Symmetrical Dimethylarginine as the Central Antigenic Determinant of Anti-Smith Autoantibodies in Systemic Lupus Erythematosus
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Objective
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease causing multi-organ damage. The most specific autoantibody response in SLE, present in 20-30% of patients, targets the Sm-protein and has been shown to recognize a linear Sm-derived B cell epitope containing a post-translational 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.
Methods
Specificity and promiscuity/cross-reactivity of anti-Sm IgG were measured by ELISA in anti-Sm+ SLE patients (n=12), anti-Sm-SLE patients (n=12) and healthy donors (HD) (n=12) using peptides containing either sDMA or unmodified arginine. Inhibition and cross-reactivity were determined using competitive ELISA and affinity purification. Recognition of endogenous EBNA1 by anti-Sm IgG was performed by Western blot using lysates of EBV-bearing lymphoblastoid cell lines.
Results
The sDMA residue is recognized by anti-Sm+ SLE patients 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 108-122 and several sDMA-containing viral-derived epitopes, including full-length EBNA1.
Conclusion
Our data implicate that the majority of anti-Sm IgGs target the sDMA residue irrespective of its Sm-context, thus representing a prototypic anti-modified protein antibody (AMPA) response. These antibodies are highly promiscuous, recognizing several sDMA-modified proteins, including naturally occurring viral sDMA-expressing proteins. These data indicate a potential link between viral infection and tolerance breach in anti-Sm+ SLE patients.
