Isotype-dependent shifts of natural autoantibody profiles in systemic lupus erythematosus-associated serological groups
Abstract
ObjectivesHomeostatic natural autoantibodies (nAAbs) are proposed regulators of inflammation and autoimmunity, studied mainly as natural IgM. Whether pathological autoantibody (pAAb) expansion in systemic lupus erythematosus (SLE)-associated serology is mirrored by isotype-divergent nAAb changes has rarely been examined.MethodspAAb positivity and co-positivity ratios (exact 95% confidence intervals) and intersection (UpSet) analyses were derived from a regional diagnostic cohort (Southern Transdanubia, Hungary, 2014–2024; 128,847 enzyme-linked immunosorbent assay (ELISA) results, 73,747 pseudonymised patients). The dominant patterns defined anti-double-stranded DNA (a-dsDNA)/anti-nucleosome-, anti-SSA/Ro- and anti-cardiolipin/β2-glycoprotein I (a-CL/β2GPI)-dominant and co-positive groups, each verified against serological follow-up. In 110 residual sera, IgG and IgM nAAbs against citrate synthase (CS) and heat shock proteins (HSP) 60 and 70 were measured by ELISA and compared by Kruskal–Wallis and Dunn–Holm tests.ResultsOf a-dsDNA IgG-positive patients, 30.36% carried an additional disease-specific pAAb, along two largely separate axes, antiphospholipid (15.90%) and extractable nuclear antigen-associated (16.51%); anti-neutrophil cytoplasmic antibody co-positivity was rare (3.02%), and 42.01% showed a-nucleosome co-reactivity. a-CS IgM was reduced in every pAAb-positive group (all pHolm < 0.001), whereas increased a-CS, a-HSP60 and a-HSP70 IgG levels were confined to a-dsDNA/a-nucleosome-containing (chromatin-reactive) profiles (a-CS IgG, pHolm ≤ 0.012). These shifts were robust to sex-, age- and measurement-year adjustment.ConclusionIsotype-resolved nAAb profiling anchored in diagnostic serology revealed a counter-directional shift (IgM↓ across pAAb-positive groups, IgG↑ in chromatin-reactive profiles). These hypothesis-generating findings are consistent with impaired homeostatic IgM-mediated regulation and with class-switched IgG nAAb reactivity as a marker of B-cell activation, and warrant clinical and functional validation in prospective cohorts.
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BibTeX
@article{szinger2026isotypedependent,
title = {{Isotype-dependent shifts of natural autoantibody profiles in systemic lupus erythematosus-associated serological groups}},
author = {Dávid Szinger and Katalin Böröcz and Diána Simon and Alain Le Roux and Szabina Erdő-Bonyár and Nancy Zeineddine and Péter Németh and Timea Berki},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1936421},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1936421},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Isotype-dependent shifts of natural autoantibody profiles in systemic lupus erythematosus-associated serological groups
AU - Dávid Szinger
AU - Katalin Böröcz
AU - Diána Simon
AU - Alain Le Roux
AU - Szabina Erdő-Bonyár
AU - Nancy Zeineddine
AU - Péter Németh
AU - Timea Berki
PY - 2026
DA - 2026/10/30
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1936421
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1936421
AB - ObjectivesHomeostatic natural autoantibodies (nAAbs) are proposed regulators of inflammation and autoimmunity, studied mainly as natural IgM. Whether pathological autoantibody (pAAb) expansion in systemic lupus erythematosus (SLE)-associated serology is mirrored by isotype-divergent nAAb changes has rarely been examined.MethodspAAb positivity and co-positivity ratios (exact 95% confidence intervals) and intersection (UpSet) analyses were derived from a regional diagnostic cohort (Southern Transdanubia, Hungary, 2014–2024; 128,847 enzyme-linked immunosorbent assay (ELISA) results, 73,747 pseudonymised patients). The dominant patterns defined anti-double-stranded DNA (a-dsDNA)/anti-nucleosome-, anti-SSA/Ro- and anti-cardiolipin/β2-glycoprotein I (a-CL/β2GPI)-dominant and co-positive groups, each verified against serological follow-up. In 110 residual sera, IgG and IgM nAAbs against citrate synthase (CS) and heat shock proteins (HSP) 60 and 70 were measured by ELISA and compared by Kruskal–Wallis and Dunn–Holm tests.ResultsOf a-dsDNA IgG-positive patients, 30.36% carried an additional disease-specific pAAb, along two largely separate axes, antiphospholipid (15.90%) and extractable nuclear antigen-associated (16.51%); anti-neutrophil cytoplasmic antibody co-positivity was rare (3.02%), and 42.01% showed a-nucleosome co-reactivity. a-CS IgM was reduced in every pAAb-positive group (all pHolm < 0.001), whereas increased a-CS, a-HSP60 and a-HSP70 IgG levels were confined to a-dsDNA/a-nucleosome-containing (chromatin-reactive) profiles (a-CS IgG, pHolm ≤ 0.012). These shifts were robust to sex-, age- and measurement-year adjustment.ConclusionIsotype-resolved nAAb profiling anchored in diagnostic serology revealed a counter-directional shift (IgM↓ across pAAb-positive groups, IgG↑ in chromatin-reactive profiles). These hypothesis-generating findings are consistent with impaired homeostatic IgM-mediated regulation and with class-switched IgG nAAb reactivity as a marker of B-cell activation, and warrant clinical and functional validation in prospective cohorts.
SN - 1664-3224
ER -