Role of natural autoantibodies in autoimmune disease

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。为了理解这些抗体是如何被控制的，我们先前产生了免疫球蛋白转基因小鼠，其中大多数B细胞表达狼疮相关的抗DNA抗体。我们已经证明，抗DNA B细胞通过自身反应性受体的缺失、功能沉默（无反应性）和改变（受体编辑）而被消除。奇怪的是，尽管病理性自身抗体的产生受到严格的调控，但正常血清中相当大比例的循环抗体表现出自身反应性。这种抗体，称为天然自身抗体（NAA），通常对保守的细胞成分如DNA，核蛋白和磷脂具有弱反应性，这些成分也是自身免疫性疾病中常见的靶标。NAA的功能目前尚不清楚，其与病理性自身抗体的关系也是如此。在这里，我们提出了两个根本不同的，但不相互排斥的作用，NAA在自身免疫：1）他们可能是一个重要的来源病理性自身抗体; 2）他们可能发挥核心作用，在维持自身耐受性。为了验证这些假设，我们建立了一种新的免疫球蛋白基因敲入小鼠模型，其中B细胞表达典型的NAA。与传统的转基因不同，敲入基因能够经历受体编辑、体细胞突变和同种型转换，所有这些在病理性抗体的发展中都是重要的。使用这个模型，我们将定义产生NAA的B细胞的性质，并确定这些B细胞是否参与抗原特异性反应。接下来，通过将NAA基因敲入小鼠与自身免疫易感背景杂交，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，通过在单个动物中共同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;如果可以，则确定实现这一目标的机制。这些研究的结果将为自身免疫性疾病的病因学提供深入的了解，并可能导致新的治疗策略。

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.