Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland.
J Am Soc Nephrol. 2012 Mar;23(3):438-46. doi: 10.1681/ASN.2011070701. Epub 2011 Dec 22.
Structural aberrations of O-linked glycans present in the IgA1 hinge region are associated with IgA nephropathy, but their contribution to its pathogenesis remains incompletely understood. In this study, mice implanted with hybridoma secreting 6-19 IgA anti-IgG2a rheumatoid factor, but not 46-42 IgA rheumatoid factor bearing the same IgA allotype, developed mesangial deposits consisting of IgA, IgG2a, and C3. Studies in immunoglobulin- and C3-deficient mice revealed that the development of these glomerular lesions required the formation of IgA-IgG2a immune complexes and subsequent activation of complement. The proportion of polymeric and monomeric forms, the IgG2a-binding affinity, and the serum levels of IgA-IgG2a immune complexes were similar between 6-19 IgA- and 46-42 IgA-injected mice. In contrast, the analysis of oligosaccharide structures revealed highly galactosylated O-linked glycans in the hinge region of 6-19 IgA and poorly O-glycosylated in the hinge region of 46-42 IgA. Furthermore, the structure of N-linked glycans in the CH1 domain was the complex type in 6-19 IgA and the hybrid type in 46-42 IgA. In summary, this study demonstrates the presence of O-linked glycans in the hinge region of mouse IgA and suggests that 6-19 IgA rheumatoid factor-induced GN could serve as an experimental model for IgA nephropathy.
IgA1 铰链区 O-连接聚糖的结构异常与 IgA 肾病有关，但它们在发病机制中的作用仍不完全清楚。在这项研究中，植入分泌 6-19 IgA 抗 IgG2a 类风湿因子但不携带相同 IgA 同种型的 46-42 IgA 类风湿因子的杂交瘤的小鼠，发展为包含 IgA、IgG2a 和 C3 的系膜沉积物。在免疫球蛋白和 C3 缺陷小鼠中的研究表明，这些肾小球病变的发展需要形成 IgA-IgG2a 免疫复合物，并随后激活补体。6-19 IgA 和 46-42 IgA 注射小鼠之间的多聚体和单体形式的比例、IgG2a 结合亲和力以及 IgA-IgG2a 免疫复合物的血清水平相似。相比之下，对寡糖结构的分析表明，6-19 IgA 的铰链区存在高度半乳糖化的 O-连接聚糖，而 46-42 IgA 的铰链区 O-糖基化程度较低。此外，6-19 IgA 的 CH1 结构域中的糖链结构为复杂型，而 46-42 IgA 的糖链结构为混合型。总之，本研究证明了小鼠 IgA 铰链区存在 O-连接聚糖，并表明 6-19 IgA 类风湿因子诱导的 GN 可以作为 IgA 肾病的实验模型。
