EVOLUTION OF ADAPTIVE IMMUNITY

免疫球蛋白(Ig)和T细胞受体(TCR)是唯一的- 获得性免疫系统的特定受体已经 具有广泛的特征。我们发现了一种新的抗原受体 偏离Ig/TCR的护士鲨Ginglymostoma Cirratum 也许是在接近适应性免疫概念的时候 系统。这种被称为NAR(新型抗原受体)的分子 血清和细胞表面的二聚体，每个链都是组成的 N-末端V结构域和5个C结构域。互补性 决定NAR的第3区(CDR3)的序列和 长度，显然部分是由于在 加入过程。体细胞突变的频率也很高。 (在已分析的cdna克隆中高达12%)集中在 CDR.假设NAR存在于细胞表面。 鲨鱼(也许还有其他脊椎动物) 二次反应，并且这种细胞可能与“二次反应”同源 哺乳动物系统中描述的B细胞。对这种分子的研究(和 其基因)对了解L对抗原的选择压力具有重要意义 特定的受体迫使它们采用特定的构象；2) 提供一个模型来检查二次免疫反应；3)供应，在 长期，一种研究体细胞突变和“寡核苷酸”的新系统 NAR将在细胞、生化、分子、 功能和进化水平与现有的特异性抗体和 基因探针。具体目标是：1)确定哪些细胞类型 表达NAR，并观察其他抗原受体(如IgM或 TCR)被排除在外；2)研究生化结构 NAR，集中在相关受体和D区的作用 NAR折叠维持中的编码蛋白；3)继续分析 连接过程中的体细胞突变和潜在的“寡核苷酸捕获” 区域；4)研究NAR的功能，以确定T依赖 亲和力成熟发生在免疫后，并检查 体细胞突变的意义；5)寻找NAR的存在 以进一步评估其结构/功能。它是 NAR很可能是第一个具有特征性的新抗原识别 分子排着长长的队伍等待发现。

Immunoglobulin (Ig) and the T cell receptor (TCR) are the only antigen- specific receptors of the adaptive immune system that have been extensively characterized. We have discovered a novel antigen receptor in the nurse shark, Ginglymostoma cirratum, that diverged from the Ig/TCR line perhaps near the time of the conception of the adaptive immune system. This molecule, referred to as NAR (novel antigen receptor) is dimeric in serum and on the cell surface, with each chain being composed of an N-terminal V domain followed by 5 C domains. The complementarity determining region 3 (CDR3) of NAR is incredibly diverse in sequence and length, in part apparently due to "oligonucleotide capture" during the joining process. There is also a very high frequency of somatic mutation (up to 12% in cDNA clones that have been analyzed) concentrated in the CDR. The hypothesis is that NAR is found on the surface of cells in the shark (and perhaps other vertebrates) that are instrumental in generating secondary responses, and that such cells may be homologous to "secondary B cells described in mammalian systems. The study of this molecule (and its gene) is significant to: l) understand selection pressures on antigen specific receptors forcing them to adopt particular conformations; 2) provide a model to examine secondary immune responses; 3) supply, in the long term, a. novel system to study somatic mutation and "oligonucleotide capture." NAR will be examined at the cellular, biochemical, molecular, functional, and phylogenetic levels with existing specific antibodies and gene probes. The Specific Aims are: 1) to determine which cell types express NAR and to observe whether other antigen receptors (like IgM or TCR) are excluded from such cells; 2) to study the biochemical structure of NAR, concentrating on associated receptors and the role of D-region encoded protein in maintenance of the NAR fold; 3) a continued analysis of somatic mutation and potential "oligonucleotide capture" in the joining regions; 4) to study the function of NAR to determine whether T-dependent affinity maturation occurs after immunization, and to examine the significance of the somatic mutation; and 5) to search for NAR's presence in diverse vertebrates to further evaluate its structure/function. It is likely that NAR will be the first characterized novel antigen recognition molecule in a long line awaiting discovery.