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

Distinct abnormalities of B cells are considered to be an important cause of systemic lupus erythematosus (SLE). One of the newly discovered B cell subsets in recent years, atypical memory B cells (AtMs), was found to be increased in kinds of diseases including SLE. Here we reported that AtMs were significantly expanded in peripheral blood of SLE, infiltrated in renal tissues of lupus nephritis (LN) patients, and exhibited to be a sensitive index in evaluating disease recurrence. AtMs showed altered BCR signaling, changed ability of antibody secretion, increased apoptosis rate and impaired ability of pro-inflammatory factors secretion, and were functionally exhausted and metabolically aberrant compared with classic memory B cells (CMs). In our study, we first time pointed out that mTORC1 signaling pathway was highly activated in AtMs of SLE patients, and played an important role in differentiation of this B cell subset. This may be a new mechanism involved in the pathogenesis of SLE. Rapamycin could specifically block the mTORC1 signaling, thus inhibiting the differentiation of AtMs induced by IFNγ and TLR7 agonist. It may be a potent treatment for SLE, especially for patients with a high proportion of AtMs.