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Sun Ying, Brian O'Connor,
Jonathan Ratoff,
Qiu Meng,
Cailong Fang,
David Cousins,
Guizhen Zhang,
Shuyan Gu,
Zhongli Gao,
Betty Shamji,
Matthew J Edwards,
Tak H Lee,
Chris J Corrigan
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ABSTRACT: Asthma and chronic obstructive pulmonary disease (COPD) are associated with Th2 and Th1 differentiated T cells. The cytokine thymic stromal lymphopoietin (TSLP) promotes differentiation of Th2 T cells and secretion of chemokines which preferentially attract them. We hypothesized that there is distinct airways expression of TSLP and chemokines which preferentially attract Th1- and Th2-type T cells, and influx of T cells bearing their receptors in asthma and COPD. In situ hybridization, immunohistochemistry, and ELISA were used to examine the expression and cellular provenance of TSLP, Th2-attracting (TARC/CCL17, MDC/CCL22, I-309/CCL1), and Th1-attracting (IP-10/CXCL10, I-TAC/CXCL11) chemokines in the bronchial mucosa and bronchoalveolar lavage fluid of subjects with moderate/severe asthma, COPD, and controls. Cells expressing mRNA encoding TSLP, TARC/CCL17, MDC/CCL22, and IP-10/CXCL10, but not I-TAC/CXCL11 and I-309/CCL1, were significantly increased in severe asthma and COPD as compared with non-smoker controls (p < 0.02). This pattern was reflected in bronchoalveolar lavage fluid protein concentrations. Expression of the same chemokines was also increased in ex- and current smokers. The cellular sources of TSLP and chemokines were strikingly similar in severe asthma and COPD. The numbers of total bronchial mucosal T cells expressing the chemokine receptors CCR4, CCR8, and CXCR3 did not significantly differ in asthma, COPD, and controls. Both asthma and COPD are associated with elevated bronchial mucosal expression of TSLP and the same Th1- and Th2-attracting chemokines. Increased expression of these chemokines is not, however, associated with selective accumulation of T cells bearing their receptors.
The Journal of Immunology 08/2008; 181(4):2790-8. · 5.79 Impact Factor
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Sun Ying, Brian O'Connor,
Jonathan Ratoff,
Qiu Meng,
Kirsty Mallett,
David Cousins,
Douglas Robinson,
Guizhen Zhang,
Jisheng Zhao,
Tak H Lee,
Chris Corrigan
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ABSTRACT: Thymic stromal lymphopoietin (TSLP) is said to increase expression of chemokines attracting Th2 T cells. We hypothesized that asthma is characterized by elevated bronchial mucosal expression of TSLP and Th2-attracting, but not Th1-attracting, chemokines as compared with controls, with selective accumulation of cells bearing receptors for these chemokines. We used in situ hybridization and immunohistochemistry to examine the expression and cellular provenance of TSLP, Th2-attracting (thymus and activation-regulated chemokine (TARC)/CCL17, macrophage-derived chemokine (MDC)/CCL22, I-309/CCL1) and Th1-attracting (IFN-gamma-inducible protein 10 (IP-10)/CXCL10, IFN-inducible T cell alpha-chemoattractant (I-TAC)/CXCL11) chemokines and expression of their receptors CCR4, CCR8, and CXCR3 in bronchial biopsies from 20 asthmatics and 15 normal controls. The numbers of cells within the bronchial epithelium and submucosa expressing mRNA for TSLP, TARC/CCL17, MDC/CCL22, and IP-10/CXCL10, but not I-TAC/CXCL11 and I-309/CCL1, were significantly increased in asthmatics as compared with controls (p </= 0.018). TSLP and TARC/CCL17 expression correlated with airway obstruction. Although the total numbers of cells expressing CCR4, CCR8, and CXCR3 did not significantly differ in the asthmatics and controls, there was evidence of selective infiltration of CD4(+)/CCR4(+) T cells in the asthmatic biopsies which correlated with TARC and MDC expression and airway obstruction. Epithelial cells, endothelial cells, neutrophils, macrophages, and mast cells were significant sources of TSLP and chemokines. Our data implicate TSLP, TARC/CCL17, MDC/CCL22, and IP-10/CXCL10 in asthma pathogenesis. These may act partly through selective development and retention, or recruitment of Th2 cells bearing their receptors.
The Journal of Immunology 07/2005; 174(12):8183-90. · 5.79 Impact Factor
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ABSTRACT: We have developed a critical test of the chromatin accessibility model of Ig isotype determination in which local unfolding of chromatin higher order structure (chromatin accessibility) in the region of specific germline genes in the H chain locus determines the Ab class to be expressed in the B cell. We show that multiple germline genes are constitutively transcribed in the majority of naive human B cells in a population. Thus, because chromatin in its higher order structure cannot be transcribed, the entire Ig H chain locus must be unfolded in naive B cells. We have also established that IL-4 and anti-CD40 act by enhancing transcription in the majority of cells, rather than by activating transcription in more of the cells. Transcriptional activity in the human H chain locus rules out the perturbation of chromatin higher order structure as a factor in isotype determination. We have also found that the levels of germline gene transcription cannot fully account for the levels of secretion of the different Ig isotypes, and that secretion of IgE, in particular, is suppressed relative to that of IgG.
The Journal of Immunology 11/2004; 173(7):4529-38. · 5.79 Impact Factor
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Simon C Pitchford,
Hiroshi Yano,
Rebecca Lever,
Yanira Riffo-Vasquez,
Silvia Ciferri,
Mark J Rose,
Silvia Giannini,
Stefania Momi,
Domenico Spina, Brian O'connor,
Paolo Gresele,
Clive P Page
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ABSTRACT: The role of platelets in inflammation is recognized but poorly characterized, and little is known of their interaction with leukocytes. However, platelet-leukocyte interactions have been demonstrated in cardiovascular disease, culminating in enhanced leukocyte recruitment.
This study was undertaken to assess the possibility and potential role of similar phenomena occurring in asthmatic patients, a murine model of allergic inflammation, and in vitro adhesion studies.
Asthmatic patients had blood taken at various time points to document the degree of leukocyte activation and the presence of platelet-leukocyte aggregates through FACS analysis before and after allergen exposure. Similar studies were carried out in mice exposed to allergen after previous sensitization, with some groups being selectively depleted of platelets through both an immunologic (antiplatelet antiserum) and nonimmunologic (busulfan) method. Additionally, lavage fluid and airway tissue were analyzed to assess the degree of pulmonary leukocyte recruitment. The importance of platelets on leukocyte adhesion to the endothelium was then assessed with in vitro incubation of radiolabeled leukocytes in the presence of activated platelets on cultured human vascular endothelial cells.
We have observed circulating platelet-leukocyte aggregates in the blood of allergic asthmatic patients during the allergen-induced late asthmatic response and in sensitized mice after allergen exposure. In platelet-depleted mice infiltration of leukocytes into airways after allergen challenge was significantly reduced and could be restored by means of infusion of platelets from allergic animals, indicating an essential role for platelets in leukocyte recruitment. CD11b expression on leukocytes involved in aggregates with platelets, although not on free leukocytes, was upregulated. Furthermore, the presence of autologous platelets augmented the adhesion of human polymorphonuclear leukocytes to cultured vascular endothelial cells, an effect that was found to be endothelial cell dependent and to involve platelet activation.
These results suggest that platelet participation in cell recruitment occurs at the level of the circulation and might involve the priming of leukocytes for subsequent adhesion and transmigration into tissues.
Journal of Allergy and Clinical Immunology 08/2003; 112(1):109-18. · 11.00 Impact Factor
