Journal of Allergy and Clinical Immunology最新文献

Histamine (C₅H₉N₃, molecular weight 111.15 g/mol) is a well-studied endogenous biogenic amine composed of an imidazole ring attached to an ethylamine side chain. It has a limited half-life of a few minutes within tissues and in circulation. Several cell types including mast cells (MCs), basophils, platelets, histaminergic neurons, and enterochromaffin cells produce varying amounts of histamine using histidine decarboxylase (HDC). However, only MCs and basophils have complex mechanisms to pack and store histamine in granules along with other mediators using serglycin and its carried glycosaminoglycan (GAG) side chains. Relatively low granule pH (app. 5.5) supports the binding of stored histamine to heparin, whereas exposure to neutral pH following degranulation weakens the binding and histamine becomes liberated. Histamine exerts multifaceted regulatory biofunctions by engaging its four types of heptahelical G protein-coupled receptors (GPCRs) (H1R-H4R), which have different expression profiles and functions. MCs express H1R, H2R, and H4R, which gives them a dual role in histamine biology as producers and responsive target cells. Histamine plays a role in a variety of physiologic and pathologic processes such as cell proliferation, differentiation, hematopoiesis, vascular permeability, embryogenesis, tissue regeneration, and wound healing. The emergence of Histamine Receptor (HR)-deficient mouse models and the development of multiple HR agonists and antagonists have helped to better understand these physiological and pathogenic functions of histamine. Here, we review the biology of histamine with a focus on immunological aspects and the role of histamine in allergy and mast cell biology.

Background: Respiratory infections in early life is one identified risk factor for asthma. We hypothesized that infection preventive measures during the COVID-19 pandemic influenced the risk of respiratory morbidity and aeroallergen sensitization in early childhood.

Objective: To compare respiratory morbidity and aeroallergen sensitization in children born before and during the pandemic.

Methods: We compared a COVID-19 category i.e., exposed children (n = 1661) to a pre-COVID-19 category i.e., non-exposed children (n = 1676) by using data from the prospective population based NorthPop Birth Cohort Study in Sweden. Data on respiratory morbidity and concomitant medication were retrieved from national registers. Prospectively collected data on respiratory morbidity using web-based questionnaires at 9 and 18 months of age were applied. At age 18 months, serum immunoglobin E levels to aeroallergens were determined (n = 1702).

Results: The risk of developing any respiratory tract infection (aOR = 0.33 [95% CI = 0.26-0.42]), bronchitis (aOR 0.50 [95% CI = 0.27-0.95]) and croup (aOR = 0.59 [95% CI = 0.37-0.94]) were decreased in the COVID-19 category. The risk of wheeze in the first 9 months was lower in the COVID-19 category (aOR = 0.70 [95% CI = 0.55-0.89]). There were also lower prescriptions of antibiotics in the COVID-19 category. The prevalence of aeroallergen sensitization was similar between the categories.

Conclusion: Children born during the COVID-19 pandemic demonstrated significantly decreased risks of respiratory infections and prescribed antibiotics until 18 months of age compared to children born before the COVID-19 pandemic. Whether this will impact the risk of developing asthma in childhood is being followed.

Background: Heterozygous immunoproteasome subunit beta-type 10 (PSMB10) mutations can cause severe combined immunodeficiency (SCID) and Omenn syndrome (OS). Hematopoietic stem cell transplantation in these patients is associated with severe complications and poor immune reconstitution, often resulting in death.

Objective: To perform immunological and molecular characterization of an infant with a PSMB10 heterozygous variant.

Methods: A heterozygous variant in PSMB10 (p.G201R) was identified in the index but not her parents. Detailed immunophenotyping and functional studies, including flow cytometry, immunoblotting, and T-cell development in artificial thymic organoids (ATO), were performed.

