Journal of Allergy and Clinical Immunology最新文献

Food allergy is a growing problem with limited treatment options. It is important to understand the mechanisms of food tolerance and allergy to promote the development of directed therapies. Dendritic cells (DCs) are specialized antigen-presenting cells (APCs) that prime adaptive immune responses, such as those involved in the development of oral tolerance and food allergies. The DC subsets in the gut and skin are defined by their surface markers and function. The default response to an ingested innocuous antigen is oral tolerance, which requires either gut DCs or a subset of newly identified RORγt⁺ APCs to induce the development of gut peripheral regulatory T cells. However, DCs in the skin, gut, and lung can also promote allergic sensitization when they are activated under certain inflammatory conditions, such as with alarmin release or gut dysbiosis. DCs also play a role in the responses to the various modalities of food immunotherapy. Langerhans cells in the skin appear to be necessary for the response to epicutaneous immunotherapy. It will be important to determine which real-world stimuli activate the DCs that prime allergic sensitization and discover methods to selectively initiate a tolerogenic program in APCs.

Background

The integrity of the airway epithelium is guarded by the airway basal cells that serve as progenitor cells and restore wounds in case of injury. Basal cells are a heterogenous population, and specific changes in their behavior are associated with chronic barrier disruption—mechanisms that have not been studied in detail in allergic rhinitis (AR).

Objective

We aimed to study basal cell subtypes in AR and healthy controls.

Methods

Single-cell RNA sequencing (scRNA-Seq) of the nasal epithelium was performed on nonallergic and house dust mite–allergic AR patients to reveal basal cell diversity and to identify allergy-related alterations. Flow cytometry, immunofluorescence staining, and in vitro experiments using primary basal cells were performed to confirm phenotypic findings at the protein level and functionally.

Results

The scRNA-Seq, flow cytometry, and immunofluorescence staining revealed that basal cells are abundantly and heterogeneously present in the nasal epithelium, suggesting specialized subtypes. The total basal cell fraction within the epithelium in AR is increased compared to controls. scRNA-Seq demonstrated that potentially beneficial basal cells are missing in AR epithelium, while an activated population of allergy-associated basal cells is more dominantly present. Furthermore, our in vitro proliferation, wound healing assay and air–liquid interface cultures show that AR-associated basal cells have altered progenitor capacity compared to nonallergic basal cells.

Conclusions

The nasal basal cell population is abundant and diverse, and it shifts toward a diseased state in AR. The absence of potentially protective subtypes and the rise of a proinflammatory population suggest that basal cells are important players in maintaining epithelial barrier defects in AR.

Background

Lactotransferrin (LTF) has an immunomodulatory function, and its expression levels are associated with asthma susceptibility.

Objectives

We sought to investigate LTF messenger RNA (mRNA) expression levels in human bronchial epithelial cells (BECs) as an anti–type 2 (T2) asthma biomarker.

Methods

Association analyses between LTF mRNA expression levels in BECs and asthma-related phenotypes were performed in the Severe Asthma Research Program (SARP) cross-sectional (n = 155) and longitudinal (n = 156) cohorts using a generalized linear model. Correlation analyses of mRNA expression levels between LTF and all other genes were performed by Spearman correlation.

Results

Low LTF mRNA expression levels were associated with asthma susceptibility and severity (P < .025), retrospective and prospective asthma exacerbations, and low lung function (P < 8.3 × 10⁻³). Low LTF mRNA expression levels were associated with high airway T2 inflammation biomarkers (sputum eosinophils and fractional exhaled nitric oxide; P < 8.3 × 10⁻³) but were not associated with blood eosinophils or total serum IgE. LTF mRNA expression levels were negatively correlated with expression levels of T_H2 or asthma-associated genes (POSTN, NOS2, and MUC5AC) and eosinophil-related genes (IL1RL1, CCL26, and IKZF2) and positively correlated with expression levels of T_H1 and inflammation genes (IL12A, MUC5B, and CC16) and T_H17-driven cytokines or chemokines for neutrophils (CXCL1, CXCL6, and CSF3) (P < 3.5 × 10⁻⁶).

Conclusions

Low LTF mRNA expression levels in BECs are associated with asthma susceptibility, severity, and exacerbations through upregulation of airway T2 inflammation. LTF is a potential anti-T2 biomarker, and its expression levels may help determine the balance of eosinophilic and neutrophilic asthma.

Background

Monoallelic loss-of-function IKZF1 (IKAROS) variants cause B-cell deficiency or combined immunodeficiency, whereas monoallelic gain-of-function (GOF) IKZF1 variants have recently been reported to cause hypergammaglobulinemia, abnormal plasma cell differentiation, autoimmune and allergic manifestations, and infections.

Objective

We studied 7 relatives with autoimmune/inflammatory and lymphoproliferative manifestations to identify the immunologic disturbances and the genetic cause of their disease.

