Decreased Numbers of Blood Dendritic Cells and Defective Function of Regulatory T Cells in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis

Rimbert, Marie; Hamidou, M.; Braudeau, Cécile; Puéchal, Xavier; Teixeira, Luis; Caillon, Hélène; Néel, A.; Audrain, Marie; Guillevin, Loı̈c; Josien, Régis

doi:10.1371/journal.pone.0018734

Cited by 67 publications

(60 citation statements)

References 62 publications

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“…DCs were identified using 6-color flow cytometry assay as described previously [22], [23]. Briefly, whole blood samples were stained with the following antibodies: CD45-Amcyan, Lineage cocktail1-FITC, HLA-DR-APC-Cy7, CD11c-PECy7 and CD123-PECy5, all from BD Biosciences.…”

Section: Methodsmentioning

confidence: 99%

Impaired Blood Dendritic Cell Numbers and Functions after Aneurysmal Subarachnoid Hemorrhage

et al. 2013

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Previous PresentationPortions of this study were presented at the Annual Congress of Société Française d’Anesthésie et de Réanimation in Paris, September 2012.BackgroundToll-like receptor (TLR) agonists are promising therapy for the prevention of nosocomial infections in critical ill patients. We aimed to analyze the TLR-reactivity of circulating dendritic cells (DC) as assessed by cytokine production after an ex vivo challenge with TLR agonists in aneurysmal subarachnoid hemorrhage (SAH) patients.Methods and FindingsA single-center prospective observational study took place in one intensive care unit of a teaching hospital. Blood samples were harvested on days 2, 5 and 10 in 21 severe SAH patients requiring mechanical ventilation and 17 healthy controls. DC production of cytokines (Tumour Necrosis Factor, TNF-α; Interleukin, IL-12; and Interferon, IFN-α) was assessed by intracellular immunostaining on TLR-3, 4, 7/8 and 9 stimulations. SAH patients had decreased numbers of blood myeloid (mDCs) and plasmacytoid DCs (pDCs) on days 2, 5 and 10. Compared with the healthy controls, the frequency of mDCs producing TNF-α after TLR-3 stimulation was decreased in the SAH patients. The frequency of myeloid DCs producing IL-12 after TLR-3 and 4 stimulations was also decreased in the SAH patients. In contrast, the mDCs response to TLR-7/8 was not impaired in the SAH patients. The frequency of pDCs producing TNF-α+ and IFN-α+ on TLR-7/8 stimulation were reduced at all of the tested times in the SAH patients, whereas reactivity to TLR-9 was preserved. On day 2, the pDCs from non-survivor patients (n = 8) had a decreased ability to produce IFN-α on TLR-9 stimulation compared with the survivors.ConclusionsThese data suggest functional abnormalities of circulating pDCs and mDCs that could be important for immunomodulation after SAH.

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Section: Methodsmentioning

confidence: 99%

Impaired Blood Dendritic Cell Numbers and Functions after Aneurysmal Subarachnoid Hemorrhage

et al. 2013

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“…They also noted that that increased circulating CD4+ Foxp3+ cells was associated with more rapid disease remission [64]. The suppressive function of Tregs from ANCA disease patients was markedly decreased in ANCA disease patients with active disease but more normal during remission [65]. Free et al reported abnormalities in the suppressive Treg network as well as increased frequency of a distinct proinflammatory suppression-resistant effector CD4+ T cell population in patients with active ANCA disease [66].…”

Section: B Cell Regulation In Anca Diseasementioning

confidence: 99%

B cell-mediated pathogenesis of ANCA-mediated vasculitis

Jennette

Falk

2014

Semin Immunopathol

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B cells and their progeny that produce and release anti-neutrophil cytoplasmic autoantibodies (ANCA) are the primary cause for an aggressive form of necrotizing small vessel vasculitis. Cytoplasmic ANCA antigens are released at the surface and in the microenvironment of cytokine-primed neutrophils. Binding of ANCA to ANCA antigens activates neutrophils by both Fc receptor engagement and direct Fab’2 binding to antigen on the cell surface. ANCA-activated neutrophils release factors that induce alternative complement pathway activation, which establishes a potent inflammatory amplification loop that causes severe necrotizing vascular inflammation. The origin of the ANCA autoimmune response is unknown but appears to involve genetically determined HLA specificities that allow the autoimmune response to develop. One putative immunogenic mechanisms begins with an immune response to a peptide that is complementary to the autoantigen and evolves through an anti-idiotypic network to produce autoantibodies to the autoantigen. Another putative immunogenic mechanism begins with an immune response to a microbe-derived molecular mimic of the autoantigen resulting in antibodies that cross-react with the autoantigen. Release of neutrophil extracellular traps, apoptosis and increased granule protein expression of ANCA antigens may facilitate the initiation of an ANCA autoimmune response, augment established pathogenic ANCA production, or both. The ANCA B cell autoimmune response is facilitated by quantitatively and qualitatively impaired T cell and B cell suppression, and by release from activated neutrophils of B cell activating factors that enhance B cell proliferation and retard B cell apoptosis.

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“…Impaired immune responses to BKV infection in KTX include decreased production of specific antibodies B cells, ineffective immune surveillance by T cells, and diminished dendritic cells [29]. Interestingly, AAV patients have been shown to have decreased dendritic cell numbers during active disease and in remission [30]. Despite this, we did not find any evidence of BKV replication in our immunosuppressed vasculitis patients.…”

Section: Discussionmentioning

confidence: 76%

BK Virus Replication in Patients with Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis

Geetha¹,

Levine²,

Manno³

et al. 2013

Am J Nephrol

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Background: BK virus (BKV) is an important cause of renal dysfunction in kidney transplant (KTX) recipients. Immunosuppression intensity is a major risk factor for BKV replication in these patients. The prevalence of BKV replication in immunosuppressed patients with granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) without transplant is not known. Methods: Consecutive patients (n = 37) with a diagnosis of GPA (n = 25) or MPA (n = 12) without history of KTX were evaluated for plasma BKV replication by quantitative PCR (group A). Descriptive data were collected. BKV replication in this nontransplant immunosuppressed vasculitis cohort was compared with a historical cohort of vasculitis KTX recipients (group B). Results: Group A patients had mean disease duration of 75 months. Mean age was 57 years and 54% were female. Mean time from vasculitis onset to BKV testing was 36 months, and 19/37 patients were tested within 24 months of induction therapy. At the time of BKV testing, 73% were on prednisone (P) with azathioprine, mycophenolate mofetil (MMF), methotrexate or leflunomide. None of the nontransplanted vasculitis patients had detectable plasma BKV. Among 35 patients in group B, 16 were tested for BKV; 5/16 (31%) had detectable virus in plasma at a mean of 6 months after TX (p = 0.002). Most (94%) were on maintenance therapy with MMF, P and tacrolimus. Conclusion: Immunosuppressed patients with GPA/MPA without KTX had no evidence of plasma BKV. However, BKV was common in GPA/MPA patients after KTX, suggesting that replication may be related to differences in immunosuppression, alloimmune activation or differences in host defense mechanisms.

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Decreased Numbers of Blood Dendritic Cells and Defective Function of Regulatory T Cells in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis

Cited by 67 publications

References 62 publications

Impaired Blood Dendritic Cell Numbers and Functions after Aneurysmal Subarachnoid Hemorrhage

Impaired Blood Dendritic Cell Numbers and Functions after Aneurysmal Subarachnoid Hemorrhage

B cell-mediated pathogenesis of ANCA-mediated vasculitis

BK Virus Replication in Patients with Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis

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