No abstract

Regulatory B cells (Breg) are crucial immunoregulators that maintain peripheral tolerance and suppress inflammatory autoimmune responses. In recent years, our understanding on the nature and mechanism of action of Bregs has revealed the important role of cytokines in promoting the regulatory properties of this unique B cell subset, both in animal and human models. In this review, we compiled the cytokines that have been reported by multiple studies to induce the expansion of Breg. The Breg-inducing cytokines which are currently known include IL-21, IL-6, IL1β, IFNα, IL-33, IL-35, BAFF and APRIL. As cytokines are also known to play a pivotal role in the pathogenesis of autoimmune diseases, in parallel we reviewed the pattern of expression of the Breg-inducing cytokines in Systemic Lupus Erythematosus (SLE), Rheumatoid Arthritis (RA), Inflammatory Bowel Diseases (IBD) and Multiple Sclerosis (MS). We show here that Breg-inducing cytokines are commonly implicated in these inflammatory diseases where they typically have a higher expression than in healthy individuals, suggesting their paradoxical nature. Interestingly, despite the general overexpression of Breg-inducing cytokines, it is known that Breg cells are often numerically or functionally impaired in various autoimmune conditions. Considering these alterations, we explored the possible parameters that may influence the function of Breg-inducing cytokines in exhibiting either their regulatory or pro-inflammatory properties in the context of autoimmune conditions.

Mesenchymal stromal cell-derived extracellular vesicles (MSC-EV) are widely considered as a cell-free therapeutic alternative to MSC cell administration, due to their immunomodulatory and regenerative properties. However, the interaction mechanisms between EV and target cells are not fully understood. The surface glycans could be key players in EV–cell communication, being specific molecular recognition patterns that are still little explored. In this study, we focused on the role of N-glycosylation of MSC-EV as mediators of MSC-EV and endothelial cells’ interaction for subsequent EV uptake and the induction of cell migration and angiogenesis. For that, EV from immortalized Wharton’s Jelly MSC (iWJ-MSC-EV) were isolated by size exclusion chromatography (SEC) and treated with the glycosidase PNGase-F in order to remove wild-type N-glycans. Then, CFSE-labelled iWJ-MSC-EV were tested in the context of in vitro capture, agarose-spot migration and matrigel-based tube formation assays, using HUVEC. As a result, we found that the N-glycosylation in iWJ-MSC-EV is critical for interaction with HUVEC cells. iWJ-MSC-EV were captured by HUVEC, stimulating their tube-like formation ability and promoting their recruitment. Conversely, the removal of N-glycans through PNGase-F treatment reduced all of these functional activities induced by native iWJ-MSC-EV. Finally, comparative lectin arrays of iWJ-MSC-EV and PNGase-F-treated iWJ-MSC-EV found marked differences in the surface glycosylation pattern, particularly in N-acetylglucosamine, mannose, and fucose-binding lectins. Taken together, our results highlight the importance of N-glycans in MSC-EV to permit EV–cell interactions and associated functions.

In the context of kidney injury, the role of Bregs is gaining interest. In a number of autoimmune diseases, the number and/or the function of Bregs has been shown to be impaired or downregulated, therefore restoring their balance might be a potential therapeutic tool. Moreover, in the context of kidney transplantation their upregulation has been linked to tolerance. However, a specific marker or set of markers that define Bregs as a unique cell subset has not been found and otherwise multiple phenotypes of Bregs have been studied. A quest on the proper markers and induction mechanisms is now the goal of many researchers. Here we summarize the most recent evidence on the role of Bregs in kidney disease by describing the relevance of in vitro and in vivo Bregs induction as well as the potential use of Bregs as cell therapy agents in kidney transplantation.