The importance of the IgG4 glycome in IgG4-related disease(s)

项目总结(见说明)： LgG4相关疾病(lgG4-RD)是一种以lgG4和IgE升高为特征的纤维炎症性疾病 表现为淋巴浆渗入、绒毛样纤维化、闭塞性静脉炎和嗜酸性粒细胞增多。B细胞耗竭 利妥昔单抗治疗可减轻疾病症状，并选择性降低lgG4水平。这一观察结果 强烈支持lgG4在疾病中的作用。然而，这一免疫球蛋白亚类表现出与 典型的、低亲和力的Fcγ受体，被认为具有有限的炎症潜力。一个 所有的Ig G Fc的重链上都有一个N-连接的糖基化位点。这种多聚糖保持着开放的 重链确认，是通过以下方式触发的促炎相互作用的绝对要求 Fc伽马受体。葡聚糖具有复杂的双天线核心结构；不同的糖添加到 在健康人的免疫球蛋白FCS上发现了30多种不同的核心糖链。重要的是，多聚糖 通过控制与免疫球蛋白结合的特定受体，组成决定了免疫球蛋白的作用。例如, 果糖基化的IGGI优先结合活化的Fc-γRIIIA，并显著增强ADCC。 活着。相反，糖链的末端唾液酸化可将免疫球蛋白抗体转化为有效的抗炎作用。 通过降低与规范的Fc-γ受体的亲和力，同时传递与树突状细胞特异性的结合，调节介质 ICAM3抓取非整合素(DC-SIGN)。重要的是，免疫球蛋白的可变糖基化是受调节的。 由于炎症和唾液酸水平降低，从患有慢性阻塞性肺疾病的患者的免疫球蛋白上发现 自身免疫性疾病。 在试点项目申请中提出的研究将检查多糖对回收的免疫球蛋白Fc的影响 来自lgG4-RD患者和健康对照组。我们将探索的主要假说 回收的lgG4-RD将具有特征的糖基化模式，赋予新的和 未知的效应器对lgG4抗体的作用。这些研究将准确地界定功能界别的角色 葡聚糖对IgG4，允许开发改进的和靶向的治疗lgG4-RD。

PROJECT SUMMARY (See instructions): lgG4-related disease (lgG4-RD) is a fibroinflammatory disease, characterized by elevated lgG4 and IgE levels, a lymphoplasmatic infitrate, storiform fibrosis, obliterative phlebitis, and eosinophila. B cell depletion by Rituximab therapy attenuates disease symptoms and selectively reduces lgG4 levels. This observation strongly supports a role for lgG4 in the disease. However, this IgG subclass exhibits weak binding to canonical, low-affinity Fc gamma receptors, and is considered to have limited inflammatory potential. A single, N-linked glycosylation site is present on heavy chains on all IgG Fc. This glycan maintains an open heavy chain confirmation, and is an absolute requirement for pro-inflammatory interactions triggered through Fc gamma receptors. The glycan has a complex, biantenarry core structure; variable sugar additions to the core account for over 30 distinct glycans identified on IgG Fcs in healthy individuals. Importantly, the glycan composition dictates IgG effortor function, by controlling the specific receptor bound by IgG. For example, afucosylated IgGI preferentially binds activating Fc gamma RIIIA, and exhibits markedly enhanced ADCC in vivo. Conversely, terminal sialylation of the glycan converts IgG antibodies into potent anti-inflammatory mediators, by reducing affinity to canonical Fc gamma receptors, while conveying binding to dendritic cell-specific ICAM3 grabbing non-integrin (DC-SIGN). Importantly, the variable glycosylation of IgG is regulated by inflammation, and reduced levels are sialic acid are found on IgG from patients suffering from chronic autoimmune diseases. The studies proposed in the pilot project application will examine the glycans on the Fc of IgG recovered from patients suffering from lgG4-RD and healthy controls. The overarching hypothesis that will be explored is that the lgG4 recovered lgG4-RD will have a characteristic glycosylation pattern that bestows a novel and unappreciated effector function on to lgG4 antibodies. These studies will precisely define the role of the Fc glycan on IgG4, allowing for the development of improved and targeted therapies for lgG4-RD.