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Contribution and underlying mechanisms of CXCR4 overexpression in patients with systemic lupus erythematosus.

ABSTRACT: Aberrant expression of CXCR4 has been indicated to play a role in the pathogenesis of systemic lupus erythematosus (SLE), but the mechanism of CXCR4 dysregulation in SLE is unclear. This study is aimed to explore the clinical significance and possible mechanisms of abnormal CXCR4 expression on B cells from patients with untreated SLE. Expression of CXCR4 on peripheral B cells was determined by flow cytometry and western blotting. Freshly isolated B cells were cultured with exogenous interleukin 21(IL-21) in the presence or absence of CD40 ligand (CD40L) plus anti-IgM antibody (aIgM), and changes in CXCR4 expression were detected. Involvement of phosphatidylinositol 3 kinase (PI3K)/Akt and Janus kinase/Signal transducer and activator of transcription (JAK/STAT) signaling pathways was assessed by adding blocking agents Ly294002 and AG490. Since CD63 is reported to mediate endosomal recruitment of CXCR4 and BCL6 is capable of silencing CD63 gene transcription, we also measured BCL6 and CD63 gene transcription with real-time PCR. It was shown that CXCR4 expression on B cells was significantly upregulated in SLE patients, especially in those with lupus nephritis, and was positively correlated with SLE Disease Activity Index scores and negatively with the serum complement 3 levels (P<0.05). Downregulation of CXCR4 by IL-21 was intact. In contrast, a similar effect of aIgM plus CD40L in downregulating CXCR4 expression was defective in SLE patients but was restored by co-stimulation with IL-21 in vitro. Both Ly294002 and AG490 promoted downregulation of surface CXCR4 expression on B cells from SLE patients (P=0.078 and P=0.064). Furthermore, B cells from SLE patients exhibited diminished CD63 mRNA and enhanced BCL6 mRNA expression (both P<0.05). To sum up, CXCR4 was overexpressed on SLE B cells, positively correlating with disease activity and kidney involvement. Overactivation of the PI3K/Akt and JAK/STAT pathways as well as defective CD63 synthesis may contribute to CXCR4 dysregulation in SLE.

SUBMITTER: Zhao LD

PROVIDER: S-EPMC5649106 | biostudies-other | 2017 Oct

REPOSITORIES: biostudies-other

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Contribution and underlying mechanisms of CXCR4 overexpression in patients with systemic lupus erythematosus.

Zhao Li-Dan LD Liang Di D Wu Xiang-Ni XN Li Yang Y Niu Jing-Wen JW Zhou Chen C Wang Li L Chen Hua H Zheng Wen-Jie WJ Fei Yun-Yun YY Tang Fu-Lin FL Li Yong-Zhe YZ Zhang Feng-Chun FC He Wei W Cao Xue-Tao XT Zhang Xuan X

Cellular & molecular immunology 20160926 10

Aberrant expression of CXCR4 has been indicated to play a role in the pathogenesis of systemic lupus erythematosus (SLE), but the mechanism of CXCR4 dysregulation in SLE is unclear. This study is aimed to explore the clinical significance and possible mechanisms of abnormal CXCR4 expression on B cells from patients with untreated SLE. Expression of CXCR4 on peripheral B cells was determined by flow cytometry and western blotting. Freshly isolated B cells were cultured with exogenous interleukin ...[more]

PMID: 27665947

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Project description:OBJECTIVE:Immunoglobulin M antibodies against phosphorylcholine (anti-PCs) may be protective in atherosclerosis, cardiovascular disease (CVD), and systemic lupus erythematosus (SLE). We study immunoglobulin G1 (IgG1) and immunoglobulin G2 (IgG2) anti-PCs, with a focus on atherosclerosis and SLE. METHODS:We determined anti-PCs by using the enzyme-linked immunosorbent assay in 116 patients with SLE and 110 age- and sex-matched controls. For functional studies, we used three in-house-generated, fully human monoclonal IgG1 anti-PCs (A01, D05, and E01). Apoptosis was induced in Jurkat T cells and preincubated with A01, D05, E01, or IgG1 isotype control, and effects on efferocytosis by human macrophages were studied. Anti-PC peptide/protein characterization was determined using a proteomics de novo sequencing approach. RESULTS:IgG1, but not IgG2, anti-PC levels were higher among patients with SLE (P = 0.02). IgG1 anti-PCs were negatively associated with Systemic Lupus International Collaborating Clinics (SLICC) damage index and Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) scores (odds ratio [OR]: 2.978 [confidence interval (CI): 0.876-10.098] and OR: 5.108 [CI 1.3-20.067], respectively) and negatively associated with CVD, atherosclerotic plaques, and echolucent plaques (potentially vulnerable plaques), but the association for the two former was not significant after controlling for confounders. D05 had a maximum effect on macrophage efferocytosis efficiency, followed by A01 and E01. The monoclonal antibodies showed differential binding specificity to PC and PC-associated neoepitopes. A peptide analysis showed a difference in the complementarity-determining region 3 of the three IgG1 anti-PC clones that are crucial for recognition of PC on apoptotic cell surfaces and other neoepitopes. CONCLUSION:IgG1 anti-PCs are negatively associated with disease activity and disease damage in SLE, but the negative association with CVD is also dependent on confounding risk factors. One potential underlying mechanism could be increased clearance of dead cells.

Dataset Information

Contribution and underlying mechanisms of CXCR4 overexpression in patients with systemic lupus erythematosus.

Publications

Contribution and underlying mechanisms of CXCR4 overexpression in patients with systemic lupus erythematosus.

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