Hypogalactosylation of serum IgG in patients with ANCA-associated systemic vasculitis
Hypogalactosylation of serum IgG in patients with ANCA-associated systemic vasculitis
复制标题
DOI：
10.1046/j.1365-2249.2002.01864.x
复制
发表时间：
2002-07-01
影响因子：
4.6
通讯作者：
Jefferis, R
中科院分区：
文献类型：
--
作者：
Holland, M;Takada, K;Jefferis, R
小血管炎三联征包括韦格纳肉芽肿病（WG）、显微镜下多血管炎（MPA）和Churg-Strauss综合征（CS）。所有这三种都与循环IgG抗神经细胞浆抗体（ANCA）的存在有关，ANCA主要针对中性粒细胞嗜天青颗粒内含有的自身抗原。广泛接受的发病机制模型表明，ANCA激活微血管系统内的嗜中性粒细胞，导致内皮细胞的旁观者损伤，以及炎症的快速升级和单核细胞的募集。活化可通过PR 3或MPO抗原（易位至细胞表面）与Fc γ RIIa/Fc γ RIIIb受体的共连接在体外启动。这表明ANCA的IgG亚类谱及其糖基化状态可能影响激活的炎症机制。通过分析从WG（13）、MPA（6）和CSS（1）患者血清中分离的总IgG的糖基化状态，测定释放的寡糖。与对照相比，所有患者样本均显示IgG半乳糖基化缺陷。对于WG、MPO和对照样品，无半乳糖基化（G 0）低聚糖的平均百分比值分别为57%（SD +/- 9.71）、47%（SD +/- 4.25）和28%（SD +/- 4.09）。从WG和MPA患者血清中分离的多克隆IgG的G 0水平与对照组相比显著增加（P < 0.0001）。因此，存在的主要糖型是无半乳糖基化（G 0）IgG。在先前的研究中，IgG的G 0糖型已显示结合并激活甘露聚糖结合凝集素，并因此激活补体级联，并促进甘露糖受体结合和IgG复合物被巨噬细胞和树突细胞摄取。这两种活动都可能影响自身免疫性疾病中自身抗原的加工和呈递。
The triad of small vessel vasculitides (SVV) comprise Wegener's granulomatosis (WG), microscopic polyangiitis (MPA) and Churg-Strauss syndrome (CS). All three are associated with presence of circulating IgG antineutrophil cytoplasm antibodies (ANCA) which target autoantigens contained, primarily, within neutrophil azurophilic granules. The widely accepted model of pathogenesis suggests that ANCA activate cytokine-primed neutrophils within the microvasculature, leading to by-stander damage to endothelial cells, and rapid escalation of inflammation with recruitment of mononuclear cells. Activation may be initiated, in vitro , by the coligation of the PR3 or MPO antigen, translocated to the cell surface, and FcgammaRIIa/FcgammaRIIIb receptors. This suggests that the IgG subclass profile of ANCA and, possibly, its glycosylation status could influence the inflammatory mechanisms activated. The glycosylation status of total IgG isolated from the sera of patients with WG (13), MPA (6) and CSS (1) was determined by analysis of the released oligosaccharides. A deficit in IgG galactosylation is demonstrated for all patient samples, compared to controls. The mean percentage values for the agalactosylated (G0) oligosaccharides were 57% (SD +/- 9.71), 47% (SD +/- 4.25) and 28% (SD +/- 4.09) for WG, MPO and control samples, respectively. The G0 levels for polyclonal IgG isolated from the sera of both WG and MPA patients were significantly increased compared to controls (P < 0.0001). The major glycoform present therefore is agalactosylated (G0) IgG. In previous studies the G0 glycoform of IgG has been shown to bind and activate mannan binding lectin, and hence to activate the complement cascade, and to facilitate mannose receptor binding and the uptake of IgG complexes by macrophages and dendritic cells. Both of these activities could impact on the processing and presentation of self-antigens in autoimmune disease.