IgE antibodies to the mammalian oligosaccharide galactose-alpha-1, 3-galactose (alpha-gal): immunology, epidemiology and relevance to allergic and inflammatory disease

哺乳动物寡糖半乳糖-α-1, 3-半乳糖 (α-gal) 的 IgE 抗体：免疫学、流行病学以及与过敏性和炎症性疾病的相关性

• 批准号: 10425338
• 负责人: THOMAS A. PLATTS-MILLS
• 金额: $ 98.62万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 1984
• 资助国家: 美国
• 起止时间: 1984-07-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10425338
• 关键词: Abdominal Pain; Allergens; Allergic; Allergic Reaction; Amblyomma; Ambylomma americanum; Anaphylaxis; Antibodies; Antibody Response; Antigens; Area; Asia; Atherosclerosis; Attention; Australia; B-Lymphocytes; Bacteria; Biological Assay; Bioprosthesis device; Bite; Blood; Blood Circulation; Cardiology; Cardiovascular Diseases; Cattle; Cells; Centers for Disease Control and Prevention (U.S.); Cetuximab; Clinic; Clinical; Collaborations; Coronary Arteriosclerosis; Country; Cytometry; Data; Disease; Eating; Ecuador; Ehrlichia; Ehrlichia chaffeensis; Eosinophilic Esophagitis; Epidemiology; Etiology; Europe; Food; Food Hypersensitivity; Geographic Distribution; Glycolipids; Glycoproteins; Health; High Prevalence; Hour; Hypersensitivity; IgE; IgG1; IgG2; IgG4; Immune response; Immunoglobulin G; Immunoglobulin M; Immunology; Incidence; Individual; Inflammatory; Ingestion; Institution; Investigation; Larva; Lipids; Low-Density Lipoproteins; Maps; Measures; Meat; Milk; Monoclonal Antibodies; Multi-Ethnic Study of Atherosclerosis; Nature; Oligosaccharides; Pain; Patients; Plasmablast; Play; Population; Prevalence; Process; Proteins; Public Health; Reaction; Reporting; Research; Rickettsia; Rickettsia rickettsii; Risk Factors; Rocky Mountain Spotted Fever; Role; Sampling; Serology; Serum; Site; Skin; South Africa; Specificity; Symptoms; Syndrome; Testing; Ticks; Time; Tissues; Urticaria; Virginia; Wheat; alpha-gal syndrome; aortic valve; base; cohort; coronary plaque; deep sequencing; design; dietary; experience; galactosyl-(1-3)galactose; high risk; improved; insight; mast cell; natural antibodies; novel; particle; prevent; response; stem; symbiont; tick bite; tick saliva; ultrasound

SUMMARY The syndrome of delayed anaphylaxis to red meat, i.e. the alpha-gal syndrome (AS), is found exclusively in patients who have serum IgE antibody (ab) to the oligosaccharide galactose-alpha-1,3-galactose (alpha-gal). This form of sensitization is related to bites of the tick Amblyomma americanum, however other ticks appear to be relevant in other countries. The objective of the studies proposed here is to investigate the epidemiology, etiology, immunology and clinical features of AS which is now known to be common in a large area of the USA. The studies focus on three aspects of the syndrome. Firstly we will use a detailed map of the cases of AS to compare with maps of tick-related diseases and the distribution of ticks. The serologic response to alpha-gal will be compared from AS cases in participating sites from different parts of the country. Additionally, to investigate the possibility that the Rickettsiae group of obligate intracellular bacteria, such as Rickettsia amblyommii or Ehrlichia chaffeensis, could be relevant to AS sensitization we will carry out assays for specific IgG ab. Secondly, in the area where there is a high prevalence of IgE to alpha-gal there are many individuals who are sensitized but either do not report symptoms or report delayed symptoms that are not recognized as allergic. These include patients with repeated episodes of abdominal pain. Our primary hypothesis about the 3- 5 hour delay in the onset of symptoms is that this reflects the time taken to process dietary mammalian glycoprotein and/or glycolipids lipids to a size that readily penetrates into tissue, for example the size of LDL (~20 nm). Another disease not traditionally considered to be related to allergy is coronary artery disease. In a preliminary investigation we have found that the presence of detectable levels of IgE to alpha-gal is significantly associated with the burden of atherosclerosis in a cohort of subjects in central Virginia. This study, which utilized intravascular ultrasound (IVUS), also demonstrated an association with coronary plaques which had unstable, i.e. high risk, features. We will further investigate this association in a larger cohort at our institution and extend the investigation to subjects in other regions with high prevalence of alpha-gal sensitization. The primary objective of the third aim is to obtain better information about the B cells that relate to the antibody response to alpha-gal. Preliminary data using mass cytometry suggests that subjects with AS have a population of plasmablasts that can respond to alpha-gal. The proposed studies will further investigate these cells with an expanded mass cytometry bead panel and use multiple samples in a single batch. In conjunction with parallel studies employing antibody deep sequencing, collective results are expected to shed insight into the B cell populations that produce `natural' antibodies to alpha-gal, i.e. IgM and IgG2 antibody, as well as those B cells that produce IgE and IgG1. Finally, we will compare the response in AS with that in eosinophilic esophagitis (EoE) which is another form of food allergy with a delayed response and a dramatically different antigen-specific IgE and IgG4 response.

