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 在 具有血清IgE抗体（AB）的患者，抗寡糖半乳糖-Alpha-1,3-乳糖糖（Alpha-gal）。 这种敏化形式与Tick Amblyomma Americanum的叮咬有关，但是其他tick似乎似乎 在其他国家有意义。这里提出的研究的目的是研究流行病学， 现在已知在美国大区域中常见的病因，免疫学和临床特征。 研究集中于综合征的三个方面。首先，我们将使用有关案例的详细地图 与与tick相关疾病的地图和tick分发进行比较。对α-gal的血清学反应 将从该国不同地区的参与地点的AS案件进行比较。此外， 调查立克人士的义务细胞内细菌的可能性，例如立克西亚 Amblyommii或Ehrlichia chaffeensis可能与我们的敏化有关，我们将进行特定的测定法 IgG AB。其次，在IgE到alpha-gal的高流行率的地区，有很多人 谁是敏感的但不报告症状或报告未被认为延迟的症状的人 过敏。其中包括重复发作腹痛的患者。我们关于3-的主要假设 症状发作的5小时延迟是，这反映了处理饮食哺乳动物所花费的时间 糖蛋白和/或糖脂脂脂，可容易渗透到组织中，例如LDL的大小 （〜20 nm）。传统上不认为与过敏有关的另一种疾病是冠状动脉疾病。在 初步调查我们发现，存在可检测水平的IgE水平到α-gal是 与中部弗吉尼亚州的一系列受试者中的动脉粥样硬化负担显着相关。这项研究， 利用血管内超声（IVU）的，也证明了与冠状动脉斑块的关联 具有不稳定的功能，即高风险。我们将进一步调查我们在我们的较大队列中 机构并将调查扩展到α-GAL高流行率的其他地区的受试者 致敏。第三个目的的主要目的是获得有关与B单元相关的B单元的更好信息 对抗体对α-gal的反应。使用质量细胞术的初步数据表明，具有AS的受试者 具有可以响应α-gal的浆膜群。拟议的研究将进一步研究 这些细胞具有扩展的质量细胞仪珠面板，并在单批中使用多个样品。在 与采用抗体深度测序的并行研究的结合，预计集体结果将脱离 对产生对α-GAL的“天然”抗体的B细胞群的见解，即IgM和IgG2抗体，AS 以及那些产生IgE和IgG1的B细胞。最后，我们将与此中的响应进行比较 嗜酸性食管炎（EOE）是食物过敏的另一种形式，反应延迟 抗原特异性IgE和IgG4响应急剧不同。