Role of natural autoantibodies in autoimmune disease

天然自身抗体在自身免疫性疾病中的作用

• 批准号: 6814821
• 负责人: Qing Chen
• 金额: $ 33.98万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6814821
• 关键词: B lymphocyte; T lymphocyte; antiantibody; antibody formation; autoantibody; autoimmune disorder; cytomegalovirus; disease /disorder model; enzyme linked immunosorbent assay; flow cytometry; gene targeting; genetically modified animals; immune tolerance /unresponsiveness; immunization; immunoglobulins; laboratory mouse; lymphocytic choriomeningitis virus; microorganism immunology

DESCRIPTION (provided by applicant): Production of autoantibodies is the hallmark of many autoimmune diseases. To understand how these antibodies are controlled, we previously generated immunoglobulin transgenic mice where the majority of B cells express lupus-associated anti-DNA antibodies. We have shown that anti-DNA B cells are eliminated by deletion, functional silencing (anergy) and alteration of self-reactive receptors (receptor editing). Paradoxically, although production of pathologic autoantibodies is 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 disease. 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 an important source of pathologic autoantibodies; 2) they may play a central role in maintaining self-tolerance. To test these hypotheses, we have created a new immunoglobulin knock-in mouse model, 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 antigen specific 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 antibody production and alleviate autoimmune disease; and if so, the mechanisms by which this is achieved. 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）：自身抗体的产生是许多自身免疫性疾病的标志。为了了解这些抗体是如何被控制的，我们之前培育了免疫球蛋白转基因小鼠，其中大多数 B 细胞表达狼疮相关的抗 DNA 抗体。我们已经证明，抗 DNA B 细胞可以通过删除、功能性沉默（无反应性）和自身反应性受体的改变（受体编辑）来消除。矛盾的是，尽管病理性自身抗体的产生受到严格控制，但正常血清中很大一部分循环抗体表现出自身反应性。此类抗体被称为天然自身抗体 (NAA)，通常对 DNA、核蛋白和磷脂等保守细胞成分具有较弱的反应性，而这些成分也是自身免疫性疾病中常见的靶标。 NAA 的功能及其与病理性自身抗体的关系目前尚不清楚。在这里，我们提出NAA在自身免疫中的两种根本不同但并不相互排斥的作用：1）它们可能是病理性自身抗体的重要来源； 2）它们可能在维持自我宽容方面发挥核心作用。为了测试这些假设，我们创建了一种新的免疫球蛋白敲入小鼠模型，其中 B 细胞表达典型的 NAA。与传统转基因不同，敲入基因能够进行受体编辑、体细胞突变和同种型转换，所有这些对于病理抗体的开发都很重要。使用该模型，我们将定义产生 NAA 的 B 细胞的性质，并确定这些 B 细胞是否会参与抗原特异性反应。接下来，通过将NAA敲入小鼠与易发生自身免疫的背景杂交，将确定天然和病理性自身抗体之间的关系，并探索NAA获得致病性的分子机制。最后，通过在单一动物中共表达天然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抗体的产生并减轻自身免疫性疾病；如果是的话，实现这一目标的机制是什么？这些研究的结果将为了解自身免疫性疾病的病因学提供深入的见解，并可能为自身免疫性疾病带来新的治疗策略。