Evolution of Adaptive Immunity

描述（由申请人提供）：关于免疫系统的进化和功能一直存在疑问。先前在非哺乳动物脊椎动物中进行的研究有助于揭示免疫系统普遍存在的基本特征。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。在我们对最古老的具有适应性免疫的动物软骨鱼（鲨鱼、鳐鱼和鳐鱼）免疫系统的研究中，我们发现了一种新的免疫球蛋白（Ig）同型（新的抗原受体或IgNAR），其结合位点由所谓的单链变量(V)区组成。这种不寻常的抗体具有潜在的治疗/诊断价值，但对于这一提议，它开辟了新的途径来研究抗体的结构和功能在整个进化过程中。由于它们的非典型基因组织，我们提出软骨鱼Ig基因是由免疫系统中的“分层”细胞表达的：在发育过程中首先表达具有固定特异性的“先天”受体，其次是表达多聚IgM的重排IgV受体的细胞，然后是产生单体IgM或IgNAR的淋巴细胞。我们认为“先天”受体和19S IgM形成了第一道防线，而7S和IgNAR提供了高度特异性的体液免疫。出乎意料的是，NAR V域也被？？T细胞受体（TCR），我们建议这些受体补充？？TCR，就像igar被认为是IgM的补充一样。最后，IgD同源物被发现是IgNAR的近亲IgW的同源物。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。

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.