Symmetrical dimethylarginine as the central antigenic determinant of anti-Smith autoantibodies in systemic lupus erythematosus.
basic_science · Level V
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- Record sourced from PubMed, PMID 42431785.
- Also identified by DOI 10.1016/j.ard.2026.06.012.
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Abstract
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease causing multiorgan damage. The most specific autoantibody response in SLE, present in 20% to 30% of patients, targets the Smith (Sm)-protein complex and has been shown to recognise a linear Sm-derived B cell epitope containing a posttranslational modification (PTM) of arginine termed symmetrical dimethyl arginine (sDMA). As autoantibodies to other PTM-modified proteins are often promiscuous, we aimed to determine the specificity and cross-reactivity of anti-Sm antibodies. Specificity and promiscuity/cross-reactivity of anti-Sm immunoglobulin G (IgG) were measured using enzyme-linked immunosorbent assay in patients with SLE and healthy donors using peptides containing either sDMA or unmodified arginine. Inhibition and cross-reactivity were determined using competitive enzyme-linked immunosorbent assay and affinity purification. Recognition of endogenous Epstein-Barr nuclear antigen 1 (EBNA1) by anti-Sm IgG was performed using a Western blot of lysates of Epstein-Barr virus-bearing lymphoblastoid cell lines. The sDMA residue is recognised by patients with anti-Sm+ SLE regardless of the peptide amino acid sequence, with a modest impact of amino acids flanking sDMA on recognition. Most notably, IgGs targeting sDMA comprise the overall majority (∼90%) of the anti-Sm antibody repertoire and are highly cross-reactive between SmD3<sub>108-122</sub> and several sDMA-containing viral-derived epitopes, including full-length (EBNA1). Our data implicate that the majority of anti-Sm IgGs target the sDMA residue irrespective of its Sm-context, thus representing a prototypic anti-PTM response. These antibodies are highly promiscuous, recognising several sDMA-modified targets, including naturally occurring viral sDMA-expressing epitopes. These findings suggest a new mechanism by which molecular mimicry of sDMA-modified viral proteins could contribute to a breach of tolerance in patients with anti-Sm+ SLE.