COBRE: OK MED RES FOUND: P2: REGULATION OF ANTIBODY PRODUCTION TO A AUTOANTIGEN

COBRE：确定医学研究发现：P2：自身抗原抗体产生的调节

• 批准号: 8168450
• 负责人: Patrick Christopher Wilson
• 金额: $ 33.06万
• 依托单位: OKLAHOMA MEDICAL RESEARCH FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-08 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8168450
• 关键词: Antibodies; Antibody Formation; Antigens; Autoantibodies; Autoantigens; Autoimmune Diseases; Autoimmunity; B cell repertoire; B-Lymphocytes; Cold Hemagglutinin Disease; Complex; Computer Retrieval of Information on Scientific Projects Database; Disease; Equilibrium; Evolution; Funding; Gene Expression; Genes; Glycolipids; Glycoproteins; Grant; Hemolytic Anemia; High Prevalence; Human; I-antigen; IGH@ gene cluster; Immune; Immune response; Immunity; Immunoglobulin G; Immunologic Memory; Immunology; Infection; Institution; Light; Lupus; Molecular; Multiple Sclerosis; Neoplastic Cell Transformation; Play; Polysaccharides; Post-Translational Protein Processing; Process; Regulation; Reporting; Research; Research Personnel; Resources; Rheumatism; Role; Source; Specificity; Testing; United States National Institutes of Health; disorder control; insight; mouse model; pathogen; polylactosamine; research study

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The Vn4-34 immunoglobulin heavy chain genes, largely independent of the antibody D or J genes or the light chains, encode natural autoantibodies that recognize the i-antigen (polylactosamine [3Gal134GlcNAc13-],) and/or I-antigen (GlcNAc136-branched polylactosamine). The iI-antigen is a post-translational modification found on various glycoproteins and glycolipids in humans and on a number of pathogens. Neoplastic transformation and particular infections causing proliferations of VH4-34 + B cells can also cause pathological cold-agglutinin disease resulting in hemolytic anemia and the accumulation of antibodyerythrocyte complexes in small vessels. The VH4-34 gene has also been reported to play an increased role in various other autoimmune diseases including lupus, rheumatism, and multiple sclerosis. Despite the dangerous specificity encoded by VH4-34-utilizing antibodies, humans utilize VH4-34 to encode nearly 10% of their initial, antigen-na'fve repertoire. B cells utilizing VH4-34 are tightly regulated in T-dependent immune responses and are normally excluded from IgG antibody responses, further demonstrating the dangerous potential of this VH gone. It is important to define why humans have evolved to over-utilize the potentially pathological VH4-34 so profoundly in their early B cells only to exclude it from classic secondary immune responses and how these processes occur. In specific aim 1 the hypothesis is tested that the high prevalence of VH4-34 utilizing naive B cells in humans is due to an important role against a dangerous pathogen expressing glycans similar to human i/I antigens and that the protective immunity provided by this VH gone is more important than its dangerous potential. In specific aim 2, the molecular reason for VH4-34 overrepresentation in the na'fve B cell repertoire will be elucidated. In specific aim 3, a mouse model of VH4-34 immunity and tolerance will be generated and analyzed. The experiments proposed will benefit the specific disease processes associated with the VH4-34 gone and will provide many valuable insights into basic immunology topics including analysis of the delicate balance between immunity and autoimmunity that so often breaks down to cause devastating autoimmune diseases, control of V gene expression, immune evolution, and immunity to glycan antigen.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 VN4-34免疫球蛋白重链基因，很大程度上独立于抗体D或J基因或光链，编码自然自身抗体，它们识别I-抗原（polylactosamine [3GAL134GLCNAC13-]，），），和/或/i-antigen（glcnacnac1366-pollylact contylact of lotylactiamine nimantigen [3GAL134GLCNAC13-] - II-抗原是翻译后的 在人类和许多病原体中的各种糖蛋白和糖脂上发现的修饰。 引起VH4-34 + B细胞增殖的肿瘤转化和特定感染也会引起病理冷 - 阿格凝集素疾病，导致溶血性贫血和小血管中抗体性截肢络合物的积累。据报道，VH4-34基因在包括狼疮，风湿病和多发性硬化症在内的其他各种自身免疫性疾病中起着提高作用。尽管通过VH4-34利用抗体编码的危险特异性，但人类利用VH4-34编码其初始抗原-na'fve曲目的近10％。利用VH4-34的B细胞在T依赖性免疫反应中受到严格调节，通常排除在IgG抗体反应中，进一步证明了该VH消失的危险潜力。重要的是要定义为什么人类进化以使潜在的病理VH4-34如此深刻地限制在其早期B细胞中，只是将其排除在经典的二次免疫反应之外以及这些过程如何发生。在特定目标1中，检验了假设，即使用人类幼稚B细胞的VH4-34的高流行率是由于对表达与人I/I抗原相似的危险病原体的重要作用，并且该VH提供的保护免疫消失比其危险潜力更重要。在特定的目标2中，将阐明Na'fve B细胞库中VH4-34过度代表性过高的分子原因。在特定的目标3中，将生成和分析VH4-34免疫力和公差的小鼠模型。提出的实验将使与VH4-34消失相关的特定疾病过程受益，并将为基本的许多有价值的见解提供 免疫学主题包括分析免疫和自身免疫之间的微妙平衡，这些平衡通常会分解以引起毁灭性自身免疫性疾病，控制V基因表达，免疫进化以及对聚糖抗原的免疫力。