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IF 11.4 1区医学 Q1 ALLERGY

Journal of Allergy and Clinical Immunology

Pub Date : 2024-11-01 DOI: 10.1016/j.jaci.2024.09.015

引用次数: 0

CME Calendar-AAAAI 高考日历-AAAAI

IF 11.4 1区医学 Q1 ALLERGY

Journal of Allergy and Clinical Immunology

Pub Date : 2024-11-01 DOI: 10.1016/S0091-6749(24)01001-7

引用次数: 0

Brief Overview of This Month's JACI 本月江淮创新论坛简介

IF 11.4 1区医学 Q1 ALLERGY

Journal of Allergy and Clinical Immunology

Pub Date : 2024-11-01 DOI: 10.1016/S0091-6749(24)00995-3

引用次数: 0

Information for Readers 读者信息

IF 11.4 1区医学 Q1 ALLERGY

Journal of Allergy and Clinical Immunology

Pub Date : 2024-11-01 DOI: 10.1016/S0091-6749(24)00999-0

引用次数: 0

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IF 11.4 1区医学 Q1 ALLERGY

Journal of Allergy and Clinical Immunology

Pub Date : 2024-11-01 DOI: 10.1016/S0091-6749(24)01000-5

引用次数: 0

Human DNA-dependent protein kinase catalytic subunit deficiency: A comprehensive review and update 人类 DNA 依赖性蛋白激酶催化亚基缺乏症：全面回顾与更新。

IF 11.4 1区医学 Q1 ALLERGY

Journal of Allergy and Clinical Immunology

Pub Date : 2024-11-01 DOI: 10.1016/j.jaci.2024.06.018

Background

DNA-dependent protein kinase catalytic subunit (DNA-PKcs) has an essential role in the non–homologous end-joining pathway that repairs DNA double-strand breaks in V(D)J recombination involved in the expression of T- and B-cell receptors. Whereas homozygous mutations in Prkdc define the Scid mouse, a model that has been widely used in biology, human mutations in PRKDC are extremely rare and the disease spectrum has not been described so far.

Objectives

To provide an update on the genetics, clinical spectrum, immunological profile, and therapy of DNA-PKcs deficiency in human.

Methods

The clinical, biological, and treatment data from the 6 cases published to date and from 1 new patient were obtained and analyzed. Rubella PCR was performed on available granuloma material.

Results

We report on 7 patients; 6 patients displayed the autosomal recessive p.L3062R mutation in PRKDC-encoding DNA-PKcs. Atypical severe combined immunodeficiency with inflammatory lesions, granulomas, and autoimmunity was the predominant clinical manifestation (n = 5 of 7). Rubella viral strain was detected in the granuloma of 1 patient over the 2 tested. T-cell counts, including naive CD4⁺CD45RA⁺ T cells and T-cell function were low at diagnosis for 6 patients. For most patients with available values, naive CD4⁺CD45RA⁺ T cells decreased over time (n = 5 of 6). Hematopoietic stem cell transplantation was performed in 5 patients, of whom 4 are still alive without transplant-related morbidity. Sustained T- and B-cell reconstitution was observed, respectively, for 4 and 3 patients, after a median follow-up of 8 years (range 3-16 years).

Conclusions

DNA-PKcs deficiency mainly manifests as an inflammatory disease with granuloma and autoimmune features, along with severe infections.

