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

项目总结（见说明）： IgG 4相关疾病（IgG 4-RD）是一种纤维炎性疾病，其特征在于IgG 4和IgE升高 水平，淋巴细胞质浸润，Storiform纤维化，闭塞性静脉炎和嗜酸性粒细胞。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lgG 4水平。该观察结果 强烈支持IgG 4在疾病中的作用。然而，该IgG亚类表现出弱结合， 典型的低亲和力Fc γ受体，并且被认为具有有限的炎症潜力。一 单个N-连接糖基化位点存在于所有IgG Fc的重链上。这种聚糖保持开放的 重链确认，并且是通过以下方式触发的促炎相互作用的绝对要求： Fc γ受体。聚糖具有复杂的双触角核心结构;可变的糖添加到聚糖中。 在健康个体中，IgG Fc上鉴定出超过30种不同的聚糖。重要的是，聚糖 组合物通过控制IgG结合的特异性受体来决定IgG作用力功能。比如说， 无岩藻糖基化IgGI优先结合活化Fc γ RIIIA，并在活化Fc γ RIIIA中表现出显著增强的ADCC。 vivo.相反，聚糖的末端唾液酸化将IgG抗体转化为有效的抗炎性抗体。 通过降低与典型Fc γ受体的亲和力，同时传递与树突细胞特异性 ICAM 3非整合素捕获（DC-SIGN）。重要的是，IgG的可变糖基化受到调节， 在患有慢性炎症的患者的IgG上发现唾液酸水平降低， 自身免疫性疾病 试点项目申请中提出的研究将检查回收的IgG Fc上的聚糖 来自患有IgG 4-RD的患者和健康对照。我们将要探讨的首要假设是， 回收的IgG 4-RD将具有特征性糖基化模式， 未被重视的效应子功能。这些研究将准确地界定Fc的作用， 因此，通过在IgG 4上修饰聚糖，可以开发用于IgG 4-RD的改进的靶向疗法。

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.