RT Journal Article
SR Electronic
T1 Lupus-associated atypical memory B cells are mTORC1-hyperactivated and functionally dysregulated
JF Annals of the Rheumatic Diseases
JO Ann Rheum Dis
FD BMJ Publishing Group Ltd and European League Against Rheumatism
SP 1090
OP 1100
DO 10.1136/annrheumdis-2019-215039
VO 78
IS 8
A1 Wu, Chunmei
A1 Fu, Qiong
A1 Guo, Qiang
A1 Chen, Sheng
A1 Goswami, Shyamal
A1 Sun, Shuhui
A1 Li, Teng
A1 Cao, Xingjian
A1 Chu, Fuying
A1 Chen, Zechuan
A1 Liu, Mei
A1 Liu, Yuanhua
A1 Fu, Ting
A1 Hao, Pei
A1 Hao, Yi
A1 Shen, Nan
A1 Bao, Chunde
A1 Zhang, Xiaoming
YR 2019
UL http://ard.bmj.com/content/78/8/1090.abstract
AB Objectives A population of atypical memory B cells (AtMs) are greatly expanded in patients with active lupus, but their generation and pathophysiological roles are poorly defined. The aim of this study was to comprehensively characterise lupus AtMs with a purpose to identify therapeutic clues to target this B cell population in lupus.Methods Peripheral B cell subsets were measured by flow cytometry. Sorting-purified B cell subsets were subject to RNA sequencing and functional studies. Plasma cytokines and secreted immunoglobulins were detected by Luminex or ELISA. In situ renal B cells were detected by multiplexed immunohistochemistry.Results CD24−CD20hi AtMs were strongly increased in two Chinese cohorts of patients with treatment-naïve lupus. Gene expression profile indicated that B cell signalling and activation, lipid/saccharide metabolism and endocytosis pathways were abnormally upregulated in lupus AtMs. In addition, the mammalian target of rapamycin complex 1 (mTORC1) pathway was remarkably activated in lupus AtMs, and blocking mTORC1 signalling by rapamycin abolished the generation of T-bet+ B cells and terminal differentiation of lupus AtMs. Furthermore, lupus AtMs displayed a dysfunctional phenotype, underwent accelerated apoptosis, poorly co-stimulated T cells and produced proinflammatory cytokines. Interestingly, lupus AtMs were in a paradoxically differentiated status with markers pro and against terminal differentiation and enriched with antinucleosome reactivity. Finally, AtMs were accumulated in the kidneys of patients with lupus nephritis and associated with disease severity.Conclusions These findings demonstrated that mTORC1-overactivated lupus AtMs are abnormally differentiated with metabolic and functional dysregulations. Inhibiting mTORC1 signalling might be an attractive option to target AtMs and to improve therapeutic effectiveness in patients with lupus.