Mapping the plasma proteomic architecture of systemic lupus erythematosus
File(s)
Author(s)
Type
Journal Article
Abstract
Systemic lupus erythematosus (SLE) is a heterogeneous systemic autoimmune disease, yet the molecular basis underlying this variability remains incompletely understood. We profiled the plasma proteome in 260 SLE patients and 86 healthy volunteers (HVs) using the SomaScan v4.1 platform, quantifying 7,288 analytes corresponding to 6,595 unique proteins. We identified
215 proteins that were robustly differentially abundant between SLE patients and HVs in both discovery (n=207 SLE, n=45 HVs) and validation sets (n=53 SLE, n=41 HVs). Within-cases analyses identified 421 proteins associated with disease activity. Network-based clustering
delineated correlated protein modules, including an interferon-associated module and a renal associated module. Autoantibody-stratified analyses further uncovered distinct proteomic endotypes: positivity for antibodies targeting RNA-binding proteins (anti-Sm, anti-Ro-60, anti RNP68, anti-RNP-A) was associated with increased interferon-stimulated protein levels (e.g.,
MX1, ISG15, CXCL10), independent of disease activity. Anti-Sm, anti-RNP-A and anti-Ro52 antibodies were associated with reduced plasma levels of their respective autoantigens. Anti-dsDNA antibodies were associated with elevated levels of CD40 ligand (CD40LG) and the
neutrophil protease proteinase-3. Moreover, we identified an association between CD40LG and disease activity specific to the anti-dsDNA positive subgroup. Together, these data define plasma protein signatures of SLE and disease activity, highlight autoantibody-specific molecular
phenotypes, and provide a basis for precision medicine.
215 proteins that were robustly differentially abundant between SLE patients and HVs in both discovery (n=207 SLE, n=45 HVs) and validation sets (n=53 SLE, n=41 HVs). Within-cases analyses identified 421 proteins associated with disease activity. Network-based clustering
delineated correlated protein modules, including an interferon-associated module and a renal associated module. Autoantibody-stratified analyses further uncovered distinct proteomic endotypes: positivity for antibodies targeting RNA-binding proteins (anti-Sm, anti-Ro-60, anti RNP68, anti-RNP-A) was associated with increased interferon-stimulated protein levels (e.g.,
MX1, ISG15, CXCL10), independent of disease activity. Anti-Sm, anti-RNP-A and anti-Ro52 antibodies were associated with reduced plasma levels of their respective autoantigens. Anti-dsDNA antibodies were associated with elevated levels of CD40 ligand (CD40LG) and the
neutrophil protease proteinase-3. Moreover, we identified an association between CD40LG and disease activity specific to the anti-dsDNA positive subgroup. Together, these data define plasma protein signatures of SLE and disease activity, highlight autoantibody-specific molecular
phenotypes, and provide a basis for precision medicine.
Date Issued
2026-07-22
Date Acceptance
2026-06-01
Citation
JCI Insight, 2026, 11 (14)
ISSN
2379-3708
Publisher
American Society for Clinical investigation
Start Page
e206938
Journal / Book Title
JCI Insight
Volume
11
Issue
14
Copyright Statement
© 2026 Leung et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
License URL
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/42228421
PII: 206938
Subjects
Autoimmunity
Clinical Research
Inflammation
Lupus
Proteomics
Rheumatology
Publication Status
Published
Coverage Spatial
United States
Article Number
e206938
Date Publish Online
2026-06-02