| Autor: |
Gomez-Bañuelos E; Division of Rheumatology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Wahadat MJ; Department of Immunology and.; Department of Paediatric Rheumatology, Sophia Children's Hospital, Erasmus University Medical Center, Rotterdam, Netherlands., Li J; Division of Rheumatology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Paz M; Division of Rheumatology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Antiochos B; Division of Rheumatology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Celia AI; Division of Rheumatology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.; Rheumatology Unit, Department of Clinical Internal, Anaesthesiolagical and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy., Andrade V; Division of Rheumatology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Ferris DP; Division of Rheumatology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Goldman DW; Division of Rheumatology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Darrah E; Division of Rheumatology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Petri M; Division of Rheumatology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Andrade F; Division of Rheumatology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. |
| Abstrakt: |
The origin and mechanisms of autoantigen generation in systemic lupus erythematosus (SLE) are poorly understood. Here, we identified SLE neutrophils activated in vivo by IFN as a prominent source of Ro52, also known as tripartite motif-containing protein 21 (TRIM21), a critical autoantigen historically thought to be primarily generated by keratinocytes in SLE. Different from mononuclear cells and keratinocytes, SLE neutrophils are enriched in several unique Ro52 species containing a core sequence encoded by exon 4 (Ro52Ex4) in TRIM21. Ro52Ex4 is the main target of anti-Ro52 antibodies and is found in 2 Ro52 variants (Ro52α and a potentially novel isoform termed Ro52γ) upregulated in SLE neutrophils. Further analysis of Ro52γ revealed a subset of autoantibodies against a unique C-terminal domain (Ro52γCT) generated from a frameshift due to the lack of exon 6 in Ro52γ. Antibodies to Ro52Ex4 and Ro52γCT distinguish SLE patient subsets characterized by distinct clinical, laboratory, treatment, and transcriptional profiles that are not discerned by the "classical" anti-Ro52 antibodies. These studies uncover IFN-activated neutrophils as a key source of unique immunogenic forms of Ro52 in SLE. Moreover, the finding of Ro52Ex4 and Ro52γCT as core targets of anti-Ro52 antibodies focus interest on Ro52γ as the potential isoform toward which immunological tolerance is initially lost in SLE. |
