Evolution of Adaptive Immunity

适应性免疫的进化

• 批准号: 8848970
• 负责人: Martin F Flajnik
• 金额: $ 13.05万
• 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/8848970
• 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; Health; 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; 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（由适用提供）：Herzenberg于1989年首次提出的“分层假设”理论上，在不同发展阶段存在淋巴细胞的谱系。提出了一个所谓的“先天淋巴细胞”的基础层，即B1细胞和？T细胞，以提供第一线免疫反应以及其他功能，例如维持组织稳态。来自小鼠和人类的最新数据强烈支持了“分层假设”，但在进化时间内鲜为人知。所谓的群集组织中的软骨鱼（鲨鱼，溜冰者和射线）中的免疫球蛋白（IG）基因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，已经选择了一些具有单域变量区域的自适应免疫学的IG重链簇，而另一些是“生殖线结合”，这意味着重排基因片段在生殖细胞中被RAG连接在一起，并以固定基因的形式在种群中永久存在。一个特定的种系重链在新生儿中占血清Ig的一半以上，并且与在小鼠中所显示的抗体一致，早期抗体识别凋亡细胞，表明它参与了稳态功能。 我们将继续研究该分子的结构和功能，集中在其配体特异性上。该IgM在浆细胞中作为发育过程中的第一波表示，其次是浆细胞的第一波。第二波仅表示IgM的多聚体形式（19S），并被识别为J链阳性/Blimp1阴性，第三波是J链阴性/Blimp1阳性（7s）。 Blimp1和J链表达中的二分法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Xenopus中测试该建议，代表另外两个高度不同的脊椎动物分类群。我们还将检查爪蟾和鲨鱼中T细胞受体的结构和功能，其中两个物种在其中以很大一部分的链中使用了免疫球蛋白可变区域。基于这一发现，并在许多其他脊椎动物中发现了这种Ig/TCR嵌合体，这表明在所有脊椎动物中都有“适应性？T细胞受体”的亚群，但尚未理解。对该系统的研究不仅会发现具有基于Ig/TCR/MHC的自适应免疫学的最古老的动物中的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围。