GENETIC ORIGIN AND STRUCTURE OF INSULIN ANTIBODIES

胰岛素抗体的遗传起源和结构

• 批准号: 6164527
• 负责人: James W Thomas
• 金额: $ 20.92万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-03-01 至 2002-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6164527
• 关键词: B cell receptor; B lymphocyte; T lymphocyte; antibody formation; antibody specificity; autoantibody; biological signal transduction; cell differentiation; gene expression; genetically modified animals; immune tolerance /unresponsiveness; insulin; insulin dependent diabetes mellitus; insulin receptor; laboratory mouse; leukocyte activation /transformation; molecular genetics; nuclear factor kappa beta; passive immunization

DESCRIPTION (Adapted from Investigator's abstract): The long term goal of this project is to develop effective strategies that will prevent insulin immunity and autoimmunity. To accomplish this goal, the sites and stages of B lymphocyte development that permit anti-insulin B cells to differentiate and produce antibody will be identified. In contrast to models where the normal immune system deletes or silences autoimmune B cells, autoantibodies to insulin routinely follow administration of autologous hormone. These antibodies may lead to allergic reactions and hormone resistance as well as covert complications that include large birth weight infants and accelerated vascular disease. Spontaneous insulin antibodies may accompany systemic autoimmune disorders and are recognized as part of the autoimmune prodrome of type I diabetes. These observations led to the assertion that the immune system ignores insulin because B cell receptor (BCR) interactions are too few or too weak to induce tolerance. Data on anti-insulin B cell repertoires, however, are not consistent with the concept of true "clonal ignorance". Anti-insulin BCR found in preimmune repertoires are not part of the expressed regions but lineages of insulin binding B cells do not arise, indicating that anti-insulin B cells are censored in stages of differentiation. These observations suggest the hypothesis that insulin autoimmunity arises as a consequence of competing forces that drive clonal expansion of B cells while eliminating self-reactivity. This hypothesis will be tested by using mice that express anti-insulin BCR transgenes that bind insulin with a range of affinities representative of a physiologic repertoire. Three specific aims will (1) determine how the affinity of the preimmune repertoire for endogenous insulin governs the outcome of B cell activation -- tolerance or differentiation; (2) identify the mechanisms that limit expansion of B cells not silenced in the preimmune repertoire; and (3) identify the cell activation events and nuclear transcription pathways that program the phenotypes of B cell differentiation or tolerance. Based on the outcomes of these aims, future strategies may be directed at deletion of low affinity anti-insulin B cells or at inducing clonal elimination in germinal center reactions. These are alternative approaches that may be rationally applied once the stages of B cell development and differentiation that fail to maintain tolerance are identified in normal immune systems and in autoimmune diabetes.

描述（改编自研究者摘要）： 该项目旨在开发有效的策略， 免疫和自身免疫。 为了实现这一目标， 允许抗胰岛素B细胞分化的B淋巴细胞发育 并产生抗体。 与模型相比， 正常的免疫系统删除或沉默自身免疫B细胞，自身抗体 在施用自体激素之后常规地施用胰岛素。 这些 抗体可能导致过敏反应和激素抵抗， 隐性并发症，包括出生体重过大的婴儿和加速 血管疾病 自发性胰岛素抗体可能伴随全身性 自身免疫性疾病，被认为是自身免疫性前驱症状的一部分 I型糖尿病 这些观察结果导致了免疫系统 系统忽略胰岛素，因为B细胞受体（BCR）相互作用太 很少或太弱而不能诱导耐受性。 抗胰岛素B细胞数据 然而，这些基因库与真正的“克隆”概念并不一致， 无知”。 免疫前库中发现的抗胰岛素BCR不是 胰岛素结合B细胞的表达区域但谱系不出现， 表明抗胰岛素B细胞在以下阶段被删失： 分化 这些观察结果表明，胰岛素 自身免疫的产生是竞争力量的结果， B细胞的扩增，同时消除自身反应性。 这一假设 将通过使用表达抗胰岛素BCR转基因的小鼠进行测试， 以代表生理活性的一系列亲和力结合胰岛素 保留曲目。 三个具体的目标将（1）决定如何亲和力的 内源性胰岛素的免疫前库控制B细胞的结果 激活-耐受或分化;（2）确定 限制免疫前库中未沉默的B细胞的扩增;和（3） 识别细胞激活事件和核转录途径， 编程B细胞分化或耐受的表型。 基于 这些目标的结果，未来的战略可能会针对删除低 亲和性抗胰岛素B细胞或诱导克隆消除 中心反应。 这些都是可能合理的替代方法， 一旦B细胞发育和分化阶段失败， 在正常免疫系统中以及在 自身免疫性糖尿病