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J W Tervaert

Publications and source records attributed to J W Tervaert.

At least 37 records · Page 2Linked to original sources
PubMed2000

Is Wegener's granulomatosis an autoimmune disease?

Wegener's granulomatosis is a multisystem disease characterized by granulomata of the respiratory tract and systemic necrotising vasculitis. There is a strong and specific association with autoantibodies directed against proteinase 3, a constituent of neutrophril azurophilic granules. Antibody titers correlate with clinical disease activity and predict relapses. The disease responds favorably to immunosuppressive therapy. The pathogenicity of antineutrophil cytoplasmic antibodies (ANCA), however, remains unproven. In vitro, the expression of proteinase-3 and other ANCA antigens on the surface of neutrophils and monocytes can be induced by priming with proinflammatory cytokines. Antineutrophil cytoplasmic antibodies are then able to activate these leukocytes, stimulating degranulation, the production of reactive oxygen species, and the secretion of further cytokines. Neutrophils activated by ANCA, and possibly ANCA alone, directly damage endothelial cells in vitro. An animal model of proteinase 3-ANCA-induced vasculitis has not been found. Antineutrophil cytoplasmic antibodies directed against another antigen, myeloperoxidase, are not sufficient to cause vasculitis but they promote damage in certain animal models. Thus, a considerable amount of evidence supports the notion that Wegener's granulomatosis is an autoimmune disease.

Antibodies, Antineutrophil Cytoplasmic↗
PubMed2000

New treatments of ANCA-associated vasculitis.

The ANCA-associated systemic vasculides are, in many cases, life-threatening conditions. Combined treatment with corticosteroids and cyclophosphamide has improved their prognosis considerably. Five year survival does, however, still not exceed 75%, due to the occurrence of treatment resistant cases and the severe adverse effects of this treatment regimen. In this review new treatment modalities are discussed. In cases resistant to conventional therapy high dose intravenous immunoglobulin and T-cell directed biologicals, that is anti-thymocyte globulin (ATG) and humanised monoclonal antibodies to CD4 and CDw52, may be effective. Also, TNF-directed treatment is being used. Less severe cases may benefit from methotrexate treatment instead of cyclophosphamide. For maintenance of remission azathioprine has been proven to be as effective as cyclophosphamide so preventing the toxicity of long-term cyclophosphamide treatment. Relapses may also be prevented by treatment based on changes in ANCA-titers or by elimination of Staphylococcus aureus carriage which is associated with relapsing disease in Wegener's Granulomatosis. Several of those new treatment modalities are now being tested in controlled studies by the European Vasculitis Study Group (EUVAS).

Antibodies, Antineutrophil Cytoplasmic↗
PubMed1999

Alternating antineutrophil cytoplasmic antibody specificity: drug-induced vasculitis in a patient with Wegener's granulomatosis.

We describe a patient who presented with Wegener's granulomatosis associated with antineutrophil cytoplasmic antibodies (ANCA) directed against proteinase 3 (PR3) with a cytoplasmic immunofluorescence pattern (cANCA), whose ANCA type changed to antimyeloperoxidase antibodies with a perinuclear immunofluorescence pattern (pANCA) when treated with propylthiouracil, and changed back to anti-PR3 antibodies with cANCA after the medication was discontinued. The patient developed flares of vasculitis symptoms associated with rises in either type of ANCA. Tests for antimyeloperoxidase ANCA were repeatedly negative before the drug was started, strongly implicating the drug as the cause of the episode. This case demonstrates that patients with idiopathic ANCA-positive vasculitis may quickly develop a superimposed drug-associated ANCA-positive vasculitis. Iatrogenic vasculitis should be suspected when a patient with idiopathic vasculitis with one type of ANCA develops the other type of ANCA.

Adult↗
PubMed1999

Fcgamma receptor polymorphisms in Wegener's granulomatosis: risk factors for disease relapse.

