The Impact of Fc gamma Receptor Signaling on Lupus-Induced Atherosclerosis

 描述(申请人提供)：系统性红斑狼疮(SLE)是一种典型的自身免疫性疾病，其特征是产生识别自身抗原的自身抗体。狼疮的临床表现包括肾炎、心包炎。最近的研究表明，狼疮会加速动脉粥样硬化，并导致过早死亡。自身抗体通过招募和激活先天免疫效应细胞而参与狼疮的病理过程。表达于炎症细胞和B淋巴细胞上的Fcγ受体(FcγR)与自身抗体-自身抗原免疫复合物(IC)相互作用，促进狼疮和动脉粥样硬化相关的炎症反应。Fcγ受体分为激活型受体和抑制性受体。激活Fc、γ受体参与先天免疫、细胞功能和炎症反应。抑制性FcγRIIb通过激活Fcγ受体调节炎症反应，并通过调节B淋巴细胞活化来控制抗体的产生。狼疮自身抗体和高脂血症时产生的氧化型低密度脂蛋白免疫复合物(oxLDL-IC)可与激活和/或抑制的Fc-γ受体结合，参与炎症过程。有趣的是，FcγRIIb基因多态性已被认为是狼疮和冠状动脉疾病的危险因素。此外，FcγRIIb缺陷已被证明可以调节I型干扰素反应，这与狼疮和动脉粥样硬化的发病机制有关。这些研究表明，抑制性FcγRIIb和I型干扰素反应之间的串扰可能在狼疮诱导的动脉粥样硬化的发病机制中起作用。虽然在狼疮患者和动物模型中发现了自身抗体的存在，但Fcγ受体在狼疮诱导的动脉粥样硬化的发生和/或发展中的作用尚未被研究。这一建议的中心假设是Fcγ受体在狼疮诱导的过早动脉粥样硬化的进展中起着重要作用。为了验证这一假说，我们将完成以下目标：目的1.确定FcγRIIb信号调节狼疮动脉粥样硬化的分子机制(S)，目的2.确定抑制性FcγRIIb信号与I型干扰素信号在狼疮诱导的动脉粥样硬化中的串扰作用，目的3.探讨人FcγR在促进狼疮相关的炎症反应中的作用。拟议的研究将具有重要意义，因为它们将提供新的信息，支持FcγR信号通路可能代表旨在改善自身免疫性疾病血管并发症的干预措施的新的治疗靶点，这是一个迫切需要开发的领域。

 DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease characterized by the production of autoantibodies recognizing self-antigens. Clinical manifestation of lupus includes nephritis, pericarditis. Recent studies have implicated that lupus accelerates atherosclerosis, and accounts for premature mortality. Autoantibodies contribute to the pathology of lupus by recruiting and activating innate-immune effector cells. Interaction between Fcγ receptors (FcγR) expressed on inflammatory cells and B-lymphocytes to autoantibody-autoantigen immune complexes (IC) promote inflammatory responses associated with lupus and atherosclerosis. FcγRs are classified into activating and inhibitory receptors. Activating FcγRs are involved in innate immune cellular functions and inflammatory responses. The inhibitory FcγRIIb regulates the inflammatory response initiated by the activating FcγRs and control antibody production by regulating B lymphocyte activation. Autoantibodies in lupus and oxidized low-density lipoprotein immune complexes (oxLDL-IC) generated during hyperlipidemia could bind to the activating and/or inhibitory FcγRs and contribute to the inflammatory processes. Interestingly, FcγRIIb polymorphisms have been implicated as a risk factor for lupus and coronary artery disease. Furthermore, FcγRIIb deficiency has been shown to regulate type I interferon response, implicated in the pathogenesis of lupus and atherosclerosis. These studies suggest that crosstalk between inhibitory FcγRIIb and type I interferon response could contribute to the pathogenesis of lupus-induced atherosclerosis. Although the presence of autoantibodies has been reported in lupus patients and animal models, the contribution of FcγRs to the initiation and/or progression of lupus-induced atherosclerosis has not been studied. The central hypothesis of this proposal is that FcγRs play an important role in the progression of lupus-induced premature atherosclerosis. To test this hypothesis, we will complete the following aims: Aim 1. To determine molecular mechanism(s) by which FcγRIIb signaling modulate lupus-induced atherosclerosis, Aim 2. To determine crosstalk between inhibitory FcγRIIb and type I IFN signaling contributing to lupus-induced atherosclerosis, and Aim 3. Investigate the role of human FcγR in promoting inflammatory responses associated with lupus-induced atherosclerosis. The proposed studies will be significant because they will provide novel information supporting the contention that FcγR signaling pathways may represent a novel therapeutic target for interventions aimed at ameliorating the vascular complications of autoimmune diseases, an area that is in dire need for development.