SIGN receptors and the antiinflammatory activity of sialylated IgG Fcs

描述(申请人提供)：免疫球蛋白抗体表现出矛盾的性质：它们可以通过形成免疫复合体来引发炎症，这些免疫复合体可以使Fc受体交联并激活细胞，反之，当静脉注射高剂量(1-2g/kg静脉免疫球蛋白)时，它们可以有效地抑制炎症。我们实验室的研究表明，Fc糖链终止于2，6-唾液酸键的免疫球蛋白抗体与这种抗炎作用有关。唾液酸化免疫球蛋白Fc可减轻类风湿关节炎和肾毒性肾炎炎症模型的炎症反应。唾液酸化的抗体结合凝集素受体SIGN-R1(在小鼠)或DC-SIGN(在人类)，触发一种抗炎介质的释放，促进炎性巨噬细胞上抑制性Fc受体Fc？RIIb的上调，从而减轻免疫复合物诱导的炎症。本文提出的研究将检验唾液酸化的免疫球蛋白抗体的调节和产生，并将表征唾液酸化的免疫球蛋白抗体促进抗炎反应的分子信号事件。具体地说，AIM 1将检查处于稳态和炎症状态的B细胞，以确定产生抗炎唾液酸化抗体的条件和B细胞群。接下来，将对B细胞进行改造，使其表达更高水平的唾液酸化免疫球蛋白，并将其转移到易患自身免疫性疾病的小鼠身上，并监测受体小鼠的疾病发生和进展。在体内操纵抗体糖基化可能被证明是治疗炎症性疾病的一种手段。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研究SIGN受体与唾液酸化的免疫球蛋白结合后所触发的抗炎级联反应。这些发现将提供对IVIG的机械性理解，这已经在临床上被常规使用。此外，了解这些途径将有助于开发更有效的抗炎治疗，靶向SIGN受体，增加Fc？RIIb的表达。这一目标中提出的实验将在已建立的指导实验室中进行，利用其资源和指导机构的资源。 免疫球蛋白抗体是免疫系统的重要组成部分，对宿主抵御癌症和传染病有重要作用。此外，治疗性免疫球蛋白抗体已被开发用于治疗癌症和炎症性疾病。本文提出的研究将阐明免疫球蛋白抗体如何作为抗炎剂的一个重要方面，并可能导致设计更有效的基于免疫球蛋白的疗法来治疗炎症性疾病或癌症。

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.