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）的研究已提供 适应性免疫学的基本发现，尤其是关于淋巴细胞谱系的基本发现，起源于 主要的组织相容性复合物（MHC），粘膜免疫和抗原受体。从 我们在鲨鱼中所做的工作，这是具有免疫球蛋白的最古老的活脊椎动物，T细胞 接收器和MHC，我们假设哺乳动物B1细胞范式可在 新生儿和年轻动物。鲨鱼还具有具有不变结合位点的抗体（种系 - 加入基因编码的抗体），该抗体在秘密B细胞中表达，但在幼稚的B中不表达 细胞。该抗体的建模为具有不寻常的结合位点，它与自我组织结合和 细菌，并被认为是哺乳动物中B1衍生抗体的模型。第二 带有独特免疫球蛋白库的鲨鱼B细胞波（也类似于B1，很少有N区域） 另外）形成新生的脾质纸浆，也建议是所有人的范式 脊椎动物，我们将在小鼠和两栖动物中进行测试。关于体液免疫反应， 众所周知，非乳腺脊椎动物的亲和力成熟较差 反应并似乎缺乏卵泡树突状细胞（FDC）；因此，本地的机制 抗原呈现给B细胞的理解很少。我们已经重新确定了抗原呈现 表达高水平MHC II的青蛙中的细胞（APC），但呈现天然抗原 在免疫后，在B细胞四菌中心的表面上。我们假设 这些APC执行了“双重”，向T细胞和B细胞呈现抗原。我们的数据 表明T细胞在响应的早期就被这些APC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）和 输入卵泡以呈现特定B细胞的抗原。我们假设该单元代表 冷血脊椎动物的体液反应的范例，以及那个常规的 哺乳动物的DC可以尤其是免疫反应来处理这种“双层”表型。