The cancer-associated glycan polysialic acid is dysregulated in systemic sclerosis and is associated with fibrosis

Lamia Khan; Tahlia Derksen; Desiree Redmond; Jan Storek; Caylib Durand; Robert Gniadecki; Benjamin Korman; Jan Willem Cohen Tervaert; Ana D'Aubeterre; Mohammed S Osman; Lisa M Willis

doi:10.1016/j.jaut.2023.103110

The cancer-associated glycan polysialic acid is dysregulated in systemic sclerosis and is associated with fibrosis

J Autoimmun. 2023 Sep 22:140:103110. doi: 10.1016/j.jaut.2023.103110. Online ahead of print.

Authors

Affiliations

¹ Faculty of Medicine & Dentistry, Division of Rheumatology, Department of Medicine, University of Alberta, Edmonton, AB, Canada.
² Faculty of Science, Department of Biological Sciences, University of Alberta, Edmonton, AB, Canada.
³ University of Calgary, Calgary, AB, Canada.
⁴ Peak Medical Specialty Centers, Calgary, AB, Canada.
⁵ Faculty of Medicine & Dentistry, Division of Dermatology, Department of Medicine, University of Alberta, Edmonton, AB, Canada.
⁶ Division of Allergy, Immunology and Rheumatology, University of Rochester Medical Center, Rochester, NY, USA.
⁷ Faculty of Medicine & Dentistry, Division of Rheumatology, Department of Medicine, University of Alberta, Edmonton, AB, Canada. Electronic address: mosman@ualberta.ca.
⁸ Faculty of Science, Department of Biological Sciences, University of Alberta, Edmonton, AB, Canada; Faculty of Medicine & Dentistry, Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, AB, Canada. Electronic address: lisa.willis@ualberta.ca.

PMID: 37742510
DOI: 10.1016/j.jaut.2023.103110

Abstract

Objective: Systemic sclerosis (SSc) is a rare but deadly disease characterized by autoimmunity, vasculopathy, and fibrosis. Fibrotic complications associated with SSc correlate with severe morbidity and mortality. Previous studies in SSc have identified fibroblasts as the primary drivers of fibrosis; however, the mechanism(s) promoting this are not well understood. Aberrant glycosylation, particularly polysialylation (polySia), has been described as a prominent feature of aggressive cancers. Inspired by this observation, we aimed to determine if polySia is dysregulated in various forms of SSc.

Methods: All patients with SSc met the 2013 ACR/EULAR. Patients were sub-classified into limited cutaneous (lSSc, N = 5 or 46 patients for polySia quantification in the dermis or serum; respectively), diffuse cutaneous (dSSc, N = 11 or 18 patients for polySia quantification in the dermis or serum; respectively), or patients with dSSc treated with an autologous stem cell transplantation (post-ASCT, N = 4 patients for quantification in the dermis). Dermal polySia levels were measured via immunofluorescence microscopy in 10 μm dermal sections, quantified in each group (healthy volunteers (HC), lSSc, dSSc, and post-ASCT) and correlated with skin fibrosis (via the modified Rodnan skin score (mRSS)). Similarly, serum polySia was quantified in each group, and correlated with the mRSS.

Results: Dermal polySia levels were highest in patients with dSSc (compared to HC < 0.001), and correlated with the degree of fibrosis in all of the groups (P = 0.008). Serum polySia was higher in all SSc groups (p < 0.001) and correlated with the severity of mRSS (p < 0.0001).

Conclusion: Polysia is more abundant in the skin and sera from patients with SSc and correlates with the degree of skin fibrosis. The aberrant expression of polySia highlights its potential use as a biomarker in patients with progressive forms of SSc. Dysregulated polySia levels in SSc further emphasizes the cancer-like phenotype present in SSc, which may promote fibrosis and immune dysregulation.

Keywords: Biomarker; Fibrosis; Glycosylation; Myofibroblasts; Polysialic acid; Systemic sclerosis.