DEVELOPMENT OF ANTIBODY REPERTOIRES TO POLYSACCHARIDES

描述(摘自申请者的摘要)：细菌抗体 衣壳多糖是抵抗感染的主要形式 来自化脓性细菌。人类抗体反应的个体发育延迟 多糖易感健康婴幼儿感染和缺陷 抗体反应导致免疫缺陷患者，包括 老年人和患有艾滋病或营养不良的患者，处于高危状态。总目标 这一建议的目的是为人类延缓的个体发育定义基础 对多糖的抗体反应。我们发现，占主导地位的VK 编码高亲和力人抗流感嗜血杆菌b抗体的基因 包膜多糖是A2基因，定位于JK-远端区域 ，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，N 区域添加。我们假设关键的VK的延迟重排 编码这些高度限制性抗体库的基因和延迟 而罕见的N区添加导致了个体发育的这种延迟。这 提案将解决是否：1)是否存在延迟的)个体发育 位于JK-末端的VK基因免疫球蛋白基因重排 人类VK基因座的区域，以及b)在VK-JK处的N区添加 连接，这似乎对扩展CDR3循环的生成至关重要 用于血清抗体与多糖的结合；2)重排 JK-远端VK基因优先发生二次VK-JK重排； 3)L链优先在VK-JK结处发生N区加成 重排发生在B细胞发育的早期；4)VK基因 表达受CK轻链多态的影响；5)肺炎球菌 在婴儿期晚期诱导抗体反应的多糖编码为b 映射到JK-远端区域，并需要在其VK-JK添加N个区域 连接；6)缺失N区衍生的连接CDR3残基 对多糖类的抗体可取消抗体结合。结果应该是 为人类抗体反应的个体发育提供了新的见解 为开发加速猪瘟病毒成熟的疫苗提供背景 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.