B Cell Homeostasis and Functional Properties Are Altered in an Hypochlorous Acid-Induced Murine Model of Systemic Sclerosis

Abstract

IntroductionDuring systemic sclerosis (SSc), peripheral B cells display alterations in subset homeostasis and functional properties and are a promising therapeutic target. However, there is only few data regarding whether these anomalies are accurately reproduced in animal models of SSc.ObjectiveIn this work, we assessed the B cell homeostasis modifications in an experimental model of SSc [hypochlorous acid (HOCl)-induced mouse], both at a phenotypic and functional level, during the course of the disease.MethodsBalb/c mice underwent daily intradermal injections of HOCl (or phosphate-buffered saline) and were then sacrificed at day 21 (early inflammatory stage) or day 42 (late fibrotic stage). For phenotypic studies, the distribution of the main spleen cell subsets (B cells, T CD4 and CD8 cells, NK cells, macrophages) and splenic B cell subsets (immature, mature naïve, germinal center, antibody-secreting, memory, B1) was assessed by flow cytometry. For functional studies, splenic B cells were immediately MACS-sorted. Production of interleukin (IL)-6, CCL3, IL-10, and transforming growth factor (TGF)-β was assessed ex vivo by RT-PCR and after 48 h of culture by ELISA. Regulatory B cell (Breg) counts were quantified by flow cytometry.ResultsPhenotypic analyses showed an early expansion of transitional B cells, followed by a late expansion of the mature naive subset and decrease in plasmablasts and memory B cells. These anomalies are similar to those encountered in SSc patients. Functional analyses revealed a B-cell overproduction of pro-inflammatory cytokines (IL-6 and CCL3) and an impairment of their anti-inflammatory capacities (decreased production of IL-10 and TGF-β, reduced levels of Bregs) at the early inflammatory stage; and an overproduction of pro-fibrotic cytokines (TGF-β and IL-6) at the late fibrotic stage. These results approximate the anomalies observed in human SSc.ConclusionThis work reports the existence of anomalies in B cell homeostasis and functional properties in an animal model of SSc that approximate those displayed by SSc patients. These anomalies vary over the course of the disease, which pleads for their participation in inflammatory and fibrotic events. This makes the HOCl mouse a relevant experimental model for the study of B cells, and therefore, B-cell-targeted therapies in SSc.

Baicalein Alleviates Fibrosis and Inflammation in Scleroderma Through Regulating B Cell Abnormalities

“…4,5). All these data suggested that B cells were hyperactivated and played important roles in brotic pathogensis of BLM-induced mice, which is comparable with the data from other SSc mice models [43][44][45]. Baicalein treatment potently attenuated serum levels of cytokines, chemokines and autoantibodies produced by T or B cells in bleomycin-induced mice (Fig.…”

Is There a Future for Anti-CD38 Antibody Therapy in Systemic Autoimmune Diseases?

“…As already mentioned for SLE, it has been also observed that SSc patients show altered number and function of IL-10 producing Breg cells [46][47][48]. Moreover, in the hypochlorous acid (HOCl) murine model of SSc, additional alterations in the B cell compartment included a decrease of plasmablasts, memory B cells and Breg, with reduced IL-10 production [49]. This abnormal distribution of B cell subsets has also been constantly described in the peripheral blood of SSc patients, that show a reduced number of plasmablasts and memory B cells and an increase of naïve B cell counts [37,47,48].…”

The Role of B Cells in Regulation of Th Cell Differentiation in Coxsackievirus B3–Induced Acute Myocarditis

“…B cells play a vital role in immune response. More and more studies demonstrate that B cells play a pathogenic role in in ammatory or autoimmune diseases, such as asthma [12], systemic sclerosis [9], and rheumatic autoimmune disease [17]. In a clinical setting, B cell depletion therapy achieves satisfactory results in the treatment of refractory autoimmune rheumatic diseases, for example SLE [18] and RA [19].…”

“…This study revealed that by producing cytokines, B cells play a key role in a mouse model of chemically-induced asthma without the help of T cells [7]. Many studies have also shown that B cells play a pathogenic role in autoimmune diseases such as systemic lupus erythematosus (SLE) [8], multiple sclerosis [9], and rheumatoid arthritis (RA) [10].…”