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Evolution of Adaptive Immunity

适应性免疫的进化

基本信息

批准号：
9270624
负责人：
Martin F Flajnik
金额：
$ 30.37万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
1991
资助国家：
美国
起止时间：
1991-02-11 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9270624
关键词：
Adaptive Immune System Amphibia Animal Model Animals Antibodies Antigens Apoptotic Autoimmunity B-Cell Development B-Lymphocytes CD4 Positive T Lymphocytes Cell Lineage Cells Characteristics Chimera organism Chondrichthyes Communicable Diseases Data Development Didelphidae Drosophila genus Evolution Gene Structure Genes Germ Cells Grant Growth Heavy-Chain Immunoglobulins Helper-Inducer T-Lymphocyte Homeostasis Human IGH@ gene cluster Immune Immune system Immunity Immunoglobulin Genes Immunoglobulin M Immunoglobulin Variable Region Immunoglobulins Immunology Intestinal Mucosa Investigation J-Chain Immunoglobulins Laboratories Life Ligands Lymphocyte Maintenance Malignant Neoplasms Mammals Mus Nature New Mexico Ornithorhynchus anatinus PRDM1 gene Plasma Cells Population Rana Receptor Cell Research Role Serum Shark Skates Specificity Structure System T-Cell Receptor Genes Testing Time Tissues Universities Vertebrates Xenopus adaptive immunity alpha-beta T-Cell Receptor base comparative fighting insight neonate public health relevance receptor theories γδ T cells

项目摘要

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.

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”的基底层，B1细胞和γδ 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。我们还将研究非洲爪蟾和鲨鱼中γδ T细胞受体的结构和功能，这两种物种中免疫球蛋白可变区在δ链中占很大比例。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存在“适应性γδ T细胞受体”亚群，这还没有被认识到。对该系统的研究不仅将揭示具有基于IG/TCR/MHC的适应性免疫的最老动物中γδ T细胞和B细胞发育的层，而且我们假设它可以作为所有其他脊椎动物中淋巴细胞谱系分层的简单范例。