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Genetic loci of Staphylococcus aureus associated with anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitides.

ABSTRACT: The proteinase 3 (PR3)-positive anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) granulomatosis with polyangiitis (GPA) has been associated with chronic nasal S. aureus carriage, which is a risk factor for disease relapse. The present study was aimed at comparing the genetic make-up of S. aureus isolates from PR3-ANCA-positive GPA patients with that of isolates from patients suffering from myeloperoxidase (MPO)-ANCA-positive AAV, and isolates from healthy controls. Based on a DNA microarray-based approach, we show that not only PR3-ANCA-positive GPA patients, but also MPO-ANCA-positive AAV patients mainly carried S. aureus types that are prevalent in the general population. Nonetheless, our data suggests that MPO-ANCA-associated S. aureus isolates may be distinct from healthy control- and PR3-ANCA-associated isolates. Furthermore, several genetic loci of S. aureus are associated with either PR3-ANCA- or MPO-ANCA-positive AAV, indicating a possible role for pore-forming toxins, such as leukocidins, in PR3-ANCA-positive GPA. Contrary to previous studies, no association between AAV and superantigens was detected. Our findings also show that a lowered humoral immune response to S. aureus is common for PR3-ANCA- and MPO-ANCA-positive AAV. Altogether, our observations imply that the presence or absence of particular virulence genes of S. aureus isolates from AAV patients contributes to disease progression and/or relapse.

SUBMITTER: Glasner C

PROVIDER: S-EPMC5610336 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Genetic loci of Staphylococcus aureus associated with anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitides.

Glasner Corinna C de Goffau Marcus C MC van Timmeren Mirjan M MM Schulze Mirja L ML Jansen Benita B Tavakol Mehri M van Wamel Willem J B WJB Stegeman Coen A CA Kallenberg Cees G M CGM Arends Jan P JP Rossen John W JW Heeringa Peter P van Dijl Jan Maarten JM

Scientific reports 20170922 1

The proteinase 3 (PR3)-positive anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) granulomatosis with polyangiitis (GPA) has been associated with chronic nasal S. aureus carriage, which is a risk factor for disease relapse. The present study was aimed at comparing the genetic make-up of S. aureus isolates from PR3-ANCA-positive GPA patients with that of isolates from patients suffering from myeloperoxidase (MPO)-ANCA-positive AAV, and isolates from healthy controls. Bas ...[more]

PMID: 28939882

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Project description:To investigate presence of circulating myeloperoxidase-positive microparticles (MPO+MPs) in relation to disease activity in patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Forty-six patients with AAV and 23 age- and sex-matched healthy controls were included. Vasculitis disease activity was assessed using the Birmingham Vasculitis Activity Score (BVAS). MPs were analyzed in citrate plasma by flow cytometry and phenotyped based on MPO expression and co-expression of pentraxin-3 (PTX3), high mobility group box 1 protein (HMGB1), and tumor necrosis factor-like weak inducer of apoptosis (TWEAK). Serum levels of PTX3, sTWEAK, and HMGB1 were also determined. Twenty-three patients had active vasculitis (BVAS ? 1). Concentrations of MPO+MPs expressing PTX3, HMGB1, and TWEAK were significantly higher in patients compared to healthy controls (p < 0.001, p < 0.01, p < 0.001, respectively), while concentrations of PTX3+ and HMGB1+MPO+MPs were significantly higher in active AAV compared to patients in remission. MPO+MPs expressing either PTX3 or HMGB1 were associated with BVAS (r = 0.5, p < 0.001; r = 0.3, p = 0.04, respectively). Significantly higher serum PTX3 levels were found in active- than in inactive AAV (p < 0.001), correlating strongly with BVAS (r = 0.7, p < 0.001). Serum levels of sTWEAK and HMGB1 did not differ between patients and controls. Concentration of MPO+MPs is increased in plasma from AAV patients compared to healthy individuals. PTX3 in serum as well as PTX3 and HMGB1 expressed on MPO+MPs were associated with disease activity in the investigated patients. KEY MESSAGES: Myeloperoxidase-positive microparticles (MPO+MPs) are increased in plasma from patients with ANCA-associated vasculitis. Concentrations of MPO+MPs expressing PTX3, HMGB1, and TWEAK were significantly higher in patients compared to healthy controls. MPO+MPs expressing PTX3 and HMGB1 are associated with disease activity in ANCA-associated vasculitis.

