Journal of allergy最新文献

The aim of the current study was to evaluate primary (human bronchial epithelial cells, HBEC) and non-primary (Calu-3, BEAS-2B, BEAS-2B R1) bronchial epithelial cell culture systems as air-liquid interface- (ALI-) differentiated models for asthma research. Ability to differentiate into goblet (MUC5AC+) and ciliated (β-Tubulin IV+) cells was evaluated by confocal imaging and qPCR. Expression of tight junction/adhesion proteins (ZO-1, E-Cadherin) and development of transepithelial electrical resistance (TEER) were assessed. Primary cells showed localised MUC5AC, β-Tubulin IV, ZO-1, and E-Cadherin and developed TEER with, however, a large degree of inter- and intradonor variation. Calu-3 cells developed a more reproducible TEER and a phenotype similar to primary cells although with diffuse β-Tubulin IV staining. BEAS-2B cells did not differentiate or develop tight junctions. These data highlight the challenges in working with primary cell models and the need for careful characterisation and selection of systems to answer specific research questions.

Aspirin-exacerbated respiratory disease (AERD) refers to the development of bronchoconstriction in asthmatics following the exposure to aspirin or other nonsteroidal anti-inflammatory drugs. The key pathogenic mechanisms associated with AERD are the overproduction of cysteinyl leukotrienes (CysLTs) and increased CysLTR1 expression in the airway mucosa and decreased lipoxin and PGE2 synthesis. Genetic studies have suggested a role for variability of genes in disease susceptibility and the response to medication. Potential genetic biomarkers contributing to the AERD phenotype include HLA-DPB1, LTC4S, ALOX5, CYSLT, PGE2, TBXA2R, TBX21, MS4A2, IL10, ACE, IL13, KIF3A, SLC22A2, CEP68, PTGER, and CRTH2 and a four-locus SNP set composed of B2ADR, CCR3, CysLTR1, and FCER1B. Future areas of investigation need to focus on comprehensive approaches to identifying biomarkers for early diagnosis.

Protease activity is a characteristic common to many allergens. Allergen source-derived proteases interact with lung epithelial cells, which are now thought to play vital roles in both innate and adaptive immune responses. Allergen source-derived proteases act on airway epithelial cells to induce disruption of the tight junctions between epithelial cells, activation of protease-activated receptor-2, and the production of thymic stromal lymphopoietin. These facilitate allergen delivery across epithelial layers and enhance allergenicity or directly activate the immune system through a nonallergic mechanism. Furthermore, they cleave regulatory cell surface molecules involved in allergic reactions. Thus, allergen source-derived proteases are a potentially critical factor in the development of allergic sensitization and appear to be strongly associated with heightened allergenicity.

The dioxins and dioxin-like compounds in cigarette smoke and environmental pollutants modulate immunological responses. These environmental toxicants are known to cause lung cancer but have also recently been implicated in allergic and inflammatory diseases such as bronchitis, asthma, and chronic obstructive pulmonary disease (COPD). In a novel pathway of this response, the activation of a nuclear receptor, arylhydrocarbon receptor (AhR), mediates the effects of these toxins through the arachidonic acid cascade, cell differentiation, cell-cell adhesion interactions, cytokine expression, and mucin production that are implicated in the pathogenesis and exacerbation of asthma/COPD. We have previously reported that human bronchial epithelial cells express AhR, and AhR activation induces mucin production through reactive oxygen species. This review discusses the role of AhR in asthma and COPD, focusing in particular on inflammatory and resident cells in the lung. We describe the important impact that AhR activation may have on the inflammation phase in the pathology of asthma and COPD. In addition, crosstalk of AhR signaling with other ligand-activated transcription factors such as peroxisome proliferator-activated receptors (PPARs) has been well documented.

Innate-like lymphocytes (ILLs) and innate lymphoid cells (ILCs) are two newly characterized families of lymphocytes with limited and no rearranged antigen receptors, respectively. These soldiers provide a first line of defense against foreign insults by triggering a prompt innate immune response and bridging the gap of innate and adaptive immunity. Type 2 innate lymphoid cells (ILCs2) are newly identified members of the ILC family that play a key role in type 2 immune responses by prompt production of type 2 cytokines (especially IL-5 and IL-13) in response to antigen-induced IL-25/33 and by recruiting type 2 "immune franchise." Regarding the two different roles of type 2 cytokines, helminth expulsion and type 2-related diseases, here we review the latest advances in ILC2 biology and examine the pivotal role of resident ILCs2 in allergen-specific airway inflammation and asthma.

