Definition of Naturally Processed Peptides Reveals Convergent Presentation of Autoantigenic Topoisomerase I Epitopes in Scleroderma

Eleni Tiniakou, Andrea Fava, Zsuzsanna H. McMahan, Tara Guhr, Robert N. O'Meally, Ami A. Shah, Fredrick M. Wigley, Robert N. Cole, Francesco Boin, Erika Darrah

Research output: Contribution to journalArticlepeer-review

Abstract

Objective: Autoimmune responses to DNA topoisomerase I (topo I) are found in a subset of scleroderma patients who are at high risk for interstitial lung disease (ILD) and mortality. Anti–topo I antibodies (ATAs) are associated with specific HLA–DRB1 alleles, and the frequency of HLA–DR–restricted topo I–specific CD4+ T cells is associated with the presence, severity, and progression of ILD. Although this strongly implicates the presentation of topo I peptides by HLA–DR in scleroderma pathogenesis, the processing and presentation of topo I has not been studied. Methods: We developed a natural antigen processing assay (NAPA) to identify putative CD4+ T cell epitopes of topo I presented by monocyte-derived dendritic cells (mo-DCs) from 6 ATA-positive patients with scleroderma. Mo-DCs were pulsed with topo I 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 topo I 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 topo I 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% of ATA-positive patients (8 of 11), and the number of epitopes recognized correlated with ILD severity (P = 0.025). Conclusion: These findings mechanistically implicate the presentation of a convergent set of topo I epitopes in the development of scleroderma.

Original languageEnglish (US)
Pages (from-to)1375-1384
Number of pages10
JournalArthritis and Rheumatology
Volume72
Issue number8
DOIs
StatePublished - Aug 1 2020

ASJC Scopus subject areas

  • Immunology and Allergy
  • Rheumatology
  • Immunology

Fingerprint

Dive into the research topics of 'Definition of Naturally Processed Peptides Reveals Convergent Presentation of Autoantigenic Topoisomerase I Epitopes in Scleroderma'. Together they form a unique fingerprint.

Cite this