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

基本信息

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
项目类别：
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

项目摘要

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.

该子项目是利用该技术的众多研究子项目之一资源由 NIH/NCRR 资助的中心拨款提供。子项目及研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金，因此可以在其他 CRISP 条目中表示。列出的机构是对于中心来说，它不一定是研究者的机构。 Vn4-34 免疫球蛋白重链基因很大程度上独立于抗体 D 或 J 基因或轻链，编码识别 i-抗原（聚乳糖胺 [3Gal134GlcNAc13-]）和/或 I-抗原（GlcNAc136-支链）的天然自身抗体聚乳糖胺）。 iI 抗原是一种翻译后抗原在人类和许多病原体的各种糖蛋白和糖脂上发现了修饰。肿瘤转化和引起 VH4-34 + B 细胞增殖的特殊感染也可引起病理性冷凝集素疾病，导致溶血性贫血和抗体红细胞复合物在小血管中积聚。据报道，VH4-34 基因在多种其他自身免疫性疾病（包括狼疮、风湿病和多发性硬化症）中发挥着越来越重要的作用。尽管利用 VH4-34 的抗体编码具有危险的特异性，但人类利用 VH4-34 来编码其初始的、无抗原的库的近 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，并且通常被排除在 IgG 抗体反应之外，这进一步证明了这种 VH 消失的危险潜力。重要的是要定义为什么人类进化到在早期 B 细胞中如此深刻地过度利用潜在病理性的 VH4-34，结果却将其排除在经典的二次免疫反应之外，以及这些过程是如何发生的。在具体目标 1 中，测试了假设：VH4-34 在人类中利用幼稚 B 细胞的高流行率是由于对表达与人类 i/I 抗原相似的聚糖的危险病原体的重要作用，以及该 VH 提供的保护性免疫消失比其潜在的危险更重要。在具体目标 2 中，将阐明 VH4-34 在幼稚 B 细胞库中过度表达的分子原因。在具体目标3中，将生成并分析VH4-34免疫和耐受性的小鼠模型。所提出的实验将有利于与 VH4-34 消失相关的特定疾病过程，并将提供许多有价值的见解免疫学主题包括分析免疫和自身免疫之间的微妙平衡（这种平衡经常被打破而导致毁灭性的自身免疫性疾病）、V 基因表达的控制、免疫进化和对聚糖抗原的免疫。