Dysregulated B cell function and disease pathogenesis in systemic sclerosis

Abstract

Systemic sclerosis (SSc) is a complex, immune-mediated rheumatic disease characterised by excessive extracellular matrix deposition in the skin and internal organs. B cell infiltration into lesional sites such as the alveolar interstitium and small blood vessels, alongside the production of defined clinically relevant autoantibodies indicates that B cells play a fundamental role in the pathogenesis and development of SSc. This is supported by B cell and fibroblast coculture experiments revealing that B cells directly enhance collagen and extracellular matrix synthesis in fibroblasts. In addition, B cells from SSc patients produce large amounts of profibrotic cytokines such as IL-6 and TGF-β, which interact with other immune and endothelial cells, promoting the profibrotic loop. Furthermore, total B cell counts are increased in SSc patients compared with healthy donors and specific differences can be found in the content of naïve, memory, transitional and regulatory B cell compartments. B cells from SSc patients also show differential expression of activation markers such as CD19 which may shape interactions with other immune mediators such as T follicular helper cells and dendritic cells. The key role of B cells in SSc is further supported by the therapeutic benefit of B cell depletion with rituximab in some patients. It is notable also that B cell signaling is impaired in SSc patients, and this could underpin the failure to induce tolerance in B cells as has been shown in murine models of scleroderma.

Keywords: B cells; autoantibodies; autoimmunity; fibrosis; systemic sclerosis (scleroderma).

Figure 1

A simplified overview of the developmental pathway of B cells. They develop in the bone marrow from hematopoietic stem cells to pro- and pre-B cells once the IgH genes are rearranged. Following successful IgL gene rearrangement the cells develop to immature B cells expressing IgM. These cells then migrate from the bone marrow to the periphery as transitional 1 (T1) B cells which pass through peripheral checkpoints with most autoreactive B cells becoming anergic-like T3 cells. T2 cells can mature to become either follicular (Fo) or marginal zone (MZ) B cells expressing IgM and IgD. Fo B cells can differentiate to low affinity antibody producing plasmablasts (PB) or undergo class switching and affinity maturation in germinal centres (GC) to become high affinity antibody producing plasma cells or memory cells. Figure created with BioRender.com.

Figure 2

Dysregulated B cell signalling in SSc patients. Overexpressed molecules are shown in blue, underexpressed molecules are shown in red and those shown in green are of interest in SSc, but are neither up or downregulated. SSc B cells are in a hyperactive state marked by differential expression of the BCR coreceptors CD19 and inhibitory CR1. TLR signalling is augmented through differential TLR4, TLR7, TLR9 and CD180 expression, whilst increased levels of serum soluble PD-1 and PD-L2 inhibit the PD-1 and PD-L2 interaction between T and B cells. Figure created with BioRender.com.

Figure 3

Potential pathway for B cell mediated fibrosis in scleroderma. Direct cell-cell contact can induce changes in gene expression in fibroblasts leading to increased collagen production and myofibroblast differentiation. In addition, B cell production of cytokines such as IL-6 and TGF-β also induce myofibroblast differentiation. Meanwhile, autoantibodies can form immune complexes which bind to fibroblasts and trigger pro-fibrotic effects, whilstsome autoantibody specificities, such as PDGF, observed in a subset of SSc patients can bind fibroblasts directly and have stimulating effects. Figure created with BioRender.com.