Evolution of Adaptive Immunity

描述（由申请人提供）：关于免疫系统的进化和功能存在持续的问题。以前在非哺乳类脊椎动物中进行的研究有助于揭示普遍存在的免疫系统的基本特征。在其他情况下，小鼠和人类以外的研究强调了与免疫相关的某些基因/分子/机制的巨大可塑性。在我们对软骨鱼（鲨鱼、冰鞋和鳐）免疫系统的研究中，我们发现了一种新的免疫球蛋白（IG）同种型（新抗原受体或IgNAR），它具有一个非常不寻常的结合位点，由所谓的单链可变区（V）组成。这种不寻常的抗体具有潜在的治疗/诊断价值，但对于这项提议，它开辟了新的途径来检查抗体在整个进化过程中的结构和功能。由于其非典型的基因组织，我们提出，软骨鱼IG基因表达的细胞是“分层”的免疫系统：“先天性”受体与固定的特异性表达的第一个发展，其次是细胞与重排的IgV受体表达为多聚体IgM，然后是淋巴细胞产生单体IgM或IgNAR。我们认为，“先天”受体和19 S IgM形成了第一道防线，7S和IgNAR提供了高度特异性的体液免疫。出乎意料的是，NAR V结构域也被一个？T细胞受体（TCR），我们认为，这种受体补充了典型的池？TCR，以与IgNAR被认为补充IgM相同的方式。最后，发现了IgD同源物，其被揭示为IgNAR的近亲IgW的直向同源物。IgD在人类中的功能尚不清楚，我们建议了解其祖先可能有助于揭示其在产生免疫反应中的作用。 公共信息：在进化树的关键步骤中发现的不寻常的动物模型被用来帮助理解人类免疫系统的基本特征我们使用鲨鱼，最古老的具有适应性免疫系统的动物，以及爪蟾，一种处于水生和陆生脊椎动物之间过渡点的两栖动物。我们特别感兴趣的是研究人类免疫分子的结构和功能（抗体同种型IgD和？T细胞受体），其功能尚未明确。

DESCRIPTION (provided by applicant): There are persistent questions regarding the evolution and function of the immune system. Previously studies performed in non-mammalian vertebrates have helped to reveal basic features of the immune system that are universal. In other cases, studies outside of mouse and human have underscored the great plasticity seen in certain genes/molecules/mechanisms related to immunity. In our studies of the immune system in cartilaginous fish (sharks, skates, and rays), the oldest animals with adaptive immunity, we have discovered a new immunoglobulin (Ig) isotype (the new antigen receptor or IgNAR) with a very unusual binding site composed of a so-called single-chain variable (V) region. This unusual antibody is of potential therapeutic/diagnostic interest, but for this proposal it has opened new avenues to examine antibody structure and function throughout evolution. Because of their atypical gene organization, we propose that the cartilaginous fish Ig genes are expressed by cells that are 'layered' in the immune system: 'innate' receptors with fixed specificities expressed first in development, followed by cells with rearranged IgV receptors expressed as multimeric IgM, followed by lymphocytes that produce monomeric IgM or IgNAR. We propose that the 'innate' receptors and 19S IgM form a first line of defense, and the 7S and IgNAR provide the highly specific humoral immunity. Unexpectedly, the NAR V domain is also used by a subset of ??? T cell receptors (TCR), and we propose that such receptors complement the canonical pool of ??? TCR, in the same ways that IgNAR is believed to complement IgM. Finally, an IgD homologue was discovered that was revealed to be an orthologue of a close cousin of IgNAR, IgW. The function of IgD in humans is not known, and we propose that an understanding its ancestry could be useful in unraveling its role in generating immune responses. Public information: Unusual animal models found at crucial steps in the evolutionary tree are used to help understand basic features of the human immune system-we use sharks, the oldest living animals with an adaptive immune system, and Xenopus, an amphibian at the transition point between aquatic and terrestrial vertebrates. We are especially interested in studying the structure and function of human immune molecules (the antibody isotype IgD and the ??? T cell receptor), whose functions have not been well defined.