{
  "abstract": "Objectives Systemic lupus erythematosus (SLE) is a chronic autoimmune disease causing multi-organ damage. Approximately 20-30% of patients are characterized by autoantibodies to the Sm protein. Although this is the most SLE-specific autoantibody response, the molecular nature of the antigenic target recognized by anti-Sm antibodies remains unknown. Previously, multiple antigenic Sm-derived B cell epitopes have been characterized, some of which are within RGG/RG-rich regions containing arginines that may undergo post-translational conversion into symmetrical dimethylarginine (sDMA). Here, we aimed to determine the specificity and cross-reactivity of anti-Sm antibodies in SLE.Methods IgG reactivity to peptides containing either sDMA or unmodified arginines were measured by ELISA using serum from anti-Sm+ SLE patients, anti-Sm- SLE patients and healthy donors. Cross-reactivity was determined using competitive inhibition ELISA and affinity purification of patient-derived sDMA targeting antibodies followed by sDMA-peptide or Sm protein ELISA. Recognition of Epstein–Barr virus (EBV) nuclear antigen 1 (EBNA1) by purified anti-Sm IgG was performed by Western blot using lysates of EBV-bearing lymphoblastoid cell lines.Results Our data indicate that the sDMA modified amino acid is crucial to recognition by IgG from anti-Sm+ SLE patients independent of protein context. Most strikingly, anti-sDMA antibodies cross-react between endogenous SmD3 and multiple viral sDMA-containing epitopes (e.g. Epstein Barr virus, influenza, hepatitis C). Remarkably, IgGs against these sDMA residues account for ~90% of the anti-Sm repertoire in SLE and the anti-Sm serum reactivity can be almost completely inhibited by incubation with sDMA-containing viral peptides.Conclusions Our findings show (1) that sDMA residues are central for recognition of antigens by the SLE-specific anti-Sm autoantibody response; and (2) that anti-sDMA antibodies are highly promiscuous, recognizing a diverse array of sDMA-modified proteins, including those from commonly acquired viruses. These data provide insight into the molecular basis underlying tolerance breach to cross-reactive epitopes present in viral antigens and Sm.",
  "authors": [
    {
      "affiliations": [
        "Leiden University Medical Center, Leiden, The Netherlands"
      ],
      "name": "Lars Van Vliet"
    },
    {
      "affiliations": [
        "Leiden University Medical Center, Leiden, The Netherlands"
      ],
      "name": "Annemarie Dorjée"
    },
    {
      "affiliations": [
        "Leiden University Medical Center, Leiden, The Netherlands"
      ],
      "name": "René Toes"
    },
    {
      "affiliations": [
        "Leiden University Medical Center, Leiden, The Netherlands"
      ],
      "name": "Jolien Suurmond"
    },
    {
      "affiliations": [
        "Leiden University Medical Center, Leiden, The Netherlands"
      ],
      "name": "Jacqueline S Dekkers"
    }
  ],
  "title": "PT1:08 A cross-reactive response to symmetrical dimethylarginine defines anti-Sm autoantibodies in systemic lupus erythematosus",
  "uid": "886361ee-ac5b-54bc-bcc4-eac86168b42c"
}