title: Dysregulated Responsiveness of Circulating Dendritic Cells to Toll-Like Receptors in ANCA-Associated Vasculitis.
abstract: OBJECTIVE
  Dendritic cells (DCs) are critical effectors of innate and adaptive immunity playing crucial roles in autoimmune responses. We previously showed that blood DC numbers were reduced in autoimmune antineutrophil cytoplasmic autoantibody-associated vasculitis (AAV). Here, we assessed toll-like receptor (TLR) responsiveness of blood DCs from patients with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA).
  
  
  METHODS
  Blood samples from healthy controls (HCs), GPA, or MPA patients, without treatment, during acute phase (AP) or remission phase (RP) were analyzed. Cytokine production by DCs and T cells was assessed on whole blood by flow cytometry after TLRs or polyclonal stimulation, respectively.
  
  
  RESULTS
  We first showed that GPA and MPA are associated with a decreased blood DC number during AP. Conventional DCs (cDCs) from patients with GPA and MPA in AP exhibited a profound decrease of IL-12/IL-23p40 production after TLR3, 4, or 7/8 stimulation compared to patients in remission and HC, with a return to normal values in RP. TNFα secretion was also affected, with a decrease in cDCs from GPA patients in AP after TLR3 stimulation but an increase after TLR7/8 stimulation. By contrast, the responsiveness of plasmacytoid DCs to TLR7 and 9 was only marginally affected. Finally, we observed that IFNγ-producing CD4+T cell frequency was significantly lower in AP-GPA patients than in HC.
  
  
  CONCLUSIONS
  We describe, for the first time, a dysregulated response to TLRs of circulating DCs in AAV patients mostly affecting cDCs that exhibit an unexpected reduced inflammatory cytokine secretion possibly contributing to an altered Th cell response.
authors.affiliation: CIMNA, Laboratoire d'Immunologie, CHU Nantes, Nantes, France; Institut de Transplantation-Urologie-Néphrologie (ITUN), CHU Nantes, Nantes, France; Centre de Recherche en Transplantation et Immunologie (UMR1064), INSERM, Université de Nantes, Nantes, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Braudeau
authors.affiliation: Centre de Recherche en Transplantation et Immunologie (UMR1064), INSERM, Université de Nantes, Nantes, France; Faculté de Médecine, Université de Nantes, Nantes, France; Service de Médecine Interne, CHU Nantes, Nantes, France.
authors.forename: Antoine
authors.initials: A
authors.lastname: Néel
authors.affiliation: CIMNA, Laboratoire d'Immunologie, CHU Nantes, Nantes, France; LabEx Immunotherapy Graft Oncology (IGO), Nantes, France.
authors.forename: Karine
authors.initials: K
authors.lastname: Amouriaux
authors.affiliation: CIMNA, Laboratoire d'Immunologie, CHU Nantes, Nantes, France; Institut de Transplantation-Urologie-Néphrologie (ITUN), CHU Nantes, Nantes, France; Centre de Recherche en Transplantation et Immunologie (UMR1064), INSERM, Université de Nantes, Nantes, France; Faculté de Médecine, Université de Nantes, Nantes, France.
authors.forename: Jérôme C
authors.initials: JC
authors.lastname: Martin
authors.affiliation: CIMNA, Laboratoire d'Immunologie, CHU Nantes, Nantes, France; Institut de Transplantation-Urologie-Néphrologie (ITUN), CHU Nantes, Nantes, France; Centre de Recherche en Transplantation et Immunologie (UMR1064), INSERM, Université de Nantes, Nantes, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Rimbert
authors.affiliation: CIMNA, Laboratoire d'Immunologie, CHU Nantes , Nantes , France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Besançon
authors.affiliation: CIMNA, Laboratoire d'Immunologie, CHU Nantes , Nantes , France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Giraudet
authors.affiliation: CIMNA, Laboratoire d'Immunologie, CHU Nantes , Nantes , France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Terrien
authors.affiliation: CIMNA, Laboratoire d'Immunologie, CHU Nantes , Nantes , France.
authors.forename: Marine
authors.initials: M
authors.lastname: Aliaga
authors.affiliation: CIMNA, Laboratoire d'Immunologie, CHU Nantes, Nantes, France; Centre de Recherche en Transplantation et Immunologie (UMR1064), INSERM, Université de Nantes, Nantes, France; LabEx Immunotherapy Graft Oncology (IGO), Nantes, France.
authors.forename: Nina
authors.initials: N
authors.lastname: Salabert-Le Guen
authors.affiliation: CIMNA, Laboratoire d'Immunologie, CHU Nantes, Nantes, France; Institut de Transplantation-Urologie-Néphrologie (ITUN), CHU Nantes, Nantes, France; Centre de Recherche en Transplantation et Immunologie (UMR1064), INSERM, Université de Nantes, Nantes, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Hémont
authors.affiliation: Centre de Recherche en Transplantation et Immunologie (UMR1064), INSERM, Université de Nantes, Nantes, France; Faculté de Médecine, Université de Nantes, Nantes, France; Service de Médecine Interne, CHU Nantes, Nantes, France.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Hamidou
authors.affiliation: CIMNA, Laboratoire d'Immunologie, CHU Nantes, Nantes, France; Institut de Transplantation-Urologie-Néphrologie (ITUN), CHU Nantes, Nantes, France; Centre de Recherche en Transplantation et Immunologie (UMR1064), INSERM, Université de Nantes, Nantes, France; Faculté de Médecine, Université de Nantes, Nantes, France; LabEx Immunotherapy Graft Oncology (IGO), Nantes, France.
authors.forename: Régis
authors.initials: R
authors.lastname: Josien
keywords: ANCA-associated vasculitis; IL-12/IL-23p40; dendritic cells; dysregulation; toll-like receptor