Functions of SWAP-70 in B Cell Activation

描述（由申请人提供）：激活B淋巴细胞和诱导核过程（如免疫球蛋白（Ig）重链切换、DNA修复和DNA复制）的信号通路尚不完全清楚。我们已经鉴定并表征了一种新的磷酸化蛋白SWAP-70，它在活化的B细胞和肥大细胞中特异性表达。SWAP-70具有信号蛋白的特征，例如rac特异性鸟嘌呤核苷酸交换活性，在细胞质和细胞核之间易位，与细胞核中的DNA修复蛋白相互作用，并与B细胞抗原受体结合。我们对小鼠SWAP-70-/-缺陷的初步分析表明，在cd40 / il - 4r触发的增殖和Ig类转换（尤其是IgE类）中需要SWAP-70。因此，本应用的中心假设表明SWAP-70蛋白对B细胞活化的重要贡献，特别是通过CD40途径。该应用程序的具体目的是了解(1)SWAP-70在B细胞增殖和Ig类转换中的细胞作用；(2) SWAP-70在CD40和IL-4信号通路中的作用和机制。B细胞活化是免疫反应的关键，如果控制不当，是几种人类免疫系统疾病的核心。因此，分析SWAP-70在B细胞活化中的作用可能有助于我们理解正常的B细胞功能以及免疫缺陷、B细胞恶性肿瘤、自身免疫和过敏。

DESCRIPTION (provided by the applicant): Signaling pathways that activate B lymphocytes and induce nuclear processes like immunoglobulin (Ig) heavy chain class switching, DNA repair, and DNA replication are incompletely understood. We have identified and characterized a novel phosphoprotein, SWAP-70, that is specifically expressed in activated B cells and in mast cells. SWAP-70 has hallmarks of signaling proteins, e.g. a Rac-specific guanine nucleotide exchange activity, translocates between cytoplasm and nucleus, interacts with DNA repair proteins in the nucleus, and associates with the B cell antigen receptor. Our preliminary analysis of a mouse deficient in SWAP-70-/- indicates a requirement for SWAP-70 in CD4O/IL-4R-triggered proliferation and Ig class switching, especially to the IgE class. Thus, the central hypothesis in this application suggests an important contribution by protein SWAP-70 to B cell activation, especially through the CD40 pathway. The specific aims of this application are to understand (1) the cellular role of SWAP-70 in B cell proliferation and Ig class switching; and (2) the function and mechanism of SWAP-70 specifically in CD40 and IL-4 signaling. B cell activation is key to the immune response and, if improperly controlled, at the heart of several human immune system diseases. Therefore, the analysis of SWAP-70 in B cell activation is likely to help in our understanding of normal B cell function as well as of immune deficiencies, B cell malignancies, autoimmunity, and allergy.