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

总结 红肉迟发性过敏综合征，即α-半乳糖综合征（AS），仅见于 具有针对寡糖半乳糖-α-1，3-半乳糖（α-gal）的血清IgE抗体（ab）的患者。 这种形式的致敏与蜱Amblyomma americanum的叮咬有关，但其他蜱似乎 与其他国家有关。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AS在美国大部分地区很常见。 研究集中在三个方面的综合征。首先，我们将使用AS病例的详细地图， 与蜱虫相关疾病和蜱虫分布图进行比较。对α-半乳糖的血清学反应 将对来自该国不同地区的参与研究中心的AS病例进行比较。此外，为了 研究立克次体属专性胞内细菌，如立克次体， 可能与AS致敏有关，我们将进行特异性检测， IgG抗体其次，在对α-gal的IgE高流行的地区， 敏感但未报告症状或报告未被识别为 过敏。这些包括反复发作腹痛的患者。我们关于3- 5小时延迟症状发作的原因是，这反映了处理哺乳动物饮食所需的时间 糖蛋白和/或糖脂的脂质达到易于渗透到组织中的尺寸，例如LDL的尺寸 （~20 nm）。另一种传统上认为与过敏无关的疾病是冠状动脉疾病。中 初步研究发现，对α-gal的IgE的可检测水平的存在， 与弗吉尼亚州中部一组受试者的动脉粥样硬化负担显著相关。这项研究， 利用血管内超声（IVUS），也证明了与冠状动脉斑块的相关性， 具有不稳定，即高风险的特征。我们将在我们的研究中在更大的队列中进一步研究这种关联。 开展研究并将研究扩展至其他α-半乳糖高患病率地区的受试者 致敏第三个目标的主要目的是获得关于与免疫相关的B细胞的更好信息。 对α-半乳糖的抗体反应。使用质谱仪的初步数据表明，AS患者 有一群能对α-半乳糖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量细胞计数珠板，并在单个批次中使用多个样品。在 结合采用抗体深度测序的平行研究，预计集体结果将 深入了解产生α-gal的“天然”抗体，即IgM和IgG 2抗体的B细胞群， 以及产生IgE和IgG 1的B细胞。最后，我们将比较AS和 嗜酸性食管炎（EoE）是另一种具有延迟反应和 显著不同的抗原特异性IgE和IgG 4应答。

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.