背景：DNA依赖性蛋白激酶催化亚基（DNA-PKcs）在非同源末端连接途径中发挥着重要作用，该途径可修复V(D)J重组中的DNA双链断裂，并参与T细胞和B细胞受体的表达。PRKDC的同源突变决定了scid小鼠这一已被广泛应用于生物学的模型，而人类的PRKDC突变却极为罕见，迄今为止尚未描述其疾病谱：提供有关人类 DNA-PKcs 缺乏症的遗传学、临床谱、免疫学特征和治疗的最新信息：方法：获取并分析迄今已发表的 6 例病例和 1 例新患者的临床、生物学和治疗数据。对现有肉芽肿材料进行风疹 PCR 检测：结果：我们报告了 7 例患者，其中 6 例患者的编码 DNA-PKcs 的 PRKDC 基因发生了常染色体隐性 p.L3062R 突变。非典型重症联合免疫缺陷病的主要临床表现为炎症病变、肉芽肿和自身免疫（n=5/7）。在两次检测中，有一名患者的肉芽肿中检测到风疹病毒株。6名患者确诊时的T细胞计数（包括幼稚CD4+CD45RA+ T细胞）和T细胞功能较低。大多数患者的幼稚CD4+CD45RA+ T细胞随时间推移而减少（5/6）。5名患者进行了造血干细胞移植（HSCT），其中4人仍然存活，没有发生移植相关的病症。中位随访8年（3-16年）后，分别有4名和3名患者观察到持续的T细胞和B细胞重建：DNA-PKcs缺乏症主要表现为具有肉芽肿和自身免疫特征的炎症性疾病，同时伴有严重感染。

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引用次数: 0

Home and school pollutant exposure, respiratory outcomes, and influence of historical redlining 家庭和学校的污染物暴露、呼吸系统结果以及历史上重新排序的影响。

IF 11.4 1区医学 Q1 ALLERGY

Journal of Allergy and Clinical Immunology

Pub Date : 2024-11-01 DOI: 10.1016/j.jaci.2024.06.020

Background

The discriminatory and racist policy of historical redlining in the United States during the 1930s played a role in perpetuating contemporary environmental health disparities.

Objective

Our objectives were to determine associations between home and school pollutant exposure (fine particulate matter [PM_2.5], NO₂) and respiratory outcomes (Composite Asthma Severity Index, lung function) among school-aged children with asthma and examine whether associations differed between children who resided and/or attended school in historically redlined compared to non-redlined neighborhoods.

Methods

Children ages 6 to 17 with moderate-to-severe asthma (N = 240) from 9 US cities were included. Combined home and school exposure to PM_2.5 and NO₂ was calculated based on geospatially assessed monthly averaged outdoor pollutant concentrations. Repeated measures of Composite Asthma Severity Index and lung function were collected.

Results

Overall, 37.5% of children resided and/or attended schools in historically redlined neighborhoods. Children in historically redlined neighborhoods had greater exposure to NO₂ (median: 15.4 vs 12.1 parts per billion) and closer distance to a highway (median: 0.86 vs 1.23 km), compared to those in non-redlined neighborhoods (P < .01). Overall, PM_2.5 was not associated with asthma severity or lung function. However, among children in redlined neighborhoods, higher PM_2.5 was associated with worse asthma severity (P < .005). No association was observed between pollutants and lung function or asthma severity among children in non-redlined neighborhoods (P > .005).

Conclusions

Our findings highlight the significance of historical redlining and current environmental health disparities among school-aged children with asthma, specifically, the environmental injustice of PM_2.5 exposure and its associations with respiratory health.

背景：20 世纪 30 年代，美国历史上的歧视性种族主义政策--红线政策--在延续当代环境健康差异方面发挥了作用：我们的目标是确定患有哮喘的学龄儿童的家庭和学校污染物暴露（细颗粒物（PM2.5）、二氧化氮（NO2））与呼吸系统结果（哮喘严重程度综合指数（CASI）、肺功能）之间的关联，并研究居住和/或上学于历史上被划为红线的社区的儿童与未被划为红线的社区的儿童之间的关联是否存在差异：方法：研究对象包括美国 9 个城市中患有中度至重度哮喘的 6 至 17 岁儿童（N=240）。根据地理空间评估的月平均室外污染物浓度，计算家庭和学校的 PM2.5 和 NO2 暴露量。收集了 CASI 和肺功能的重复测量数据：总体而言，37.5%的儿童居住和/或就读于历史上被划为红线的社区。与非红线社区的儿童相比，红线社区的儿童暴露于二氧化氮的程度更高（中位数：15.4 ppb 对 12.1 ppb），与高速公路的距离更近（中位数：0.86 km 对 1.23 km）（p2.5 与哮喘严重程度或肺功能无关）。然而，在红线社区的儿童中，PM2.5越高，哮喘严重程度越严重（P0.005）：我们的研究结果凸显了历史上的红线区和当前环境对哮喘学龄儿童健康的影响，特别是 PM2.5 暴露的环境不公正性及其与呼吸系统健康的关系。

