title: Activation-induced necroptosis contributes to B-cell lymphopenia in active systemic lupus erythematosus.
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.
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, China.
authors.forename: H
authors.initials: H
authors.lastname: Fan
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, China.
authors.forename: F
authors.initials: F
authors.lastname: Liu
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, China.
authors.forename: G
authors.initials: G
authors.lastname: Dong
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, China.
authors.forename: D
authors.initials: D
authors.lastname: Ren
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Xu
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, China.
authors.forename: J
authors.initials: J
authors.lastname: Dou
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, China.
authors.forename: T
authors.initials: T
authors.lastname: Wang
authors.affiliation: Department of Immunology and Rheumatology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China.
authors.forename: L
authors.initials: L
authors.lastname: Sun
authors.affiliation: 1] The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, China [2] Jiangsu Key Laboratory of Molecular Medicine, Nanjing, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Hou
mesh_terms: D017209:Apoptosis; D001402:B-Lymphocytes / Q000166:cytology* / Q000276:immunology; D005260:Female; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology / Q000503:physiopathology*; D008213:Lymphocyte Activation; D008231:Lymphopenia / Q000235:genetics / Q000276:immunology / Q000503:physiopathology*; D008297:Male; D051199:Toll-Like Receptor 7 / Q000235:genetics / Q000276:immunology
chemical_list: C495348:TLR7 protein, human; D051199:Toll-Like Receptor 7