CRAC Channel Controls the Differentiation of Pathogenic B Cells in Lupus Nephritis.

Xue Li,Binfeng Chen,Siyuan Zhao,Hui Zhang,Yimei Lai,Yuefang Huang,Qin Zeng,Mengyuan Li,Shuyi Wang,Chaohuan Guo,Xionghui Chen,Mianjing Zhou,Niansheng Yang

doi:10.3389/fimmu.2021.779560

Xue Li, Binfeng Chen + Show 11 more

Open Access

https://doi.org/10.3389/fimmu.2021.779560

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Abstract

Store-operated Ca2+ release-activated Ca2+ (CRAC) channel is the main Ca2+ influx pathway in lymphocytes and is essential for immune response. Lupus nephritis (LN) is an autoimmune disease characterized by the production of autoantibodies due to widespread loss of immune tolerance. In this study, RNA-seq analysis revealed that calcium transmembrane transport and calcium channel activity were enhanced in naive B cells from patients with LN. The increased expression of ORAI1, ORAI2, and STIM2 in naive B cells from patients with LN was confirmed by flow cytometry and Western blot, implying a role of CRAC channel in B-cell dysregulation in LN. For in vitro study, CRAC channel inhibition by YM-58483 or downregulation by ORAI1-specific small-interfering RNA (siRNA) decreased the phosphorylation of Ca2+/calmodulin-dependent protein kinase2 (CaMK2) and suppressed Blimp-1 expression in primary human B cells, resulting in decreased B-cell differentiation and immunoglobulin G (IgG) production. B cells treated with CaMK2-specific siRNA showed defects in plasma cell differentiation and IgG production. For in vivo study, YM-58483 not only ameliorated the progression of LN but also prevented the development of LN. MRL/lpr lupus mice treated with YM-58483 showed lower percentage of plasma cells in the spleen and reduced concentration of anti-double-stranded DNA antibodies in the sera significantly. Importantly, mice treated with YM-58483 showed decreased immune deposition in the glomeruli and alleviated kidney damage, which was further confirmed in NZM2328 lupus mice. Collectively, CRAC channel controlled the differentiation of pathogenic B cells and promoted the progression of LN. This study provides insights into the pathogenic mechanisms of LN and that CRAC channel could serve as a potential therapeutic target for LN.

Highlights

Systemic lupus erythematous (SLE) is a prototype of autoimmune disease, which is characterized by the production of a spectrum of autoantibodies including antinuclear antibodies and anti-double-stranded DNA antibodies [1, 2]
We found that naive population was decreased in patients with Lupus nephritis (LN), while the naive B cells were not different in rheumatoid arthritis (RA) and primary Sjögren’s syndrome (pSS) patients (Figure 1B)
By searching the public databases, RNA-seq analysis, using patient blood samples and mouse models, we found that the expression of Ca2+ release-activated Ca2+ (CRAC) channel and Ca2+ influx was increased in B

Summary

Introduction

Systemic lupus erythematous (SLE) is a prototype of autoimmune disease, which is characterized by the production of a spectrum of autoantibodies including antinuclear antibodies and anti-double-stranded DNA antibodies [1, 2]. Autoreactive B cells and production of autoantibodies are critical for the initiation and progression of LN [3, 4]. Memory B cells have been shown to be increased in the blood of SLE patients [6]. CD138+ plasma cells are found to be increased in patients with active SLE [7]. The activation of autoreactive B cells leads to increased production of autoantibodies, which results in the deposition of immune complexes in the glomeruli, causing kidney damages by the subsequent activation of complement system [8]. For the critical role of B cells in the initiation and development of LN, B-celltargeting therapies should have an important place in the therapeutic management of LN

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