Activation-induced necroptosis contributes to B-cell lymphopenia in active systemic lupus erythematosus.

H Fan,Y Xu,T Wang,G Dong,Y Hou,F Liu,L Sun,J Dou,D Ren

doi:10.1038/cddis.2014.375

Abstract

B-cell abnormality including excessive activation and lymphopenia is a central feature of systemic lupus erythematosus (SLE). Although activation threshold, auto-reaction and death of B cells can be affected by intrinsical and/or external signaling, the underlying mechanisms are unclear. Herein, we demonstrate that co-activation of Toll-like receptor 7 (TLR7) and B-cell receptor (BCR) pathways is a core event for the survival/dead states of B cells in SLE. We found that the mortalities of CD19+CD27- and CD19+IgM+ B-cell subsets were increased in the peripheral blood mononuclear cells (PBMCs) of SLE patients. The gene microarray analysis of CD19+ B cells from active SLE patients showed that the differentially expressed genes were closely correlated to TLR7, BCR, apoptosis, necroptosis and immune pathways. We also found that co-activation of TLR7 and BCR could trigger normal B cells to take on SLE-like B-cell characters including the elevated viability, activation and proliferation in the first 3 days and necroptosis in the later days. Moreover, the necroptotic B cells exhibited mitochondrial dysfunction and hypoxia, along with the elevated expression of necroptosis-related genes, consistent with that in both SLE B-cell microarray and real-time PCR verification. Expectedly, pretreatment with the receptor-interacting protein kinase 1 (RIPK1) inhibitor Necrostatin-1, and not the apoptosis inhibitor zVAD, suppressed B-cell death. Importantly, B cells from additional SLE patients also significantly displayed high expression levels of necroptosis-related genes compared with those from healthy donors. These data indicate that co-activation of TLR7 and BCR pathways can promote B cells to hyperactivation and ultimately necroptosis. Our finding provides a new explanation on B-cell lymphopenia in active SLE patients. These data suggest that extrinsic factors may increase the intrinsical abnormality of B cells in SLE patients.

Highlights

The abnormality of B cells includes the decrease of absolute number,[5,6,7] the altered frequency of their subsets[8,9] and hyperactivation and hyperresponsiveness to a variety of self-antigens and stimuli.[10,11] The defects of intrinsic signalings (such as Toll-like receptor 7 (TLR7) and B-cell receptor (BCR)) in B cells directly lead to lupus-like autoimmunity in mouse models,[12,13,14] the efficacy in clinical trials with
The results revealed that the activation marker CD86 was significantly upregulated in active Systemic lupus erythematosus (SLE) B cells compared with healthy donors (4.8±0.4% versus 7.8±1.0%; Figure 1a), whereas the expression of CD40 and CD80 was unchanged (Figures 1b and c)
We first showed an increased mortality of CD19 þ CD27 À and CD19 þ IgM þ B-cell subsets from active SLE patients and a differential expression profile correlated to signaling pathways including IFN, TLR and BCR as well as the apoptosis, necroptosis and immune pathways

Summary

Introduction

The abnormality of B cells includes the decrease of absolute number,[5,6,7] the altered frequency of their subsets[8,9] and hyperactivation and hyperresponsiveness to a variety of self-antigens and stimuli.[10,11] The defects of intrinsic signalings (such as Toll-like receptor 7 (TLR7) and B-cell receptor (BCR)) in B cells directly lead to lupus-like autoimmunity in mouse models,[12,13,14] the efficacy in clinical trials with. One reported that there were 174 differentially expressed transcripts in active SLE B cells,[17] whereas the other stated that 14 differentially expressed genes existed in quiescent SLE B cells,[18] both of which provided a reference for the early onset of SLE. These studies suggest that extrinsic factors may induce abnormalities of B cells by acting on intrinsic signaling. We report that co-activation of TLR7 and BCR pathways promotes B cells to hyperactivation and necroptosis, suggesting that extrinsic factors may increase intrinsical abnormality of B cells in SLE patients. This study provides a new explanation on B-cell lymphopenia in active SLE patients

Methods

Results

Conclusion