SIGN receptors and the antiinflammatory activity of sialylated IgG Fcs

描述（由申请方提供）：IgG抗体显示出矛盾的性质：它们可以通过形成免疫复合物引发炎症，该免疫复合物交联Fc受体并激活细胞，相反，当以高剂量静脉内给药（1 - 2 g/kg静脉内免疫球蛋白）时，它们可以有效抑制炎症。我们实验室的研究表明，具有以α 2，6唾液酸键终止的Fc聚糖的IgG抗体负责这种抗炎。唾液酸化IgG Fc可以减轻类风湿性关节炎和肾毒性肾炎炎症模型中的炎症。唾液酸化IgG抗体结合凝集素受体SIGN-R1（小鼠）或DC-SIGN（人类），触发释放抗炎介质，促进抑制性Fc受体Fc？RIIb对炎性巨噬细胞的作用，从而减弱免疫复合物诱导的炎症。本文提出的研究将检查IgG抗体唾液酸化的调节和产生，并将表征唾液酸化IgG抗体促进的抗炎反应的分子信号传导事件。具体而言，目的1将检查稳态和炎症状态下的B细胞，以确定产生抗炎唾液酸化IgG抗体的条件和B细胞群。接下来，将改造B细胞以表达增加水平的唾液酸化IgG，并将其转移到自身免疫性疾病易感小鼠中，并在受体小鼠中监测疾病的发作和进展。体内IgG抗体糖基化的操纵可能被证明是治疗炎性疾病的一种手段。这些实验所需的工具将在指导实验室开发，但体内实验将在独立实验室进行。目的2提出了解剖与唾液酸化IgG的SIGN受体连接后触发的抗炎级联反应。这些发现将提供一个机制的理解IVIG已经在临床上常规使用。此外，了解这些途径将有助于开发更有效的抗炎疗法，靶向SIGN受体，以增加Fc？RIIb.为此目的提出的实验将在现有的辅导实验室内进行，利用实验室的资源和辅导机构的资源。 IgG抗体是免疫系统的重要组成部分，并显著有助于保护宿主免受癌症和传染病的侵害。此外，已经开发了治疗性IgG抗体用于治疗癌症和炎性疾病。本文提出的研究将阐明IgG抗体如何作为抗炎剂的一个重要方面，并可能导致设计用于治疗炎性疾病或癌症的更有效的基于IgG的疗法。

DESCRIPTION (provided by applicant): IgG antibodies display paradoxical properties: they can initiate inflammation by forming immune complexes that crosslink Fc receptors and activate cells, and conversely when given intravenously at high doses (1-2 g/kg intravenous immunoglobulin) actively suppress inflammation. Studies from our laboratory have indicated that IgG antibodies with Fc glycans terminating in a2,6 sialic acid linkages are responsible for this anti-inflammatory. Sialylated IgG Fc can attenuate inflammation in rheumatoid arthritic and nephrotoxic nephritis inflammatory models. The sialylated IgG antibodies bind lectin receptors SIGN-R1 (in mice) or DC-SIGN (in humans), triggering the release of an anti-inflammatory mediator that promotes upregulation of the inhibitory Fc receptor, Fc?RIIb on inflammatory macrophages, thereby attenuating immune complex induced inflammation. The studies proposed herein will examine the regulation and production of sialylation of IgG antibodies, and will characterize the molecular signaling events of the anti-inflammatory response promoted by sialylated IgG antibodies. Specifically, aim 1 will examine B cells in homeostatic and inflammatory states to determine the conditions and B cell populations that produce anti-inflammatory sialylated IgG antibodies. Next, B cells will be engineered to express increased levels of sialylated IgGs, and transferred to autoimmune disease prone mice, and the onset and progress of disease monitored in the recipient mice. Manipulation of IgG antibody glycosylation in vivo might prove to be a means to treat inflammatory diseases. The tools required for these experiments will be developed in the mentoring laboratory, but the in vivo experiments will be conducted in the independent laboratory. Aim 2 proposes to dissect the anti-inflammatory cascade triggered upon ligation of SIGN receptors with sialylated IgG. These findings will provide a mechanistic understanding of IVIG that is already used routinely in the clinic. Furthermore, understanding these pathways will aid in the development of more effective anti-inflammatory therapies that target SIGN receptors to increase expression of Fc?RIIb. The experiments proposed in this aim will be carried out in the established mentoring laboratory, using its resources and the resources at the mentoring institution. IgG antibodies are a crucial component of the immune system, and significantly contribute to host protection against cancer and infectious diseases. Additionally, therapeutic IgG antibodies have been developed for treatment of cancer and inflammatory diseases. The studies proposed herein will elucidate one important aspect of how IgG antibodies act as anti-inflammatory agents, and may lead to the design of more effective IgG based therapies for the treatment of inflammatory diseases or cancer.