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1.
Clin Exp Allergy ; 40(9): 1353-64, 2010 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-20618347

RESUMEN

BACKGROUND: Sensitization to cockroach allergen is one of the strongest predictors of asthma morbidity, especially among African Americans. OBJECTIVE: Our aims were to determine the genomic basis of cockroach sensitization and the specific response to cockroach antigen. METHODS: We investigated the Th1/Th2 cytokine profile of co-cultured plasmacytoid dendritic cells (pDCs) and CD4+ T cells and the 'transcript signature' of the immune response to cockroach antigen using high-throughput expression profiling of co-cultured cells. RESULTS: We observed significantly elevated levels of IL-13, IL-10, and TNF-alpha, but undetectable levels of IL-12p70 and IFN-alpha, when cultures were exposed to crude cockroach antigen. A significant difference was observed for IL-13 between cockroach-allergic and non-allergic individuals (P=0.039). Microarray analyses demonstrated a greater response at 48 h compared with 4 h, with 50 genes being uniquely expressed in cockroach antigen-treated cells, including CD14, S100A8, CCL8, and IFI44L. The increased CD14 expression was further observed in purified pDCs, human monocytic THP-1 cells, and the supernatant of co-cultured pDCs and CD4+ T cells on exposure to cockroach extract. Furthermore, the most differential expression of CD14 between cockroach allergy and non-cockroach allergy was only observed among individuals with the CC 'high-risk' genotype of the CD14-260C/T. Ingenuity Pathways Analysis analyses suggested the IFN signalling as the most significant canonical pathway. CONCLUSION: Our results suggest that these differentially expressed genes, particularly CD14, and genes in the IFN signalling pathway may be important candidates for further investigation of their role in the immune response to cockroach allergen.


Asunto(s)
Alérgenos/inmunología , Asma/genética , Cucarachas/inmunología , Citocinas/biosíntesis , Perfilación de la Expresión Génica , Predisposición Genética a la Enfermedad , Interferón-alfa/inmunología , Receptores de Lipopolisacáridos/genética , Adolescente , Adulto , Negro o Afroamericano , Animales , Asma/etnología , Asma/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Técnicas de Cocultivo , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Genotipo , Humanos , Interferón-alfa/metabolismo , Persona de Mediana Edad , Células Th2
2.
Eur Respir J ; 34(1): 103-10, 2009 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-19196818

RESUMEN

Only a fraction of all smokers develop chronic obstructive pulmonary disease (COPD), suggesting a large role for genetic susceptibility. The leptin receptor (LEPR) is present in human lung tissue and may play a role in COPD pathogenesis. The present study examined the association between genetic variants in the LEPR gene and lung function decline in COPD. In total, 429 European Americans were randomly selected from the National Heart Lung and Blood Institute Lung Health Study. 36 single nucleotide polymorphisms (SNPs) in LEPR were genotyped using the Illumina GoldenGate platform (Broad Institute, Cambridge, MA, USA). Mean annual decline in forced expiratory volume in 1 s % predicted over the 5-yr period was calculated using linear regression. Linear regression models were also used to adjust for potential confounders. In addition, in vivo expression of the receptor gene was assessed with immunohistochemistry on lungs from smoke-exposed inbred mice. We identified significant associations (p<0.05) between lung function decline and 21 SNPs. Haplotype analyses confirmed several of these associations seen with individual markers. Immunohistochemistry results in inbred mice strains support a potential role of LEPR in COPD pathogenesis. We identified genetic variants in the LEPR gene significantly associated with lung function decline in a population of smokers with COPD. Our results support a role for LEPR as a novel candidate gene for COPD.


Asunto(s)
Pulmón/fisiopatología , Polimorfismo de Nucleótido Simple , Enfermedad Pulmonar Obstructiva Crónica/sangre , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Receptores de Leptina/genética , Adulto , Alelos , Animales , Femenino , Regulación de la Expresión Génica , Genotipo , Humanos , Inmunohistoquímica , Pulmón/metabolismo , Masculino , Ratones , Persona de Mediana Edad
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