OBJECTIVE: Several studies have recently identified polymorphisms of receptors for the Fc fragment of IgG (FcgammaR) as genetic factors influencing susceptibility to multiple autoimmune and infectious diseases. This genetic predisposition could also influence the expression of Wegener's granulomatosis (WG), a systemic autoimmune disease with chronic nasal carriage of Staphylococcus aureus as an important risk factor for disease relapses. Therefore, we analyzed 3 functional FcgammaR polymorphisms from 91 patients with WG and 154 controls for a possible relationship with disease expression and occurrence of relapses. METHODS: FcgammaR phenotypes were determined using amplification of FcgammaR-genomic regions in allotype-specific polymerase chain reactions. Of particular interest in the analysis were 2 allotypic forms of FcgammaRIIa (R131 or H131) and 2 allotypic forms of FcgammaRIIIa (V158 or F158), all of which are functionally different. RESULTS: Analysis of FcgammaR phenotypes demonstrated that patients with WG were more prone to disease relapse in the first 5 years after diagnosis if they were homozygous for both the R131 form of FcgammaRIIa and the F158 form of FcgammaRIIIa (relative risk 3.3, 95% confidence interval 1.6-6.8). These polymorphisms are both associated with decreased FcR-mediated clearance, which may be relevant to the chronic nasal carriage of S aureus. CONCLUSION: Both the R/H131 polymorphism of FcgammaRIIa and the V/F158 polymorphism of FcgammaRIIIa represent heritable risk factors for the development of disease relapses in WG.

Adult↗
PubMed1999

Differential B- and T-cell activation in Wegener's granulomatosis.

BACKGROUND: Autoimmune mechanisms are postulated to play a role in the development and progression of Wegener's granulomatosis (WG), a form of systemic, idiopathic necrotizing vasculitis. OBJECTIVE: We investigated the relation between lymphocyte activation and disease activity in patients with WG. METHODS: B- and T-lymphocyte activation was studied by cytometric assessment of the expression of the activation markers CD38 on B cells and CD25 and HLA-DR on CD4(+) and CD8(+) T-cell subsets, respectively. Activation at the cellular level was related to serum levels of antineutrophil cytoplasmic antibodies and soluble IL-2 receptor, which can be regarded as soluble activation markers of B and T cells. RESULTS: Percentages of CD38(bright) activated B cells were higher in patients with active WG than in patients experiencing disease remission (P <.05) or in healthy control subjects (P <.05). Percentages of activated CD4(+) and CD8(+) T cells were higher in patients with active WG (CD4 subset, P <.0001; CD8 subset, P <.005) than in healthy individuals. An increased percentage of activated T cells of both subsets was also seen in patients whose condition was in remission, as compared with healthy control subjects (CD4 subset, P <.0005; CD8 subset, P <. 001). Lymphocyte activation at the cellular level did not correlate with plasma levels of antineutrophil cytoplasmic antibodies or soluble IL-2 receptor. CONCLUSION: In WG, B-cell activation is related to active disease, whereas T-cell activation persists during remission of the disease, which points to an intrinsic disordered immune system in this disease.

Adult↗
PubMed1999

The central role of monocytes in the pathogenesis of sepsis: consequences for immunomonitoring and treatment.

Despite important advances in critical care medicine during the last two decades, the mortality rate of sepsis has remained high, probably because the pathogenesis of sepsis is still incompletely understood. Recent studies have shown that sepsis is a bimodal entity. The first phase is characterized by the systemic release of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1), and IL-8, and by activation of the complement and coagulation cascades. In the second phase, anti-inflammatory mediators such as transforming growth factor-beta (TGF-beta), IL-10 and prostaglandin E2 (PGE2) may be released in an effort to counteract ongoing inflammation. Depending whether the pro- or anti-inflammatory response predominates, sepsis results in a systemic inflammatory response syndrome (SIRS), or a compensatory anti-inflammatory response syndrome (CARS). So far, most efforts to intervene in the immunopathogenesis of sepsis have been directed at the pro-inflammatory response. None of these interventions has been shown to improve the prognosis of sepsis, possibly because many patients were already in a state in which anti-inflammatory responses dominated. Recently, it has been shown that decreased expression of HLA-DR on monocytes in patients with sepsis constitutes a marker for CARS. We suggest that HLA-DR expression on monocytes might constitute a useful indicator of the immunological status of the individual patient with sepsis and a guide for treatment. Patients with CARS, as manifested by low HLA-DR expression, might benefit from immunostimulants, while patients with SIRS and normal or high monocyte HLA-DR expression should receive treatment directed to interfere with pro-inflammatory pathways.

