Department of Medicine, Yale University, New Haven, CT, USA.
Department of Pathology, Yale University, New Haven, CT, USA.
Mol Genet Metab. 2020 Apr;129(4):286-291. doi: 10.1016/j.ymgme.2020.01.009. Epub 2020 Feb 5.
In Gaucher disease type 1 (GD1), genetic deficiency of lysosomal glucocerebrosidase results in the accumulation of glucosylceramide and glucosylsphingosine (GlcSph), that underlie chronic lipid-mediated metabolic inflammation. An important age-related phenotype is high risk of monoclonal gammopathy (MG), including multiple myeloma. We identified GlcSph, a pathological lyso-sphingolipid exclusively elevated in GD, as a mediator of B cell activation and as an antigenic target for GD1-associated MG. Saposin C (SapC), is a lipid-binding protein and activator of lysosomal glucocerebrosidase, which when mutated, cause a rare variant of GD. Sera of GD1 patients with MG of diverse immunoglobulin types were compared to GD patients without gammopathy for reactivity against GlcSph and SapC. We show reactivity of clonal immunoglobulin in GD1 to GlcSph but not to SapC. In two patients with GD1 and gammopathy, GlcSph-reduction therapy with eliglustat resulted in reduction in clonal Ig. Together, our data show that GlcSph but not SapC is the antigenic target in GD1-associated MG and that therapy aimed at reducing the levels of immunogenic lipid resulted in reduction of clonal immunoglobulin in vivo.
在 1 型戈谢病（GD1）中，溶酶体葡萄糖脑苷脂酶的遗传缺陷导致葡糖脑苷脂和葡糖神经酰胺（GlcSph）的积累，这是慢性脂质介导的代谢炎症的基础。一个重要的与年龄相关的表型是单克隆丙种球蛋白病（MG）的高风险，包括多发性骨髓瘤。我们发现 GlcSph，一种专门在 GD 中升高的病理性溶酶体神经酰胺，是 B 细胞激活的介质，也是与 GD1 相关的 MG 的抗原靶标。脑苷脂激活蛋白 C（SapC）是一种脂质结合蛋白和溶酶体葡萄糖脑苷脂酶的激活剂，当其发生突变时，会导致一种罕见的 GD 变体。比较了具有不同免疫球蛋白类型的 GD1 患者 MG 的血清与无丙种球蛋白病的 GD 患者对 GlcSph 和 SapC 的反应性。我们显示了 GD1 中克隆免疫球蛋白对 GlcSph 的反应性，但对 SapC 没有反应性。在两名患有 GD1 和丙种球蛋白病的患者中，用伊曲康唑进行 GlcSph 还原治疗导致克隆 Ig 减少。总之，我们的数据表明，GlcSph 而不是 SapC 是 GD1 相关 MG 的抗原靶标，并且旨在降低免疫原性脂质水平的治疗导致体内克隆免疫球蛋白减少。
