Journal of Allergy and Clinical Immunology最新文献

Background: IgG can mediate murine and human systemic anaphylaxis (SA). The roles of mast cells (MCs) and histamine in IgG-mediated anaphylaxis are controversial for mice and have not been studied in vivo for humans. We now investigate these issues.

Methods: Actively or passively sensitized wild-type and immune-deficient mice were induced to develop anaphylaxis by i.v. antigen challenge. Anaphylaxis was characterized by evaluating hypothermia, hypomobility, histamine, and mast cell protease responses.

Results: In contrast to our previous results with protein-immunized mice from a conventional colony, IgG-mediated passive SA in our SPF colony mice depended considerably on histamine produced by connective tissue MCs (CTMCs) in response to FcγRIII crosslinking. This was found for C57BL/6 and young male and female BALB/c mice, including BALB/c mice freshly arrived from 3 vendors. IgG-mediated anaphylaxis was less histamine-dependent in old than young mice. Although both mucosal MC (MMC) and CTMC responses were severely depleted in c-kit-deficient mice, MMC responses depended considerably more than CTMC responses on c-kit for maintenance. In immunologically naïve mice, FcγRIII crosslinking strongly activated a subset of CTMCs, but had little ability to activate MMCs. In vivo LPS + poly I.C treatment decreased histamine-dependence of IgG-mediated anaphylaxis while a strong Th2 immune response increased FcγRIII crosslinking-induced MMC activation. IgG-mediated activation of human MCs in reconstituted immunodeficient mice induced histamine-dependent anaphylaxis.

Conclusion: IgG-dependent SA can be mediated largely by histamine released by mouse CTMCs and human MCs; histamine dependence is influenced by mouse age, sex, immune and infectious history, and the anaphylaxis model studied.

Background: Inflammation is a double-edged state of immune activation required to resolve threats harmful to the host but can also cause severe collateral damage. Polymorphonuclear neutrophils (PMN) the primary leukocyte population in humans, mediate inflammation through the release of cytokines and neutrophil extracellular traps (NETs). Whilst the pathophysiological importance of NETs is unequivocal, the multiple molecular pathways driving NET release are not fully defined. Recently, NET release was linked to the NLRP3 inflammasome which is regulated by Bruton's tyrosine kinase in macrophages.

Objective: As NLRP3 inflammasome regulation by BTK has not been studied in neutrophils, we here explored a potential regulatory role of BTK in primary murine and human neutrophils and matched monocytes or macrophages from Btk-deficient vs WT mice or healthy donors (HD) vs BTK-deficient X-linked agammaglobulinemia (XLA) patients, respectively.

Methods: Cytokine, MPO and MMP-9 release were quantified by ELISA, NET release and inflammasome formation by immunofluorescence microscopy.

Results: Surprisingly, in both mouse and human primary neutrophils, we observed a significant increase in NLRP3 inflammasome-dependent IL-1β and NETs when BTK was absent or inhibited, whereas IL-1β release was decreased in corresponding primary mouse macrophages or human PBMC, respectively. This suggests a novel negative regulatory role of BTK in terms of neutrophil NLRP3 activation. Both IL-1β and NET release in mouse and human primary neutrophils were strictly dependent of NLRP3, caspase-1 and, surprisingly, MMP-9.

Conclusion: This highlights BTK and MMP-9 as novel and versatile inflammasome regulators and may have implications for the clinical use of BTK inhibitors.

Microbial interactions mediating colonization resistance play key roles within the human microbiome, shaping susceptibility to infection from birth. To gain insight into microbiome-mediated defenses and respiratory pathogen colonization dynamics, we sequenced and analyzed nasal (n=229) and oral (n=210) microbiomes with associated health/environmental data from our Wisconsin Infant Study Cohort at age 24-months. Participants with early-life lower respiratory tract infection (LRTI) were more likely to be formula-fed, attend daycare, and experience wheezing. Shotgun metagenomic sequencing with detection of viral and bacterial respiratory pathogens revealed nasal microbiome composition to associate with prior LRTI - namely lower alpha diversity, depletion of Prevotella, and enrichment of Moraxella catarrhalis including drug-resistant strains. Prevotella originating from healthy microbiomes had higher biosynthetic gene cluster abundance and exhibited contact-independent inhibition of M. catarrhalis, suggesting interbacterial competition impacts nasal pathogen colonization. This work advances understanding of protective host-microbial interactions occurring in airway microbiomes that alter infection susceptibility in early-life.

