Journal of Allergy and Clinical Immunology最新文献_第2页

Utility of eosinophil peroxidase as a biomarker of eosinophilic inflammation in asthma 嗜酸性粒细胞过氧化物酶作为哮喘嗜酸性粒细胞炎症生物标志物的实用性。

IF 11.4 1区医学 Q1 ALLERGY

Journal of Allergy and Clinical Immunology

Pub Date : 2024-09-01 DOI: 10.1016/j.jaci.2024.03.023

Background

The relative utility of eosinophil peroxidase (EPX) and blood and sputum eosinophil counts as disease biomarkers in asthma is uncertain.

Objective

We sought to determine the utility of EPX as a biomarker of systemic and airway eosinophilic inflammation in asthma.

Methods

EPX protein was measured by immunoassay in serum and sputum in 110 healthy controls to establish a normal reference range and in repeated samples of serum and sputum collected during 3 years of observation in 480 participants in the Severe Asthma Research Program 3.

Results

Over 3 years, EPX levels in patients with asthma were higher than normal in 27% to 31% of serum samples and 36% to 53% of sputum samples. Eosinophils and EPX correlated better in blood than in sputum (r_s values of 0.74 and 0.43, respectively), and high sputum EPX levels occurred in 27% of participants with blood eosinophil counts less than 150 cells/μL and 42% of participants with blood eosinophil counts between 150 and 299 cells/μL. Patients with persistently high sputum EPX values for 3 years were characterized by severe airflow obstruction, frequent exacerbations, and high mucus plug scores. In 59 patients with asthma who started mepolizumab during observation, serum EPX levels normalized in 96% but sputum EPX normalized in only 49%. Lung function remained abnormal even when sputum EPX normalized.

Conclusions

Serum EPX is a valid protein biomarker of systemic eosinophilic inflammation in asthma, and sputum EPX levels are a more sensitive biomarker of airway eosinophilic inflammation than sputum eosinophil counts. Eosinophil measures in blood frequently miss airway eosinophilic inflammation, and mepolizumab frequently fails to normalize airway eosinophilic inflammation even though it invariably normalizes systemic eosinophilic inflammation.

背景：嗜酸性粒细胞过氧化物酶（EPX）和血液及痰液中嗜酸性粒细胞计数作为哮喘疾病生物标志物的相对效用尚不确定：确定 EPX 作为哮喘患者全身和气道嗜酸性粒细胞炎症生物标志物的效用：用免疫测定法测定了 110 名健康对照者血清和痰液中的 EPX 蛋白，以确定正常参考值范围，并对严重哮喘研究项目（SARP）-3 的 480 名参与者在三年观察期间重复采集的血清和痰液样本进行了测定：结果发现：在三年中，哮喘患者血清样本中有 27% 至 31% 的 EPX 水平高于正常值，痰样本中有 36% 至 53% 的 EPX 水平高于正常值。嗜酸性粒细胞和 EPX 在血液中的相关性比在痰中更好（rs 值分别为 0.74 和 0.43），痰中 EPX 含量高的患者中，血液中嗜酸性粒细胞计数小于 150 cells/uL 的占 27%，血液中嗜酸性粒细胞计数为 150-299 cells/uL 的占 42%。痰液 EPX 值在三年内持续偏高的患者具有严重的气流阻塞、频繁的病情加重和高粘液栓评分等特征。59 名哮喘患者在观察期间开始使用甲泼尼单抗，96% 的患者血清 EPX 水平恢复正常，但只有 49% 的患者痰液 EPX 恢复正常。即使痰中的 EPX 恢复正常，肺功能仍然异常：结论：血清 EPX 是哮喘患者全身嗜酸性粒细胞炎症的有效蛋白质生物标志物，而痰液 EPX 水平是比痰液嗜酸性粒细胞计数更灵敏的气道嗜酸性粒细胞炎症生物标志物。血液中的嗜酸性粒细胞测量值经常会漏掉气道嗜酸性粒细胞炎症，而mepolizumab 经常无法使气道嗜酸性粒细胞炎症恢复正常，尽管它总是能使全身嗜酸性粒细胞炎症恢复正常。

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引用次数: 0

Impaired high-density lipoprotein function and endothelial barrier stability in severe anaphylaxis 严重过敏性休克患者的高密度脂蛋白功能和内皮屏障稳定性受损。

IF 11.4 1区医学 Q1 ALLERGY

Journal of Allergy and Clinical Immunology

Pub Date : 2024-09-01 DOI: 10.1016/j.jaci.2024.03.031

Background

Growing evidence demonstrates the importance of high- and low-density lipoprotein cholesterol in certain immune and allergy-mediated diseases.

