RATIONALE: Pulmonary mast cells (MC) have been associated with asthma pathogenesis. We have previously shown differences in MC phenotype by location in the lung (submucosa and epithelium) [Balzar, AJRCCM, 2011]. Little is known regarding the relative importance of luminal MCs to asthma. We hypothesized that distal/luminal MCs would better predict more severe clinical outcomes than proximal/epithelial MCs. METHODS: In 102 University of Pittsburgh asthmatics enrolled in NHLBI trials, bronchial epithelial brushings, bronchoalveolar (BAL) cells and fluid were obtained at bronchoscopy. Expression of the MC protease, tryptase mRNA was determined by qRT-PCR. Using the median tryptase mRNA values for epithelial brushings and BAL cells, subjects were classified as proximal and distal MC ''Hi'' or ''Lo.'' Regression analysis was performed to assess the effect of MC ''Hi'' on the outcomes of history of recent exacerbation, baseline FEV1% predicted and FEV1/FVC. RESULTS: Distal MCHi asthma significantly predicted exacerbation [OR53.6, p50.004], while proximal MCHi asthma did not [OR51.7, p50.2]. Distal MCHi asthma negatively associated with baseline FEV1% predicted [Beta5 -12.5, p50.006, R250.07] and baseline FEV1/FVC [Beta5 -0.06, p50.019, R250.05]. This relationship was not seen with proximal MCHi asthma [p for FEV1% predicted50.6, p for FEV1/ FVC50.8]. CONCLUSIONS: In matched samples from asthmatic subjects, the distal/ BAL cell MC signature better predicted asthma exacerbation, lower FEV1%predicted and decreased FEV1/FVC than the proximal/epithelial MC signature. In asthma, this suggests an important difference in MC function based on the location in the lung. Use of distal MC biomarkers should better identify more clinically severe asthma. 900 Association study in African-admixed J ALLERGY CLIN IMMUNOL FEBRUARY 2019 AB296 Abstracts MONDAY

A large number of allergens have been discovered but we know little about their potential to induce inflammation (allergenic activity) and symptoms. Nowadays, the clinical importance of allergens is determined by the frequency and intensity of their IgE antibody binding (allergenicity). This is a rather limited parameter considering the development of experimental allergology in the last 20 years and the criteria that support personalized medicine. Now it is known that some allergens, in addition to their IgE antibody binding properties, can induce inflammation through non IgE mediated pathways, which can increase their allergenic activity. There are several ways to evaluate the allergenic activity, among them the provocation tests, the demonstration of non-IgE mediated pathways of inflammation, case control studies of IgE-binding frequencies, and animal models of respiratory allergy. In this review we have explored the current status of basic and clinical research on allergenic activity of indoor allergens and confirm that, for most of them, this important property has not been investigated. However, during recent years important advances have been made in the field, and we conclude that for at least the following, allergenic activity has been demonstrated:

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Asthma is a complex disease with striking disparities across racial and ethnic groups. Despite its relatively high burden, representation of individuals of African ancestry in asthma genome-wide association studies (GWAS) has been inadequate, and true associations in these underrepresented minority groups have been inconclusive. We report the results of a genome-wide meta-analysis from the Consortium on Asthma among African Ancestry Populations (CAAPA; 7009 asthma cases, 7645 controls). We find strong evidence for association at four previously reported asthma loci whose discovery was driven largely by non-African populations, including the chromosome 17q12–q21 locus and the chr12q13 region, a novel (and not previously replicated) asthma locus recently identified by the Trans-National Asthma Genetic Consortium (TAGC). An additional seven loci reported by TAGC show marginal evidence for association in CAAPA. We also identify two novel loci (8p23 and 8q24) that may be specific to asthma risk in African ancestry populations.

T cells expressing the cutaneous lymphocyte antigen (CLA) mediate pathogenic inflammation in atopic dermatitis (AD). The molecular alterations contributing to their dysregulation remain unclear. With the aim to elucidate putative altered pathways in AD we profiled DNA methylation levels and miRNA expression in sorted T cell populations (CD4+, CD4+CD45RA+ naïve, CD4+CLA+, and CD8+) from adult AD patients and healthy controls (HC). Skin homing CD4+CLA+ T cells from AD patients showed significant differences in DNA methylation in 40 genes compared to HC (p < 0.05). Reduced DNA methylation levels in the upstream region of the interleukin-13 gene (IL13) in CD4+CLA+ T cells from AD patients correlated with increased IL13 mRNA expression in these cells. Sixteen miRNAs showed differential expression in CD4+CLA+ T cells from AD patients targeting genes in 202 biological processes (p < 0.05). An integrated network analysis of miRNAs and CpG sites identified two communities of strongly interconnected regulatory elements with strong antagonistic behaviours that recapitulated the differences between AD patients and HC. Functional analysis of the genes linked to these communities revealed their association with key cytokine signaling pathways, MAP kinase signaling and protein ubiquitination. Our findings support that epigenetic mechanisms play a role in the pathogenesis of AD by affecting inflammatory signaling molecules in skin homing CD4+CLA+ T cells and uncover putative molecules participating in AD pathways.