Center for Cancer and Immunology Research, Children's National Medical Center, Washington, 20010, DC, USA.
Cell Mol Immunol. 2019 Feb;16(2):154-164. doi: 10.1038/cmi.2017.160. Epub 2018 Mar 5.
A recent meta-analysis revealed the contribution of the SIGLEC6 locus to the risk of developing systemic lupus erythematosus (SLE). However, no specific Siglec (sialic acid-binding immunoglobulin-like lectin) genes (Siglecs) have been implicated in the pathogenesis of SLE. Here, we performed in silico analysis of the function of three major protective alleles in the locus and found that these alleles were expression quantitative trait loci that enhanced expression of the adjacent SIGLEC12 gene. These data suggest that SIGLEC12 may protect against the development of SLE in Asian populations. Consistent with human genetic data, we identified two missense mutations in lupus-prone B6.NZM (Sle1-3) mice in Siglece, which is the murine Siglec with the greatest homology to human SIGLEC12. Since the mutations resulted in reduced binding of Siglec E to splenic cells, we evaluated whether Siglece mice had SLE phenotypes. We found that Siglece mice showed increased autoantibody production, glomerular immune complex deposition and severe renal pathology reminiscent of human SLE nephropathy. Our data demonstrate that the Siglec genes confer resistance to SLE in mice and humans.
最近的一项荟萃分析揭示了 SIGLEC6 基因座对系统性红斑狼疮（SLE）发病风险的贡献。然而，在 SLE 的发病机制中尚未涉及特定的 Siglec（唾液酸结合免疫球蛋白样凝集素）基因（Siglecs）。在这里，我们对该基因座中三个主要保护等位基因的功能进行了计算机分析，发现这些等位基因是表达数量性状基因座，可增强相邻 SIGLEC12 基因的表达。这些数据表明，SIGLEC12 可能在亚洲人群中预防 SLE 的发生。与人类遗传数据一致，我们在狼疮易感 B6.NZM（Sle1-3）小鼠中鉴定出 Siglece 中的两个错义突变，Siglece 是与人类 SIGLEC12 同源性最大的鼠类 Siglec。由于突变导致 Siglec E 与脾脏细胞的结合减少，我们评估了 Siglece 小鼠是否具有 SLE 表型。我们发现 Siglece 小鼠表现出增加的自身抗体产生、肾小球免疫复合物沉积和严重的肾脏病理，类似于人类 SLE 肾病。我们的数据表明，Siglec 基因在小鼠和人类中赋予对 SLE 的抗性。