Objective

This study aimed to evaluate levels of high- and low-density lipoprotein cholesterol and apolipoproteins A1 and B in sera from a cohort of patients presenting with hypersensitivity reactions. We further assessed the function of high-density lipoprotein particles as well as their involvement in the molecular mechanisms of anaphylaxis.

Methods

Lipid profile determination was performed in paired (acute and baseline) serum samples from 153 patients. Thirty-eight experienced a non-anaphylactic reaction and 115 had an anaphylactic reaction (88 moderate and 27 severe). Lecithin cholesterol acyl transferase activity was assessed in patient sera, and we also evaluated macrophage cholesterol efflux in response to the serum samples. Last, the effect of anaphylactic-derived high-density lipoprotein (HDL) particles on the endothelial barrier was studied. Detailed methods are provided in the Methods section in this article’s Online Repository available at www.jacionline.org.

Results

Serum samples from severe anaphylactic reactions show statistically significant low levels of HDL cholesterol, low-density lipoprotein cholesterol, and apolipoproteins A1 and B, which points to their possible role as biomarkers. Specifically, HDL particles play a protective role in cardiovascular diseases. Using functional human serum cell assays, we observed impaired capacity of apolipoprotein B–depleted serum to induce macrophage cholesterol efflux in severe anaphylactic reactions. In addition, purified HDL particles from human anaphylactic sera failed to stabilize and maintain the endothelial barrier.

Conclusion

These results encourage further research on HDL functions in severe anaphylaxis, which may lead to new diagnostic and therapeutic strategies.

背景：越来越多的证据表明，高、低密度脂蛋白胆固醇在某些免疫和过敏介导的疾病中具有重要作用：本研究旨在评估一组超敏反应患者血清中高密度和低密度脂蛋白胆固醇以及载脂蛋白 (Apo) A1 和 B 的水平。我们进一步评估了高密度脂蛋白颗粒的功能及其参与过敏性休克分子机制的情况：方法：对 153 名患者的成对（急性和基线）血清样本进行了血脂谱测定。其中 38 人出现非过敏性反应，115 人出现过敏性反应（88 人中度，27 人重度）。我们评估了患者血清中卵磷脂胆固醇酰基转移酶的活性，还评估了巨噬细胞胆固醇外流对血清样本的反应。最后，我们还研究了过敏性高密度脂蛋白颗粒对内皮屏障的影响。详细方法请参见本文在线资料库中的方法部分：www.jacionline.org.Results：严重过敏性反应患者体内的高密度脂蛋白胆固醇、低密度脂蛋白胆固醇、载脂蛋白A1和载脂蛋白B水平明显偏低，这表明它们可能是一种生物标志物。具体来说，高密度脂蛋白颗粒对心血管疾病具有保护作用。利用功能性人血清-细胞试验，我们观察到在严重过敏反应中，缺失载脂蛋白B的血清诱导巨噬细胞胆固醇外流的能力受损。此外，从过敏性血清中纯化的高密度脂蛋白颗粒也不能稳定和维持血管内皮屏障：这些结果鼓励人们进一步研究高密度脂蛋白在严重过敏性休克中的功能，这可能会带来新的诊断和治疗策略。

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引用次数: 0

Nasal solitary chemosensory cells govern daily rhythm in mouse model of allergic rhinitis 过敏性鼻炎小鼠模型中的鼻腔孤独化感细胞控制着日节律。

IF 11.4 1区医学 Q1 ALLERGY

Journal of Allergy and Clinical Immunology

Pub Date : 2024-09-01 DOI: 10.1016/j.jaci.2024.04.024

Background

While the daily rhythm of allergic rhinitis (AR) has long been recognized, the molecular mechanism underlying this phenomenon remains enigmatic.

Objective

We aimed to investigate the role of circadian clock in AR development and to clarify the mechanism by which the daily rhythm of AR is generated.

Methods

AR was induced in mice with ovalbumin. Toluidine blue staining, liquid chromatography–tandem mass spectrometry analysis, real-time quantitative PCR, and immunoblotting were performed with AR and control mice.

