Evolution of Adaptive Immunity

描述（由申请人提供）：“分层假说”于1989年由Herzenberg首次提出，该假说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”的底层，即B1细胞和γδ T细胞，被认为提供了免疫防御的第一道防线，以及其他功能，如维持组织稳态。最近来自小鼠和人类的数据有力地支持了“分层假说”，但在进化过程中对这种谱系知之甚少。软骨鱼类（鲨鱼、鳐鱼和鳐鱼）的免疫球蛋白（Ig）基因组织，即所谓的集群组织，允许基因类型的可塑性，可以以不同的方式选择和使用；例如，一些具有单域可变区域的Ig重链簇被选择用于适应性免疫，而另一些则是“种系连接”的，这意味着重排基因片段在生殖细胞中由RAG连接，并作为固定基因在群体中永久存在。一种特殊的生殖系连接的重链构成了新生儿血清Ig的一半以上，并且与小鼠的结果一致，早期抗体识别凋亡细胞，表明它参与了体内平衡功能。

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 γδ 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 γδ T cell receptors in Xenopus and sharks, two species in which immunoglobulin variable regions are used in a large proportion of the δ chains. Based on this finding, as well as uncovering such Ig/TCR chimeras in many other vertebrates, suggests that there are subpopulations of "adaptive γδ T cell receptors" in all vertebrates, which has not been appreciated. The study of this system will not only uncover layers of γδ 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.