Novel IgG and IgA autoantibodies validated in two independent cohorts are associated with disease activity and determine organ manifestations in systemic lupus erythematosus: implications for anti-LIN28A, anti-HMGN5, anti-IRF5, and anti-TGIF1.

Lindblom, Julius;Lagutkin, Denis;Sherina, Natalia;Idborg, Helena;Maudoux, Anne-Lise;et.al.
(2025) Annals of the rheumatic diseases — Vol. 84, n° 7, p. 1164-1179 (2025)

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Authors
  • Lindblom, Julius
    Author
  • Lagutkin, Denis
    Author
  • Sherina, Natalia
    Author
  • Idborg, Helena
    Author
  • Lauwerys, BernardUCLouvain
    Collaborator
  • Ducreux, JulieUCLouvain
    Collaborator
  • Maudoux, Anne-LiseUCLouvain
    Collaborator
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Abstract
(en) OBJECTIVES: This study aimed to identify and validate novel autoantibodies that reflect global and organ-specific disease activity in systemic lupus erythematosus (SLE). METHODS: Plasma samples were screened for IgG and IgA seroreactivity against 1609 protein autoantigens using a microarray (i-Ome Discovery; Sengenics). We determined differentially abundant autoantibodies (daAAbs) in patients with SLE vs healthy controls within a discovery (n = 196 vs n = 110; NTC02890121) and an independent validation cohort (n = 30 vs n = 83; NCT02890134) from the European PRECISESADS project. Validated daAAbs were analysed in relation to global and organ-specific disease activity using linear and logistic regression, along with daAAb target pathway enrichment analysis. RESULTS: We validated 89 IgG and 66 IgA daAAbs. IgG anti-LIN28A, IgG anti-HMGN5, and both isotypes for anti-IRF5 and anti-TGIF1 were associated with a SLE disease activity index 2000 score of ≥10, negatively associated with lupus low disease activity state, and highly prevalent in subgroups with active disease across organ manifestations. IgG anti-LIN28A levels exceeded the cutoff for positivity in 53% of patients with central nervous system (CNS) involvement, a prevalence higher than that observed for anti-double-stranded DNA (20%) and 47% of patients with renal activity. A cluster of IgG and IgA daAAbs against RNA-binding proteins, including anti-LIN28A, was linked to CNS involvement. IgA anti-FOSL2 was elevated uniquely in patients with musculoskeletal activity. Enriched pathways involving DNA binding and repair showed considerable overlap across manifestations. CONCLUSIONS: Novel IgG and IgA autoantibodies, including IgG anti-LIN28A, IgG anti-HMGN5, IgG and IgA anti-IRF5, and IgG and IgA anti-TGIF1 were associated with SLE disease activity and highly abundant across organ manifestations.
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Lindblom, J., Lagutkin, D., Sherina, N., Idborg, H., Beretta, L., Borghi, M. O., PRECISESADS Clinical Consortium, Peyper, J. M., Barturen, G., Jakobsson, P.-J., Alarcón-Riquelme, M. E., Nikolopoulos, D., & Parodis, I. (2025). Novel IgG and IgA autoantibodies validated in two independent cohorts are associated with disease activity and determine organ manifestations in systemic lupus erythematosus: implications for anti-LIN28A, anti-HMGN5, anti-IRF5, and anti-TGIF1. Annals of the rheumatic diseases, 84(7), 1164-1179. https://doi.org/10.1016/j.ard.2025.04.008 (Original work published 2025)