2020
DOI: 10.1002/art.41248
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Definition of Naturally Processed Peptides Reveals Convergent Presentation of Autoantigenic Topoisomerase I Epitopes in Scleroderma

Abstract: words):Objective: Autoimmune responses to DNA topoisomerase-I (TOP1) are found in a subset of patients with scleroderma at high risk for interstitial lung disease (ILD) and mortality. Anti-TOP1 antibodies (ATA) are associated with specific HLA-DRB1 alleles, and the frequency of HLA-DR-restricted TOP1-specific CD4+ T cells is associated with the presence, severity, and progression of ILD.Although this strongly implicates the presentation of TOP1 peptides by HLA-DR in scleroderma pathogenesis, the processing and… Show more

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Cited by 13 publications
(16 citation statements)
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“…The observation that B. burgdorferi -induced changes led to robust expression of HLA-DR on the surface of monocyte-derived dendritic cells in a time- and dose-dependent manner led us to reason that the HLA-DR associated self-immunopeptidome was altered, and formed the premise for this study. Using the natural processing and presentation capabilities of mo-DCs, we isolated sufficient peptide-HLA-DR complexes ( 13 ) to define the self-immunopeptidome at steady state, and its variation during stimulation with the TLR-2 ligand lipoteichoic acid or with live B. burgdorferi . In all conditions, we isolated peptides that varied in length (seven to 65 amino acids long) ( 25 ) averaging 15 residues, the optimal length of MHC class II presented antigens.…”
Section: Discussionmentioning
confidence: 99%
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“…The observation that B. burgdorferi -induced changes led to robust expression of HLA-DR on the surface of monocyte-derived dendritic cells in a time- and dose-dependent manner led us to reason that the HLA-DR associated self-immunopeptidome was altered, and formed the premise for this study. Using the natural processing and presentation capabilities of mo-DCs, we isolated sufficient peptide-HLA-DR complexes ( 13 ) to define the self-immunopeptidome at steady state, and its variation during stimulation with the TLR-2 ligand lipoteichoic acid or with live B. burgdorferi . In all conditions, we isolated peptides that varied in length (seven to 65 amino acids long) ( 25 ) averaging 15 residues, the optimal length of MHC class II presented antigens.…”
Section: Discussionmentioning
confidence: 99%
“…We performed a natural antigen processing assay (NAPA) as described previously ( 13 ). Briefly, immature mo-DCs were seeded in 6-well plates at a density of 1 × 10 6 cells in 1 mL of RPMI 1640 and 10% fetal bovine serum, supplemented with 2 mM L-glutamine and 20 μM ß-mercaptoethanol in duplicate.…”
Section: Methodsmentioning
confidence: 99%
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“…Nevertheless, those approaches have mainly focused on proteins previously described as autoantibody targets and have not taken into consideration the restrictions imposed by antigen-processing and peptide-loading onto HLA molecules. These limitations can be circumvented by the isolation of peptide/HLA complexes (pHLA) and further sequencing of naturally presented peptides (NPPs) by liquid chromatography coupled to mass spectrometry (LC-MS/MS), a technology that has already identified several autoimmunity-associated T-cell epitopes,17–19 as well as post-translationally modified NPPs 20 21…”
Section: Introductionmentioning
confidence: 99%