Results

Ovalbumin-induced AR is diurnally rhythmic and associated with clock gene disruption in nasal mucosa. In particular, Rev-erbα is generally downregulated and its rhythm retained, but with a near-12-hour phase shift. Furthermore, global knockout of core clock gene Bmal1 or Rev-erbα increases the susceptibility of mice to AR and blunts AR rhythmicity. Importantly, nasal solitary chemosensory cells (SCCs) are rhythmically activated, and inhibition of the SCC pathway leads to attenuated AR and a loss of its rhythm. Moreover, rhythmic activation of SCCs is accounted for by diurnal expression of ChAT (an enzyme responsible for the synthesis of acetylcholine) and temporal generation of the neurotransmitter acetylcholine. Mechanistically, Rev-erbα trans-represses Chat through direct binding to a specific response element, generating a diurnal oscillation in this target gene.

Conclusion

SCCs, under the control of Rev-erbα, are a driver of AR rhythmicity; targeting SCCs should be considered as a new avenue for AR management.

背景：尽管过敏性鼻炎（AR）的日节律早已得到公认，但这一现象的分子机制仍是一个谜：目的：我们旨在研究昼夜节律钟在 AR 发生过程中的作用，并阐明 AR 日节律的产生机制：方法：用卵清蛋白法诱导小鼠产生 AR。方法：用卵清蛋白法诱导小鼠产生 AR，并对 AR 和对照组小鼠进行甲苯胺蓝染色、LC-MS/MS 分析、qPCR 和免疫印迹分析：结果：卵清蛋白诱导的 AR 具有昼夜节律性，与鼻粘膜中的时钟基因紊乱有关。特别是，Rev-erbα普遍下调，其节律保持不变，但有近12小时的相移。此外，全面敲除核心时钟基因 Bmal1 或 Rev-erbα 会增加小鼠对 AR 的易感性，并减弱 AR 的节律性。重要的是，鼻腔 SCC（孤独化感细胞）是有节律地激活的，抑制 SCC 通路会导致 AR 减弱并丧失其节律性。此外，ChAT（一种负责合成乙酰胆碱的酶）的昼夜表达和神经递质乙酰胆碱的时间性生成也是 SCCs 节律性激活的原因。从机理上讲，REV-ERBα通过直接与特定的反应元件结合来转抑Chat，从而使该靶基因产生昼夜振荡：这些发现确定了在 REV-ERBα 控制下的 SCC 是 AR 节律性的驱动因素，并建议将 SCC 作为 AR 管理的新途径。

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引用次数: 0

Clinical and humoral response after SARS-CoV-2 breakthrough infection in patients receiving immunosuppressant therapy 使用免疫抑制剂的患者发生 SARS-CoV-2 突破性感染后的临床反应和体液反应

IF 11.4 1区医学 Q1 ALLERGY

Journal of Allergy and Clinical Immunology

Pub Date : 2024-09-01 DOI: 10.1016/j.jaci.2024.04.031

Background

Despite impaired humoral response in patients treated with immunosuppressants (ISPs), recent studies found similar severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) breakthrough infection compared to controls. One potential explanation is the rapid generation of humoral response on infection, but evidence is lacking.

Objectives

We investigated the longitudinal dynamics of the SARS-CoV-2 antibody repertoire after SARS-CoV-2 delta and omicron breakthrough infection in patients with immune-mediated inflammatory diseases (IMIDs) receiving ISP therapy and controls.

Methods

As a prospective substudy of the national Target-to-B! (T2B!) consortium, we included IMID patients receiving ISPs therapy and controls who reported SARS-CoV-2 breakthrough infection between July 1, 2021, and April 1, 2022. To get an impression of the dynamics of the antibody repertoire, 3 antibody titers of wild-type RBD, wild-type S, and omicron RBD were measured at 4 time points after SARS-CoV-2 breakthrough infection.

Results

We included 302 IMID patients receiving ISPs and 178 controls. Antibody titers increased up to 28 days after breakthrough infection in both groups. However, in IMID patients receiving therapy with anti-CD20 and sphingosine-1 phosphate receptor modulators, antibody titers were considerably lower compared to controls. In the anti-TNF group, we observed slightly lower antibody titers in the early stages and a faster decline of antibodies after infection compared to controls. Breakthrough infections were mostly mild, and hospitalization was required in less than 1% of cases.

Conclusions

Most ISPs do not influence the dynamics of the SARS-CoV-2 antibody repertoire and exhibit a rapid recall response with cross-reactive antibody clones toward new virus variants. However, in patients treated with anti-CD20 therapy or sphingosine-1 phosphate receptor modulators, the dynamics were greatly impaired, and to a lesser extent in those who received anti-TNF. Nevertheless, only a few severe breakthrough cases were reported.

