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Background An emerging paradigm holds that resistance to the development of allergic diseases, including allergic rhinoconjunctivitis, relates to an intact epithelial/epidermal barrier during early childhood. Conceivably, the immunologic and genomic footprint of this resistance is preserved in nonatopic, nonallergic adults and is unmasked during exposure to an aeroallergen. Objective The aim of this study was to obtain direct support of the epithelial/epidermal barrier model for allergic rhinoconjunctivitis. Methods Twenty-three adults allergic to house dust mites (HDMs) (M+) and 15 nonsensitive, nonallergic (M−) participants completed 3-hour exposures to aerosolized HDM ( Dermatophagoides pteronyssinus ) powder on 4 consecutive days in an allergen challenge chamber. We analyzed: (1) peripheral blood leukocyte levels and immune responses; and (2) RNA sequencing–derived expression profiles of nasal cells, before and after HDM exposure. Results On HDM challenge: (1) only M+ persons developed allergic rhinoconjunctivitis symptoms; and (2) peripheral blood leukocyte levels/responses and gene expression patterns in nasal cells were largely concordant between M+ and M− participants; gross differences in these parameters were not observed at baseline (pre-exposure). Two key differences were observed. First, peripheral blood CD4 + and CD8 + T-cell activation levels initially decreased in M− participants versus increased in M+ participants. Second, in M− compared with M+ participants, genes that promoted epidermal/epithelial barrier function (eg, filament-aggregating protein [filaggrin]) versus inflammation (eg, chemokines) and innate immunity (interferon) were upregulated versus muted, respectively. Conclusion An imprint of resistance to HDM challenge in nonatopic, nonallergic adults was muted T-cell activation in the peripheral blood and inflammatory response in the nasal compartment, coupled with upregulation of genes that promote epidermal/epithelial cell barrier function. [ABSTRACT FROM AUTHOR]

Background Modifiers of symptom severity in patients with allergic rhinoconjunctivitis (AR) are imprecisely characterized. The hygiene hypothesis implicates childhood microbial exposure as a protective factor. Cockroach sensitization (C+) might be a proxy for microbial exposure. Objective We sought to determine whether C+ assayed by means of skin prick tests influenced AR symptom severity in controlled and natural settings. Methods Total symptom scores (TSSs) were recorded by 21 participants with house dust mite allergy (M+) in the natural setting and during repeated exposures of 3 hours per day to house dust mite allergen in an allergen challenge chamber (ACC). In M+ participants the peripheral blood and nasal cells were assayed for T-cell activation and transcriptomic profiles (by using RNA sequencing), respectively. Participants allergic to mountain cedar (n = 21), oak (n = 34), and ragweed (n = 23) recorded TSSs during separate out-of-season exposures to these pollens (any pollen sensitization [P+]) in the ACC; a subset recorded TSSs in the pollination seasons. Results The hierarchy of TSSs (highest to lowest) among M+ participants tracked the following skin prick test sensitization statuses: M+P+C− > M+P+C+ > M+P−C− > M+P−C+. In nasal cells and peripheral blood the immune/inflammatory responses were rapidly resolved in M+P+C+ compared with M+P+C− participants. Among those allergic to pollen, C+ was associated with a lower TSS during pollen challenges and the pollination season. After aggregated analysis of all 4 ACC studies, C+ status was associated with a 2.8-fold greater likelihood of a lower TSS compared with C− status (odds ratio, 2.78; 95% CI, 1.18-6.67; P = .02). Conclusions C+ status is associated with mitigation of AR symptom severity in adults with AR. [ABSTRACT FROM AUTHOR]

