GENETIC ORIGIN AND STRUCTURE OF INSULIN ANTIBODIES

描述(改编自调查者摘要)：的长期目标 这个项目是为了开发有效的策略来预防胰岛素 豁免权和自身免疫力。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 并产生抗体将被鉴定。与模型不同的是， 正常免疫系统删除或沉默自身免疫B细胞、自身抗体 在注射自体激素后常规进行胰岛素治疗。这些 抗体可能导致过敏反应和激素抵抗以及 隐蔽的并发症，包括出生体重过大和加速出生 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，被认为是自身免疫前驱症状的一部分 患有I型糖尿病。这些观察结果导致了以下断言：免疫 系统忽略了胰岛素，因为B细胞受体(BCR)的相互作用也 很少或太弱而不能产生耐受性。关于抗胰岛素B细胞的数据 然而，曲目并不与真正的“克隆”概念一致 在免疫前曲目中发现的抗胰岛素BCR不是 胰岛素结合B细胞的表达区域和谱系没有出现， 这表明抗胰岛素B细胞在以下阶段被审查 差异化。这些观察结果表明，假设胰岛素 自身免疫的产生是驱使克隆的竞争力量的结果 B细胞的扩增，同时消除自我反应性。这一假设 将通过使用表达抗胰岛素bcr转基因基因的小鼠进行测试 将胰岛素与一系列代表生理的亲和力结合 曲目。三个具体的目标将(1)决定如何 内源性胰岛素免疫前谱系决定B细胞的结局 激活--耐受或分化；(2)确定 限制B细胞的扩增，而不是在免疫前谱系中沉默；以及(3) 识别细胞激活事件和核转录途径 对B细胞分化或耐受的表型进行编程。基于 这些目标的结果，未来的战略可能指向删除LOW 亲和抗胰岛素B细胞或诱导生殖细胞克隆性消除 集中反应。这些都是替代方法，可能是理性的 一旦B细胞发育和分化阶段失败就应用 维持耐受性在正常免疫系统和 自身免疫性糖尿病。

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.