Control of immediate hypersensitivity responses in parasitic and other diseases

控制寄生虫病和其他疾病的速发型超敏反应

• 批准号: 8555829
• 负责人: Thomas Nutman
• 金额: $ 15.84万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 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/8555829
• 关键词: 3-Dimensional; Allergens; Allergic; Allergic Disease; Amino Acid Sequence; Amino Acids; Antibodies; Antibody Formation; Antigens; Bacteria; Binding; Bioinformatics; Computer Simulation; Databases; Dictyoptera; Disease; Epitope Mapping; Epitopes; Filaria bancrofti; Glutathione S-Transferase; Helminth Proteins; Helminths; Homologous Gene; Human; Hypersensitivity skin testing; IgE; IgG4; Immediate hypersensitivity; Immunoglobulin G; Infection; Inflammation; Lead; Literature; Lymphatic; Measures; Modeling; Molecular; Mus; N-terminal; Nature; Parasites; Patients; Peptides; Population; Prevalence; Proteins; Proteome; Recruitment Activity; Regulation; Relative (related person); Serum; Site; Skin; Testing; airborne allergen; allergic response; base; cockroach allergen; cross reactivity; environmental allergen; eosinophil; fungus; immunogenicity; microbial; pathogen; response; tool

An exhaustive search for parasite allergens that may cross-react with aeroallergens has been performed. We have identified a number of parasite antigens and the allergens orthologues and have studied the IgE and IgG responses to these. We have demonstrated unequivocally that parasite infections induced both parasite-specific IgE and IgE that interacts with environmental allergens to which the parasite antigens are closely related. Specifically,we investigates the cross-reactivity between a major glutathione-S transferase allergen of cockroach (Bla g 5) and the glutathione-S transferase of Wuchereria bancrofti (WbGST), a major lymphatic filarial pathogen of humans. We compared the molecular and structural similarities between Bla g 5 and WbGST by in silico analysis and by linear epitope mapping. The levels of IgE, IgG, and IgG(4) antibodies were measured in filarial-infected and filarial-uninfected patients. Mice were infected with Heligmosomoides bakeri, and their skin was tested for cross-reactive allergic responses. We were able to show that these 2 proteins are 30% identical at the amino acid level with remarkable similarity in the N-terminal region and overall structural conservation based on predicted 3-dimensional models. Filarial infection was associated with IgE, IgG, and IgG(4) anti-Bla g 5 antibody production, with a significant correlation between antibodies (irrespective of isotype) to Bla g 5 and WbGST. Preincubation of sera from cockroach-allergic subjects with WbGST partially depleted (by 50%-70%) anti-Bla g 5 IgE, IgG, and IgG(4) antibodies. IgE epitope mapping of Bla g 5 revealed that 2 linear N-terminal epitopes are highly conserved in WbGST corresponding to Bla g 5 peptides partially involved in the inhibition of WbGST binding. Finally, mice infected with H bakeri developed anti-HbGST IgE and showed immediate-type skin test reactivity to Bla g 5. We next used an exhaustive bioinformatics approach to understand the interface between parasite proteins and allergenicty. Because the current paradigm suggests that structural homology of allergenic proteins to microbial (particularly helminths) or human proteins underlie their allergenic nature, we examined systematically the structural relationships among allergens and proteins of pathogens (helminths, protozoans, fungi and bacteria) as they relate to allergenicity, we compared the amino acid sequence of 499 molecularly-defined allergens with the predicted proteomes of fifteen known pathogens, including Th2 inducing helminths and Th1-inducing protozoans, and humans using a variety of bioinformatic tools. Allergenicity was assessed based on IgE prevalences using publicly accessible databases and the literature. We found multiple homologues of common allergens among proteins of helminths, protozoans, fungi and humans, but not of bacteria. In contrast, 187 allergens showed no homology with any of the microbial genera studied. Interestingly, allergens without homologues or those with limited levels of sequence conservation were the most allergenic displaying high IgE prevalences in the allergic population. There was an inverse relationship between allergenicity and amino acid conservation levels with either parasite, including helminth, or human proteins. Our results suggest that allergenicity may be associated with the relative "uniqueness" of an antigen, i.e. immunogenicity, while similarity would lead to immunological tolerance.

对可能与空气变应原发生交叉反应的寄生虫变应原进行了详尽的搜索。我们已经鉴定了一些寄生虫抗原和过敏原同源物，并研究了对它们的IgE和Ig G反应。我们已经明确地证明，寄生虫感染诱导了寄生虫特异性IgE和与寄生虫抗原密切相关的环境过敏原相互作用的IgE。 具体地说，我们研究了蟑螂的主要谷胱甘肽-S转移酶变应原(Bla-g5)与班氏吴氏杆菌的谷胱甘肽-S转移酶(WbGST)之间的交叉反应。通过电子分析和线性表位定位，比较了Bla g5和WbGST在分子和结构上的相似性。检测丝虫感染者和非丝虫感染者血清中的IgE、Ig G和Ig G(4)抗体水平。小鼠被感染了贝克氏螺杆菌，并对它们的皮肤进行了交叉反应过敏反应测试。根据预测的三维模型，我们能够证明这两个蛋白质在氨基酸水平上有30%的同源性，在N-末端区域有显着的相似性，并且总体结构保守。丝虫感染与IgE、Ig G和Ig G(4)抗Bla g5抗体的产生有关，Bla g 5抗体与WbGST显著相关(不论同种类型)。将蟑螂过敏受试者的血清与WbGST部分耗尽(50%-70%)的抗Bla g5 IgE、Ig G和Ig G(4)抗体进行预培养。Bla-g5的抗原表位图谱显示，在WbGST中有2个线性N-末端表位高度保守，对应于部分参与WbGST结合抑制的Bla-g-5多肽。最后，感染HbBkeri的小鼠产生了抗HbGST IgE，并对Bla g5表现出即刻类型的皮肤试验反应。 接下来，我们使用一种详尽的生物信息学方法来了解寄生虫蛋白和过敏性之间的接口。由于目前的范式表明致敏蛋白与微生物(特别是蠕虫)或人类蛋白质的结构同源性是其致敏性质的基础，我们系统地研究了过敏原和病原体(蠕虫、原生动物、真菌和细菌)蛋白质之间的结构关系，因为它们与过敏性有关，我们使用各种生物信息学工具将499种分子定义的过敏原的氨基酸序列与15种已知病原体的预测蛋白质组进行了比较，其中包括Th2诱导蠕虫和Th1诱导原虫，以及人类。过敏性评估是基于公众可访问的数据库和文献中的IgE流行率。我们在蠕虫、原生动物、真菌和人类的蛋白质中发现了常见过敏原的多种同源物，但没有发现细菌的同源物。相比之下，187种过敏原与所研究的任何微生物属都没有同源性。有趣的是，在过敏人群中，没有同源的过敏原或序列保守水平有限的过敏原是表现出高IgE流行率的最敏感的过敏原。无论是寄生虫，包括蠕虫，还是人类蛋白质，过敏性和氨基酸保守水平之间都存在相反的关系。我们的结果表明，过敏性可能与抗原的相对“唯一性”有关，即免疫原性，而相似性会导致免疫耐受。