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.

Identification and validation of anti-protein arginine methyltransferase 5 (PRMT5) antibody as a novel biomarker for systemic sclerosis (SSc)

“…In brief, we constructed an antigen pool using lysates from a variety of cell lines, including human umbilical vein endothelial cells, human dermal fibroblasts, Jurkat T cells and THP-1 monocytes, as sources of antigens for subsequent proteomics profiling. The corresponding cell types have been linked to the pathogenesis of SSc 4 13 14. Antigen-antibody complexes were then enriched by coincubating global antibodies with the antigen pool, in conjunction with immunoprecipitation (IP) using protein A/G beads.…”

“…This highlights the necessity to explore novel autoantibodies that are specific to SSc. There is a growing body of studies focusing on the identification of novel autoantibodies and the definition of their clinical implications, such as antiplatelet-derived growth factor receptor (PDGFR), antiangiotensin receptor type 1, antigephyrin and antieukaryotic initiation factor 2B antibodies 9–14. Mechanistically, single-cell analysis reveals broad differences in cell cluster gene expression profiles, showing distinctions in clinical phenotypes and distinct skin score trajectories across autoantibody subgroups of diffuse cutaneous SSc (dcSSc) 15.…”