Inhaled bacterial lipopolysaccharides (LPSs) induce an acute tumour necrosis factor-alpha (TNF-α-) dependent inflammatory response in the murine airways mediated by Toll-like receptor 4 (TLR4) via the myeloid differentiation MyD88 adaptor protein pathway. However, the contractile response of the bronchial smooth muscle and the role of endogenous TNFα in this process have been elusive. We determined the in vivo respiratory pattern of C57BL/6 mice after intranasal LPS administration with or without the presence of increasing doses of methacholine (MCh). We found that LPS administration altered the basal and MCh-evoked respiratory pattern that peaked at 90 min and decreased thereafter in the next 48 h, reaching basal levels 7 days later. We investigated in controlled ex vivo condition the isometric contraction of isolated tracheal rings in response to MCh cholinergic stimulation. We observed that preincubation of the tracheal rings with LPS for 90 min enhanced the subsequent MCh-induced contractile response (hyperreactivity), which was prevented by prior neutralization of TNFα with a specific antibody. Furthermore, hyperreactivity induced by LPS depended on an intact epithelium, whereas hyperreactivity induced by TNFα was well maintained in the absence of epithelium. Finally, the enhanced contractile response to MCh induced by LPS when compared with control mice was not observed in tracheal rings from TLR4- or TNF- or TNF-receptor-deficient mice. We conclude that bacterial endotoxin-mediated hyperreactivity of isolated tracheal rings to MCh depends upon TLR4 integrity that signals the activation of epithelium, which release endogenous TNFα.

Aspirin-exacerbated respiratory disease (AERD) refers to chronic rhinosinusitis, nasal polyposis, bronchoconstriction, and/or eosinophilic inflammation in asthmatics following the exposure to nonsteroidal anti-inflammatory drugs (NSAIDs). A key pathogenic mechanism associated with AERD is the imbalance of eicosanoid metabolism focusing on prostanoid and leukotriene pathways in airway mucosa as well as blood cells. Genetic and functional metabolic studies on vital and non-vital cells pointed to the variability and the crucial role of lipid mediators in disease susceptibility and their response to medication. Eicosanoids, exemplified by prostaglandin E(2) (PGE(2)) and peptidoleukotrienes (pLT), are potential metabolic biomarkers contributing to the AERD phenotype. Also other mediators are implicated in the progress of AERD. Considering the various pathogenic mechanisms of AERD, a multitude of metabolic and genetic markers is suggested to be implicated and were introduced as potential biomarkers for in vitro diagnosis during the past decades. Deduced from an eicosanoid-related pathogenic mechanism, functional tests balancing PGE(2) and pLT as well as other eicosanoids from preferentially vital leukocytes demonstrated their applicability for in vitro diagnosis of AERD.

Background. An in vitro basophil activation test, based on the detection of CD63 upregulation induced by NSAIDs, has been described. Its clinical significance remains controversial. Objectives. In patients with a history of nonallergic NSAID hypersensitivity, stratified according to the severity of the symptoms, to assess with NSAIDs the predictive value of basophil (BAT) and monocyte (MAT) activation tests. Patients/Methods. Sixty patients who had NSAIDs-induced or exacerbated urticaria/angiooedema and 20 controls was included. After incubation with NSAIDs or acetaminophen, leukocytes were analysed for CD63 upregulation. Results. With aspirin, the sensitivity (37%) and specificity (90%) of BAT agree with already published results. In contrast, when patients had had cutaneous and visceral reactions, the frequency of positive BAT 14/22 (64%, P < 0.001) or MAT 10/22 (46%, P < 0.01) were increased. Conclusions. Positive tests were more frequent among patients having a severe hypersensitivity contrasting with the other patients who had results similar to controls.

Phototherapy has still great importance in the treatment of atopic dermatitis, though costs, compliance, and long-term risks narrow its relevance. In spite of its long history, up to now, the therapeutic regimes are mostly empirical. Narrowband UVB und UVA1 are the most frequently applied regimens in atopic dermatitis with proven efficacy. However, even for these modalities randomized prospective and controlled studies are still pending. Advances in photoimmunology and molecular biology had demonstrated that phototherapy targets inflammatory cells, alters cytokine production, and has a significant antimicrobial effect within atopic skin. This paper summarizes the current literature on the different regimes of phototherapy and also discusses therapeutic modalities like photochemotherapy and extracorporeal photopheresis. These more complex regimes should be restricted to severe cases of atopic dermatitis, which are refractory to topical treatment.

Objective. Genetic heterogeneity and risk factor distribution was analyzed in two previously proposed asthma phenotypes. Method. A sample of 412 subjects was investigated at 7-8, 12-13, and 21-22 years of age with questionnaires, skin prick tests, and genetic analysis of IL-4 receptor (IL4R) single-nucleotide polymorphisms. The sample was subdivided in one group with no asthma, and two groups with asthma separated by age of onset of symptoms, namely, early onset asthma (EOA) and late onset asthma (LOA). Risk factors and IL4R markers were analyzed in respect to asthma phenotypes. Results. EOA and LOA groups were both associated with atopy and a maternal history of asthma. Female gender was more common in LOA, whereas childhood eczema, frequent colds in infancy, and a paternal history of asthma were more common in EOA. The AA genotype of rs2057768 and the GG genotype of rs1805010 were more common in LOA, whereas the GG genotype of rs2107356 was less common in EOA. Conclusion. Our data suggest that early and late onset asthma may be of different endotypes and genotypes.