背景尽管接受免疫抑制剂（ISPs）治疗的患者体液反应受损，但最近的研究发现严重急性呼吸系统综合征冠状病毒2（SARS-CoV-2）突破性感染的严重程度与对照组相似。我们调查了接受 ISP 治疗的免疫介导炎症性疾病（IMIDs）患者和对照组在 SARS-CoV-2 δ 和 Ω 突破性感染后 SARS-CoV-2 抗体复合物的纵向动态变化！(T2B!)联盟的前瞻性子研究，我们纳入了在2021年7月1日至2022年4月1日期间报告SARS-CoV-2突破性感染的接受ISPs治疗的IMID患者和对照组。为了了解抗体库的动态变化，我们在 SARS-CoV-2 突破性感染后的 4 个时间点测量了野生型 RBD、野生型 S 和 omicron RBD 的 3 种抗体滴度。两组患者的抗体滴度在突破性感染后 28 天内都有所上升。然而，在接受抗 CD20 和磷酸鞘氨醇-1 受体调节剂治疗的 IMID 患者中，抗体滴度大大低于对照组。在抗肿瘤坏死因子组，我们观察到与对照组相比，早期抗体滴度略低，感染后抗体下降较快。结论大多数 ISPs 不会影响 SARS-CoV-2 抗体库的动态变化，并表现出快速的召回反应，对新的病毒变种产生交叉反应的抗体克隆。然而，在接受抗 CD20 治疗或磷酸鞘氨醇-1 受体调节剂治疗的患者中，这种动态变化受到很大影响，而在接受抗肿瘤坏死因子治疗的患者中，这种动态变化受到的影响较小。不过，只有少数严重的突破性病例被报道。

{"title":"Clinical and humoral response after SARS-CoV-2 breakthrough infection in patients receiving immunosuppressant therapy","authors":"","doi":"10.1016/j.jaci.2024.04.031","DOIUrl":"10.1016/j.jaci.2024.04.031","url":null,"abstract":"<div><h3>Background</h3><p>Despite impaired humoral response in patients treated with immunosuppressants (ISPs), recent studies found similar severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) breakthrough infection compared to controls. One potential explanation is the rapid generation of humoral response on infection, but evidence is lacking.</p></div><div><h3>Objectives</h3><p>We investigated the longitudinal dynamics of the SARS-CoV-2 antibody repertoire after SARS-CoV-2 delta and omicron breakthrough infection in patients with immune-mediated inflammatory diseases (IMIDs) receiving ISP therapy and controls.</p></div><div><h3>Methods</h3><p>As a prospective substudy of the national Target-to-B! (T2B!) consortium, we included IMID patients receiving ISPs therapy and controls who reported SARS-CoV-2 breakthrough infection between July 1, 2021, and April 1, 2022. To get an impression of the dynamics of the antibody repertoire, 3 antibody titers of wild-type RBD, wild-type S, and omicron RBD were measured at 4 time points after SARS-CoV-2 breakthrough infection.</p></div><div><h3>Results</h3><p>We included 302 IMID patients receiving ISPs and 178 controls. Antibody titers increased up to 28 days after breakthrough infection in both groups. However, in IMID patients receiving therapy with anti-CD20 and sphingosine-1 phosphate receptor modulators, antibody titers were considerably lower compared to controls. In the anti-TNF group, we observed slightly lower antibody titers in the early stages and a faster decline of antibodies after infection compared to controls. Breakthrough infections were mostly mild, and hospitalization was required in less than 1% of cases.</p></div><div><h3>Conclusions</h3><p>Most ISPs do not influence the dynamics of the SARS-CoV-2 antibody repertoire and exhibit a rapid recall response with cross-reactive antibody clones toward new virus variants. However, in patients treated with anti-CD20 therapy or sphingosine-1 phosphate receptor modulators, the dynamics were greatly impaired, and to a lesser extent in those who received anti-TNF. Nevertheless, only a few severe breakthrough cases were reported.</p></div>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":null,"pages":null},"PeriodicalIF":11.4,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0091674924005037/pdfft?md5=21c4b3c0d46978f1176a33440e2dfe91&pid=1-s2.0-S0091674924005037-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141055922","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

New light on an old syndrome: Role of Api g 7 in mugwort pollen–related celery allergy 古老综合征的新发现：Api g 7 在艾草花粉相关芹菜过敏症中的作用

IF 11.4 1区医学 Q1 ALLERGY

Journal of Allergy and Clinical Immunology

Pub Date : 2024-09-01 DOI: 10.1016/j.jaci.2024.04.030

Background

Celery root is known to cause severe allergic reactions in patients sensitized to mugwort pollen.

