Evolution of Adaptive Immunity

描述(申请人提供)：由Herzenberg在1989年首次提出的“分层假说”理论认为，在不同的发育阶段，淋巴细胞有不同的谱系。所谓的“先天淋巴细胞”的基础层，即B1细胞和T细胞，被认为是提供免疫防御的第一道防线，以及其他功能，如维持组织的动态平衡。来自老鼠和人类的最新数据有力地支持了“分层假说”，但随着进化时间的推移，人们对这种血统知之甚少。软骨鱼(鲨鱼、溜冰鞋和鲟鱼)中的免疫球蛋白(Ig)基因组织，即所谓的簇组织，允许各种类型的基因具有可塑性，可以选择并以不同的方式使用；例如，一些Ig重链簇被选择用于单域可变区的适应性免疫，另一些簇是“生殖线连接的”，这意味着重排的基因片段被RAG连接在生殖细胞中，并作为固定基因在种群中永久存在。一种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，与在小鼠身上显示的情况一致，早期抗体识别凋亡细胞，表明它参与了体内平衡功能。 我们将继续研究这个分子的结构和功能，重点是它的配体特异性。这种IgM在浆细胞中的表达是发育过程中的第一波，随后是至少另外两波浆细胞。第二波仅表达多聚体形式的IgM(19S)，鉴定为J链阳性/BLIMP1阴性，第三波为J链阴性/BLIMP1阳性(7S)。BLIMP1和J链表达的二分性表明，BLIMP1可能被用作浆细胞谱系的通用标记，我们计划在另外两个高度分化的脊椎动物类群的代表小鼠和非洲爪鼠身上测试这一假设。我们还将研究非洲爪哇和鲨鱼的T细胞受体的结构和功能，这两个物种的免疫球蛋白可变区在很大程度上使用了链。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，表明在所有脊椎动物中都存在“适应性T细胞受体”亚群，这一点还没有被认识到。对这个系统的研究不仅将揭示基于Ig/TCR/MHC的适应性免疫的最老动物的T细胞和B细胞发育的层次，而且我们假设它可能为所有其他脊椎动物的淋巴谱系分层提供一个简单的范例。

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.