Evolution of Adaptive Immunity

描述（由申请人提供）：1989年由Herzenberg首次提出的“分层假说”理论认为，淋巴细胞在不同的发育阶段产生谱系。所谓的“先天淋巴细胞”，B1细胞和？T细胞被提出提供第一道免疫防御以及其他功能，如维持组织稳态。最近从小鼠和人类的数据强烈支持“分层假说”，但很少有人知道这样的谱系在进化的时间。软骨鱼类免疫球蛋白（IG）基因的组织结构（鲨鱼、冰鞋和鳐），即所谓的集群组织，允许基因类型的可塑性，可以选择和以不同的方式使用;例如，已经选择了一些IG重链簇用于具有单结构域可变区的适应性免疫，而其它的是“种系连接的”，这意味着重新排列的基因片段在生殖细胞中通过RAG连接，并作为固定基因在群体中永久存在。一个特定的生殖系连接的重链构成了新生儿血清IG的一半以上，并且与小鼠中显示的一致，早期抗体识别凋亡细胞，表明其参与稳态功能。 我们将继续研究这种分子的结构和功能，集中在其配体特异性。这种IgM在发育过程中作为第一波在浆细胞中表达，随后是至少两个浆细胞的其他波。第2波仅表达IgM的多聚体形式（19 S），并被鉴定为J链阳性/BLIMP 1阴性，第3波为J链阴性/BLIMP 1阳性（7S）。 BLIMP 1和J链表达的二分法表明，它可能被用作浆细胞谱系的通用标志物，我们计划在小鼠和非洲爪蟾中测试这一建议，这两个其他高度分歧的脊椎动物类群的代表。 我们还将研究的结构和功能？爪蟾和鲨鱼中的T细胞受体，这两个物种的免疫球蛋白可变区在大部分的链中使用。基于这一发现，以及在许多其他脊椎动物中发现的这种IG/TCR嵌合体，表明存在“适应性？”T细胞受体”在所有脊椎动物中，这还没有得到重视。对这一系统的研究不仅会揭示？T细胞和B细胞发育的最古老的动物与适应性免疫的基础上IG/TCR/MHC，但我们假设，它可能作为一个简单的范例分层的淋巴细胞谱系在所有其他脊椎动物。

DESCRIPTION (provided by applicant): The 'Layering Hypothesis,' first proposed in by Herzenberg in 1989, theorized that there are lineages of lymphocytes arising at different stages of development. A basal stratum of so-called "innate lymphocytes," the B1 cells and ?¿ T cells, was proposed to provide a first line of immune defense as well as other functions such as maintenance of tissue homeostasis. Recent data from mouse and human strongly support the 'layering hypothesis,' but little is known of such lineages over evolutionary time. The immunoglobulin (Ig) gene organization in cartilaginous fish (sharks, skates, and rays), the so-called cluster organization, allows for plasticity in the types of genes that can be selected and used in different ways; for example, some Ig heavy chain clusters have been selected for adaptive immunity with single-domain variable regions and others are 'germline-joined,' meaning that the rearranging gene segments were joined by RAG in germ cells and perpetuated in the population as fixed genes. One particular germline-joined heavy chain makes up over half of the serum Ig in neonates, and consistent with what has been shown in mice, the early antibody recognizes apoptotic cells, suggesting that it is involved in homeostatic functions. We will continue to study the structure and function of this molecule, concentrating on its ligand specificity. This IgM is expressed in plasma cells as a first wave during development, followed by at least two other waves of plasma cells. The 2nd wave expresses exclusively a multimeric form of IgM (19S) and is identified as J chain- positive/BLIMP1-negative, and the 3rd wave is J chain-negative/BLIMP1-positive (7S). The dichotomy in BLIMP1 and J chain expression suggests that it might be used as a universal marker for plasma cell lineages, and we plan to test this proposal in mouse and Xenopus, representatives of two other highly divergent vertebrate taxa. We will also examine the structure and function of ?¿ T cell receptors in Xenopus and sharks, two species in which immunoglobulin variable regions are used in a large proportion of the ¿ chains. Based on this finding, as well as uncovering such Ig/TCR chimeras in many other vertebrates, suggests that there are subpopulations of "adaptive ?¿ T cell receptors" in all vertebrates, which has not been appreciated. The study of this system will not only uncover layers of ?¿ T cell and B cell development in the oldest animals with adaptive immunity based on Ig/TCR/MHC, but we hypothesize that it may serve as a simple paradigm for layering of lymphocyte lineages in all other vertebrates.