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引用次数: 0

Why EoE is different: Liminality and parent-reported outcomes in food allergy 为什么肠易激综合征与众不同？食物过敏的局限性和家长报告的结果。

IF 11.4 1区医学 Q1 ALLERGY

Journal of Allergy and Clinical Immunology

Pub Date : 2024-11-01 DOI: 10.1016/j.jaci.2024.09.010

Paul J. Turner FRACP, PhD

引用次数: 0

Nonspecific lipid-transfer proteins trigger TLR2 and NOD2 signaling and undergo ligand-dependent endocytosis in epithelial cells 非特异性脂质转移蛋白触发 TLR2 和 NOD2 信号，并在上皮细胞中进行配体依赖性内吞。

IF 11.4 1区医学 Q1 ALLERGY

Journal of Allergy and Clinical Immunology

Pub Date : 2024-11-01 DOI: 10.1016/j.jaci.2024.07.015

Nicola Cavallari PhD , Alexander Johnson PhD , Christoph Nagl BSc , Saskia Seiser MSc , Gerald N. Rechberger PhD , Thomas Züllig PhD , Thomas A. Kufer PhD , Adelheid Elbe-Bürger PhD , Sabine Geiselhart PhD , Karin Hoffmann-Sommergruber PhD

Background

Allergens can cross the epithelial barrier to enter the body but how this cellular passage affects protein structures and the downstream interactions with the immune system are still open questions.

Objective

We sought to show the molecular details and the effects of 3 nonspecific lipid transfer proteins (nsLTPs; Mal d 3 [allergenic nsLTP1 from apple], Cor a 8 [allergenic nsLTP1 from hazelnut], and Pru p 3 [allergenic nsLTP1 from peach]) on epithelial cell uptake and transport.

Methods

We used fluorescent imaging, flow cytometry, and proteomic and lipidomic screenings to identify the mechanism involved in nsLTP cellular uptake and signaling on selected epithelial and transgenic cell lines.

Results

nsLTPs are transported across the epithelium without affecting cell membrane stability or viability, and allergen uptake was largely impaired by inhibition of clathrin-mediated endocytosis. Analysis of the lipidome associated with nsLTPs showed a wide variety of lipid ligands predicted to bind inside the allergen hydrophobic cavity. Importantly, the internalization of nsLTPs was contingent on these ligands in the protein complex. nsLTPs were found to initiate cellular signaling via Toll-like receptor 2 but not the cluster of differentiation 1 protein receptor, despite neither being essential for nsLTP endocytosis. We also provide evidence that the 3 allergens induced intracellular stress signaling through activation of the NOD2 pathway.

Conclusions

Our work consolidates the current model on nsLTP-epithelial cell interplay and adds molecular details about cell transport and signaling. In addition, we have developed a versatile toolbox to extend these investigations to other allergens and cell types.

