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。为了了解这些抗体是如何被控制的，我们之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细胞通过缺失、功能性沉默（能量）和自我反应受体的改变（受体编辑）被消除。矛盾的是，尽管病理性自身抗体的产生受到严格调节，但正常血清中相当大比例的循环抗体表现出自我反应性。这种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的反应性较弱，而这些细胞成分也是自身免疫性疾病的常见靶标。NAA的功能和与病理性自身抗体的关系目前尚不清楚。在这里，我们提出了NAA在自身免疫中的两个根本不同但并非相互排斥的作用：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容忍方面发挥核心作用。为了验证这些假设，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、体细胞突变和同型转换，所有这些在病理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细胞是否会参与抗原特异性反应。接下来，通过将NAA敲入小鼠与自身免疫易感性背景杂交，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，通过在单个动物体内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缓解自身免疫性疾病；如果是这样，实现这一目标的机制是什么？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。

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.