Paradoxical role of Breg-inducing cytokines in autoimmune diseases

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.

Pathogenesis and Function of Interleukin-35 in Rheumatoid Arthritis

“…Besides, a series of non-immune cells including tumor cells can also secrete IL-35 ( Long et al, 2013 ; Wang et al, 2013 ). In general, IL-35 is inducible in Tregs, Bregs, immature dendritic cells, vascular endothelial cells, epithelial cells, and smooth muscle cells in the human body ( Shen et al, 2014 ; Dambuza et al, 2017 ; Haller et al, 2017 ; Mohd Jaya et al, 2019 ). Two subunits of IL-35 have a high expression level in mice, and the p35 subunit is revelated in blood, liver, thymus, and bone marrow ( Li et al, 2012 ).…”

In Vitro Characterization of Human CD24hiCD38hi Regulatory B Cells Shows CD9 Is Not a Stable Breg Cell Marker

“…In addition, although IL-10 is regarded as the main distinguishing and undisputed feature of various Breg subsets, a recent report demonstrated the plasticity and transient nature of IL-10 expression in B cells [ 22 ]. Therefore, the lack of stability and ambiguity in Breg-related phenotypes may suggests that Bregs are not a specific subset with innate characteristics but their development is, rather, driven by the immune microenvironment as part of the adaptation to different stimuli [ 21 , 22 , 23 ].…”

Early Treatment of Interleukin-33 can Attenuate Lupus Development in Young NZB/W F1 Mice

“…The conflicting findings may also be due to the possible paradoxical roles of IL-33 in different immune subsets and disease stages [41]. In SLE patients, IL-33 level was significantly correlated to acute pro-inflammatory biomarkers suggesting that IL-33 is more involved during early disease initiation [11].…”