Symmetrical Dimethylarginine as the Central Antigenic Determinant of Anti-Smith Autoantibodies in Systemic Lupus Erythematosus
Notice bibliographique
Résumé
ABSTRACT 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 SLE patients and healthy donors 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-PTM response. These antibodies are highly promiscuous, recognizing 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 anti-Sm+ SLE patients. KEY MESSAGES What is already known on this topic Symmetrical dimethylarginine (sDMA) residues are present on RGG/RG repeat regions within the SmD1, SmD3, and SmB/B⍰ subunits of the Sm protein complex in vivo . The introduction of sDMA is essential for recognition of minimal antigenic epitopes spanning amino acids #95–119 on the SmD1 and #108–122 on the SmD3 subunits by a specific subset of anti-Sm autoantibodies. What this study adds We show that autoantibodies targeting sDMA residues are common in anti-Sm+ SLE patients and represent the majority of the anti-Sm autoantibody repertoire. We demonstrate that anti-sDMA autoantibodies are highly cross-reactive and can also bind to sDMA residues on other targets, including several virus-derived epitopes, thus representing a prototypic anti-modified protein antibody (AMPA) response directed against post-translationally modified proteins through symmetrical dimethylation of arginine. How this study might affect research, practice, or policy The high cross-reactivity of Sm antibodies to various sDMA-containing epitopes, combined with a dominant antigenic specificity, provides mechanistic insight in the potential link between viral infection and tolerance breach in anti-Sm+ SLE patients.
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Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,001 | 0,001 |
| Méta-épidémiologie (sens strict) | 0,001 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,000 |
| Bibliométrie | 0,001 | 0,002 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,001 | 0,000 |
| Intégrité de la recherche | 0,001 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».