Exploring Frequencies of Circulating Specific Th17 Cells against Myeloperoxidase and Proteinase 3 in ANCA Associated Vasculitis (original) (raw)
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Review article: The role of CD4 + T cells in ANCA-associated systemic vasculitis
Nephrology, 2009
Antineutrophil cytoplasmic autoantibody (ANCA)-associated systemic vasculitis (AASV) constitutes a group of primary vasculitides associated with antineutrophil cytoplasmic autoantibodies, which are either directed to proteinase-3 or myeloperoxidase. In contrast to other forms of vasculitis, immuohistologic evaluation of affected tissues in patients with AASV, particularly the kidneys, demonstrated an absence or paucity of immunoglobulins, which could suggest involvement of cell-mediated injury in this disorder. Several studies have shed light on T cell-mediated immune responses playing a role in the pathophysiology of AASV. Imbalance of CD4 + T-cell subsets has been demonstrated in the peripheral blood of patients with AASV. The trigger that leads to this imbalance remains to be defined, but clinical evidence shows that nasal carriage of Staphylococcus aureus constitutes a risk factor for disease exacerbation. Recent data show that superantigens and peptidoglycans from these Gram-positive bacteria can induce skewing of T-cell responses towards pathogenic interleukin (IL)-17producing T-helper cells (Th17). Overproduction of IL-17 in response to this infection might aggravate inflammatory responses and contribute to the production of autoantibodies as well as to granuloma formation and tissue injury in patients with AASV. Next to Th17 cells, memory CD4 + T cells with the effector cytotoxic phenotype (CD4 + TEM) have also been demonstrated to constitute a major effector pathway of tissue injury in patients with pauci-immune glomerulonephritis. Therefore, future perspectives for treatment of AASV could be built on neutralization of IL-17 and depletion of CD4 + TEM cells.
Archives of Medical Research, 2009
Background and Aims. Dysregulation of cell-mediated immune response likely plays a role in the pathogenesis of anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV), but it has not yet been fully established. The aim of this study was to assess the intracellular cytokine production in patients with AAV at different stages of the disease, in particular, in relation to the long-term prognosis. Methods. We included 69 patients with AAVand 24 healthy controls. Using flow cytometry, the following intracellular cytokines (IC) were measured in all patients: interferon-g (IFNg), tumor necrosis factor alpha (TNF-a), interleukin-2 and interleukin-4 in CD3 þ T cells and interleukin-10 (IL-10) and interleukin 12 (IL-12) in monocytes. Patients were then prospectively followed for a median of 43 months and cytokine production was related to the long-term prognosis. Results. When compared to healthy controls, increased IL-12 production was observed in AAV patients, both active ( p !0.01) and in remission ( p !0.05). In remission, increased IFN-g production was also found ( p !0.01). IL-10 production was higher in active patients than in patients in remission ( p !0.05) but did not differ from controls. Patients in remission who developed a relapse during follow-up had significantly lower IL-10 production than those without relapse ( p !0.01). Results of this prospective study of IC production in AAV confirm findings of previous studies measuring circulating cytokine levels.
T cells in the pathogenesis of ANCA-associated vasculitis: Current knowledge
Folia biologica
Abbreviations: AAV -ANCA-associated vasculitides, ANCAanti-neutrophil cytoplasmic autoantibodies, DTH -delayed-type hypersensitivity, IFN -interferon, IL -interleukin, MPA -microscopic polyangiitis, MPO -myeloperoxidase, PR3 -proteinase 3, RLV -renal-limited vasculitis, TCR -T-cell receptor, TEM -effector memory T cells, WG -Wegener's granulomatosis.
Phenotypic Characterization of Circulating CD4+ T Cells in ANCA-Associated Vasculitis
Journal of Immunology Research
T cell-mediated immune responses are thought to play an important role in the pathogenesis of anti-neutrophil cytoplasmic antibody- (ANCA-) associated vasculitides (AAV). CD4+ T cells can be divided into subsets depending on their expression of chemokine receptors. In this study, different CD4+ T cell populations in patients with AAV were analysed and compared to healthy blood donors as well as therapy controls. 18 patients with active AAV, 46 in remission, 21 healthy controls (HBD), and 15 therapy controls (TC) were enrolled. CD4+ T cells were divided into Th1, Th2, and Th17 cells and further subdivided into naïve, central memory, effector memory, and effector cells. Regulatory T cells were also analysed. Concentrations of cytokines and chemokines produced by the respective CD4+ T cell subset in plasma from 33 of the patients were measured by ELISA and compared to HBD. Clinical data were collected on all patients. CCL20 concentrations and percentages of Th17 cells (p=0.019) were el...
