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: 7364100
• 负责人: Qing Chen
• 金额: $ 23.41万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 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/7364100
• 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）：自身免疫性疾病的生产是许多自身免疫性疾病的标志。为了了解这些抗体的控制方式，我们先前产生了免疫球蛋白转基因小鼠，其中大多数B细胞表达与狼疮相关的抗DNA抗体。我们已经表明，通过缺失，功能沉默（反应）和自反应受体的改变（受体编辑）消除了抗DNA B细胞。矛盾的是，尽管严格调节病理自身抗体的产生，但正常血清中循环抗体的很大一部分表现出自我反应性。这种称为天然自身抗体（NAA）的这种抗体通常对保守细胞成分（例如DNA，核蛋白和磷脂）的反应性较弱，这些反应也是自身免疫性疾病中的共同靶标。 NAA的功能目前未知，它们与病理自身抗体的关系也是如此。在这里，我们提出了NAA在自身免疫性中的根本不同但不是相互排斥的作用：1）它们可能是病理自身抗体的重要来源； 2）它们可能在保持自我耐受方面发挥核心作用。为了检验这些假设，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。与常规转基因不同，敲入基因能够进行受体编辑，体细胞突变和同型切换，所有这些都在病理抗体的发展中很重要。使用此模型，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定反应。接下来，通过将NAA敲入小鼠跨到自身免疫性的背景，将确定自然和病理自身抗体之间的关系，并将探索NAA获得致病性的分子机制。最后，通过单一动物中天然自身抗体和病理抗DNA抗体的共表达，我们将确定NAA是否可以抑制病理抗体的产生并减轻自身免疫性疾病。如果是这样，那么实现这一目标的机制。这些研究的结果将为自身免疫的病因提供深刻的见解，并可能导致自身免疫性疾病的新治疗策略。