背景：过敏原可以穿过上皮屏障进入人体，但这种细胞通道如何影响蛋白质结构以及下游与免疫系统的相互作用仍是未决问题：我们展示了三种非特异性脂质转移蛋白（nsLTPs；Mal d 3、Cor a 8和Pru p 3）的分子细节及其对上皮细胞摄取和转运的影响：方法：我们使用荧光成像、流式细胞仪、蛋白质组和脂质组学筛选方法来确定参与 nsLTP 细胞摄取和信号转导的特定上皮细胞和转基因细胞系的机制：结果：NsLTP可在不影响细胞膜稳定性或存活率的情况下通过上皮细胞转运，而抑制凝集素介导的内吞作用（CME）会在很大程度上阻碍过敏原的摄取。与 nsLTPs 相关的脂质体分析表明，有多种脂质配体可与过敏原疏水腔结合。重要的是，nsLTPs 的内化取决于蛋白复合物中的这些配体。研究发现，nsLTPs 可通过 TLR2 而非 CD1d 受体启动细胞信号传导，尽管这两种受体对于 nsLTP 的内吞作用都不是必需的。我们还提供了三种过敏原通过激活 NOD2 通路诱导细胞内应激信号的证据：我们的研究巩固了当前 nsLTP 与上皮细胞相互作用的模型，并增加了细胞转运和信号转导的分子细节。此外，我们还开发了一个多功能工具箱，可将这些研究扩展到其他过敏原和细胞类型。

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引用次数: 0

TH2 cell compensatory effect following benralizumab treatment for eosinophilic gastritis 本拉珠单抗治疗嗜酸性胃炎后的 Th2 补偿效应

IF 11.4 1区医学 Q1 ALLERGY

Journal of Allergy and Clinical Immunology

Pub Date : 2024-11-01 DOI: 10.1016/j.jaci.2024.07.018

Netali Ben-Baruch Morgenstern PhD , Yrina Rochman PhD , Julie M. Caldwell PhD , Margaret H. Collins MD , Vincent A. Mukkada MD , Philip E. Putnam MD , Scott M. Bolton MD , Kara L. Kliewer PhD , Marc E. Rothenberg MD, PhD

Background

Eosinophil accumulation is a main feature of eosinophilic gastritis (EoG) and is associated with its histologic diagnosis and pathology. However, a recent clinical trial has demonstrated that EoG endoscopic, noneosinophil histologic, and clinical features remain persistent despite complete eosinophil depletion.

Objective

Our aim was to examine gastric T-cell composition and associated cytokine levels of patients with EoG following benralizumab-induced eosinophil depletion versus following administration of placebo.

Methods

A cohort of subjects with EoG from a subset of subjects who participated in a recent phase 2 benralizumab trial was treated for 12 weeks with administration of 3 doses of benralizumab (anti–IL–5 receptor α antibody [n = 5]) or placebo (n = 4). Single-cell suspensions obtained by gastric biopsy were stimulated with phorbol 12,13-dibutyrate and ionomycin in the presence of brefeldin A and monensin. Harvested cells were fixed, stained, and analyzed by flow cytometry to examine T-cell populations and associated cytokines.

Results

Following benralizumab treatment but not placebo, blood and gastric eosinophil levels decreased 16-fold and 10-fold, respectively. Whereas histologic score and features were significantly decreased, no change was observed in endoscopic score and features. Following complete eosinophil depletion with benralizumab, gastric T_H2 cell levels were 3-fold higher than the levels in the patients with EoG who were given placebo; and the levels of associated type 2 cytokine production of IL-4, IL-5, and IL-13 in the benralizumab-treated patients were, respectively, 4-, 5.5-, and 2.5-fold, higher than those in the placebo-treated patients.

Conclusion

We have identified a putative positive feedback loop whereby eosinophil depletion results in a paradoxic increase in levels of T_H2 cells and derived cytokines; this finding suggests an explanation for the limited success of eosinophil depletion as monotherapy in eosinophil-associated gastrointestinal disorders.

