Systemic sclerosis (SSc) is characterized by immune activation, vascular injury, and progressive fibrosis. Despite advances in targeted therapies, its marked clinical heterogeneity continues to challenge mechanistic interpretation and therapeutic precision. The six studies assembled in this Research Topic suggest that SSc can be understood as a layered regulatory architecture, in which serological structure, molecular convergence, vascular remodeling, and therapeutic modulation intersect along identifiable axes of control.
Komura reviews the clinical utility and standardization of SSc-related autoantibodies, emphasizing that ACA, ATA, and RNAP III are not merely diagnostic markers but define organ-risk trajectories and disease evolution across populations. A harmonized workflow (ANA/ICAP followed by core ELISAs and reflex assays) provides a reproducible framework for stratifying heterogeneity, establishing serology as a structural baseline for downstream molecular and clinical interpretation.
At the molecular level, Wu et al. identify NOX4 and NEK6 as shared elements linking SSc and sarcopenia through integrative transcriptomics and machine learning. Their findings highlight convergence within oxidative–immune regulatory networks beneath divergent clinical phenotypes, suggesting that heterogeneous manifestations may arise from intersecting molecular control points rather than isolated pathogenic cascades.
Napolitano et al. demonstrate fibrinolytic–vascular imbalance in SSc, characterized by reduced free uPA and elevated PAI-1, with PAI-1 levels correlating with capillaroscopic loop shortening. This directly connects circulating biochemical alterations to structural microvascular remodeling. Their comparison of suPAR assay platforms further underscores that biological interpretation depends on molecular form detection, bridging serum profiling with tissue architecture.
Moving toward regulatory restoration, Lee et al. show that lipid nanoparticle–mediated delivery of A20 mRNA suppresses TRAF6/NF-κB signaling and attenuates fibrosis in vivo. Rather than targeting a single cytokine, this strategy recalibrates a central regulatory brake within the immune–fibrotic network, illustrating how pathway-level modulation can exert broad downstream influence.
Clinical translation of layered intervention is exemplified by Fu et al., who report stabilization of severe cardiac involvement using sequential cyclophosphamide followed by tocilizumab. This phased modulation of immune axes demonstrates that multi-level therapeutic strategies can reverse life-threatening organ manifestations, supporting the concept of systemic recalibration through coordinated intervention.
Finally, recent comprehensive analyses of SSc pathogenesis emphasize the intricate interplay among immune activation, cytokine networks, TGF-β–driven fibroblast signaling, and extracellular matrix remodeling (Jimenez et al.). This multidimensional framework underscores the density and redundancy of immune–fibrotic interactions in SSc. In such a networked context, therapeutic impact may depend less on suppressing isolated mediators and more on understanding where coordinated regulatory influence can propagate across layers.
Collectively, these studies define a vertically organized regulatory architecture encompassing serological structure, molecular convergence, fibrinolytic–vascular balance, regulatory brake restoration, clinical layered intervention, and upstream immune modulation. Although SSc appears clinically heterogeneous, structural analysis reveals points where multiple regulatory processes intersect. These are not necessarily the most abundant mediators but loci where distinct layers converge. This vertically organized regulatory model is illustrated in Figure 1.
Figure 1
Rather than expanding catalogs of dysregulated molecules, future progress may depend on clarifying how regulatory layers interact and where convergence occurs. A structurally informed perspective may therefore support more precise and reproducible therapeutic strategies in complex autoimmune disease.
Statements
Author contributions
KK: Writing – original draft, Writing – review & editing. TM: Writing – review & editing.
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Summary
Keywords
convergence, framework & architecture, precision medicine, systemic scleroderma, systemic scleroderma (PSS)
Citation
Komura K and Matsushita T (2026) Editorial: Systemic sclerosis: immunological impacts. Front. Immunol. 17:1814196. doi: 10.3389/fimmu.2026.1814196
Received
20 February 2026
Revised
20 February 2026
Accepted
25 February 2026
Published
05 March 2026
Volume
17 - 2026
Edited and reviewed by
Silvano Sozzani, Sapienza University of Rome, Italy
Updates
Copyright
© 2026 Komura and Matsushita.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Kazuhiro Komura, komuraka@me.com
Disclaimer
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.