Methods

We analyzed biopsy results and performed whole-exome sequencing and immunologic studies.

Results

Disease onset occurred at a mean age of 25.2 years (range, 10-64, years). Six patients suffered from autoimmune/inflammatory diseases, 4 had confirmed IG4-related disease (IgG4-RD), and 5 developed B-cell malignancies: lymphoma in 4 and multiple myeloma in the remaining patient. Patients without immunosuppression were not particularly prone to infectious diseases. Three patients suffered from life-threatening coronavirus disease 2019 pneumonia, of whom 1 had autoantibodies neutralizing IFN-α. The recently described IKZF1 GOF p.R183H variant was found in the 5 affected relatives tested and in a 6-year-old asymptomatic girl. Immunologic analysis revealed hypergammaglobulinemia and high frequencies of certain lymphocyte subsets (exhausted B cells, effector memory CD4 T cells, effector memory CD4 T cells that have regained surface expression of CD45RA and CD28⁻CD57⁺ CD4⁺ and CD8⁺ T cells, T_H2, and Tfh2 cells) attesting to immune dysregulation. Partial clinical responses to rituximab and corticosteroids were observed, and treatment with lenalidomide, which promotes IKAROS degradation, was initiated in 3 patients.

Conclusions

Heterozygosity for GOF IKZF1 variants underlies autoimmunity/inflammatory diseases, IgG4-RD, and B-cell malignancies, the onset of which may occur in adulthood. Clinical and immunologic data are similar to those for patients with unexplained IgG4-RD. Patients may therefore benefit from treatments inhibiting pathways displaying IKAROS-mediated overactivity.

Background

Previous studies implied that local M2 polarization of macrophage promoted mucosal edema and exacerbated T_H2 type inflammation in chronic rhinosinusitis with nasal polyps (CRSwNP). However, the specific pathogenic role of M2 macrophages and the intrinsic regulators in the development of CRS remains elusive.

Objective

We sought to investigate the regulatory role of SIRT5 in the polarization of M2 macrophages and its potential contribution to the development of CRSwNP.

Methods

Real-time reverse transcription–quantitative PCR and Western blot analyses were performed to examine the expression levels of SIRT5 and markers of M2 macrophages in sinonasal mucosa samples obtained from both CRS and control groups. Wild-type and Sirt5-knockout mice were used to establish a nasal polyp model with T_H2 inflammation and to investigate the effects of SIRT5 in macrophage on disease development. Furthermore, in vitro experiments were conducted to elucidate the regulatory role of SIRT5 in polarization of M2 macrophages.

Results

Clinical investigations showed that SIRT5 was highly expressed and positively correlated with M2 macrophage markers in eosinophilic polyps. The expression of SIRT5 in M2 macrophages was found to contribute to the development of the disease, which was impaired in Sirt5-deficient mice. Mechanistically, SIRT5 was shown to enhance the alternative polarization of macrophages by promoting glutaminolysis.

Conclusions

SIRT5 plays a crucial role in promoting the development of CRSwNP by supporting alternative polarization of macrophages, thus providing a potential target for CRSwNP interventions.

Background

Reaction threshold and severity in food allergy are difficult to predict, and noninvasive predictors are lacking.

Objective

We sought to determine the relationships between pre-challenge levels of peanut (PN)-specific antibodies in saliva and reaction threshold, severity, and organ-specific symptoms during PN allergic reactions.

Methods

We measured PN-specific antibody levels in saliva collected from 127 children with suspected PN allergy before double-blind, placebo-controlled PN challenges in which reaction threshold, severity, and symptoms were rigorously characterized. Low threshold (LT) PN allergy was defined as reaction to <300 mg of PN protein cumulatively consumed. A consensus severity grading system was used to grade severity. We analyzed associations between antibody levels and reaction threshold, severity, and organ-specific symptoms.

Results

Among the 127 children, those with high pre-challenge saliva PN IgE had higher odds of LT PN allergy (odds ratio [OR] 3.9, 95% CI 1.6-9.5), while those with high saliva PN IgA:PN IgE ratio or PN IgG₄:PN IgE ratio had lower odds of LT PN allergy (OR 0.3, 95% CI 0.1-0.8; OR 0.4, 95% CI 0.2-0.9). Children with high pre-challenge saliva PN IgG₄ had lower odds of severe PN reactions (OR 0.4, 95% CI 0.2-0.9). Children with high saliva PN IgE had higher odds of respiratory symptoms (OR 8.0, 95% CI 2.2-26.8). Saliva PN IgE modestly correlated with serum PN IgE levels (Pearson r = 0.31, P = .0004). High and low saliva PN IgE levels further distinguished reaction threshold and severity in participants stratified by serum PN IgE, suggesting endotypes.

Conclusions

Saliva PN antibodies could aid in noninvasive risk stratification of PN allergy threshold, severity, and organ-specific symptoms.