Distinctive Reactivity to the C-terminal Epitope of BP180 Characterizes Immune Checkpoint Inhibitor–associated Bullous Pemphigoid, and an ELISA Based on the BP180 Ectodomain Enables Prompt Diagnosis in a Subset of Patients

Authors

  • Anna Pira Molecular and Cell Biology Laboratory, Istituto Dermopatico dell'Immacolata (IDI)-IRCCS, Rome, Italy https://orcid.org/0000-0001-7172-619X
  • Martina Merli Section of Dermatology, Department of Medical Sciences, University of Turin, Turin, Italy; Dermatology Clinic, Department of Medical Sciences, A.O. Ordine Mauriziano, Turin, Italy https://orcid.org/0000-0002-7224-6507
  • Feliciana Mariotti Molecular and Cell Biology Laboratory, Istituto Dermopatico dell'Immacolata (IDI)-IRCCS, Rome, Italy https://orcid.org/0000-0002-7004-5031
  • Marco Andreani Laboratorio di Immunogenetica dei Trapianti, IRCCS Ospedale Pediatrico Bambino Gesù, Rome, Italy https://orcid.org/0000-0003-3451-3624
  • Angelo Valerio Marzano Dermatology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy; Department of Pathophysiology and Transplantation, Università Degli Studi di Milano, Milan, Italy https://orcid.org/0000-0002-8160-4169
  • Clara De Simone Dermatology, Department of Medical and Surgery Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy; Dermatology, Department of Medicine and Translational Surgery, Università Cattolica del Sacro Cuore, Rome, Italy https://orcid.org/0000-0002-0898-0045
  • Rosa Falcone Department of Oncology and Dermatological Oncology, Istituto Dermopatico dell'Immacolata (IDI)-IRCCS, Rome, Italy https://orcid.org/0000-0001-9679-4711
  • Giuseppe Testa Laboratorio di Immunogenetica dei Trapianti, IRCCS Ospedale Pediatrico Bambino Gesù, Rome, Italy
  • Mariarosa Battarra Laboratorio di Immunogenetica dei Trapianti, IRCCS Ospedale Pediatrico Bambino Gesù, Rome, Italy https://orcid.org/0000-0002-7506-2383
  • Maurizio Romagnuolo Dermatology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy; Department of Medical Biotechnologies, University of Siena, Siena, Italy https://orcid.org/0000-0002-7015-8319
  • Pietro Sollena Dermatology, Department of Medicine and Translational Surgery, Università Cattolica del Sacro Cuore, Rome, Italy; Dermatology, Gemelli Isola - Ospedale Isola Tiberina, Rome, Italy https://orcid.org/0000-0002-1632-7791
  • Federica De Galitiis Department of Oncology and Dermatological Oncology, Istituto Dermopatico dell'Immacolata (IDI)-IRCCS, Rome, Italy https://orcid.org/0000-0001-9041-8141
  • Emiliano Antiga Section of Dermatology, Department of Health Sciences, University of Florence, Florence, Italy https://orcid.org/0000-0001-7787-4433
  • Roberto Maglie Section of Dermatology, Department of Health Sciences, University of Florence, Florence, Italy
  • Dario Didona Rare Diseases Unit, Istituto Dermopatico dell'Immacolata (IDI)-IRCCS, Rome, Italy; Dermatology Clinic, Istituto Dermopatico dell'Immacolata (IDI)-IRCCS, Rome, Italy https://orcid.org/0000-0002-6119-1870
  • Jo Linda Maria Sinagra Rare Diseases Unit, Istituto Dermopatico dell'Immacolata (IDI)-IRCCS, Rome, Italy https://orcid.org/0000-0002-4971-5985
  • Marzia Caproni Immunopathology and Rare Skin Diseases Unit, Section of Dermatology, Department of Health Sciences, Azienda Unità Sanitaria Locale Toscana Centro, University of Florence, Florence, Italy https://orcid.org/0000-0002-7471-3471
  • Michael Hertl Department of Dermatology and Allergology, Philipps-Universität Marburg, Marburg, Germany https://orcid.org/0000-0002-5494-2461
  • Emanuele Cozzani Section of Dermatology, Department of Health Sciences (DISSAL), IRCCS San Martino Polyclinic Hospital, University of Genoa, Genoa, Italy https://orcid.org/0000-0003-3108-4123
  • Pamela Vezzoli Dermatology Unit, ASST Papa Giovanni XXIII Hospital, Bergamo, Italy
  • Laura Calabrese Dermatology, Department of Medicine and Translational Surgery, Università Cattolica del Sacro Cuore, Rome, Italy; Department of Medical, Surgical and Neurological Sciences, Dermatology Section, University of Siena, Siena, Italy https://orcid.org/0000-0001-5238-2336
  • Giovanni Paolino Unit of Dermatology, IRCCS Ospedale San Raffaele, Milan, Italy https://orcid.org/0000-0002-3032-2217
  • Sofia Verkhovskaia Department of Oncology and Dermatological Oncology, Istituto Dermopatico dell'Immacolata (IDI)-IRCCS, Rome, Italy https://orcid.org/0009-0008-2599-807X
  • Luca Fania Dermatology Clinic, Istituto Dermopatico dell'Immacolata (IDI)-IRCCS, Rome, Italy; Department of Life Science, Health, and Health Professions, Link University of Rome, Rome, Italy https://orcid.org/0000-0003-4194-932X
  • Giulia Gasparini Section of Dermatology, Department of Health Sciences (DISSAL), IRCCS San Martino Polyclinic Hospital, University of Genoa, Genoa, Italy https://orcid.org/0000-0003-1049-4676
  • Anna Rita Giampetruzzi Dermatology Clinic, Istituto Dermopatico dell'Immacolata (IDI)-IRCCS, Rome, Italy https://orcid.org/0000-0002-9147-4249
  • Biagio Didona Rare Diseases Unit, Istituto Dermopatico dell'Immacolata (IDI)-IRCCS, Rome, Italy https://orcid.org/0000-0001-6635-0490
  • Pietro Quaglino Section of Dermatology, Department of Medical Sciences, University of Turin, Turin, Italy https://orcid.org/0000-0003-4185-9586
  • Giovanni Di Zenzo Molecular and Cell Biology Laboratory, Istituto Dermopatico dell'Immacolata (IDI)-IRCCS, Rome, Italy https://orcid.org/0000-0001-6106-599X

