Evolution of Adaptive Immunity

适应性免疫的进化

• 批准号: 9899205
• 负责人: Martin F Flajnik
• 金额: $ 38.63万
• 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 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9899205
• 关键词: Adopted; Adult; Affinity; Amphibia; Animals; Antibodies; Antibody Response; Antigen Presentation; Antigen Receptors; Antigen-Presenting Cells; Antigens; Area; Autoimmunity; B-Lymphocyte Subsets; B-Lymphocytes; Bacteria; Binding; Binding Sites; Birds; Blood; Carbohydrates; Cells; Communicable Diseases; Crystallization; Data; Dendritic Cells; Development; Evolution; Fishes; Follicular Dendritic Cells; Genes; Growth; Histocompatibility Antigens Class II; Human; Humoral Immunities; Immune; Immune response; Immune system; Immunity; Immunization; Immunoglobulin Genes; Immunoglobulin M; Immunoglobulins; Immunology; Jaw; Lampreys; Licensing; Licensing Factor; Light; Lymphocyte; Lymphoid Tissue; Major Histocompatibility Complex; Malignant Neoplasms; Malpighian corpuscles; Mammals; Modeling; Movement; Mucosal Immunity; Mus; Newborn Animals; Osteichthyes; Phenotype; Rana; Reptiles; Research; Shark; Specificity; Structure; Surface; T-Cell Receptor; T-Lymphocyte; Testing; Time; Tissues; Tumor Necrosis Factor-Beta; Vertebrates; Work; adaptive immune response; adaptive immunity; base; chemokine; cold blooded vertebrate; comparative; fighting; juvenile animal; prospective; response

SUMMARY Studies of nonmammalian vertebrates (fish, amphibians, reptiles, and birds) have provided essential discoveries in adaptive immunity, especially regarding lymphocyte lineages, origins of the major histocompatibility complex (MHC), mucosal immunity, and antigen receptors. From work that we have done in sharks, the oldest living vertebrates with immunoglobulins, T cell receptors and the MHC, we hypothesize that the mammalian B1 cell paradigm is operable in neonatal and young animals. Sharks also have antibodies with invariant binding sites (germline- joined gene-encoded antibodies), which are expressed in secretory B cells but not in naïve B cells. The antibody is modeled to have an unusual binding site, it binds to self tissues and bacteria, and it is proposed to be a model for B1-derived antibodies in mammals. A second wave of shark B cells with a unique immunoglobulin repertoire (also B1-like, with little N-region addition) forms the nascent splenic white pulp, also proposed to be the paradigm for all vertebrates, which we will test in mice and amphibians. Regarding humoral immune responses, it is well known that nonmammalian vertebrates have poor affinity maturation of the antibody response and seem to lack follicular dendritic cells (FDC); thus the mechanism of how native antigen is presented to B cells is poorly understood. We have re-identified an antigen presenting cell (APC) in frogs that expresses high levels of MHC class II, and yet presents native antigen on its surface in the center of B cell follicles relatively late after immunization. We hypothesize that these APC perform a `double-duty,' presenting antigen to both T cells and B cells. Our data suggest that T cells are stimulated by these APC early in a response, and then the activated T cells license the APC to stop degrading antigen, upregulate B cell chemokines (cxcl13), and enter the follicle to present antigen to specific B cells. We hypothesize that this cell represents the paradigm for humoral responses in cold-blooded vertebrates, and that conventional mammalian DC can take on this `double-duty' phenotype in particular immune responses.

概括 对非哺乳动物脊椎动物（鱼类、两栖动物、爬行动物和鸟类）的研究提供了 适应性免疫的重要发现，特别是关于淋巴细胞谱系、起源 主要组织相容性复合体 (MHC)、粘膜免疫和抗原受体。 我们在鲨鱼身上所做的工作，鲨鱼是现存最古老的脊椎动物，具有免疫球蛋白、T 细胞 受体和 MHC，我们发现哺乳动物 B1 细胞范例可在 新生儿和幼年动物也有具有不变结合位点的抗体（种系-）。 连接基因编码抗体），在分泌性 B 细胞中表达，但在初始 B 细胞中不表达 该抗体被建模为具有不寻常的结合位点，它与自身组织和细胞结合。 细菌，并且它被提议作为哺乳动物中 B1 衍生抗体的模型。 具有独特免疫球蛋白库的鲨鱼 B 细胞波（也类似于 B1，具有很少的 N 区） 另外）形成新生的脾白髓，也被提议作为所有的范例 关于体液免疫反应，我们将在小鼠和两栖动物中进行测试。 众所周知，非哺乳动物脊椎动物的抗体亲和力成熟度较差 反应并似乎缺乏滤泡树突状细胞（FDC），从而了解天然的机制； 我们对抗原呈递给 B 细胞的了解甚少。 青蛙体内表达高水平 MHC II 类细胞 (APC)，但仍呈递天然抗原 免疫后较晚在 B 细胞滤泡中心的表面出现。 这些 APC 执行“双重职责”，向 T 细胞和 B 细胞呈递抗原。 表明 T 细胞在反应早期受到这些 APC 的刺激，然后激活的 T 细胞许可 APC 停止降解抗原、上调 B 细胞趋化因子 (cxcl13)，以及 进入滤泡将抗原呈递给特定的 B 细胞，我们敢说这种细胞代表了这一点。 冷血脊椎动物体液反应的范例，以及传统的 哺乳动物 DC 在特定的免疫反应中可以呈现这种“双重作用”表型。