Role played by Th2 type cytokines in IgE mediated allergy and asthma.

OBJECTIVE: Recent evidence suggest that allergen type 2 helper T cells (Th2) play a triggering role in the activation/recruitment of IgE antibody producing B cells, mast cells and eosinophils. Reduced microbial exposure in early life is responsible for a shift of Th1/Th2 balance in the immune system towards the pre-allergic Th2 response. The Th1 predominantly produce IFNgamma and delayed type hypersensitivity while Th2 secrete IL-4, IL-5, IL-6, IL-13 and regulate B cell and eosinophil mediated responses. To assess regulatory changes in the immune system, in patients with allergy and asthma, we studied the cytokine profile in serum in comparison with normal healthy controls. PATIENTS AND METHODS: A total of 170 patients with various allergies and asthmatic conditions were studied, for cytokines in the serum by ELISA using kits from Immunotech, and analyzed to identify the triggering factors or main contributors towards allergy and asthma. RESULTS: Our study showed increase in the levels of IL-4, IL-5 and IL-6 in all groups which were non- significant. But the levels of IL-10, IL-13 and TNF alpha were highly significant. Besides, we found correlation of GM-CSF with IL-10. Significant correlation with different cytokines was observed. Most of these patients showed increase in IgE levels. CONCLUSIONS: This study gives a better understanding of how cytokines are the mediators of balance of Th1 and Th2 immune responses and IgE synthesis is controlled by cytokines. Further studies will eventually lead to improved treatment strategies in the clinical management of IgE mediated allergy.

A genetic variation in inositol polyphosphate 4 phosphatase a enhances susceptibility to asthma.

RATIONALE: Microarray data from mouse studies have identified a number of genes to be differentially expressed in allergen-sensitized mice lungs. OBJECTIVES: Taking leads from these datasets, we attempted to identify novel genes associated with atopic asthma in humans. METHODS: We performed family-based genetic association analysis on selected markers within or in proximity of 21 human homologs of genes short-listed from ovalbumin-sensitized mouse studies in the Gene Expression Omnibus database of the National Center for Biotechnology Information. Family-based and case-control studies were undertaken for fine mapping and functional variation analysis of INPP4A (inositol polyphosphate 4 phosphatase type I). Western blot analysis was performed to analyze INPP4A protein stability from human platelets. MEASUREMENTS AND MAIN RESULTS: Our genetic association studies of 21 human genes in 171 trios led to the identification of a biallelic repeat (rs3217304) in INPP4A, associated with atopic asthma (P = 0.009). Further studies using additional three single nucleotide polymorphisms (SNPs), +92031A/T, +92344C/T, and +131237C/T, and two microsatellite markers, D2S2311 and D2S2187, revealed significant genetic associations with loci +92031A/T (P = 0.0012) and +92344C/T (P = 0.004). A nonsynonymous SNP, +110832A/G (Thr/Ala), present within a sequence enriched with proline, glutamic acid, serine, and threonine (PEST), in proximity of these two loci, showed a significant association with atopic asthma (P = 0.0006). The association results were also replicated in an independent cohort of 288 patients and 293 control subjects (P = 0.004). PEST score and Western blot analyses indicated a functional role of this SNP in regulating INPP4A protein stability. CONCLUSIONS: In our study, INPP4A was identified as a novel asthma candidate gene, whereby the +110832A/G (Thr/Ala) variant affected its stability and was significantly associated with asthma.

TGFbeta1 haplotypes and asthma in Indian populations.

BACKGROUND: Asthma is a complex disorder of the airways of the lungs. TGF-beta1 plays a key role in airway remodeling and asthma by having both proinflammatory and anti-inflammatory activities, making TGFbeta1 an important candidate gene to study. OBJECTIVE: To investigate the association of TGFbeta1 gene polymorphisms with asthma. METHODS: A case-control study was designed for identifying polymorphisms and haplotypes associated with asthma and associated phenotypes. We have verified our results in 2 independent cohorts collected from northern (number of patients, 187; number of controls, 187) and western India (number of patients, 209; number of controls, 190). We measured the serum TGF-beta1 levels of selected individuals and correlated them with genotypes and haplotypes. RESULTS: A novel (CT)n(CA)m repeat polymorphism (BV209662) 24.9 kb upstream of TGFbeta1 was identified. A significant association was seen at the level of alleles and genotypes with asthma in the 2 cohorts studied independently (P < .05). Interestingly, a novel 3-locus haplotype, 23_G_T, was found to be significantly associated with asthma (P = .00001 in cohorts A and B) as well as with higher serum TGF-beta1 level (P = .01). On the other hand, a novel haplotype, 22_G_C, was negatively associated with asthma (P = .00001 for cohorts A and B) and with lower serum TGF-beta1 level (P = .0019). CONCLUSION: This is the first study identifying novel risk and protective haplotypes--23_G_T and 22_G_C, respectively--in the TGFbeta1 gene that are associated with asthma. We also demonstrate the functional significance of these haplotypes with serum TGF-beta1 levels. These results would be valuable in elucidating the role of TGF-beta1 in asthma pathogenesis.

Uteroglobin-related protein 1(UGRP1) gene polymorphisms and atopic asthma in the Indian population.

BACKGROUND: The secretory protein, uteroglobin-related protein 1 (UGRP1), is mainly expressed in the lung and trachea and has recently been implicated in asthma. The -112 G to A transition in the promoter was reported to be associated with asthma in the Japanese population. However, this has not been replicated in other studies. The aim of this study was to find the association of UGRP1 gene polymorphisms with atopic asthma in the Indian population using a case-control (NP=165, NC=160) and a family-based (60 trios) design. METHODS: Polymorphisms in the promoter region and the first exon and first intron of the UGRP1 gene were determined by direct sequencing. RESULTS: The previously identified G-112A and C222A polymorphisms were found to be in complete linkage disequilibrium (LD) (D'=1) in our population. However, no new polymorphism has been identified in this region. When G-112A polymorphism was analyzed in the cases and controls, no significant difference was observed either at the allele (p=0.68) or at the genotype (p=0.83) levels. Moreover, in our family-based study, we observed no significant deviation of allelic transmission from random proportions (p=0.41). Similarly, when we analyzed our genotypic results for serum total IgE levels, no significant association was observed, in both case-control as well as family-based designs. CONCLUSIONS: Our results suggest that the G-112A and C222A polymorphisms do not play a significant role in the genetic predisposition of UGRP1 gene in atopic asthma in the Indian population.