DOI:

https://doi.org/10.2340/actadv.v106.adv-2026-0336

Keywords:

autoantibodies, BP180, bullous pemphigoid, epitope profile, humoral response, immune checkpoint inhibitors

Abstract

Growing evidence has linked bullous pemphigoid (BP) to immune checkpoint inhibitor (ICI) therapy in cancer treatment. However, the immunological features of ICI-associated BP (ICI-BP) are not yet fully elucidated. In order to characterize the humoral response in ICI BP patients and investigate whether their epitope profile differs from idiopathic BP (IBP), 53 ICI-BP patients were enrolled, immunologically characterized and compared with 59 IBP patients. ICI-BP had a distinctive IgG humoral profile, with reduced reactivity toward BP230 and recognition of multiple BP180 epitopes beyond the immunodominant extracellular noncollagenous 16A domain (NC16A). Specifically, reactivity to BP180 ectodomain was present in 94% of ICI-BP and 78% of IBP (p=0.044). Moreover, BP180 C-terminal epitope was more frequently targeted in ICI-BP than IBP (72% vs 41%, p=0.002). Notably, the combined use of an in-house BP180 ectodomain ELISA and the commercial BP180 test increased diagnostic sensitivity from 83% to 100%. Enhanced IgG reactivity toward nonimmunodominant epitopes, and especially C-terminal epitope recognition, characterize the humoral immune response in ICI-BP. Our data suggest that combining NC16A and fulllength BP180 ectodomain ELISAs may help reduce diagnostic delay in ICI-BP patients, in whom a timely diagnosis is crucial to appropriately manage the disease and ultimately avoid discontinuation of
cancer therapy.

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2026-06-29

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Pira, A., Merli, M., Mariotti, F., Andreani, M., Marzano, A. V., De Simone, C., … Di Zenzo, G. (2026). Distinctive Reactivity to the C-terminal Epitope of BP180 Characterizes Immune Checkpoint Inhibitor–associated Bullous Pemphigoid, and an ELISA Based on the BP180 Ectodomain Enables Prompt Diagnosis in a Subset of Patients. Acta Dermato-Venereologica, 106, adv–2026. https://doi.org/10.2340/actadv.v106.adv-2026-0336

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Vol. 106 (2026)

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