Background: The severity of allergic rhinoconjunctivitis (AR) symptomatology elicited after exposure to pollen in the absence versus the presence of confounding cofactors, such as in a pollen challenge chamber (PCC) and the natural pollinating season, respectively, might differ. Objective: We sought to determine the correlation of AR severity in the natural season versus out-of-season PCC exposures. Methods: Twenty-four Virginia live oak (VLO)–positive, 14 VLO-negative, 16 mountain cedar (MC)−positive, 8 MC-negative, and 26 ragweed-positive participants recorded AR symptoms (total symptom score [TSS]) during the VLO, MC, and ragweed pollinating seasons and during 2 consecutive PCC exposures of 3 hours each to these pollens separately. Results: The TSSs recorded before the natural season were higher than the pre-PCC values. This prepriming was greater among VLO+ than MC+ participants, and it blunted further increases in TSSs during the VLO natural season. Nonatopic participants were nonreactive in the PCC. There was wide variation in the level of AR symptomatology after exposure to VLO, MC, or ragweed pollen in the PCC. Prepriming formed the basis for higher AR responses observed in the natural season than in the PCC, resulting in the identification of distinct PCC/natural season endophenotypes and a partial correlation between the TSSs recorded in the natural season versus those recorded in the PCC (r = 0.34, 0.54, and 0.65 for VLO+, MC+, and ragweed-positive participants, respectively). Conclusions: Prepriming in the natural pollinating season might obscure the true correlation between AR severity in the natural season versus the PCC. By mitigating confounding cofactors, PCC exposures have utility for evaluation of novel AR therapeutics. [Copyright &y& Elsevier]

Background: The level of concordance between allergic symptoms induced on exposure to pollen in a pollen challenge chamber (PCC) versus the natural season is unknown. Objective: We sought to test the hypothesis that the symptom levels of allergic rhinoconjunctivitis elicited after out-of-season exposure to short ragweed in a PCC and during the natural season for giant ragweed pollen are highly correlated. Methods: Thirty-one ragweed-sensitive participants recorded symptoms for 15 days during the natural giant ragweed season in San Antonio, Texas. Twenty-six of these participants were challenged to short ragweed pollen in a PCC for 3 hours per day for up to 4 days. Results: In the PCC participants were dichotomized into those in whom low versus high levels of symptoms developed slowly or rapidly (ie, slow/low vs rapid/high). Each successive exposure visit associated with a progressive increase in symptom levels that approximated those experienced during the natural season. Hierarchic clustering identified 3 endotypes: endotypes I and II reflected concordantly low (n = 7) versus high (n = 14) total symptom scores (TSSs) in both the natural season and the PCC, respectively. Accordingly, the correlation between the TSSs recorded in the natural season and in the PCC for these 21 participants was very high. Although participants with endotype III (n = 5) had greater TSSs in the natural season than in the PCC, the degree of correlation between the TSSs remained high. Conclusions: Our findings affirm our hypothesis, underscore the high cross-reactivity between distinct pollens, and highlight the utility of the PCC to identify novel allergy endotypes that might have contrasting mechanistic underpinnings and potentially therapeutic responses. [ABSTRACT FROM AUTHOR]

Abstract: Members of the chemokine system, play a central role in inflammatory processes that underlie the pathogenesis of atherosclerosis and possibly, aortic valve sclerosis. Here we show that genetic inactivation of CC chemokine receptor 5 (CCR5) in the atherosclerosis-prone Apoe −/− mice (Apoe −/− Ccr5 −/−) fed a normal chow or a high-fat diet (HFD) are protected against advanced atherosclerosis as well as age-associated aortic valve thickening (AAAVT)—a murine correlate of aortic valve sclerosis. Notably, human sclerotic valves contained CCR5+ cells. We confirm that Apoe −/− Ccr5 −/− mice does not influence early-atherosclerotic stage. Adoptive transfer studies showed that the atheroprotective effect of CCR5 inactivation resided in the bone marrow compartment, but was not dependent on T-cells. The CCR5-null state was associated with phenotypes postulated to be atheroprotective such as reduced macrophage accumulation in the plaque, and lower circulating levels of IL-6 and MCP-5. The lack of CCR5 expression in Apoe −/− mice was also associated with higher numbers of endothelial progenitor cells (EPCs)—another postulated athero-protective factor. Compared with controls, carriers of a polymorphism in the Ccr5 gene that leads to the lack of CCR5 in the cell surface had an increased mean percentage of EPCs, but this difference did not reach statistical significance. Collectively, these findings underscore a critical role of CCR5 in age-associated cardiovascular diseases, and highlight that the effects of the chemokine system can be temporally constrained to distinct stages of these disease processes. [Copyright &y& Elsevier]