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

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。所列机构为中心机构，不一定是研究者机构。在很大程度上独立于抗体D或J基因或轻链的Vn 4 -34免疫球蛋白重链基因编码识别i-抗原（聚乳糖胺[3Gal 134 GlcNAc 13-]）和/或I-抗原（GlcNAc 136-分支的聚乳糖胺）的天然自身抗体。II-抗原是在人类和许多病原体的各种糖蛋白和糖脂上发现的翻译后修饰。引起VH 4 -34 + B细胞增殖的肿瘤转化和特定感染也可引起病理性冷凝集素病，导致溶血性贫血和抗体红细胞复合物在小血管中的积累。据报道，VH 4 -34基因在各种其他自身免疫性疾病中发挥着越来越大的作用，包括狼疮，风湿病和多发性硬化症。尽管由利用VH 4 -34的抗体编码的危险特异性，但人类利用VH 4 -34编码其初始抗原初始库的近10%。利用VH 4 -34的B细胞在T依赖性免疫应答中受到严格调节，并且通常被排除在IgG抗体应答之外，进一步证明了该VH消失的危险潜力。重要的是要确定为什么人类已经进化到过度利用其早期B细胞中的潜在病理性VH 4 -34，而只是将其从经典的二次免疫应答中排除，以及这些过程是如何发生的。在具体目的1中，检验了以下假设：在人中利用幼稚B细胞的VH 4 -34的高流行率是由于针对表达与人i/I抗原相似的聚糖的危险病原体的重要作用，并且由该VH gone提供的保护性免疫比其危险潜力更重要。在具体目标2中，将阐明幼稚B细胞库中VH 4 -34过表达的分子原因。在具体目标3中，将产生并分析VH 4 -34免疫和耐受性的小鼠模型。提出的实验将有利于与VH 4 -34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，这种平衡经常会导致毁灭性的自身免疫性疾病，控制V基因表达，免疫进化和对聚糖抗原的免疫。

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.