DEVELOPMENT OF ANTIBODY REPERTOIRES TO POLYSACCHARIDES

描述（改编自申请人摘要）：细菌抗体 荚膜多糖是抵抗感染的主要形式 从化脓性细菌。 人类抗体应答的个体发育延迟 对多糖的依赖使健康的婴儿易于感染和缺陷 抗体反应使患者免疫缺陷，包括 老年人和艾滋病患者或营养不良者，高危。 总目标 这一建议的目的是确定人类延迟个体发育的基础， 对多糖的抗体反应。 我们发现，占主导地位的Vk 编码抗流感嗜血杆菌B的高亲和力人抗体的基因 荚膜多糖是A2基因，其定位于Jk远端区域 基因座，优先用于生殖系形式，并编码抗体 当在Vk-Jk连接处用精氨酸表达时， 区域添加。 我们假设临界Vk的延迟重排 编码这些高度限制性抗体库的基因， 和不频繁的N区添加有助于这种延迟的个体发育。 这 建议将解决以下问题：1）a）个体发育延迟 免疫球蛋白基因重排的Vk基因位于Jk-远端 B）在人Vk基因座的N区，和 连接，其对于产生延伸的CDR 3环似乎是关键的 用于血清抗体与多糖的结合; 2） Jk-远端Vk基因优先发生次级Vk-Jk重排; 3)在Vk-Jk连接处的N区添加优先发生在L链 重排发生在B细胞发育的早期; 4）Vk基因 表达受Ck轻链多态性的影响; 5）肺炎球菌 在婴儿后期诱导抗体反应的多糖由B编码 映射到Jk远端区域，并需要在其Vk-Jk处添加N区域 6）缺失N区衍生的连接性CDR 3残基; 多糖的抗体消除抗体结合。 结果应 为人类抗体应答的个体发生提供了新的见解， 为开发疫苗提供了背景， 抗体反应。

DESCRIPTION (Adapted from applicant's abstract): Antibody to bacterial capsular polysaccharides are the major form of protection against infections from pyogenic bacteria. The delay in ontogeny of human antibody responses to polysaccharides predisposes the healthy infant to infection and defective antibody responses renders patients with immunodeficiency, including the aged and patients with AIDS or malnutrition, at high risk. The overall goal of this proposal is to define the basis for the delayed ontogeny of human antibody responses to polysaccharides. We have found that the dominant Vk gene encoding high affinity human antibody to the Haemophilus influenzae b capsular polysaccharides is the A2 gene, which maps to the Jk-distal region of the locus, is used preferentially in germline form, and encodes antibody when expressed with an arginine at the Vk-Jk junction that arises by N region addition. We hypothesize that delayed rearrangement of critical Vk genes that encode these highly restricted antibody repertoires and delayed and infrequent N region addition contribute to this delay in ontogeny. This proposal will address whether: 1) there is a delay in a) ontogeny of immunoglobulin gene rearrangement of Vk genes located in the Jk-distal region of the human Vk locus, and b) N region addition at the Vk-Jk junction, which appears critical for the generation of an extended CDR3 loop for binding of serum antibody to polysaccharides; 2) rearrangements of Jk-distal Vk genes occur preferentially as secondary Vk-Jk rearrangements; 3) N region addition at Vk-Jk junctions occurs preferentially when L chain rearrangement occurs at an early state of B cell development; 4) Vk gene expression is affected by Ck light chain polymorphism; 5) pneumococcal polysaccharides that induce antibody responses late in infancy are encoded b map to the Jk-distal-region and require N region addition at their Vk-Jk junction; 6) deletion of the N region-derived junctional CDR3 residue of antibody to polysaccharides abolishes antibody binding. The results should provide novel insights into the ontogeny of human antibody responses and provide a background for developing vaccines that accelerate maturation of antibody responses.