B(effector)reaking bad in systemic sclerosis: role of a novel B cell subset

Systemic sclerosis (SSc) is an autoimmune idiopathic connective tissue disease characterized by fibrosis of skin and internal organs such as lung, heart and gut. The disease results from an interplay between vascular damage, autoimmunity, inflammation [1], cytokine dysregulation and resulting differentiation of fibroblasts to myofibroblasts that deposit copious amounts of extracellular matrix molecules, including collagen and fibronectin [2].

Although the disease is complex and has an unpredictable clinical course, recent discoveries have uncovered a role for the immune system in the disease – especially that of the adaptive immune system [3,4]. In this issue, Higashioka et al. describe the generation of granulocyte–macrophage colony-stimulating factor (GM-CSF)-producing B cell effector cells which are enriched in SSc patients, particularly those with the diffuse cutaneous subtype (dcSSc) [5]. Furthermore, they demonstrated that these cells generated under T helper type 2 (Th2)-polarized conditions could enable the differentiation of CD14⁺ monocytes to a dendritic cell that promoted proliferation of naive T cells.

Within a complex and incompletely understood pathogenesis, B cells have been found to be aberrant in SSc [6], and specific autoantibodies reacting to various intracellular components, including RNA polymerase, are indeed diagnostic in the disease. In fact, it has been shown that B regulatory cells, that are anti-inflammatory and potentially regulatory in autoimmune disease, are reduced both numerically and functionally in SSc [6]. The authors of this study examined the GM-CSF-producing B effector cells and their generation in vitro. They found that interleukin (IL)-4 significantly promoted the generation of these GM-CSF-producing B effector cells. This is of interest, as IL-4 is a Th2-polarizing cytokine and SSc is characterized by a Th2 domination [3,7], and elevated serum levels of IL-4 and IL-13. IL-4 and IL-13 are virtually identical cytokines. Interestingly, the master profibrotic cytokine, transforming growth factor (TGF)-β1, involved in many fibrotic conditions, further potentiated the induction of GM-CSF-producing B effector cells by the Th2-polarizsing cytokines IL-4 and IL-13, which suggests that a TGF-β1 niche promotes the development of this specific cell type. Furthermore, tofacitinib reduced IL-4-mediated, but not TGF-β-mediated, induction of GM-CSF in these effector B cells. Tofacitinb is a small-molecule Janus kinase (JAK) inhibitor with a good safety profile, which is licensed for treatment of rheumatoid arthritis (RA) and has shown clinical efficacy in psoriatic arthritis [8]. Tofacitinib works by blocking JAKs, being a pan-inhibitor with potent inhibition of JAK1 and JAK3, and subsequent downstream phosphorylation of signal transducers and activators of transcription (STATs). STAT signalling has also been found to be critical in SSc fibrosis [9], and highly targeted JAK2 inhibition in vitro has shown some anti-fibrotic effects [10]. We have found the use of tofacitinib in vitro to be extremely effective in reducing fibrosis using cultured dermal fibroblasts from SSc patients (unpublished observations).

Furthermore, Higashioka et al. demonstrated that GM-CSF-producing B effector cells cultured in Th2-polarizing conditions facilitated the differentiation of CD14⁺ monocytes to DC-SIGN⁺CD1a⁺CD14⁻CD86⁺ cells, presumably by IL-4 and GM-CSF. These DCs subsequently promoted naive T cell proliferation; however, the reproducibility of this is not clear.

Rituximab is a chimeric monoclonal antibody that specifically targets the transmembrane CD20 receptor on B cells, leading to a significant depletion of autoreactive B cells. In light of that, in a study in 20 patients with dcSSc treatment with rituximab led to significant improvements in skin fibrosis scores and preservation of lung function [11]. A recent study in a Japanese cohort also showed significant benefit in both skin fibrosis and lung preservation in comparison to cyclophosphamide in anti-topo1 antibody-positive patients [12]. Although both studies are small, they offer a positive indication towards B cell depletion therapy and suggest that a specific subset of patients may respond well to treatment with rituximab. Indeed, in the study in this issue of Clinical and Experimental Immunology, the authors found overall higher numbers of GM-CSF-producing B effector cells, but this was particularly high in the dcSSc with concomitant interstitial lung disease. The implication is that this particular subset of B effector cells could be used as a possible predictor to select patients for B cell-depleting biological therapy in diffuse SSc with concomitant lung disease. Heterogeneity in clinical trials of interventions in SSc is a critical issue, so a predictor of who will respond to a specific therapy would be useful.

The observation that tofacitinib, a JAK inhibitor, blocked production of GM-CSF-producing B effector cells suggests that targeting JAKs could be therapeutic in SSc. Indeed, a clinical trial is under way for examining the safety and tolerability of tofacitinib in diffuse SSc (NCT03274076). Although the authors show evidence of this specific B effector cell in the blood of SSc patients, demonstration of these cells in lesional skin would substantiate the pathogenic role of this cell type. Direct action of this particular B effector cell on myofibroblast transition was not demonstrated in this study; indeed, SSc fibroblasts have been shown to have higher expression of the GM-CSF receptor [13], and therefore could be particularly sensitive to this cytokine.