Braudeau Cécile, Néel Antoine, Amouriaux Karine, Martin Jérôme C, Rimbert Marie, Besançon Audrey, Giraudet Stéphanie, Terrien Caroline, Aliaga Marine, Salabert-Le Guen Nina, Hémont Caroline, Hamidou Mohamed, Josien Régis
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.
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.
Front Immunol. 2017 Feb 9;8:102. doi: 10.3389/fimmu.2017.00102. eCollection 2017.
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).
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.
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.
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.
树突状细胞（DCs）是先天性和适应性免疫的关键效应细胞，在自身免疫反应中起关键作用。我们之前表明，在自身免疫性抗中性粒细胞胞浆自身抗体相关血管炎（AAV）中血液DC数量减少。在此，我们评估了肉芽肿性多血管炎（GPA）或显微镜下多血管炎（MPA）患者血液DC的Toll样受体（TLR）反应性。
分析了来自健康对照（HCs）、未经治疗的GPA或MPA患者在急性期（AP）或缓解期（RP）的血样。分别在TLR或多克隆刺激后，通过流式细胞术在全血上评估DC和T细胞产生的细胞因子。
我们首先表明，GPA和MPA与AP期间血液DC数量减少有关。与缓解期患者和HC相比，AP期GPA和MPA患者的常规DC（cDCs）在TLR3、4或7/8刺激后IL-12/IL-23p40产生显著减少，在RP期恢复到正常值。TNFα分泌也受到影响，TLR3刺激后AP期GPA患者的cDCs分泌减少，但TLR7/8刺激后增加。相比之下，浆细胞样DC对TLR7和9的反应性仅受到轻微影响。最后，我们观察到AP-GPA患者中产生IFNγ的CD4 T细胞频率显著低于HC。
我们首次描述了AAV患者循环DC对TLR的反应失调，主要影响cDCs，其表现出意外减少的炎性细胞因子分泌，可能导致Th细胞反应改变。
