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Definition of naturally processed peptides reveals convergent presentation of autoantigenic topoisomerase-I epitopes in scleroderma.

  • Author(s): Tiniakou, Eleni
  • Fava, Andrea
  • McMahan, Zsuzsanna H
  • Guhr, Tara
  • O'Meally, Robert N
  • Shah, Ami A
  • Wigley, Fredrick M
  • Cole, Robert N
  • Boin, Francesco
  • Darrah, Erika
  • et al.

Published Web Location

https://doi.org/10.1002/art.41248
Abstract

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 presentation of TOP1 has not been studied. METHODS:We developed a natural antigen processing assay (NAPA) to identify putative CD4+ T cell epitopes of TOP1 presented by monocyte-derived dendritic cells (mo-DCs) from six ATA-positive patients with scleroderma. Mo-DCs were pulsed with TOP1 protein, HLA-DR:peptide complexes were isolated, and eluted peptides were analyzed by mass spectrometry. We then examined the ability of these naturally presented peptides to induce CD4+ T cell activation in 11 ATA-positive and 11 ATA-negative scleroderma patients. RESULTS:We found that a common set of 10 TOP1 epitopes was presented by mo-DCs from scleroderma patients with diverse HLA-DR variants. Sequence analysis revealed shared peptide-binding motifs within the HLA-DRβ chains of ATA-positive patients and a subset of TOP1 epitopes with distinct sets of anchor residues capable of binding to multiple different HLA-DR variants. The NAPA-derived epitopes elicited robust CD4+ T cell responses in 73% (8/11) ATA-positive patients, and the number of epitopes recognized correlated with ILD severity (p=0.025). CONCLUSION:These findings mechanistically implicate presentation of a convergent set of TOP1 epitopes in the development of scleroderma.

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