Autoantibodies in systemic sclerosis: From disease bystanders to pathogenic players

Abstract

Autoantibodies (Aab) are recognized as key indicators in the diagnosis, classification, and monitoring of systemic autoimmune diseases (AID). Recent studies have expanded knowledge through the discovery of new antigenic targets, advanced methods for measuring Aab levels, and understanding their possible pathogenic roles in AID. This narrative review uses systemic sclerosis (SSc) as an example to highlight the importance of Aab associated with HEp-2 immunofluorescence assay positivity (traditionally referred as antinuclear antibodies [ANA]), exploring recent developments in the field. Firstly, we outline the various types of ANA found in SSc and their links with specific disease features. Newly discovered antibodies shed light on SSc cases where Aab had previously gone unidentified. Secondly, we emphasize the necessity for novel quantitative techniques to track Aab levels over time by gathering data regarding the timing of Aab occurrence relative to SSc symptoms and the relationships between Aab concentrations and disease severity. Finally, we discuss the experimental findings suggesting a potential direct role of Aab in the development of SSc. The advancements surrounding Aab provide insights into new disease mechanisms and may lead to innovative diagnostic and treatment approaches.

Keywords: Antinuclear antibodies; Autoantibodies; Pathogenic autoantibodies; Systemic sclerosis.

Fig. 1

SSc-Aab antigenic targets localization, and their IFA-associated pattern on HEp2 cells Each antigenic specificity targeted by an Aab during ScS is depicted in a bubble. Its subcellular localization (cytoplasmic, nuclear, nucleolar) is presented in the cell picture. The colored portion of the circle to which each bubble corresponds indicates which category of Aab is associated with this specificity (Classification ANA, other specific ANA, SSc-associated and overlap ANA, and “new Aab”. The IFA on HEp2 cells associated with each Aab is shown on the outer part of the figure. The color of the beam connecting the name of the Aab and its localization on the cell picture corresponds to the denomination of the fluorescence pattern: violet for speckled nuclear, yellow for speckled and nucleolar (or speckled-nucleolar-speckled), orange for nucleolar, green for cytoplasmic, and blue for undetermined.Aab: auto-antibody, ATA: anti-topoisomerase 1, ACA: anti-centromere, IFA: indirect immunofluorescence assay; ARA: anti-RNA polymerase III Figure created with Biorender: https://www.biorender.com IFA pictures are sourced from the ANAPatterns website (https://www.anapatterns.org/index.php) except for RuvBL1/2 (Kaji et al., Arthritis Care & Research, 2014), and eIF2B (Koizumi et al., Rheumatology, 2023).