Characterization of Lamprey B cells and Antibodies

项目总结 七鳃鳗作为现存的两种无颌脊椎动物之一，在研究人类的进化过程中占有举足轻重的地位。 适应性免疫系统。拟议的研究建立在之前的研究结果基础上，这些发现表明互动的B-和 T淋巴细胞是无颌骨和有颌骨的适应性免疫系统的基本特征 脊椎动物，尽管无颌骨脊椎动物产生可变的淋巴细胞受体(VLR)来识别抗原 通过将不完整的VLRA、VLRB和VLRC胚系基因组合转化为完全组装的VLR 基因使用邻近的富含亮氨酸重复序列(LRR)作为模板。先前的研究表明， 而VLRA和VLRC基因组装与胞苷脱氨酶1(CDA1)的表达一致。 胸腺等效鳃区域，VLRB和CDA2的同时表达主要发生在造血组织。 对VLRB-B的发育、分布和功能进行了全面的分析。 七鳃鳗体内的类细胞及其抗体产物。第一个明确的目标是阐明这一代人， VLRB抗体库的多样化和表达，特别强调新的作用 鉴定出CDA2亚型。第二个具体目标是定义的组成和功能功能 鳗鱼B样淋巴细胞的三个关键受体，即复合型VLRB受体、IL-17D受体和 Baff/APRIL受体，通过使用互补和新的策略来扩增可评估的VLRB 淋巴细胞群。第三个特定目标是产生针对人类肿瘤细胞的特异性VLRB抗体 并对其进行修饰以用于诊断和潜在的治疗用途。这些研究的总体目标是 是为了更好地了解无颌脊椎动物B细胞生物学的基本方面，特别是 产生VLRB抗体多样性，发挥七鳃鳗抗体在生物医学中的优势 目的。

PROJECT SUMMARY As one of two extant jawless vertebrates, lampreys occupy a pivotal position for study of the evolution of our adaptive immune system. The proposed studies build on previous findings indicating that interactive B- and T-like lymphocytes are fundamental features of the adaptive immune system in both jawless and jawed vertebrates, although jawless vertebrates generate variable lymphocyte receptors (VLR) for antigen recognition by combinatorial conversion of incomplete VLRA, VLRB and VLRC germ-line genes into fully assembled VLR genes using neighboring leucine-rich repeat (LRR) sequences as templates. Prior studies indicate that whereas VLRA & VLRC gene assemblies coincide with expression of cytidine deaminase 1 (CDA1) in the thymus equivalent gill region, concurrent VLRB and CDA2 expression occurs primarily in hematopoietic tissues. A comprehensive analysis is proposed to elucidate the development, distribution and function of the VLRB B- like cells and their antibody products in lampreys. The first specific aim is to elucidate the generation, diversification and expression of the VLRB antibody repertoire, with special emphasis on the role of newly identified CDA2 isoforms. The second specific aim is to define the composition and functional capabilities of three key receptors of lamprey B-like lymphocytes, namely the composite VLRB receptor, IL-17D receptor and BAFF/APRIL receptors, through the use of complementary and novel strategies to amplify the assessable VLRB lymphocyte population. The third specific aim is to generate specific VLRB antibodies against human tumor cell antigens and to modify them for diagnostic and potential therapeutic uses. The overall goals of these studies are to better understand basic aspects of B cell biology in a jawless vertebrate, in particular the mechanism of generating VLRB antibody diversity, and to exploit the advantages of lamprey antibodies for biomedical purposes.