背景：嗜酸性粒细胞聚集是嗜酸性粒细胞性胃炎（EoG）的主要特征，与其组织学诊断和病理学相关。然而，多项临床试验表明，尽管嗜酸性粒细胞被完全清除，但EoG的内镜、非嗜酸性粒细胞组织学和临床特征仍然持续存在：与安慰剂治疗的EoG患者相比，研究苯拉利珠单抗诱导嗜酸性粒细胞清除后的胃T细胞组成和相关细胞因子水平：一组嗜酸性粒细胞增多症患者接受了为期12周的治疗，共使用了3次benralizumab（抗IL-5受体α抗体，n = 5）或安慰剂（n = 4）。胃活检组织的单细胞悬浮液在溴苯蝶啶 A 和莫能菌素存在的情况下受到 12,13-二丁酸光甘油酯（PDBU）和离子霉素的刺激。对收获的细胞进行固定、染色和流式细胞术分析，以检查 T 细胞群和相关细胞因子：结果：苯拉珠单抗治疗后，血液和胃中的嗜酸性粒细胞水平分别下降了16倍和10倍，而安慰剂治疗无效。组织学评分和特征明显降低，但内镜评分和特征没有变化。与使用安慰剂的EoG患者相比，使用苯拉利珠单抗完全清除嗜酸性粒细胞后，胃T辅助2型（Th2）细胞增加了3倍，与之相关的2型细胞因子IL-4、IL-5和IL-13的产生量分别增加了4倍、5.5倍和2.5倍：我们发现了一个假定的正反馈回路，即嗜酸性粒细胞耗竭会导致 Th2 细胞和衍生细胞因子的增加；这一发现为嗜酸性粒细胞耗竭作为单一疗法治疗嗜酸性粒细胞相关性胃肠病（EGID）的有限成功提供了解释。

{"title":"TH2 cell compensatory effect following benralizumab treatment for eosinophilic gastritis","authors":"Netali Ben-Baruch Morgenstern PhD , Yrina Rochman PhD , Julie M. Caldwell PhD , Margaret H. Collins MD , Vincent A. Mukkada MD , Philip E. Putnam MD , Scott M. Bolton MD , Kara L. Kliewer PhD , Marc E. Rothenberg MD, PhD","doi":"10.1016/j.jaci.2024.07.018","DOIUrl":"10.1016/j.jaci.2024.07.018","url":null,"abstract":"<div><h3>Background</h3><div>Eosinophil accumulation is a main feature of eosinophilic gastritis (EoG) and is associated with its histologic diagnosis and pathology. However, a recent clinical trial has demonstrated that EoG endoscopic, noneosinophil histologic, and clinical features remain persistent despite complete eosinophil depletion.</div></div><div><h3>Objective</h3><div>Our aim was to examine gastric T-cell composition and associated cytokine levels of patients with EoG following benralizumab-induced eosinophil depletion versus following administration of placebo.</div></div><div><h3>Methods</h3><div>A cohort of subjects with EoG from a subset of subjects who participated in a recent phase 2 benralizumab trial was treated for 12 weeks with administration of 3 doses of benralizumab (anti–IL–5 receptor α antibody [n = 5]) or placebo (n = 4). Single-cell suspensions obtained by gastric biopsy were stimulated with phorbol 12,13-dibutyrate and ionomycin in the presence of brefeldin A and monensin. Harvested cells were fixed, stained, and analyzed by flow cytometry to examine T-cell populations and associated cytokines.</div></div><div><h3>Results</h3><div>Following benralizumab treatment but not placebo, blood and gastric eosinophil levels decreased 16-fold and 10-fold, respectively. Whereas histologic score and features were significantly decreased, no change was observed in endoscopic score and features. Following complete eosinophil depletion with benralizumab, gastric T<sub>H</sub>2 cell levels were 3-fold higher than the levels in the patients with EoG who were given placebo; and the levels of associated type 2 cytokine production of IL-4, IL-5, and IL-13 in the benralizumab-treated patients were, respectively, 4-, 5.5-, and 2.5-fold, higher than those in the placebo-treated patients.</div></div><div><h3>Conclusion</h3><div>We have identified a putative positive feedback loop whereby eosinophil depletion results in a paradoxic increase in levels of T<sub>H</sub>2 cells and derived cytokines; this finding suggests an explanation for the limited success of eosinophil depletion as monotherapy in eosinophil-associated gastrointestinal disorders.</div></div>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":"154 5","pages":"Pages 1325-1332.e2"},"PeriodicalIF":11.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141874876","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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