Symmetric Dimethylarginine Modification Drives Shared and Divergent Antigen Reactivity in Lupus

Systemic lupus erythematosus (SLE) features a broad array of autoantibodies against nuclear components, but the mechanisms driving this diversity are poorly understood. We investigated whether posttranslational arginine methylation creates common neo-epitopes that could unify this response. Using methylome-wide peptide arrays, we identified anti-symmetric dimethylarginine (SDMA) autoantibodies in 30-40% of SLE patients, with individualized reactivity fingerprints. A single anti-SDMA monoclonal antibody from MRL-lpr mice recognized multiple SDMA-modified antigens, and EBNA-1, an Epstein-Barr virus protein, bound SLE plasma in an SDMA-dependent manner, pointing to potential molecular mimicry. In a validation cohort of 201 patients, anti-SDMA titers correlated with SLEDAI-2K scores and inversely with C3/C4; seropositivity was overrepresented in younger patients, those with renal involvement, and anti-Sm-positive individuals. These results establish that anti-SDMA responses are common in SLE, target methylated arginine motifs across self and viral proteins, and serve as markers of active, complement-consuming disease. The patient-specific recognition of SDMA epitopes may underlie the serological heterogeneity that defines SLE.