Biomarkers↗
PubMed1999

The role of superantigens in vasculitis.

Multiple risk factors are involved in susceptibility to vasculitis. Inherited determinants may increase the risk but are insufficient to induce the disease. Environmental factors, such as infections, are important modulators and probably trigger the disease in most cases. One of the possible triggers may be a bacterial superantigen (SAg). SAgs may activate autoreactive T cells that mediate autoimmune vessel wall destruction. Furthermore, SAgs may activate autoreactive B cells to produce autoantibodies that are involved in the pathophysiology of vasculitis, such as antineutrophil cytoplasmic autoantibodies or anti-endothelial cell antibodies. In patients with Kawasaki disease, Wegener's granulomatosis, and infection-related forms of vasculitis, SAg-producing microorganisms have regularly been found. Activation of circulating T cells and skewing of the T-cell repertoire have been reported in most forms of vasculitis. In the past year, for the first time, patients were described in which T-cell receptor V beta expansions were documented simultaneously with the typing of the microbial SAgs, providing evidence that the observed changes in the T-cell repertoire could be caused by these bacterial SAgs. In the future, elucidation of the immunologic mechanisms by which SAgs may play a role in the pathophysiology of vasculitis will provide more effective methods for the treatment of vasculitis.

Antigens, Bacterial↗
PubMed1999

What is new with anti-neutrophil cytoplasmic antibodies: diagnostic, pathogenetic and therapeutic implications.

Anti-neutrophil cytoplasmic antibodies, as detected by indirect immunofluorescence, have limited diagnostic significance as they occur in a variety of inflammatory disorders. The presence of antibodies to defined target antigens of anti-neutrophil cytoplasmic antibodies, that is proteinase 3 and myeloperoxidase, is, however, highly specific for one of the systemic vasculitides, in particular Wegener's granulomatosis, microscopic polyangiitis, Churg-Strauss syndrome, and idiopathic pauci-immune necrotizing crescentic glomerulonephritis. In general, anti-proteinase-3-positive patients show more widespread organ involvement, more granuloma formation, and a more severe initial course of their renal lesions than anti-myeloperoxidase-positive patients; however, there is considerable overlap, and either antibody specificity may be found in the different clinical syndromes. In vitro, anti-neutrophil cytoplasmic antibodies are able further to activate pre-activated neutrophils and monocytes, which can result in endothelial damage. A direct activating effect of anti-neutrophil cytoplasmic antibodies on endothelial cells has been suggested, but those studies should be confirmed. In vivo, experimental data support a pathogenetic role for anti-neutrophil cytoplasmic antibodies, particularly anti-myeloperoxidase, but besides anti-neutrophil cytoplasmic antibodies a second pro-inflammatory stimulus seems to be required to induce lesions. Whether anti-neutrophil cytoplasmic antibodies can be a direct target for treatment has still to be proved. Current immunosuppressive treatment regimens for the anti-neutrophil cytoplasmic antibody-associated vasculitides are, however, unsatisfactory because of side-effects, that is opportunistic infections and malignancies. New treatment regimens, based on new pathogenetic concepts, are currently being tested.

Animals↗
PubMed1999

Monocyte activation in patients with Wegener's granulomatosis.

