Natural Autoantibody and Autoimmune Diseases

天然自身抗体和自身免疫性疾病

• 批准号: 6702244
• 负责人: Qing Chen
• 金额: $ 12.29万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-02-01 至 2005-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6702244
• 关键词: B lymphocyte; antibody formation; antinuclear autoantibody; autoantibody; autoimmune disorder; autoimmunity; genetically modified animals; laboratory mouse; pathologic process

DESCRIPTION (provided by applicant): Production of autoantibodies is the hallmark of many autoimmune diseases. To understand how these self-destructive antibodies are controlled, we generated transgenic mice where the majority of B cells express disease-associated anti-DNA antibodies. We have shown that anti-DNA B cells are eliminated by deletion, functional silencing (anergy) and revision of self-reactive receptors (receptor editing). Paradoxically, although auto reactive B cells are strictly regulated, a substantial proportion of circulating antibodies in normal sera exhibits self- reactivity. Such antibodies, referred as natural autoantibodies (NAA), often have weak reactivity toward conserved cell components such as DNA, nucleoproteins and phospholipids that are also the common targets seen in autoimmune diseases. The function of NAA is presently unknown, as is their relationship to pathologic autoantibodies. Here, we propose two fundamentally different but not mutually exclusive roles of NAA in autoimmunity: 1) they may be a major source of pathological autoantibodies; 2) they may play a central role in maintaining self-tolerance. To test these hypotheses, a new immunoglobulin knock-in mouse model will be generated, where the B cells express a typical NAA. Unlike conventional transgenes, the knock-in gene is able to undergo receptor editing, somatic mutation and isotype switching, all of which are important in development of pathologic antibodies. Using this model, we will define the nature of B cells that produce NAA, and determine whether these B cells will participate in T cell-independent and T cell- dependent antigen responses. Next, by crossing the NAA knock-in mice to an autoimmune-prone background, the relationship between natural and pathologic autoantibodies will be determined, and the molecular mechanisms by which NAA acquire pathogenicity will be explored. Finally, by co-expression of natural autoantibodies and pathologic anti-DNA antibodies in a single animal, we will determine whether NAA can suppress pathologic autoantibody production, and determine whether NAA can alleviate autoimmune diseases. Results from these studies will provide great insight into the etiology of autoimmunity and may lead to new therapeutic strategies for autoimmune diseases.

描述（由申请人提供）：自身抗体的生产是 许多自身免疫性疾病的标志。了解这些自我毁灭性的行为是如何发生的 抗体受到控制，我们产生了转基因小鼠，其中大多数 B 细胞表达与疾病相关的抗 DNA 抗体。我们已经证明 抗 DNA B 细胞通过缺失、功能沉默（无反应性）和 自我反应受体的修订（受体编辑）。 矛盾的是，尽管自身反应性 B 细胞受到严格调控，但 正常血清中相当大比例的循环抗体表现出自身 反应性。此类抗体通常称为天然自身抗体 (NAA) 对 DNA 等保守细胞成分具有弱反应性， 核蛋白和磷脂也是常见的目标 自身免疫性疾病。 NAA 的功能及其作用目前尚不清楚 与病理性自身抗体的关系。在这里，我们提出两个基本建议 NAA 在自身免疫中具有不同但不相互排斥的作用：1）它们可能 是病理性自身抗体的主要来源； 2）他们可能扮演核心角色 维持自我宽容的作用。为了检验这些假设，一个新的 将生成免疫球蛋白敲入小鼠模型，其中 B 细胞 表达典型的NAA。与传统的转基因不同，敲入基因是 能够进行受体编辑、体细胞突变和同种型转换，所有 其中对于病理抗体的发展很重要。使用这个 模型中，我们将定义产生 NAA 的 B 细胞的性质，并确定 这些 B 细胞是否会参与 T 细胞非依赖性和 T 细胞依赖性 依赖性抗原反应。接下来，通过将 NAA 敲入小鼠与 自身免疫倾向背景、自然与病理之间的关系 自身抗体将被确定，NAA 的分子机制 将探讨获得致病性。最后，通过自然的共同表达 在单个动物中检测自身抗体和病理性抗 DNA 抗体，我们将 确定 NAA 是否可以抑制病理性自身抗体的产生，以及 确定 NAA 是否可以缓解自身免疫性疾病。这些结果 研究将为了解自身免疫的病因提供深入的见解，并可能 导致自身免疫性疾病的新治疗策略。