Project description:The anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are a group of disorders characterized by necrotizing inflammation of the small to medium vessels in association with autoantibodies against the cytoplasmic region of the neutrophil. Included in this definition are granulomatosis with polyangiitis (GPA, formerly known as Wegener's granulomatosis), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (formerly known as Churg-Strauss syndrome). AAV are chronic, often relapsing diseases that can be organ or life threatening. Despite immunosuppression, the morbidity and mortality remain high. Renal involvement contributes significantly to the morbidity with high numbers of patients progressing to end-stage kidney disease. Current therapies have enabled improvements in renal function in the short term, but evidence for long-term protection is lacking. In MPA, renal involvement is common at presentation (90%) and often follows a more severe course than that seen in paediatric GPA. Renal biopsy remains the 'gold standard' in diagnosing ANCA-associated glomerulonephritis. While GPA and MPA are considered separate entities, the two are managed identically. Current treatment regimens are extrapolated from adult studies, although it is encouraging to see recruitment of paediatric patients to recent vasculitis trials. Traditionally more severe disease has been managed with the 'gold standard' treatment of glucocorticoids and cyclophosphamide, with remission rates achieved of between 70 and 100%. Other agents employed in remission induction include anti-tumor necrosis factor-alpha therapy and mycophenolate mofetil. Recently, however, increasing consideration is being given to rituximab as a therapy for children in severe or relapsing disease, particularly for those at risk for glucocorticoid or cyclophosphamide toxicity. Removal of circulating ANCA through plasma exchange is a short-term measure reserved for severe or refractory disease. Maintenance therapy usually involves azathioprine. The aim of this article is to provide a comprehensive review of paediatric AAV, with a focus on renal manifestations, and to highlight the recent advances made in therapeutic management.

Project description:IntroductionThe complement system is crucial for the development of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). In particular, C5a plays a central role. In this study, plasma and urinary levels of C5a as well as renal C5a receptors (CD88 and C5L2) expression were investigated in patients with AAV.MethodsTwenty-four patients with AAV in the active phase, 19 patients with AAV in the remission phase, and 20 patients with lupus nephritis (LN) were included. Plasma and urinary levels of C5a were measured with enzyme-linked immunosorbent assay (ELISA). The staining of CD88 and C5L2 in renal specimens was detected with immunohistochemistry.ResultsThe level of plasma C5a was significantly higher in patients with AAV in the active phase than that in patients in remission, that in patients with LN, and that in normal controls. The urinary C5a level was significantly higher in patients with AAV in the active phase than that in patients in remission and that in normal controls, but not significantly different between patients with active AAV and patients with LN. The mean optical density of CD88 staining in the tubulointerstitium was significantly lower in AAV patients than that in normal controls (0.0052 ± 0.0011 versus 0.029 ± 0.0042; P = 0.005). The mean optical density of C5L2 in glomeruli was significantly higher in AAV patients than that in normal controls (0.013 ± 0.0027 versus 0.0032 ± 0.0006; P < 0.001). The mean optical density of CD88 staining closely correlated with the initial eGFR (r = 0.835; P < 0.001) in AAV patients. Double-labeling immunofluorescence assay suggested that CD88 did not express on neutrophils, monocytes, or macrophages, but C5L2 expressed on neutrophils (or monocytes) and macrophages.ConclusionThe elevated plasma and urinary C5a levels indicated complement activation in human AAV. The level of renal CD88 expression could reflect the disease severity of ANCA-associated glomerulonephritis. CD88 expression was downregulated, and C5L2 was upregulated in ANCA-associated glomerulonephritis.

Dataset Information

Genetic loci of Staphylococcus aureus associated with anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitides.

Publications

Genetic loci of Staphylococcus aureus associated with anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitides.

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