Lupus-associated atypical memory B cells are mTORC1-hyperactivated and functionally dysregulated.

Abstract

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. 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. CD24^-CD20^hi 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. 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.