B Cell Tolerance in Lupus

描述（由申请方提供）：有大量证据表明，自身抗体（autoAb）是通过体细胞超突变产生的，并且系统性红斑狼疮（SLE）中通过该过程获得自身反应性的B细胞的耐受性受损。虽然最近的研究已经提供了相当多的见解，参与者和细胞动力学的生发中心（GC）反应，其中体细胞超突变（SHM）发生，有很少的进展，在了解机制，维持耐受性的新产生的自我反应B细胞，主要是因为缺乏一个适当的模型。我们与其他研究者合作，最近使用了一种新的32 α-巨自身抗原（Ag）转基因（Tg）系统，以显示Fas缺陷小鼠在审查已获得对表面结合的Ag的自身反应性的B细胞方面有缺陷。然而，该模型利用了具有与SLE中声称的autoAg显著不同的特征的人工Ag。为了解决这些局限性，我们已经制定了一个新的B细胞受体Tg模型，将允许更换一个无害的抗原受体与DNA结合受体的B细胞进行类转换重组（CSR）/SHM，并寻求开发这个模型，并使用它来研究后SHM耐受机制在正常和自身免疫小鼠。为了实现这一点，提出了三个目标，其将：1）产生FLEx-autoAb模型系统，2）表征非自身免疫小鼠中CSR/SHM后B细胞的耐受性，和3）表征狼疮易感B6-Faslpr小鼠中CSR/SHM后的耐受性。这种新的方法有可能显着提高我们的能力，研究B细胞，获得自身反应性的外周，产生新的和重要的见解，这一过程，并大大推进这一领域的调查，这是高度相关的SLE和其他autoAb介导的疾病。 公共卫生相关性：B细胞对自身的耐受性缺陷被认为是系统性红斑狼疮（SLE）的主要原因之一，其负责产生有害的自身抗体;然而，该过程的许多方面仍然知之甚少，特别是在体细胞超变期间保持检查获得自身反应性的B细胞的耐受机制。目前，没有一种现有的动物模型能够直接研究成熟的B细胞，其获得对SLE中通常靶向的自身抗原的自身反应性。为了解决这个问题，我们提出了一种新的方法来生成一个新的和更相关的模型，称为FLEx-autoAb。

DESCRIPTION (provided by applicant): There is abundant evidence that autoantibodies (autoAbs) are generated through somatic hypermutation and that tolerance of B cells that acquire self-reactivity through this process is impaired in systemic lupus erythematosus (SLE). Although recent studies have provided considerable insights into the participants and cellular dynamics in germinal center (GC) reactions where somatic hypermutation (SHM) takes place, there has been little progress in understanding the mechanisms for maintaining tolerance of newly generated self- reactive B cells, largely because of the absence of an appropriate model. We, in collaboration with other investigators, have recently used a novel 32a-macroself antigen (Ag) transgenic (Tg) system to show that Fas- deficient mice are defective in censoring B cells that have acquired autoreactivity to a surface-bound Ag. This model, however, utilizes an artificial Ag with characteristics that differ substantially from the purported autoAgs in SLE. To address these limitations, we have formulated a new B cell receptor Tg model that will allow replacement of an innocuous antigen-receptor with a DNA-binding receptor in B cells undergoing class switch recombination (CSR)/SHM, and seek to develop this model and use it to investigate post-SHM tolerance mechanisms in normal and autoimmune mice. To accomplish this, three aims are proposed that will: 1) generate the FLEx-autoAb model system, 2) characterize tolerance of post-CSR/SHM B cells in non- autoimmune mice, and 3) characterize tolerance of post-CSR/SHM in lupus-prone B6-Faslpr mice. This novel approach has the potential for significantly improving our ability to study tolerance of B cells that acquire autoreactivity in the periphery, to generate new and important insights into this process, and to substantially advance this area of investigation, which is highly relevant to SLE and other autoAb-mediated diseases. PUBLIC HEALTH RELEVANCE: Defective tolerance of B cells to self is considered to be one of the major causes of systemic lupus erythematosus (SLE) responsible for the production of harmful autoantibodies; yet many aspects of this process remain poorly understood particularly tolerance mechanisms that keep in check B cells that acquire self-reactivity during somatic hypermutation. Currently none of the existing animal models are able to directly study mature B cells that acquire autoreactivity to self-antigens commonly targeted in SLE. To address this issue, we proposed to generate a new and more relevant model, called FLEx-autoAb, using a novel approach.