Objective

We studied clinically well-characterized patients with celery allergy by IgE testing with a comprehensive panel of celery allergens to disentangle the molecular basis of what is known as the celery–mugwort syndrome.

Methods

Patients with suspected food allergy to celery underwent a standardized interview. Main inclusion criteria were a positive food challenge with celery or an unambiguous case history of severe anaphylaxis. IgE to celery allergens (rApi g 1.01, rApi g 1.02, rApi g 2, rApi g 4, nApi g 5, rApi g 6, rApi g 7) and to mugwort allergens (rArt v 1, rArt v 3, rArt v 4) were determined. IgE levels ≥0.35 kU_A/L were regarded positive.

Results

Seventy-nine patients with allergy to celery were included. Thirty patients had mild oral or rhinoconjunctival symptoms, and 49 had systemic reactions. Sixty-eight percent had IgE to celery extract, 80% to birch pollen, and 77% to mugwort pollen. A combination of Api g 1.01, 1.02, 4, 5, and 7 increased the diagnostic sensitivity for celery allergy to 92%. The lipid transfer proteins Api g 2 and Api g 6 were not relevant in our celery-allergic population. IgE to Api g 7, detected in 52% of patients, correlated closely (r = 0.86) to Art v 1 from mugwort pollen. Eleven of 12 patients with monosensitization to Api g 7 were IgE negative to celery extract. The odds ratio for developing a severe anaphylactic reaction rather than only mild oral symptoms was about 6 times greater (odds ratio, 5.87; 95% confidence interval, 1.08-32.0; P = .0410) for Api g 7–sensitized versus –nonsensitized subjects.

Conclusion

There is an urgent need for routine diagnostic tests to assess sensitization to Api g 7, not only to increase test sensitivity but also to identify patients at risk of a severe allergic reaction to celery.

背景众所周知，芹菜根会导致对艾草花粉过敏的患者出现严重过敏反应。目的我们通过对芹菜过敏原进行全面的 IgE 检测，研究了临床上特征明确的芹菜过敏患者，以揭示所谓的芹菜艾草综合征的分子基础。主要纳入标准为芹菜食物挑战阳性或有明确的严重过敏性休克病史。测定芹菜过敏原（rApi g 1.01、rApi g 1.02、rApi g 2、rApi g 4、nApi g 5、rApi g 6、rApi g 7）和艾草过敏原（rArt v 1、rArt v 3、rArt v 4）的 IgE。IgE水平≥0.35 kUA/L为阳性。30 名患者有轻微的口腔或鼻结膜症状，49 名患者有全身反应。68%的患者对芹菜提取物产生 IgE，80%的患者对桦树花粉产生 IgE，77%的患者对艾草花粉产生 IgE。Api g 1.01、1.02、4、5 和 7 的组合可将芹菜过敏的诊断灵敏度提高到 92%。脂质转移蛋白 Api g 2 和 Api g 6 与我们的芹菜过敏人群无关。在 52% 的患者中检测到的 Api g 7 IgE 与艾草花粉中的 Art v 1 密切相关（r = 0.86）。在对 Api g 7 单敏的 12 名患者中，有 11 人对芹菜提取物的 IgE 呈阴性。Api g 7致敏受试者与非致敏受试者发生严重过敏反应而非仅出现轻微口腔症状的几率比较大，前者约为后者的 6 倍（几率比，5.87；95% 置信区间，1.08-32.0；P = .0410）。

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引用次数: 0

Nasal brushing molecular endotyping distinguishes patients with chronic rhinosinusitis with nasal polyps with better response to dupilumab 鼻刷分子内分型可区分对杜匹单抗反应更好的 CRSwNP 患者。

IF 11.4 1区医学 Q1 ALLERGY

Journal of Allergy and Clinical Immunology

Pub Date : 2024-09-01 DOI: 10.1016/j.jaci.2024.05.030

Background

There is evidence of pathophysiologic diversity in chronic rhinosinusitis with nasal polyps (CRSwNP), but data characterizing the molecular endotypes of CRSwNP and their association with treatment are lacking.

Objective

This study aimed to identify gene signatures associated with CRSwNP endotypes, clinical features, and dupilumab treatment response.

Methods

Nasal brushing samples were collected from 89 patients randomized to dupilumab 300 mg every 2 weeks or placebo in the SINUS-52 trial (NCT02898454). Microarrays were used to identify transcriptional clusters and assess the relationship between gene expression and baseline clinical features and clinical response to dupilumab. Endotype signatures were determined using differential expression analysis.