概括 对红肉的迟发性过敏反应综合症，即α-半乳糖综合症（AS），仅见于 血清中存在针对寡糖半乳糖-α-1,3-半乳糖 (α-gal) 的 IgE 抗体 (ab) 的患者。 这种形式的致敏与美洲钝蜱的叮咬有关，但其他蜱似乎也有这种情况。 在其他国家具有相关性。这里提出的研究的目的是调查流行病学， AS 的病因学、免疫学和临床特征目前已知在美国大部分地区很常见。 研究重点关注该综合征的三个方面。首先我们将使用AS案例的详细地图来 与蜱相关疾病和蜱分布的地图进行比较。对α-gal的血清学反应 将与全国不同地区参与地点的 AS 病例进行比较。另外，为了 研究专性细胞内细菌的立克次氏菌群（例如立克次氏体）的可能性 amblyommii 或恰菲埃里希体，可能与 AS 致敏有关，我们将针对特定的情况进行检测 IgG 抗体。其次，在α-gal IgE流行率高的地区，有很多人 过敏但不报告症状或报告延迟症状但不被认为是 过敏。其中包括反复发作腹痛的患者。我们关于 3-的主要假设 症状出现延迟 5 小时，这反映了哺乳动物处理饮食所需的时间 糖蛋白和/或糖脂脂质的大小易于渗透到组织中，例如 LDL 的大小 （~20 纳米）。另一种传统上不被认为与过敏相关的疾病是冠状动脉疾病。在一个 初步调查我们发现 α-gal 的 IgE 水平可检测到 与弗吉尼亚州中部一组受试者的动脉粥样硬化负担显着相关。这项研究， 利用血管内超声（IVUS），也证明了与冠状动脉斑块的关联 具有不稳定的，即高风险的特征。我们将在更大的队列中进一步研究这种关联 建立并将调查范围扩大到其他α-半乳糖患病率高地区的受试者 敏化。第三个目标的主要目的是获得有关 B 细胞的更好信息。 对α-gal的抗体反应。使用质谱流式细胞术的初步数据表明，患有 AS 的受试者 有一群可以对 α-gal 做出反应的浆母细胞。拟议的研究将进一步调查 这些细胞具有扩展的质谱流式细胞仪珠组，并在单个批次中使用多个样品。在 与采用抗体深度测序的平行研究相结合，预计集体结果将得到证实 深入了解产生针对 α-gal 的“天然”抗体（即 IgM 和 IgG2 抗体）的 B 细胞群，如 以及产生 IgE 和 IgG1 的 B 细胞。最后，我们将 AS 中的响应与 嗜酸性粒细胞性食管炎（EoE）是另一种形式的食物过敏，具有延迟反应和 显着不同的抗原特异性 IgE 和 IgG4 反应。