PD-L1+ Regulatory B Cells Are Significantly Decreased in Rheumatoid Arthritis Patients and Increase After Successful Treatment

Abstract

Background: B cells play an important role in the development and maintenance of rheumatoid arthritis (RA). Although IL-10–producing B cells represent a major subset of regulatory B cells (Bregs) able to suppress autoimmune and inflammatory responses, recent reports showed that B cell-mediated immune suppression may also occur independent of IL-10. For instance, B cells can modulate T cell immune responses through the expression of regulatory molecules such as PD-L1. So far, PD-L1-expressing B cells have not been analyzed in RA patients.Objective: To analyze the frequency of PD-L1-expressing B cells in the peripheral blood of RA patients compared to healthy controls (HC) matched for sex and age, their function on T cell response and their changes in response to therapy.Methods: Fresh peripheral blood B cells from RA patients and HC were characterized by flow cytometry and their functionality assessed in a co-culture system with autologous T cells.Results: The frequencies of CD19+PD-L1+ B cells, CD24hiCD38−PD-L1+ and CD24hiCD38hiPD-L1+ B cells were significantly lower in untreated RA patients than in HC. In a follow-up study, the frequencies of PD-L1+ B cells (CD19+PD-L1+ B cells, CD24hiCD38−PD-L1+ and CD24hiCD38hiPD-L1+ B cells) increased significantly after treatment in good responder patients, although the frequency of total CD24hiCD38hi B cells decreased. CD19+ B cells from untreated RA patients and HC upregulated PD-L1 expression similarly upon stimulation with CpG plus IL-2 and were able to suppress, in vitro, CD8+ T cell proliferation and cytokine production in a PD-L1-dependent manner.Conclusions: Our results show that PD-L1+ B cells exhibiting T cell suppressive capacity are significantly decreased in untreated RA patients but increase in response to successful treatment. PD-L1 expression on B cells from RA patients can be modulated in vitro and PD-L1+ B cells could thus provide new perspectives for future treatment strategies.

The blockade of PD‐1/PD‐L1 pathway promotes the apoptosis of CD19+CD25+ Bregs and suppresses the secretion of IL‐10 in patients with allergic rhinitis

“…Comparing with the HCs, it has been reported that invasive breast cancer patients had significantly increased quantity of PD‐L1 + Bregs, which possibly related to the immune escape . Similarly in rheumatoid arthritis patients, the amount of PD‐L1 + Bregs increased significantly after treatment . In our study, we confirmed that AR patients had less PD‐L1 + Bregs.…”

CD38: An Immunomodulatory Molecule in Inflammation and Autoimmunity

“…However, other findings suggest instead that CD38 can also play regulatory roles in RA. For instance, reduced CD38 hi PDL1 + CD24 hi circulating regulatory transitional B cells have been reported in RA patients (129). In summary, many CD38 + pathogenic populations appear to increase during RA.…”

Peripheral B Cell Subsets in Autoimmune Diseases: Clinical Implications and Effects of B Cell-Targeted Therapies

“…Relevant intrinsic factors include changes in major histocompatibility complex (MHC) class II [55], BCR signaling responses [56][57][58], and TLR responses [59,60]. These factors in addition to deficient Breg cells [61,62] and abnormal of extrafollicular germinal centers (GC) formation [6,63] result in alterations to B cell subsets highly connected to autoreactive ASCs (Figure 2). [64].…”