Self-reported food allergies (FAs) affect approximately 8% of the US pediatric and approximately 10% of the adult population, which reflects potentially disproportionate increases among ethnically and racially minoritized groups. Multiple gaps and unmet needs exist regarding FA disparities. There is reported evidence of disparities in FA outcomes, and the FA burden may also be disproportionate in low-income families. Low family income has been associated with higher emergency care spending and insecure access to allergen-free food. Pharmacoinequity arises in part as a result of structural racism still experienced by historically marginalized populations today. Historically redlined communities continue to experience greater rates of neighborhood-level air pollution and indoor allergen exposure, lack of transportation to medical appointments, poverty, and lower prescription rates of necessary medications. Clinical research needs racially and ethnically diverse participation to ensure generalizability of research findings and equitable access to medical advances, but race reporting in clinical trials has been historically poor. Addressing health disparities in FA is a priority of clinical care, with professional organizations such as the American Academy of Allergy, Asthma & Immunology having a prominent role to play in mitigating the challenges faced by these individuals. In this position statement we recommend some key steps to address this important issue.

IgE and mast cells play key roles in the pathophysiology of allergic diseases. In 2003, omalizumab was the first anti-IgE mAb licensed in the United States when initially US Food and Drug Administration-approved for the treatment of allergic asthma. Since that time, the number of US Food and Drug Administration-approved indications for treatment with omalizumab has grown to include chronic spontaneous urticaria, chronic rhinosinusitis with nasal polyps, and food allergy. Although omalizumab is generally considered relatively safe and well tolerated, a number of safety concerns have been raised since its initial approval. These concerns focus on specific adverse events of interest, including anaphylaxis, pregnancy, malignancy, cardiovascular events, and infections. For each of these issues, data from clinical trials and postmarketing surveillance have been evaluated extensively. In this review, we examine these safety data, provide context for safety and risk assessments, and summarize a safety profile for each of the adverse events of interest. In doing so, we aim to provide a resource for shared decision making when treatment with omalizumab is being considered.

Background: An understanding of the phenotypes and endotypes of atopic dermatitis (AD) is essential for developing precision therapies. Recent studies have demonstrated evidence for the gut-skin axis in AD.

Objective: To determine the natural course and clinical characteristics of AD phenotypes and investigate their mechanisms based on multi-omics analyses.

Methods: Latent class trajectory analysis was used to AD phenotype in 2247 children who were followed until 9 years of age from the COhort for Childhood Origin of Asthma and allergic diseases (COCOA) birth cohort study. Multi-omics analyses (microbiome, metabolites, and gut epithelial cell transcriptome) using stool samples collected at 6 months of age were performed to elucidate the underlying mechanisms of AD phenotypes.

Results: Five AD phenotypes were classified as follows: never/infrequent, early-onset transient, intermediate-transient, late-onset, and early-onset persistent. Early-onset persistent and late-onset phenotypes showed increased risks of food allergy and wheezing treatment ever, with bronchial hyperresponsiveness only evident in the early-onset persistent phenotype. Multi-omics analyses revealed a significantly lower relative abundance of Ruminococcus gnavus and a decreased gut acetate level in the early-onset persistent phenotype, with potential associations to ACSS2, JAK-STAT signaling, and systemic Th2 inflammation. The early-onset transient phenotype was associated with AMPK and/or chemokine signaling regulation, whereas the late-onset phenotype was linked with IL-17 and barrier dysfunction.

Conclusions: Multi-omics profiling in early life may offer insights into different mechanisms underlying AD phenotypes in children.

