Abstract
BackgroundSystemic 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.MethodsUsing 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 CD19hi 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.ResultsIt 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 CD19hi 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.ConclusionsOur 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.
Highlights
Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterized by the pres‐ ence of pathogenic autoantibodies associated with polyclonal B cell hyperreactivity
Up‐regulation of Leucine-rich repeat kinase 2 (LRRK2) in B cells from SLE patients as well as in activated B cells To explore the possible relationship between LRRK2 and SLE pathogenesis, the expression levels of LRRK2 in Peripheral blood mononuclear cells (PBMCs) were firstly compared between SLE patients and healthy controls (HCs) donors (Table 1)
Consistent with the previous study [9], LRRK2 expression in PBMCs was significantly increased in SLE patients when compared to HCs (Fig. 1a). CD4+ T cells and B cells from SLE patients or HCs were further isolated separately with high purity (Additional file 1: Figure S1) and the expression levels of LRRK2 in cell subsets were determined
Summary
Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterized by the pres‐ ence 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. Systemic lupus erythematosus (SLE) is a severe heterogeneous systemic autoimmune disease characterized by the production of autoantibodies against certain self-antigens. It is demonstrated that B cell activation in SLE is comprehensively regulated by both intrinsically genetic and extrinsically environmental factors [5]. An autophagy-related gene encoding leucine-rich repeat kinase 2 (LRRK2) was recently identified [9]. LRRK2 contains 2527 amino acid residues with several functional domains, including a leucine-rich repeats (LRR) domain, a Ras of complex proteins (ROC) domain, a C-terminal of ROC (COR) domain, a kinase domain and a WD40repeat domain [10]. It has recently been reported to be associated with multiple diseases including Parkinson’s disease [12, 13], leprosy [14], inflammatory bowel disease (IBD) [15, 16] and cancers [17]
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