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Pathogenesis and Treatment of Anaphylaxis

过敏反应的发病机制和治疗

基本信息

批准号：
10927844
负责人：
melody c carter
金额：
$ 35.81万
依托单位：
NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10927844
关键词：
Adverse reactions Allergic Anaphylaxis Antigens Basophils Biological Markers Biopsy Bone Marrow Bone Marrow Aspiration CD14 gene Canada Clinical Clinical Immunology Collaborations Core Facility Data Diagnosis Disease Drug Hypersensitivity Etiology European Food Food Hypersensitivity Germany High Prevalence Hypersensitivity Idiopathic anaphylaxis Immunotherapy Inherited Inpatients Insect Sting Investigation Journals Laboratories Manuscripts Measures Mediator Mutation Myelogenous Pathogenesis Pathway interactions Patient Admission Patients Permeability Pharmaceutical Preparations Prevalence Procedures Prospective Studies Proto-Oncogene Protein c-kit Protocols documentation Reaction Recurrence Reporting Role Safety Serum Syndrome Systemic Mastocytosis United States National Institutes of Health Validation Venoms alpha-gal syndrome clinical center cohort experience insight intestinal fatty acid binding protein mast cell mastocytosis microbial participant enrollment pharmacologic specific biomarkers targeted treatment zonulin

项目摘要

We have evaluated 112 patients referred for idiopathic anaphylaxis (IA) and antigen-specific anaphylaxis (SA) to explore pathogenesis and identify patients with clonal mast cell disease. Overall, 22% have been diagnosed with a clonal mast cell disease, 13.4% with IA, 7.1% with venom anaphylaxis and 1.8% with food or drug-induced anaphylaxis. In addition, 8.9% were diagnosed with alpha-gal syndrome, and 13.4% were diagnosed with hereditary alpha-tryptasemia syndrome. Among patients with antigen-induced anaphylaxis, those with venom anaphylaxis in European cohorts have been reported to have a higher prevalence of clonal mast cell disease. In our cohort of patients referred for venom anaphylaxis to date (n=10), seven (80%) have been diagnosed with clonal mast cell disease. Of the ten patients enrolled with food or drug-induced anaphylaxis, thus far, two (20%) have been diagnosed with clonal mast cell disease. In FY 2023, we continue to admit patients with IA and antigen-specific anaphylaxis (SA). Most patients are admitted to the inpatient unit and undergo a bone marrow procedure in an attempt to elucidate the etiology and evaluate the pathogenesis of their disease. In collaboration with the NIH Clinical Center's myeloid core facility, we assess all patient bone marrow aspirates and biopsies obtained based on the current WHO criteria to diagnose systemic mastocytosis. This cohort was also used to contribute to the validation of mast cell activation syndromes and further elucidate pathways of activation for targeted therapy and thus, important for management strategies. In FY 2023, we contributed to manuscripts utilizing our anaphylaxis patient cohort. Our patient cohort of patients with IA were compared to patients with mastocytosis highlighting specific biomarkers of GI permeability that were elevated in both cohorts. Serum concentrations of zonulin, intestinal fatty acid binding protein (I-FABP), and soluble CD14 (sCD14) measured in 54 patients with IA were compared with concentrations in healthy controls (HCs); and correlated with clinical and laboratory parameters. The I-FABP and sCD14 are elevated in the serum of patients with IA. We found both an overlap and a divergence in the microbial translocation markers (MTM) profiles associated with IA versus mastocytosis, Elevations in both intestinal fatty acid binding protein (I-FABP) and soluble CD14 (sCD14) are thus observed in both conditions. However, the MTM profile of IA diverges from that of mastocytosis, with a lack of zonulin elevation in those with IA. One conclusion appears to be that various mast cell disorders carry specific profiles of MTMs. Elevations in these biomarkers of IA provides evidence that increased GI permeability, as is observed in other allergic conditions such as food allergy, is a common finding in those with IA and offers possible insight into the pathogenesis of this disease. I was the co-Editor for a themed issue on Anaphylaxis in the Journal of Allergy and Clinical Immunology: In Practice. I also contributed to a manuscript in this journal with authors from Canada and Germany regarding the role of intrinsic and extrinsic modulators in anaphylaxis.

