Evolution of Adaptive Immunity

适应性免疫的进化

• 批准号: 9760130
• 负责人: Martin F Flajnik
• 金额: $ 25.75万
• 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/9760130
• 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.

总结 对非哺乳类脊椎动物（鱼类、两栖动物、爬行动物和鸟类）的研究提供了 获得性免疫的基本发现，特别是关于淋巴细胞谱系， 主要组织相容性复合体（MHC）、粘膜免疫和抗原受体。从 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， 受体和MHC，我们假设哺乳动物B1细胞范例是可操作的， 新生儿和年轻的动物。鲨鱼也有抗体与不变的结合位点（生殖系- 连接的基因编码的抗体），其在分泌型B细胞中表达，但在幼稚型B细胞中不表达 细胞抗体被建模为具有不寻常的结合位点，它结合自身组织， 细菌，并建议将其作为哺乳动物中B1衍生抗体的模型。第二 一波鲨鱼B细胞具有独特的免疫球蛋白库（也是B1样，几乎没有N区 此外）形成新生脾白色髓，也被认为是所有 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，非哺乳类脊椎动物具有差的抗体亲和力成熟， 反应，似乎缺乏滤泡树突状细胞（FDC）;因此，如何天然的机制， 抗原呈递给B细胞的机制知之甚少。我们重新鉴定了一种抗原呈递 青蛙的一种APC细胞，表达高水平的MHCII类，但仍能呈递天然抗原 免疫后较晚出现在其表面的B细胞滤泡中心。我们假设 这些APC执行“双重任务”，将抗原呈递给T细胞和B细胞。我们的数据 这表明T细胞在应答早期被这些APC刺激，然后活化的T 细胞许可APC停止降解抗原，上调B细胞趋化因子（cxcl 13）， 进入卵泡将抗原呈递给特定的B细胞。我们假设这个细胞代表了 冷血脊椎动物体液反应的范例，以及传统的 哺乳动物DC可以在特定的免疫应答中呈现这种“双重职责”表型。