenges compared with the baseline value (P ¼ 0.03). Conclusion These findings support the view that neutrophil recruitment together with mast cells may contribute to the bronchoconstriction induced by GD. A possible involvement of IL-8 was suggested.
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