Results

Two distinct transcriptional clusters (C1 and C2) were identified, both with elevated type 2 biomarkers. At baseline, C2 patients had higher mean Nasal Polyp Score and higher type 2 biomarker levels than C1 patients. At week 24, significant improvements in clinical outcomes (dupilumab vs placebo) were observed in both clusters, although the magnitude of improvements was significantly greater in C2 than in C1, and more C2 patients demonstrated clinically meaningful responses. Gene set enrichment analysis supported the existence of 2 molecular endotypes: C2 was enriched in genes associated with type 2 inflammation (including periostin, cadherin-26, and type 2 cysteine protease inhibitors), while C1 was enriched in genes associated with T cell activation and IL-12 production.

Conclusions

Two distinct gene signatures associated with CRSwNP clinical features were identified; the endotype signatures were associated with clinical outcome measures and magnitude of dupilumab response.

背景：有证据表明，伴有鼻息肉的慢性鼻炎（CRSwNP）的病理生理学具有多样性，但目前还缺乏描述CRSwNP分子内型特征及其与治疗相关性的数据：目的：确定与 CRSwNP 内型、临床特征和杜匹单抗治疗反应相关的基因特征：方法：从SINUS-52试验（NCT02898454）中随机接受每2周300毫克的杜比鲁单抗或安慰剂治疗的89名患者中收集刷鼻样本。微阵列用于识别转录群，评估基因表达与基线临床特征和对杜比单抗的临床反应之间的关系。通过差异表达分析确定内型特征：结果：确定了两个不同的转录集群（C1 和 C2），这两个集群的 2 型生物标志物均升高。基线时，C2 患者的平均鼻息肉评分和 2 型生物标志物水平均高于 C1 患者。第 24 周时，两组患者的临床结果（dupilumab 与安慰剂对比）均有明显改善，但 C2 患者的改善程度明显高于 C1，而且更多的 C2 患者表现出了有临床意义的反应。基因组富集分析证实了两种分子内型的存在：C2富集于与2型炎症相关的基因（包括包膜蛋白、粘连蛋白-26和2型半胱氨酸蛋白酶抑制剂），而C1富集于与T细胞活化和白细胞介素-12产生相关的基因：结论：发现了与CRSwNP临床特征相关的两种不同的基因特征；内型特征与临床结果指标和杜匹单抗反应的程度相关。

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引用次数: 0

L-plastin associated syndrome of immune deficiency and hematologic cytopenia 免疫缺陷和全血细胞减少的 L-弹性蛋白相关综合征（PASIC）。

IF 11.4 1区医学 Q1 ALLERGY

Journal of Allergy and Clinical Immunology

Pub Date : 2024-09-01 DOI: 10.1016/j.jaci.2024.05.001

Background

LCP1 encodes L-plastin, an actin-bundling protein primarily expressed in hematopoietic cells. In mouse and fish models, LCP1 deficiency has been shown to result in hematologic and immune defects.

Objective

This study aimed to determine the nature of a human inborn error of immunity resulting from a novel genetic variant of LCP1.

Methods

We performed genetic, protein, and cellular analysis of PBMCs from a kindred with apparent autosomal dominant immune deficiency. We identified a candidate causal mutation in LCP1, which we evaluated by engineering the orthologous mutation in mice and Jurkat cells.

Results

A splice-site variant in LCP1 segregated with lymphopenia, neutropenia, and thrombocytopenia. The splicing defect resulted in at least 2 aberrant transcripts, producing an in-frame deletion of 24 nucleotides, and a frameshift deletion of exon 8. Cellular analysis of the kindred revealed a proportionate reduction of T and B cells and a mild expansion of transitional B cells. Similarly, mice carrying the orthologous genetic variant exhibited the same in-frame aberrant transcript, reduced expression Lcp1 and gene dose-dependent leukopenia, mild thrombocytopenia, and lymphopenia, with a significant reduction of T-cell populations. Functional analysis revealed that LCP1^c740^-^1G>A confers a defect in platelet development and function with aberrant spreading on collagen. Immunologic analysis revealed defective actin organization in T cells, reduced migration of PBMCs from patients, splenocytes from mutant mice, and a mutant Jurkat cell line in response to CXCL12; impaired germinal center B-cell expansion after immunization; and reduced cytokinesis during T cell proliferation.

Conclusions

We describe a unique human hematopoietic defect affecting neutrophils, lymphocytes, and platelets arising from partial LCP1 deficiency.

