Regulation of Persistent Antibody Responses by FC Receptors

描述（由申请人提供）：IgG Fc受体Fc3RIIB （RIIB）是一种抑制性FcR，在小鼠和人类许多造血细胞类型的活性调节中起核心作用。从RIIB发出的几个信号通路参与其负调控功能。在小鼠中，RIIB缺乏或表达改变有助于自身免疫的发展。在人类中，多种RIIB基因多态性导致该受体表达水平或膜分布的改变，与几种自身免疫性疾病的易感性密切相关。也有人提出RIIB在人类对感染性病原体的免疫反应中起着关键的调节作用，这一观点得到了对RIIB缺陷小鼠免疫反应的各种研究的支持。这些效应的机制基础尚不完全清楚。在之前的资助期内，我们利用为此目的而创建的新型小鼠模型系统，获得了关于B细胞上的RIIB如何调节免疫和自身免疫的一些新的机制见解。我们发现，与自身免疫发展相关的B细胞RIIB缺陷或RIIB等位基因的表达可导致抗体形成细胞（AFC）的定量增强，而不是生发中心（GC）反应。我们还发现RIIB在正常小鼠的GC B细胞上表达上调，而在自身免疫易感性菌株的B细胞上表达上调。这些和其他数据导致了几个假设的发表，这些假设表明RIIB在GC及其他部位的B细胞耐受性和记忆发育的调节中起着核心作用。在下一个资助期内，我们建议使用我们已建立的以及新的小鼠模型系统来测试这些假设。我们的研究结果的分辨率将通过使用单个B细胞活性和抗原受体结构和特异性的实验读数来增强。

DESCRIPTION (provided by applicant): The IgG Fc receptor Fc3RIIB (RIIB) is an inhibitory FcR that plays a central role in regulation of the activity of many hematopoietic cell types in mice and humans. Several signaling pathways emanating from RIIB are involved in its negative regulatory function. In mice, deficiency or altered expression of RIIB contributes to development of autoimmunity. In humans, a variety of RIIB gene polymorphisms resulting in altered expression levels or membrane distribution of this receptor are strongly associated with susceptibility to the development of several autoimmune diseases. It has also been proposed that RIIB plays a key regulatory role in the immune response to infectious pathogens in humans, a notion supported by a variety of studies on the immune responses of RIIB deficient mice. The mechanistic bases for these effects are incompletely understood. In the previous funding period we gained several new mechanistic insights into how RIIB on B cells regulates immunity and autoimmunity using novel mouse model systems created for this purpose. We found that a B cell RIIB deficiency or expression of an RIIB allele associated with development of autoimmunity resulted in quantitatively enhanced antibody forming cell (AFC), but not germinal center (GC) responses. We also found that expression of RIIB was up regulated on GC B cells from normal mice but not on B cells from autoimmune- prone strains. These and other data have led to the publication of several hypotheses suggesting a central role for RIIB in the regulation of the development of B cell tolerance and memory in the GC and beyond. In the next funding period we propose to test these hypotheses using our established as well as new mouse model systems. The resolution of our findings will be enhanced by the use of experimental readouts of individual B cell activity and antigen receptor structure and specificity.