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Rituximab tunes desmoglein-3-specific follicular T cells in patients with pemphigus vulgaris
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  • Vivien Hébert,
  • Julien Novarino,
  • Maud Maho-Vaillant,
  • Corine Perals,
  • Cyrielle Bories,
  • Fanny Martinez,
  • Sébastien Calbo,
  • Marie-Laure Golinski,
  • Manuelle Viguier,
  • Pascal Joly,
  • Nicolas Fazilleau
Vivien Hébert
Centre Hospitalier Universitaire de Rouen
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Julien Novarino
Universite Toulouse III Paul Sabatier Bibliotheque Universitaire Sante Rangueil
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Maud Maho-Vaillant
Centre Hospitalier Universitaire de Rouen Laboratoire d'immunologie et biotherapies
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Corine Perals
Universite Toulouse III Paul Sabatier Bibliotheque Universitaire Sante Rangueil
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Cyrielle Bories
Universite Toulouse III Paul Sabatier Bibliotheque Universitaire Sante Rangueil
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Fanny Martinez
Universite Toulouse III Paul Sabatier Bibliotheque Universitaire Sante Rangueil
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Sébastien Calbo
Centre Hospitalier Universitaire de Rouen Laboratoire d'immunologie et biotherapies
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Marie-Laure Golinski
Centre Hospitalier Universitaire de Rouen Laboratoire d'immunologie et biotherapies
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Manuelle Viguier
Universite de Reims Champagne-Ardenne
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Pascal Joly
Centre Hospitalier Universitaire de Rouen
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Nicolas Fazilleau
Universite Toulouse III Paul Sabatier Bibliotheque Universitaire Sante Rangueil

Corresponding Author:[email protected]

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Abstract

Background: Pemphigus vulgaris (PV) is characterized by pathogenic auto-antibodies targeting interkeratinocytes desmoglein (Dsg) 1 and 3, and by the HLA-DRB1-0402 predisposition allele. Treatment using rituximab (RTX) combined with short-term corticosteroids (CS) allows disease control and long-lasting remission. The aim of this study is to evaluate the impact of RTX on the circulating subpopulations of Dsg-3-specific T lymphocytes that specifically regulate B cell responses: follicular helper (Tfh) and follicular regulatory T (Tfr) lymphocytes. Methods: Using the HLA-DRB1-0402 tetramer loaded with the Dsg-3 immunodominant peptide, we analysed by flow cytometry the frequency, the polarisation and the activation status of blood Dsg-3-specific follicular T cell populations at baseline, Month 6 and long-term follow-up (Month 60-90) from PV patients. Results: At baseline, we observed a predominance of Tfh1* and Tfh17 subsets and an underrepresentation of the Tfh2 subset among autoreactive Dsg-3-specific Tfh cells as compared with non-autoreactive Tfh cells. RTX treatment induced a decrease of autoreactive Tfh cells with no effect on their polarisation during patients’ follow-up. In parallel, we observed the emergence of a Dsg-3-specific Tfr subpopulation with a significant overexpression of the surface activation markers PD1, ICOS, and CD25 that was not observed at the surface of autoreactive Tfh and non-autoreactive Tfr cells of the same PV patients. In contrast, a very few Dsg-3 specific Tfr cells were observed in PV patients treated with CS alone. Conclusion: Here we show that the emergence of activated autoreactive Dsg-3-specific Tfr cells is associated with the long-term efficacy of RTX in PV patients.