背景：LCP1编码L-弹性蛋白，这是一种主要在造血细胞中表达的肌动蛋白。在小鼠和鱼类模型中，LCP1 缺乏会导致血液学和免疫学缺陷：目的：确定一种由 LCP1 的新型基因变异导致的人类先天性免疫错误的性质：方法：我们对一个患有明显常染色体显性遗传性免疫缺陷症的同种异体的 PBMCs 进行了基因、蛋白质和细胞分析。我们确定了 LCP1 的一个候选致病突变，并通过在小鼠和 Jurkat 细胞中进行直向同源突变工程对其进行了评估：结果：LCP1的剪接位点变异与淋巴细胞减少症、中性粒细胞减少症和血小板减少症分离。剪接缺陷导致至少两个异常转录本，产生24个核苷酸的框内缺失和外显子8的移码缺失。对该种小鼠的细胞分析表明，T 细胞和 B 细胞按比例减少，过渡性 B 细胞轻度增多。同样，携带同源基因变异体的小鼠也表现出相同的框架内异常转录本、Lcp1表达减少、基因剂量依赖性白细胞减少症、轻度血小板减少症和淋巴细胞减少症，T细胞群显著减少。功能分析显示，LCP1c740-1G>A 导致血小板发育和功能缺陷，在胶原上的铺展异常。免疫学分析表明，T 细胞的肌动蛋白组织存在缺陷，患者的 PBMCs、突变小鼠的脾脏细胞和突变 Jurkat 细胞系对 CXCL12 的迁移能力降低，免疫后生殖中心 B 细胞扩增能力受损，T 细胞增殖过程中的细胞分裂减少：我们描述了一种由 LCP1 部分缺乏引起的影响中性粒细胞、淋巴细胞和血小板的独特人类造血缺陷。

{"title":"L-plastin associated syndrome of immune deficiency and hematologic cytopenia","authors":"","doi":"10.1016/j.jaci.2024.05.001","DOIUrl":"10.1016/j.jaci.2024.05.001","url":null,"abstract":"<div><h3>Background</h3><p><em>LCP1</em> encodes L-plastin, an actin-bundling protein primarily expressed in hematopoietic cells. In mouse and fish models, <em>LCP1</em> deficiency has been shown to result in hematologic and immune defects.</p></div><div><h3>Objective</h3><p>This study aimed to determine the nature of a human inborn error of immunity resulting from a novel genetic variant of <em>LCP1</em>.</p></div><div><h3>Methods</h3><p>We performed genetic, protein, and cellular analysis of PBMCs from a kindred with apparent autosomal dominant immune deficiency. We identified a candidate causal mutation in <em>LCP1</em>, which we evaluated by engineering the orthologous mutation in mice and Jurkat cells.</p></div><div><h3>Results</h3><p>A splice-site variant in <em>LCP1</em> segregated with lymphopenia, neutropenia, and thrombocytopenia. The splicing defect resulted in at least 2 aberrant transcripts, producing an in-frame deletion of 24 nucleotides, and a frameshift deletion of exon 8. Cellular analysis of the kindred revealed a proportionate reduction of T and B cells and a mild expansion of transitional B cells. Similarly, mice carrying the orthologous genetic variant exhibited the same in-frame aberrant transcript, reduced expression <em>Lcp1</em> and gene dose-dependent leukopenia, mild thrombocytopenia, and lymphopenia, with a significant reduction of T-cell populations. Functional analysis revealed that LCP1<sup>c740</sup><sup>-</sup><sup>1G>A</sup> confers a defect in platelet development and function with aberrant spreading on collagen. Immunologic analysis revealed defective actin organization in T cells, reduced migration of PBMCs from patients, splenocytes from mutant mice, and a mutant Jurkat cell line in response to CXCL12; impaired germinal center B-cell expansion after immunization; and reduced cytokinesis during T cell proliferation.</p></div><div><h3>Conclusions</h3><p>We describe a unique human hematopoietic defect affecting neutrophils, lymphocytes, and platelets arising from partial <em>LCP1</em> deficiency.</p></div>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":null,"pages":null},"PeriodicalIF":11.4,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0091674924004585/pdfft?md5=f717528e0f6936d2f99adfab420804ae&pid=1-s2.0-S0091674924004585-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140849165","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Genetically proxied IL-6 receptor inhibition is associated with increased risk of atopic dermatitis 白细胞介素-6 受体抑制的基因代型会增加患特应性皮炎的风险。

IF 11.4 1区医学 Q1 ALLERGY

Journal of Allergy and Clinical Immunology

Pub Date : 2024-09-01 DOI: 10.1016/j.jaci.2024.05.016

Background

Dermatitis has been reported after initiation of IL-6 receptor (IL-6R) inhibitors (IL-6Ri), while genetic association studies of atopic dermatitis (AD) have implicated IL-6R pathway signaling. However, causality remains unclear. As the indications for IL-6Ri expand, so do the clinical importance of determining whether there is mechanistic evidence linking it to AD.

