Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
Department of Public Health and Clinical Medicine/Rheumatology, Umeå University, Umeå, Sweden.
J Autoimmun. 2024 Feb;143:103166. doi: 10.1016/j.jaut.2023.103166. Epub 2024 Jan 13.
The complement system plays a central role in the pathogenesis of Systemic Lupus Erythematosus (SLE), but most studies have focused on the classical pathway. Ficolin-3 is the main initiator of the lectin pathway of complement in humans, but its role in systemic autoimmune disease has not been conclusively determined. Here, we combined biochemical and genetic approaches to assess the contribution of ficolin-3 to SLE risk and disease manifestations. Ficolin-3 activity was measured by a functional assay in serum or plasma samples from Swedish SLE patients (n = 786) and controls matched for age and sex (n = 566). Genetic variants in an extended 300 kb genomic region spanning the FCN3 locus were analyzed for their association with ficolin-3 activity and SLE manifestations in a Swedish multicenter cohort (n = 985). Patients with ficolin-3 activity in the highest tertile showed a strong enrichment in an SLE cluster defined by anti-Sm/DNA/nucleosome antibodies (OR 3.0, p < 0.001) and had increased rates of hematological disease (OR 1.4, p = 0.078) and lymphopenia (OR = 1.6, p = 0.039). Genetic variants associated with low ficolin-3 activity mapped to an extended haplotype in high linkage disequilibrium upstream of the FCN3 gene. Patients carrying the lead genetic variant associated with low ficolin-3 activity had a lower frequency of hematological disease (OR 0.67, p = 0.018) and lymphopenia (OR 0.63, p = 0.031) and fewer autoantibodies (p = 0.0019). Loss-of-function variants in the FCN3 gene were not associated with SLE, but four (0.5 %) SLE patients developed acquired ficolin-3 deficiency where ficolin-3 activity in serum was depleted following diagnosis of SLE. Taken together, our results provide genetic and biochemical evidence that implicate the lectin pathway in hematological SLE manifestations. We also identify lectin pathway activation through ficolin-3 as a factor that contributes to the autoantibody response in SLE.
补体系统在系统性红斑狼疮（SLE）的发病机制中起着核心作用，但大多数研究都集中在经典途径上。甘露聚糖结合凝集素（MBL）相关的丝氨酸蛋白酶 2（MASP-2）是补体经典途径的关键酶，甘露聚糖结合凝集素（MBL）是人类补体凝集素途径的主要启动子，但它在系统性自身免疫性疾病中的作用尚未得到明确确定。在这里，我们结合生化和遗传方法来评估 ficolin-3 对 SLE 风险和疾病表现的贡献。在来自瑞典的 SLE 患者（n=786）和年龄和性别匹配的对照者（n=566）的血清或血浆样本中，通过功能测定法测量 ficolin-3 活性。在一个瑞典多中心队列（n=985）中，分析了跨越 FCN3 基因座的扩展的 300kb 基因组区域内的遗传变异与 ficolin-3 活性和 SLE 表现之间的关联。在最高 tertile 组中，ficolin-3 活性最高的患者中，抗 Sm/DNA/核小体抗体定义的 SLE 簇明显富集（OR 3.0，p<0.001），并且血液疾病的发生率更高（OR 1.4，p=0.078）和淋巴细胞减少症（OR=1.6，p=0.039）。与低 ficolin-3 活性相关的遗传变异映射到 FCN3 基因上游的高度连锁不平衡的扩展单倍型。携带与低 ficolin-3 活性相关的主要遗传变异的患者血液疾病的发生率较低（OR 0.67，p=0.018）和淋巴细胞减少症（OR 0.63，p=0.031），并且自身抗体较少（p=0.0019）。FCN3 基因中的功能丧失性变异与 SLE 无关，但是有 4 名（0.5%）SLE 患者在诊断为 SLE 后出现获得性 ficolin-3 缺乏症，血清中的 ficolin-3 活性被耗尽。总之，我们的结果提供了遗传和生化证据，表明凝集素途径与血液学 SLE 表现有关。我们还发现，通过 ficolin-3 激活凝集素途径是导致 SLE 自身抗体反应的一个因素。