我们评估了 112 名因特发性过敏反应 (IA) 和抗原特异性过敏反应 (SA) 转诊的患者，以探讨发病机制并识别患有克隆性肥大细胞病的患者。总体而言，22% 的人被诊断患有克隆性肥大细胞病，13.4% 患有 IA，7.1% 患有毒液过敏反应，1.8% 患有食物或药物引起的过敏反应。此外，8.9%的人被诊断为α-gal综合征，13.4%的人被诊断为遗传性α-胰蛋白酶血症综合征。据报道，在抗原诱导过敏反应的患者中，欧洲队列中出现毒液过敏反应的患者克隆性肥大细胞病的患病率较高。迄今为止，在我们因毒液过敏反应而转诊的患者队列中（n=10），有 7 名（80%）被诊断患有克隆性肥大细胞病。迄今为止，在 10 名因食物或药物引起的过敏反应的患者中，有 2 名 (20%) 被诊断患有克隆性肥大细胞病。 2023 财年，我们继续收治 IA 和抗原特异性过敏反应 (SA) 患者。大多数患者被送入住院部并接受骨髓手术，以试图阐明病因并评估其疾病的发病机制。我们与 NIH 临床中心的骨髓核心设施合作，根据当前的 WHO 标准评估所有患者的骨髓抽吸物和活检组织，以诊断系统性肥大细胞增多症。该队列还用于促进肥大细胞激活综合征的验证，并进一步阐明靶向治疗的激活途径，因此对于管理策略很重要。 2023 财年，我们利用过敏反应患者队列撰写了手稿。我们将 IA 患者队列与肥大细胞增多症患者进行比较，突出显示两个队列中胃肠道通透性的特定生物标志物均升高。将 54 名 IA 患者的连蛋白、肠脂肪酸结合蛋白 (I-FABP) 和可溶性 CD14 (sCD14) 的血清浓度与健康对照 (HC) 的浓度进行比较；并与临床和实验室参数相关。 IA 患者血清中 I-FABP 和 sCD14 升高。我们发现与 IA 和肥大细胞增多症相关的微生物易位标记 (MTM) 谱存在重叠和分歧，因此在两种情况下都观察到肠脂肪酸结合蛋白 (I-FABP) 和可溶性 CD14 (sCD14) 的升高。然而，IA 的 MTM 谱与肥大细胞增多症的 MTM 谱不同，IA 患者缺乏连蛋白升高。一个结论似乎是，各种肥大细胞疾病都携带特定的 MTM 特征。这些 IA 生物标志物的升高提供了证据，表明胃肠道通透性增加（如在食物过敏等其他过敏性疾病中观察到的那样）是 IA 患者的常见发现，并为了解该疾病的发病机制提供了可能的见解。我是《过敏与临床免疫学杂志：实践》中过敏反应主题期刊的联合编辑。我还在该杂志上与来自加拿大和德国的作者共同撰写了一篇关于内在和外在调节剂在过敏反应中的作用的手稿。

项目成果

期刊论文数量（32）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Diminution of signal transducer and activator of transcription 3 signaling inhibits vascular permeability and anaphylaxis.

DOI：
10.1016/j.jaci.2015.11.024
发表时间：
2016-07
期刊：
The Journal of allergy and clinical immunology
影响因子：
0
作者：
Hox V;O'Connell MP;Lyons JJ;Sackstein P;Dimaggio T;Jones N;Nelson C;Boehm M;Holland SM;Freeman AF;Tweardy DJ;Olivera A;Metcalfe DD;Milner JD
通讯作者：
Milner JD

Distinct PGE2-responder and non-responder phenotypes in human mast cell populations: "all or nothing" enhancement of antigen-dependent mediator release.

人类肥大细胞群中不同的 PGE2 应答者和非应答者表型：抗原依赖性介质释放的“全有或全无”增强。

DOI：
10.1016/j.imlet.2011.07.002
发表时间：
2011
期刊：
Immunology letters
影响因子：
4.4
作者：
Kuehn,HyeSun;Jung,Mi-Yeon;Beaven,MichaelA;Metcalfe,DeanD;Gilfillan,AlasdairM
通讯作者：
Gilfillan,AlasdairM

Mast cell biology: introduction and overview.