Objective

Our aim was to examine the association between IL-6Ri and risk of AD.

Methods

To genetically mimic IL-6Ri, we selected single-nucleotide polymorphisms within or near the IL6R gene associated with C-reactive protein at genome-wide significance among 343,524 individuals. Genetic data were obtained from 10,788 individuals with AD and 30,047 controls of European ancestry. We used inverse variance–weighted and pleiotropy-robust methods and examined genetic confounding using colocalization. Analyses were replicated by using 13,473 Finnish and 2,385 East Asian individuals with AD. The results from 3 independent analyses were pooled by meta-analysis.

Results

Genetically proxied IL-6Ri was associated with increased risk of AD (odds ratio [OR] = 1.78 per 4.4-mg/L reduction in C-reactive protein level [95% CI = 1.28-2.48] [P = 6.5 × 10^–4]). The results were replicated using Finnish outcome data (OR = 2.07 [95% CI = 1.58-2.72] [P = 1.57 × 10^–7]) and Eastern Asian data (OR = 1.68 [95% CI = 1.12-2.54] [P = .013]). Meta-analysis of 3 independent populations (OR = 1.89 [95% CI = 1.57-2.28] [P = 2.68 × 10^–11]) showed no evidence of heterogeneity (P = .65). We found no statistical evidence for pleiotropy or genetic confounding.

Conclusion

This genetic investigation provides consistent evidence (across independent multiancestry populations) that IL-6R signaling is causally implicated in AD susceptibility. Clinicians should remain vigilant for adverse effects resembling AD when using IL-6R inhibitors for immune-mediated inflammatory diseases.

背景：据报道，开始使用 IL-6 受体抑制剂（IL-6Ri）后会出现皮炎，而特应性皮炎（AD）的遗传关联研究与 IL-6R 通路信号有关。然而，因果关系仍不明确。随着IL-6Ri适应症的扩大，确定IL-6Ri是否与特应性皮炎有机理关联的临床重要性也在增加：研究 IL-6Ri 与 AD 风险之间的关联：为了在基因上模拟 IL-6Ri，我们在 343524 人中选择了与 C 反应蛋白（CRP）相关的 IL6R 基因内或附近的单核苷酸多态性，这些多态性在全基因组范围内具有重要意义。我们从 10,788 例病例和 30,047 例欧洲血统的对照组中获得了注意力缺失症的基因数据。我们使用了反方差加权法和多向性稳健法，并使用共定位法检验了遗传混杂因素。我们使用 13,473 例AD 芬兰病例和 2,385 例东亚病例进行了重复分析。通过荟萃分析对三项独立分析的结果进行了汇总：结果：IL-6Ri基因代偿与AD风险增加有关（CRP每降低4.4毫克/升，OR为1.78；95%CI为1.28，2.48；p=6.5x10-4）。芬兰的结果数据（OR 2.07；95%CI 1.58，2.72；p=1.57x10-7）和东亚数据集（OR 1.68；95%CI 1.12，2.54；p=0.013）重复了这一结果。对三个独立人群的 Meta 分析（OR 1.89；95%CI 1.57，2.28；p=2.68x10-11）显示没有异质性的统计学证据（p=0.65）。我们没有发现多效性或遗传混杂的统计学证据：这项基因调查在独立的多种族人群中提供了一致的证据，表明 IL-6R 信号与 AD 易感性有因果关系。临床医生在使用IL-6R抑制剂治疗免疫介导的炎症性疾病时，应继续警惕类似AD的不良反应。

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引用次数: 0

When Dumbo meets IKAROS: Fear and hubris 当小飞象遇到伊卡洛斯：恐惧与狂妄。

IF 11.4 1区医学 Q1 ALLERGY

Journal of Allergy and Clinical Immunology

Pub Date : 2024-09-01 DOI: 10.1016/j.jaci.2024.06.012

引用次数: 0

“Where are they now?” Catching up with the 2019 AAAAI Faculty Development Awardees "他们现在在哪里？"追访2019年AAAAI教师发展奖获得者。

IF 11.4 1区医学 Q1 ALLERGY

Journal of Allergy and Clinical Immunology

Pub Date : 2024-09-01 DOI: 10.1016/j.jaci.2024.07.007

引用次数: 0