Evolution of Adaptive Immunity

适应性免疫的进化

• 批准号: 8697164
• 负责人: Martin F Flajnik
• 金额: $ 31.97万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-15 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8697164
• 关键词: 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; Research; Role; Serum; Shark; Skates; Skating; Specificity; Staging; Structure; System; T-Cell Receptor; T-Lymphocyte; Taxon; Testing; Time; Tissues; Universities; Vertebrates; Xenopus; adaptive immunity; base; comparative; fighting; insight; neonate; public health relevance; receptor; theories

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.

描述（由申请人提供）：“分层假说”由 Herzenberg 于 1989 年首次提出，其理论认为，在不同的发育阶段会出现淋巴细胞谱系，即所谓的“先天淋巴细胞”B1 细胞的基底层。和 ？ T细胞被认为可以提供第一道免疫防御以及其他功能，例如强烈维持组织稳态，来自小鼠和人类的最新数据支持“分层假说”，但人们对进化过程中的此类谱系知之甚少。软骨鱼（鲨鱼、鳐鱼和鳐鱼）中的免疫球蛋白 (Ig) 基因组织，即所谓的簇组织，允许以不同方式选择和使用的基因类型的可塑性，例如， Ig 重链簇已被选择用于具有单域可变区的适应性免疫，而其他簇则为“种系连接”，这意味着重排基因片段通过生殖细胞中的 RAG 连接，并作为一种特定的种系基因在群体中永久存在。连接的重链占新生儿血清 Ig 的一半以上，与小鼠中显示的结果一致，早期抗体可识别凋亡细胞，表明它参与稳态功能。 我们将继续研究该分子的结构和功能，重点关注其配体特异性，该 IgM 在发育过程中作为第一波在浆细胞中表达，随后至少有另外两波浆细胞表达。 IgM (19S) 的多聚体形式，被识别为 J 链阳性/BLIMP1 阴性，第 3 波为 J 链阴性/BLIMP1 阳性 (7S)。 BLIMP1 和 J 链表明它可以用作浆细胞谱系的通用标记，我们计划在小鼠和非洲爪蟾（另外两个高度分化的脊椎动物类群的代表）中测试这一提议，我们还将检查其结构和功能。 ?¿非洲爪蟾和鲨鱼中的 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此类 Ig/TCR 嵌合体，表明所有脊椎动物中都存在“适应性 T 细胞受体”亚群，但对此系统的研究尚未得到重视。不仅会揭开层层？¿最古老的动物中 T 细胞和 B 细胞的发育具有基于 Ig/TCR/MHC 的适应性免疫，但我们发现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。