Defective PTEN regulation contributes to B cell hyperresponsiveness in systemic lupus erythematosus

Abstract

PTEN regulates normal signaling through the B cell receptor (BCR). In systemic lupus erythematosus (SLE), enhanced BCR signaling contributes to increased B cell activity, but the role of PTEN in human SLE has remained unclear. We performed fluorescence-activated cell sorting analysis in B cells from SLE patients and found that all SLE B cell subsets, except for memory B cells, showed decreased expression of PTEN compared with B cells from healthy controls. Moreover, the level of PTEN expression was inversely correlated with disease activity. We then explored the mechanisms governing PTEN regulation in SLE B cells. Notably, in normal but not SLE B cells, interleukin-21 (IL-21) induced PTEN expression and suppressed Akt phosphorylation induced by anti-immunoglobulin M and CD40L stimulation. However, this deficit was not primarily at the signaling or the transcriptional level, because IL-21-induced STAT3 (signal transducer and activator of transcription 3) phosphorylation was intact and IL-21 up-regulated PTEN mRNA in SLE B cells. Therefore, we examined the expression of candidate microRNAs (miRs) that could regulate PTEN: SLE B cells were found to express increased levels of miR-7, miR-21, and miR-22. These miRs down-regulated the expression of PTEN, and IL-21 stimulation increased the expression of miR-7 and miR-22 in both normal and SLE B cells. Indeed, a miR-7 antagomir corrected PTEN-related abnormalities in SLE B cells in a manner dependent on PTEN. Therefore, defective miR-7 regulation of PTEN contributes to B cell hyperresponsiveness in SLE and could be a new target of therapeutic intervention.

MicroRNA regulation of lymphocyte tolerance and autoimmunity

“…Pten +/-mice develop splenomegaly and lymphadenopathy, have increased serum IgG and anti-ssDNA antibodies, and develop lung and kidney inflammation (34). Interestingly, PTEN expression is decreased in SLE patient B cells, and this correlates with increased expression of miR-22 and two other miRNAs, miR-7, and miR-21, that also target PTEN (35).…”

MicroRNAs in the key events of systemic lupus erythematosus pathogenesis

“…mir-1246 inhibits, by interacting with its 3′-UTr, early B cell factor 1 (eBF1), which is necessary for B cell maturation (pro-B cells, mZ B cells and peripheral B cells) and signalling, including the expression of costimulatory molecules such as cd40, cd80 and cd86 (ref. 144 ). in active sle, B cells showed activation of the pi3K/aKT-p53 signalling pathway leading to alleviation of mir-1246 and enhanced eBF-1 expression 143 .…”

A 50‐Year‐Old Woman With Cowden Syndrome and Joint Pains

“…There was also diminished expression of the Foxp3 transcription factor, possibly reflecting deficiency of regulatory T cells linked to activation of mTOR. B cells from SLE patients are found to have decreased expression of PTEN that correlates with disease activity (21). Further investigation showed that microRNA (miRs) that downregulate the expression of PTEN miR-7, miR-21, and miR-22 were increased.…”