Authors: Nicky de Vrij, Elise Pepermans, Louise Laurijssen, Thao-Thy Pham, Lauren Thijs, Kurt Boonen, Kadrie Ramadan, Ilse Maes, Yetemwork Aleka, Mekibib Kassa, Tigist Mekonnen, Mezgebu Silamsaw Asres, Mikias Woldetensay, Seid Hassen, Fentaw Bialfew, Feleke Tilahun Zewdu, Seid Getahun Abdela, Malgorzata Anna Domagalska, Bart Cuypers, Saskia van Henten, Johan van Griensven, Pieter Meysman, Geert Baggerman, Kris Laukens and Wim Adriaensen (Unit of Neglected Tropical Diseases, Department of Clinical Sciences, Institute of Tropical Medicine, Antwerp, Belgium)
Journal: Frontiers in Immunology
Published: 20 February 2026
DOI: doi.org/10.3389/fimmu.2026.1765843
Abstract
Introduction:
Cutaneous leishmaniasis (CL) is a skin disease caused by Leishmania infection, for which no licensed human vaccine exists. Protective immunity is largely T cell–mediated and depends on antigen presentation by MHC molecules, yet the naturally presented epitopes during human disease remain poorly defined.
Methods:
To address this gap, we performed mass spectrometry–based immunopeptidomics on lesional biopsies from 27 Ethiopian CL patients spanning the full clinical spectrum.
Results:
We newly identified 333 MHC-I and 247 MHC-II epitopes from 398 L. aethiopica proteins, including 19 peptides and 51 antigens recurrently presented across patients of which several were also epitope-rich. Some peptides were also detected during early infection in a L. aethiopica–infected THP-1 monocyte model, highlighting their relevance from disease onset. Notably, despite the broad predictive coverage of NetMHCpan and NetMHCIIpan, these tools missed 20–70% of the naturally presented epitopes while predicting millions of candidates, underscoring the limitations of prediction-only vaccine pipelines.
Discussion:
This first comprehensive map of the Leishmania immunopeptidome in human disease reveals conserved and prevalent antigens that can inform rational vaccine design and deepen our understanding of protective T cell responses in leishmaniasis.
