Guillain-Barré syndrome (GBS), including its variant Miller Fisher syndrome (MFS), is an acute peripheral neuropathy that involves autoimmune mechanisms leading to the production of autoantibodies to gangliosides; sialic acid-containing glycosphingolipids. Although association with various genetic polymorphisms in the major histocompatibility complex (MHC) is shown in other autoimmune diseases, GBS is an exception, showing no such link. No significant association was found by genome wide association studies, suggesting that GBS is not associated with common variants. To address the involvement of rare variants in GBS, we analyzed Siglec-10, a sialic acid-recognizing inhibitory receptor expressed on B cells. Here we demonstrate that two rare variants encoding R47Q and A108V substitutions in the ligand-binding domain are significantly accumulated in patients with GBS. Because of strong linkage disequilibrium, there was no patient carrying only one of them. Recombinant Siglec-10 protein containing R47Q but not A108V shows impaired binding to gangliosides. Homology modeling revealed that the R47Q substitution causes marked alteration in the ligand-binding site. Thus, GBS is associated with a rare variant of the SIGLEC10 gene that impairs ligand binding of Siglec-10. Because Siglec-10 regulates antibody production to sialylated antigens, our finding suggests that Siglec-10 regulates development of GBS by suppressing antibody production to gangliosides, with defects in its function predisposing to disease.

吉兰-巴雷综合征 (GBS)，包括其变异型米勒费舍尔综合征 (MFS)，是一种急性周围神经病变，涉及自身免疫机制，导致产生针对神经节苷脂的自身抗体；含唾液酸的鞘糖脂。尽管在其他自身免疫性疾病中显示出与主要组织相容性复合体 (MHC) 中各种遗传多态性的关联，但 GBS 是一个例外，没有显示出这种联系。全基因组关联研究未发现显着关联，表明 GBS 与常见变异无关。为了解决 GBS 中罕见变异的参与，我们分析了 Siglec-10，一种在 B 细胞上表达的唾液酸识别抑制性受体。在这里，我们证明了在 GBS 患者中，在配体结合域中编码 R47Q 和 A108V 替换的两种罕见变体显着积累。由于强连锁不平衡，没有患者只携带其中之一。含有 R47Q 但不含 A108V 的重组 Siglec-10 蛋白显示与神经节苷脂的结合受损。同源性建模显示 R47Q 取代导致配体结合位点的显着改变。因此，GBS 与罕见的损害 Siglec-10 配体结合的SIGLEC10基因。因为 Siglec-10 调节针对唾液酸化抗原的抗体产生，我们的发现表明 Siglec-10 通过抑制神经节苷脂抗体的产生来调节 GBS 的发展，但其功能缺陷会导致疾病。