Results: The patient presented with severe B-, NK-, as well as T-cell lymphopenia, with a progressive increase in memory CD4+ and loss of CD8+ T-cells, diminished Vbeta family diversity, and abnormal IL-7 signaling. Immunoproteasome protein expression (PSMB10 and 9) was markedly reduced in the patient's cells, including PBMCs, EBV-transformed B cells, and fibroblasts, the mutation likely acting in a dominant negative fashion. Patient CD34+ cells showed a normal early T-cell development but slightly impaired generation of CD3+TCRαβ+ cells in ATO, and human thymus single cell RNA sequencing demonstrated that PSMB10 is expressed in different subsets of cortical and medullary thymic epithelial cells. Collectively, these data indicate that PSMB10 mutations affect positive selection of CD8 T-cells, generation of a diverse T-cell repertoire, and negative selection of autoreactive T-cells.

Conclusion: The PSMB10 G201R variant is associated with reduced immunoproteasome expression levels that appear to play vital roles in hematopoietic and extra-hematopoietic immune system development and function. PSMB10-associated thymoproteasome dysfunction leads to impaired thymopoiesis and the development of SCID and OS, suggesting possible benefit from thymus implantation.

Background: There is no global agreement on the definition of Chronic Spontaneous Urticaria (CSU) remission.

Objective: To generate a consensus for clinical definitions in CSU focused on remission.

Methods: The World Allergy Organization (WAO) Urticaria Committee systematically reviewed current available longitudinal articles. Based on this review, a consensus agreement was reached for the CSU "remission" definition. Additionally, a scheme was constructed for when and how therapeutic de-escalation should be done.

Results: Almost all groups that have carried out longitudinal studies to evaluate the frequency of CSU remission agreed to use this term if the patient remains without urticaria signs and symptoms without pharmacologic treatment (omalizumab, cyclosporine, antihistamines or systemic corticosteroids). After our systematic review, the available evidence does not define the best time to consider CSU remission. However, current evidence suggests that there is not a significant difference in CSU relapse between 6- and 12-month periods of remission. So far, no evidence exists to propose any biomarkers for defining inflammatory/mechanistic remission in CSU or identifying patients with a high probability of cure. It can be reasonable to consider a reduction of treatment after six months of CSU control, with evaluation 2 to 6 months after stepping-down treatment.

Conclusion: The WAO Urticaria Committee proposes defining CSU clinical remission based on the total resolution of urticaria signs and symptoms without pharmacotherapy for at least six months. The implications of this definition in clinical practice must be evaluated and validated in future studies.

Background: Eosinophilic esophagitis (EoE) is a chronic T_H2-associated inflammatory disorder triggered by food allergens, resulting in esophageal dysfunction through edema, fibrosis, and tissue remodeling. The role of epithelial remodeling in EoE pathogenesis is critical but not fully understood.

Objective: We investigated the role of epithelial IKKβ/NF-κB signaling in EoE pathogenesis using a mouse model with conditional Ikkβ knockout in esophageal epithelial cells (Ikkβ^EEC-KO).

Methods: EoE was induced in Ikkβ^EEC-KO mice through skin sensitization with MC903/ovalbumin followed by intraesophageal ovalbumin challenge. Histologic and transcriptional analyses were performed to assess EoE features. Single-cell RNA sequencing was used to profile esophageal mucosal cell populations and gene expression changes.

Results: Ikkβ^EEC-KO/EoE mice exhibited hallmark EoE features, including eosinophil infiltration, intraepithelial eosinophils, microabscesses, basal cell hyperplasia, and lamina propria remodeling. RNA sequencing revealed significant alterations in IKKβ/NF-κB signaling pathways, with decreased expression of RELA and increased expression of IKKβ-negative regulators. Sequencing analyses identified disrupted epithelial differentiation and barrier integrity alongside increased type 2 immune responses and peptidase activity.

Conclusion: Loss of epithelial IKKβ signaling exacerbates EoE pathogenesis, highlighting the critical role of this pathway in maintaining epithelial homeostasis and preventing allergic inflammation. The Ikkβ^EEC-KO/EoE mouse model closely mirrors human EoE, providing a valuable tool for investigating disease mechanisms and therapeutic targets. This model can facilitate the development of strategies to prevent chronic inflammation and tissue remodeling in EoE.