Altered peripheral B lymphocyte homeostasis and functions mediated by IL‐27 via activating the mammalian target of rapamycin signaling pathway in patients with rheumatoid arthritis

Abstract

B cell dysfunction and inflammatory cytokine over‐production participate in the pathogenesis of rheumatoid arthritis (RA). Here we compared peripheral B cell homeostasis and immune functions between RA patients and healthy controls (HC) and explored vital signaling pathways involved in altered RA B cells. We found that RA patients showed significantly decreased frequencies of peripheral CD19+CD27+CD24high regulatory B (Breg) cells but increased frequencies of CD19+CD27+CD38high plasmablasts and CD19+CD138+ plasma cells, and higher levels of serum immunoglobulin (Ig)M and IgG. Compared to HC peripheral B cells, RA peripheral B cells had more increased proliferation and higher expression of activation markers. Importantly, our results showed that RA peripheral B cells displayed the mTOR signaling pathway to be more activated, and inhibition of mTOR could restore RA B cell homeostasis and functions. RA serum‐treated B cells exhibited more increased expressions of mTOR, which could be restored with the addition of anti‐interleukin (IL)‐27 neutralizing antibody. Serum IL‐27 levels were significantly increased in RA patients and positively correlated with disease activity, the frequencies of plasma cells and the levels of autoantibodies. In vitro, IL‐27 notably promoted immune dysfunction of RA B cells, which were inhibited by anti‐IL‐27 neutralizing antibody. Also, the mTOR pathway was more activated in IL‐27‐treated RA B cells, and mTOR inhibition apparently reversed abnormalities of RA B cells mediated by IL‐27. These results suggest that increased serum IL‐27 levels could promote peripheral B cell dysfunction in RA patients via activating the mTOR signaling pathway. Thus, IL‐27 may play a pro‐pathogenic role in the development of RA, and antagonizing IL‐27 could be a novel therapy strategy for RA.

mTOR inhibitors improve both humoral and cellular response to SARS-CoV-2 messenger RNA BNT16b2 vaccine in kidney transplant recipients

“…These observations suggest a possible enhancement of mTOR‐I on the immune response to mRNA vaccines. To date, limited reports suggest that inhibition of mTOR could restore B cell homeostasis and functions in autoimmune diseases 17 …”

“…To date, limited reports suggest that inhibition of mTOR could restore B cell homeostasis and functions in autoimmune diseases. 17 …”

Pathogenesis of rheumatoid arthritis: one year in review 2022

“…As far as B lymphocyte subsets are concerned, a broad characterisation of seropositive RA B cell phenotype and their activities demonstrated that these cells secrete less IL-10 after in vitro activation, and they decreased their plasma cell differentiation frequency and IgM production. Furthermore, it has also been observed an increased number of atypical CD27-IgM-IgD-CD21-B lymphocytes (78), a reduced level of CD19 + CD27 + CD24 high Breg cells with higher proportions of circulating CD19 + CD27 + CD38 high plasmablasts (79). Finally, with regard to autoantibodies and based on the knowledge that antimodified protein antibodies (AMPA) IgG display cross-reactivity to multiple post-translational modifications, AMPA-IgM from RA patients were shown to exert the same cross-reactivity features of AMPA IgG and were also more potent then AMPA-IgG in complement-activation (80).…”

“…• RA-T-cells, B-cells and plasmacells are able to drive RANKL-dependent osteoclast differentiation (68,69). • In RA CD27-IgM-IgD-CD21-B lymphocytes are increased while CD19 + CD27 + CD24 high Breg cells with higher proportions of circulating CD19 + CD27 + CD38 high plasmablasts are reduced (79).…”

IL-27 enhances peripheral B cell glycolysis of rheumatoid arthritis patients via activating mTOR signaling

“…Circulating IL-27 is elevated in RA patients and can in uence RA development by regulating synovial broblasts and various immune cell responses [16][17][18]. Our previous study has demonstrated that increased IL-27 could promote RA B cell dysfunction via activating the mTOR signaling pathway [19], which indicates that IL-27 signaling may induce RA B cell hyperactivation by controlling cellular metabolism. However, further researches still need to be done.…”