Asthma is a common respiratory condition with various phenotypes, non-specific symptoms and variable clinical course. The occurrence of other respiratory conditions with asthma, respiratory co-morbidities (RCs), is not unusual. A literature search was performed for asthma and a variety of respiratory co-morbidities using Pub-Med for the years 2019-2024. The 5 conditions with the largest number of references, other than rhinitis and rhinosinusitis addressed in another paper in this issue, or which are the most problematic in the authors' clinical experience are summarized. Others are briefly discussed. The diagnosis and treatment of both asthma and RCs are complicated by the overlap of symptoms and signs. Recognizing RCs is especially problematic in adult onset, non-type 2 asthma as there are no biomarkers to assist in confirming non-type 2 asthma. Treatment decisions in subjects with suspected asthma and RCs are complicated by the potential similarities between the symptoms or signs of the RC and asthma, the absence of a sine quo non for the diagnosis of asthma, the likelihood that many RCs improve with systemic corticosteroids, and the possibility that the manifestations of the RCs are misattributed to asthma or vice versa. Recognition of RCs is critical to the effective management of asthma, particularly severe or difficult to treat asthma.

Background: The nasal epithelial barrier is the first line of defense against the deep entry of pathogens or aeroallergens, and is more critical in allergic rhinitis (AR). Restoring epithelial barrier dysfunction might be a promising strategy for AR. Recent studies reported that mesenchymal stem cell (MSC)-derived small extracellular vesicles (MSC-sEV) potentially inhibit the inflammation response and promote tissue regeneration. However, their effect on nasal epithelial cells remains unknown.

Objectives: This study sought to describe the therapeutic effect of MSC-sEV on AR, particularly focusing their effect on nasal epithelial cells and underlying molecular mechanisms.

Methods: We utilized an ovalbumin (OVA)-induced mouse model to study AR. Both primary and immortalized human nasal epithelial cells were used to further validate the therapeutic effects of MSC-sEV on epithelial cell function. Then we constructed miR-143 overexpressing and low-expressing HNEpC and MSC-sEV to elucidate molecular mechanisms. Transcriptome analysis was performed to identify the downstream pathways involved.

Results: MSC-sEV successfully maintained nasal barrier integrity in AR mouse model. The MSC-sEV therapeutic effect on the nasal barrier was substantiated in HNEpC. Mechanistically, microRNA (miR)-143 was a candidate mediator of the above effects. Subsequently, transfecting HNEpC with miR-143 partially mimicked the restoring effect of MSC-sEV. MSC-sEV overexpressing miR-143 exerted more therapeutic effects on tight junctions and barrier integrity. Moreover, miR-143 regulated the GSK3β pathway.

Conclusions: Our results indicated that MSC-sEV mitigated AR and restored nasal epithelial barrier dysfunction through the miR-143-GSK3β axis, which suggested that MSC-sEV have the remarkable ability to treat AR.

Background: Regulatory T cells (Tregs) are pivotal in immune tolerance to allergens. Low-dose IL-2 (IL-2_LD) activates Tregs.

Objective: To assess IL-2_LD efficacy for controlling clinical responses to allergen exposures.

Methods: RHINIL-2 was a phase-2a, randomised, double-blind, placebo-controlled trial. Patients with allergic rhinitis to birch pollen (BP) were included, 66% having concomitant asthma. All had a total nasal symptom score (TNSS) ≥5 following nasal exposure to BP in an environmental-exposure-chamber (EEC). Patients received 1 MUI/day of IL-2 (n=12) or Placebo (n=12) for 5 days, followed by weekly injections for 4 weeks. Clinical responses to subsequent BP exposures in the EEC were evaluated using TNSS, the rhinitis visual analogue scale (VAS) and spirometry. The primary efficacy endpoint was the difference in TNSS area under the curve between inclusion and day 40 (TNSSΔAUC).

Results: IL-2_LD treatment induced a significant expansion of Tregs. The TNSSΔAUC in the IL-2 and Placebo groups was non significantly different. TNSS and VAS AUCs were significantly reduced from baseline to day 40 in the IL-2_LD group only (p=0.04 and p=0.01, respectively). The ratio of forced expiratory volume in 1 second/forced vital capacity (FEV_1P) and the forced mid-expiratory flow (FEF_25-75%) showed improvement in the IL-2_LD vs Placebo groups at day 40 (p=0.04 and 0.04, respectively). However, the short treatment duration used in this study cannot have effects on specific IgE or IgG4 levels given their half-life. There was no severe treatment-related adverse events.

Conclusion: IL-2_LD is well-tolerated in allergic patients, even with asthma, clearing the path for further therapeutic development. Our work suggests that Treg can safely attenuate an ongoing allergic response. It paves the way for larger studies with longer treatment periods, which are needed to properly evaluate the therapeutic potential of IL-2 in allergy.