Kidney International, 2006
In antineutrophil cytoplasm autoantibody (ANCA)-associated systemic vasculitis (ASV), autoantibody-induced neutrophil activation is believed to cause organ damage. In vitro, tumor necrosis factor a (TNFa) primes neutrophils for ANCA stimulation and TNFa blockade has been successfully used to treat ASV. Nonetheless, irreversible organ damage can still occur, suggesting that other cytokines may circumvent TNFa blockade. We report that interleukin (IL)-18 deposition, as assessed by immunoperoxidase staining, is increased in renal biopsies from ASV patients. Immunofluorescence microscopy demonstrated that podocytes are the predominant glomerular IL-18-positive cell type, whereas in the interstitium, myofibroblasts, distal tubular epithelium, and infiltrating macrophages stained for IL-18. In vitro, IL-18 primed superoxide production by ANCA-activated neutrophils comparably to TNFa. IL-18-primed, ANCA-induced superoxide production was unaffected by anti-TNFa antibody, which abrogated TNFa priming. Furthermore, TNFa and IL-18 phosphorylated neutrophil p38 mitogen-activated protein kinase (MAPK), but IL-18-mediated p38 MAPK phosphorylation was unaffected by anti-TNFa antibody. The p38 MAPK inhibitor, SB20358, reduced IL-18-primed, ANCA-induced superoxide production in a concentration-dependent manner. ANCA-induced superoxide release was also sensitive to the Leukotriene B4 (LTB4) inhibitor MK-886. IL-18 priming was not associated with increased ANCA antigen expression on isolated neutrophils. We conclude that IL-18 is likely to be important for neutrophil recruitment and priming in ASV. Therapies targeting single priming agents may have limited efficacy in controlling disease.
Clinical and Experimental Immunology, 2003
In systemic small vessel vasculitides, patients form autoantibodies against neutrophil granular proteins, anti-neutrophilic cytoplasmic autoantibodies (ANCA). Some correlation is seen between ANCA titre and disease activity, but whether this is cause or effect is still unknown. It has been reported that levels of proteinase 3 (PR3), one of the main ANCA antigens, are increased in patients with active disease. An increased level of circulating antigen could mean a predisposition to autoimmunity. In order to explore this we measured PR3 levels in patients with stable disease. In addition we measured neutrophil gelatinase-associated lipocalin (NGAL) as a specific marker of neutrophil degranulation, cystatin C as a marker of renal function as well as C-reactive protein (CRP), IL-6 and sTNFr1 as markers of inflammation. PR3, NGAL, IL-6 and sTNFr1 were measured in plasma by the ELISA technique. In the PR3 ELISA, we used anti-PR3 monoclonal antibodies as capture-antibodies and affinity-purified rabbitanti-PR3 antibodies for detection. PR3-ANCA, myeloperoxidase (MPO)-ANCA, CRP and cystatin C were measured by routine methods. PR3 was significantly raised ( P < 0·0001) in vasculitis patients (median 560 m g/l, range 110-3940, n = 59) compared with healthy blood donors (350 m g/l, 110-580, n = 30) as well as disease controls (360, 110-580, n = 46). No correlation was seen with disease activity, inflammation or renal function. The raised NGAL levels correlated strongly with decreased renal function ( r = 0·8, P < 0·001). After correcting for this, slightly increased levels (110, 42-340, n = 59) were observed compared with healthy blood donors (81, 38-130, n = 25), but not compared with the disease controls (120, 57-260, n = 48). In the disease controls, there was a significant correlation between NGAL and proteinase 3 ( r = 0·3, p < 0·05), but this was not the case in the vasculitis patients. Whether patients had PR3-ANCA or MPO-ANCA was of no significance. In our measurements, we found significantly raised levels of PR3 in plasma from patients with small vessel vasculitis, regardless of ANCA specificity. This was not due to decreased renal function, ongoing inflammation or neutrophil activation. Plausible mechanisms for this include defects in the reticuloendothelial system, genetic factors and selective neutrophil degranulation or leakage.