A broad look into the future of systemic sclerosis

Abstract

Systemic sclerosis (SSc) is a systemic autoimmune disease with the key features of inflammation, vasculopathy and fibrosis. This article focussed on emerging fields based on the authors' current work and expertise. The authors provide a hierarchical structure into the studies of the pathogenesis of SSc starting with the contribution of environmental factors. Regulatory autoantibodies (abs) are discussed, which are parts of the human physiology and are specifically dysregulated in SSc. Abs against the angiotensin II receptor subtype 1 (AT1R) and the endothelin receptor type A (ETAR) are discussed in more detail. Extracellular vesicles are another novel player to possess disease processes. Fibroblasts are a key effector cell in SSc. Therefore, the current review will provide an overview about their plasticity in the phenotype and function. Promising nuclear receptors as key regulators of transcriptional programmes will be introduced as well as epigenetic modifications, which are pivotal to maintain the profibrotic fibroblast phenotype independent of external stimuli. Fibroblasts from SSc patients exhibit a specific signalling and reactivate developmental pathways and stem cell maintenance such as by employing hedgehog and WNT, which promote fibroblast-to-myofibroblast transition and extracellular matrix generation. Pharmacological interventions, although for other indications, are already in clinical use to address pathologic signalling.

Keywords: autoantibodies; fibrosis; signalling; systemic sclerosis.

Figure 1.

Proposed concept for the development of SSc. Briefly, environmental factors determine the GPCR signature and, under the influence of genetic background and if chronically present, also the anti-GPCR signature. The anti-GPCR signature affects the function of abs from regulatory to disease-driving effector molecules. Specifically, the abs determine the threshold for and direction of immune cell migration, the place and severity of inflammation, and ab-mediated signalling. In severe inflammation, this will lead to loss of tolerance towards other autoantigens, epitope spreading and the development of SSc.

Figure 2.

Concept of cell activation by abs and EVs and of therapeutic targets derived from this concept.