Natural Autoantibody and 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。为了理解这些自我毁灭的 抗体是受控的，我们产生了转基因小鼠，其中大多数 B细胞表达疾病相关的抗DNA抗体。我们已经证明 抗DNA B细胞通过缺失、功能性沉默（无反应性）和 自我反应受体（self-reactive receptor） 奇怪的是，尽管自身反应性B细胞受到严格的调节， 正常血清中相当大比例的循环抗体表现出自身抗体， 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具有弱反应性， 核蛋白和磷脂，也是常见的目标， 自身免疫性疾病NAA的功能目前尚不清楚， 与病理性自身抗体的关系。在这里，我们从根本上提出两个建议， NAA在自身免疫中的不同但不相互排斥的作用：1）它们可能 是病理性自身抗体的主要来源; 2）它们可能起中心作用， 保持自我宽容的作用。为了验证这些假设，一个新的 将产生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， 能够经历受体编辑、体细胞突变和同种型转换，所有 其中的蛋白质在病理性抗体的形成中是重要的。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T细胞非依赖性和T细胞- 依赖性抗原反应。接下来，通过将NAA基因敲入小鼠与 自身免疫易感背景，自然与病理的关系 将确定自身抗体，以及NAA 将探索获得致病性。最后，通过共同表达自然 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自身抗体的产生， 确定NAA是否可以减轻自身免疫性疾病。从这些 研究将提供对自身免疫的病因学的深入了解， 从而为自身免疫性疾病带来新的治疗策略。

DESCRIPTION (provided by applicant): Production of autoantibodies is the hallmark of many autoimmune diseases. To understand how these self-destructive antibodies are controlled, we generated transgenic mice where the majority of B cells express disease-associated anti-DNA antibodies. We have shown that anti-DNA B cells are eliminated by deletion, functional silencing (anergy) and revision of self-reactive receptors (receptor editing). Paradoxically, although auto reactive B cells are 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 diseases. 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 a major source of pathological autoantibodies; 2) they may play a central role in maintaining self-tolerance. To test these hypotheses, a new immunoglobulin knock-in mouse model will be generated, 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 T cell-independent and T cell- dependent antigen 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 autoantibody production, and determine whether NAA can alleviate autoimmune diseases. Results from these studies will provide great insight into the etiology of autoimmunity and may lead to new therapeutic strategies for autoimmune diseases.