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，通过缺失、功能性沉默(无能)和改变自身反应性受体(受体编辑)，可以消除抗DNA B细胞。矛盾的是，尽管病理性自身抗体的产生受到严格控制，但正常血清中相当大比例的循环抗体表现出自我反应性。这类抗体被称为天然自身抗体(NAA)，通常对保守的细胞成分，如DNA、核蛋白和磷脂具有较弱的反应性，这些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，它们与病理性自身抗体的关系也不清楚。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)它们可能在维持自身耐受方面发挥核心作用。为了验证这些假设，我们创建了一个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，所有这些都在病理抗体的产生中起着重要的作用。利用这个模型，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。下一步，通过将NAA基因敲入小鼠与自身免疫倾向背景杂交，将确定自然自身抗体和病理性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，通过天然自身抗体和病理性抗DNA抗体在单个动物中的共同表达，我们将确定NAA是否可以抑制病理性抗体的产生和缓解自身免疫性疾病；如果是，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更多的见解，并可能导致自身免疫性疾病的新的治疗策略。

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.