IL-21 acts as a promising therapeutic target in systemic lupus erythematosus by regulating plasma cell differentiation

Deng, Xiaomei; Su, Yan; Wei, Wei

doi:10.1038/cmi.2014.58

Cited by 23 publications

(14 citation statements)

References 87 publications

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“…21 However, the role of IL-21 in regulating human CXCR4 expression in autoimmunity has not been examined to date. IL-21, which is mainly produced by activated CD4 + T and T FH cells, is essential in regulating B cell responsiveness, 25,[32][33][34] and has been suggested that IL-21 might serve as a therapeutic target in lupus. 35 As demonstrated in our study, SLE B cells expressed higher levels of IL-21R than HC.…”

Section: Discussionmentioning

confidence: 99%

“…23,24 IL-21, produced mainly by follicular helper T cells (T FH ), which have a central role in GC B-cell selection, is able to directly induce B-cell activation, mediate B-cell proliferation and promote plasma cell development, most likely through the downstream pathway of the Janus kinase/Signal transducer and activator of transcription (JAK/STAT) signaling. 25 Furthermore, a recent study indicated that phosphatidylinositol 3 kinase (PI3K)/Akt may be involved in CXCR4 regulation. 26 Thus, the JAK/STAT and PI3K/Akt pathways are involved in many physical and pathological activities.…”

Section: Introductionmentioning

confidence: 99%

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

Liang

et al. 2016

Cell Mol Immunol

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Liang

et al. 2016

Cell Mol Immunol

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“…12 IL-21, a wellknown signature factor of follicular helper T cells, is a pleiotropic cytokine that can influence the activation, differentiation, and expansion of germinal center B cells and is critically involved in the pathogenesis of SLE. [13][14][15] It has been reported that MRL/lpr mice develop lupus-like disease in an IL-21-dependent manner. 16 Collectively, IL-6, IL-10 and IL-21, which are pro-inflammatory mediators in humoral immunity, are regarded as biomarkers of SLE.…”

Section: Introductionmentioning

confidence: 99%

Therapeutic effects of the artemisinin analog SM934 on lupus-prone MRL/lpr mice via inhibition of TLR-triggered B-cell activation and plasma cell formation

Bai

et al. 2015

Cell Mol Immunol

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We previously reported that SM934, a water-soluble artemisinin derivative, was a viable treatment in murine lupus models. In the current study, we further investigated the therapeutic effects of a modified dosage regimen of SM934 on lupus-prone MRL/lpr mice and explored its effects on B cell responses, a central pathogenic event in systemic lupus erythematosus (SLE). When orally administered twice-daily, SM934 significantly prolonged the life-span of MRL/lpr mice, ameliorated the lymphadenopathy symptoms and decreased the levels of serum anti-nuclear antibodies (ANAs) and of the pathogenic cytokines IL-6, IL-10 and IL-21. Furthermore, SM934 treatment restored the B-cell compartment in the spleen of MRL/lpr mice by increasing quiescent B cell numbers, maintaining germinal center B-cell numbers, decreasing activated B cell numbers and reducing plasma cell (PC) numbers. Ex vivo, SM934 suppressed the Toll-like receptor (TLR)-triggered activation and proliferation of B cells, as well as antibody secretion. Moreover, the present study demonstrated that SM934 interfered with the B-cell intrinsic pathway by downregulating TLR7/9 mRNA expression, MyD88 protein expression and NF-kB phosphorylation. In human peripheral blood mononuclear cells (PBMCs), consistent with the results in MRL/lpr mice, SM934 inhibited TLR-associated B-cell activation and PC differentiation. In conclusion, a twice daily dosing regimen of SM934 had therapeutic effects on lupus-prone MRL/lpr mice by suppressing B cell activation and plasma cell formation. Cellular & Molecular Immunology

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“…Increased numbers of TFH and its association with autoantibody production have been reported in SLE patients and mice [117][118][119]. IL-21, as one of the signature molecules of TFH, is up-regulated in SLE and leads to expansion of TFH [120][121][122]. But the precise mechanism that expanded TFH leading to release of autoreacive B cells is not clear.…”

Section: B Cell Tolerance Checkpointsmentioning

confidence: 99%

“…IL-21 is an essential cytokine to co-stimulate B cells differentiating into plasma cells [122,145]. IL-21 is mainly produced by TFH in GC and TFH is essential for GC B cells selection [146,147].…”

Section: Other Cytokinesmentioning

confidence: 99%

B cells biology in systemic lupus erythematosus—from bench to bedside

Zhang

2015

Sci. China Life Sci.

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Systemic lupus erythematosus (SLE) is a debilitating autoimmune disease that can involve multi-organs. B cells play a central role in the immunopathogenesis via antibody-dependent and antibody-independent ways. Excessive autoantibodies production, hyperresponsiveness and prolonged survival of autoreactive B cells are characteristics of SLE. In this article, mechanisms of self-tolerance loss of B cells and promising B cell-targeting therapies in lupus are reviewed and discussed. Systemic lupus erythematosus (SLE), the paradigm of autoimmune disease with the underlying mechanisms involving multiple immunological abnormalities, is a severely debilitating disease with multi-organ involvement and diverse autoantibodies spectrum [1]. Among the multiple elements in the pathogenesis, B cells play a central role in SLE through antibody dependent and independent manners [2]. Presence of pathogenic autoantibodies is not only the hallmark of SLE and the clue for diagnosis, but also associated with characteristic pathological injury and specific clinical manifestations [3][4][5]. In addition, the pathogenic role of B cells is also attributed to its antibody independent functions, including but not limited to antigen presentation, T cell crosstalk, dendritic cells (DCs) recruitment, pro-inflammatory cytokine secretion. Why and how auto-reactive B cells in lupus lose self-tolerance, escape from central and peripheral checkpoints, become over-activated and spontaneously produce autoantibodies, are always the focus of clinical and basic research. Therefore, it is important to summarize our current knowledge about the underlying mechanisms of self-tolerance breakdown and pathogenic functioning pathways of B cells in SLE. So we review here about B cell biology in SLE, including its differentiation and selection, functioning and signaling, surviving and apoptosis, and the resulting potential therapeutic targets both in mice and human lupus.

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IL-21 acts as a promising therapeutic target in systemic lupus erythematosus by regulating plasma cell differentiation

Cited by 23 publications

References 87 publications

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

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

Therapeutic effects of the artemisinin analog SM934 on lupus-prone MRL/lpr mice via inhibition of TLR-triggered B-cell activation and plasma cell formation

B cells biology in systemic lupus erythematosus—from bench to bedside

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