Type 2 T-Cell Responses against Distinct Epitopes of the Desmoglein 3 Ectodomain in Pemphigus Vulgaris

Dario Didona, Luca Scarsella,Christoph Hudemann, Karolin Volkmann, Christine L. Zimmer,Benedikt Beckert, Ritva Tikkanen,Vera Korff, Katja Kuehn,Sandra Wienzek-Lischka, Gregor Bein,Giovanni Di Zenzo, Jaqueline Boehme,Tomas Cunha, Farzan Solimani,Josquin Pieper, Hazem A. Juratli,Manuel Goebel, Thomas Schmidt,Luca Borradori, Amir S. Yazdi,Cassian Sitaru,Holger Garn, Rudiger Eming, Sabine Fleischer,Michael Hertl


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Pemphigus vulgaris (PV) is an autoimmune blistering disorder of the skin and/or mucous membranes caused by IgG autoantibodies that predominantly target two transmembrane desmosomal cadherins: desmoglein (DSG)1 and DSG3. DSG-specific T cells play a central role in PV pathogenesis because they provide help to autoreactive B cells for autoantibody production. In this study, we characterized DSG3-specific peripheral T cells in a cohort of 52 patients with PV and 41 healthy controls with regard to cytokine profile and epitope specificity. By ELISpot analysis, type 2 T cells reactive with the DSG3 ectodomain were significantly increased in patients with PV compared with those in healthy controls. By dextramer analysis, CD4 thorn T cells specific for an epitope within the extracellular domain of DSG3, DSG3(206-220), were found at significantly higher frequencies in patients with PV than in HLA-matched healthy controls. T-cell recognition of two distinct DSG3 epitopes, that is, DSG3(206-220) and DSG3(378-392), correlated significantly, suggesting a synergistic effect in B-cell help. Immunization of HLADRB1*04:02-transgenic mice with PV with the same set of DSG3 peptides induced pathogenic DSG3-specific IgG antibodies, which induced loss of keratinocyte adhesion in vitro. Thus, DSG3 peptide-specific T cells are of particular interest as surrogate markers of disease activity and potential therapeutic targets in PV.
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