Isotype-dependent shifts of natural autoantibody profiles in systemic lupus erythematosus-associated serological groups

Objectives Homeostatic 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. Methods pAAb 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. Results Of 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 p Holm < 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, p Holm ≤ 0.012). These shifts were robust to sex-, age- and measurement-year adjustment. Conclusion Isotype-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.