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

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。Vn4-34免疫球蛋白重链基因在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-支链聚乳糖胺)的天然自身抗体。II抗原是一种翻译后修饰，存在于人类的各种糖蛋白和糖脂上，也存在于许多病原体上。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，导致溶血性贫血和小血管内抗体红细胞复合体的积聚。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各种其他自身免疫性疾病中也发挥着越来越大的作用。尽管利用VH4-34的抗体编码了危险的特异性，但人类利用VH4-34编码了近10%的初始抗原纯系。利用VH4-34的B细胞在T依赖的免疫反应中受到严格调控，通常被排除在免疫球蛋白抗体反应之外，进一步表明这种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的B细胞中如此深刻地过度利用潜在的病理性VH4-34，只是为了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，验证了这一假设，即VH4-34在人类中利用幼稚B细胞的高流行率是由于对一种危险的病原体具有重要作用，该病原体表达类似于人类I/I抗原的糖链，并且这种VH GONE提供的保护性免疫比其危险的潜力更重要。在特定的目标2中，将阐明VH4-34在NAFVE B细胞库中过度表达的分子原因。在具体目标3中，将建立VH4-34免疫耐受的小鼠模型并进行分析。建议的实验将有利于与VH4-34病毒相关的特定疾病过程，并将为基本免疫学主题提供许多有价值的见解，包括分析免疫和自身免疫之间的微妙平衡，这些平衡经常被破坏，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，以及对糖蛋白抗原的免疫。

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.