Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
Department of Pathology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
J Transl Med. 2019 Jan 22;17(1):37. doi: 10.1186/s12967-019-1786-6.
Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterized by the presence of pathogenic autoantibodies associated with polyclonal B cell hyperreactivity. Previous study reported that autophagy-related gene Leucine-rich repeat kinase 2 (LRRK2) was likely a susceptible gene for SLE. However, the pathogenic function of LRRK2 in SLE is undefined.
Using quantitative PCR, we compared the expression levels of LRRK2 in B cells between SLE patients and healthy controls. The expression levels of LRRK2 in in vitro induced CD19 B cells and naïve B cells were compared as well based on RNA-seq assay. A pristane-induced lupus-like mouse model was used to explore the effects of LRRK2 on the development of SLE. IgG level, B cell subsets in the spleens and bone marrows and pathological features in the kidneys were compared between wildtype (WT) and Lrrk2 littermates.
It was obvious that LRRK2 expression was dramatically up-regulated in primary B cells from SLE patients compared to those from healthy controls, as well as in activated CD19 B cells. More significantly, LRRK2 expression in B cells was positively correlated with system lupus erythematosus disease activity index (SLEDAI), an indicator for disease severity, and serum IgG levels in SLE patients. Negative correlations were observed between LRRK2 expression and serum C3 or C4 levels, two clinical features associated with SLE-related nephritis. LRRK2 deficiency reduced the death rate of pristane treated mice. Decreased levels of total IgG and autoantibody were detected in the serum with less deposition of immune complexes and attenuated pathological symptoms in the kidneys of Lrrk2 mice. Consistent with the reduction in IgG production, the percentages of germinal center B cells and plasma cells decreased significantly as well with LRRK2 deficiency.
Our study demonstrates that LRRK2 expression is upregulated in B cells from SLE patients with strong correlations to disease severity. LRRK2 deficiency largely attenuates the pathogenic progress of lupus-like features in pristane-induced mice. This is probably achieved through affecting B cell terminal differentiation and subsequent immunoglobulin production.
系统性红斑狼疮（SLE）是一种典型的自身免疫性疾病，其特征是存在与多克隆 B 细胞过度反应相关的致病性自身抗体。先前的研究报道，自噬相关基因亮氨酸丰富重复激酶 2（LRRK2）可能是 SLE 的易感基因。然而，LRRK2 在 SLE 中的致病功能尚不清楚。
我们使用定量 PCR 比较了 SLE 患者和健康对照者 B 细胞中 LRRK2 的表达水平。还通过 RNA-seq 检测比较了体外诱导的 CD19 B 细胞和幼稚 B 细胞中 LRRK2 的表达水平。使用降植烷诱导的狼疮样小鼠模型探讨 LRRK2 对 SLE 发展的影响。比较野生型（WT）和 Lrrk2 同窝仔鼠的 IgG 水平、脾脏和骨髓中的 B 细胞亚群以及肾脏的病理特征。
与健康对照组相比，SLE 患者的原发性 B 细胞以及激活的 CD19 B 细胞中 LRRK2 的表达明显上调。更重要的是，B 细胞中 LRRK2 的表达与系统性红斑狼疮疾病活动指数（SLEDAI）呈正相关，SLEDAI 是疾病严重程度的指标，与 SLE 患者的血清 IgG 水平相关。在 SLE 患者中，LRRK2 表达与血清 C3 或 C4 水平呈负相关，C3 和 C4 是与 SLE 相关肾炎相关的两个临床特征。LRRK2 缺失降低了降植烷处理小鼠的死亡率。LRRK2 缺失小鼠的血清总 IgG 和自身抗体水平降低，免疫复合物沉积减少，肾脏病理症状减轻。与 IgG 产生减少一致，LRRK2 缺失也显著降低了生发中心 B 细胞和浆细胞的比例。
我们的研究表明，SLE 患者 B 细胞中 LRRK2 的表达上调，与疾病严重程度密切相关。LRRK2 缺失在很大程度上减轻了降植烷诱导的狼疮样特征在小鼠中的发病进展。这可能是通过影响 B 细胞终末分化和随后的免疫球蛋白产生来实现的。