OBJECTIVE: Wegener's granulomatosis (WG) is an inflammatory disorder characterised by granulomatous inflammation, vasculitis, and necrotising vasculitis and is strongly associated with anti-neutrophil cytoplasmic antibodies (ANCA). Activated monocytes/macrophages are present in renal biopsy specimens and participate in granuloma formation by synthesising and secreting a variety of chemoattractants, growth factors, and cytokines. In view of these findings, in vivo monocyte activation was evaluated in patients with WG and the findings related to parameters of clinical disease activity. METHODS: Monocyte activation was analysed by measuring plasma concentrations of soluble products of monocyte activation, that is neopterin and interleukin 6 (IL6), by ELISA, and by quantitating the surface expression of activation markers on circulating monocytes by flow cytometry. RESULTS: Twenty-four patients with active WG were included in this study. Ten of these patients were also analysed at the time of remission. Twelve patients with sepsis served as positive controls, and 10 healthy volunteers as negative controls for monocyte activation. Patients with active disease had increased monocyte activation compared with healthy controls as shown by increased concentrations of neopterin (p < 0.0001) and increased surface expression of CD11b (p < 0.05) and CD64 (p < 0.05). In those patients with increased concentrations of IL6 during active disease plasma concentrations of IL6 decreased during follow up when patients went into remission (p < 0.0001). In addition, neopterin (r = 0.37, r = 0.44), IL6 (r = 0.37, r = 0.60) and CD63 expression (r = 0.39, r = 0.45) correlated significantly with disease activity as measured by the Birmingham Vasculitis Activity Score and C reactive protein values, respectively. Compared with patients with sepsis, all markers of monocyte activation in patients with vasculitis were lower. CONCLUSION: It is concluded that disease activity in WG correlates with the extent of activation of monocytes, compatible with their role in the pathophysiology of this disease.

Acute Disease↗
PubMed1999

Antimyeloperoxidase-associated lung disease. An experimental model.

The lung is a common target in systemic vasculitides associated with antineutrophil cytoplasmic antibodies (ANCA). In the present study, we tested the hypothesis that the presence of antibodies directed against myeloperoxidase (MPO) induces pulmonary (vasculitic) lesions when neutrophils release lysosomal enzymes. Brown Norway (BN) rats were immunized with human MPO in complete Freund's adjuvant (CFA) or with CFA alone. Two weeks after immunization, rats had developed antibodies to human and rat MPO. Next, isolated single left lung perfusion was performed with human neutrophil lysosomal extract containing MPO and proteolytic enzymes. Rats were killed at 15 min, 4 h, and 10 d after perfusion. Tissue samples from the left and right lung were examined for vasculitic lesions and inflammatory cell infiltrates. At 15 min and 4 h, left lungs from control and MPO-immunized rats showed a mild influx of polymorphonuclear cells. At 10 d, patchy inflammatory cell infiltrates, consisting predominantly of polymorphonuclear leukocytes (PMNs) and monocytes, were observed throughout the parenchyma of the left lung in MPO-immunized rats. Occasionally, granuloma-like lesions, giant cells, and foci of alveolar hemorrhage were observed as well. Far less severe lesions were seen in control immunized rats. Strikingly, at 10 d after perfusion, severe pulmonary tissue injury was observed also in right lungs from MPO-immunized rats whereas right lungs from control immunized rats appeared normal. The lesions were characterized by influx of PMNs and monocytes and, in some rats, foci of alveolar hemorrhage. These studies suggest that the presence of an anti-MPO directed autoimmune response contributes to generalized pulmonary tissue injury after local release of products of activated neutrophils, which supports a pathogenic role of MPO-ANCA.

Animals↗
PubMed1999

In vitro neutrophil activation by antibodies to proteinase 3 and myeloperoxidase from patients with crescentic glomerulonephritis.

Previously, it was found that patients with necrotizing crescentic glomerulonephritis (NCGN) and anti-neutrophil cytoplasmic autoantibodies (ANCA) directed against proteinase 3 (anti-PR3) had a faster deterioration of renal function and more active renal vasculitic lesions than patients with ANCA directed against myeloperoxidase (anti-MPO). Because ANCA-mediated neutrophil activation is thought to play an important role in the pathophysiology of this form of glomerulonephritis, this study was conducted to determine whether anti-PR3 are capable of inducing a more pronounced activation of neutrophils in vitro than anti-MPO. To test this hypothesis, the release of reactive oxygen radicals, as assessed by ferricytochrome c reduction and by dihydrorhodamine 123 oxidation, and the release of granule constituents from healthy donor neutrophils upon stimulation with IgG fractions were measured from 17 anti-PR3- and 14 anti-MPO-positive patients with active NCGN. Patients with anti-PR3 had a higher renal activity index (P < 0.05) compared with patients with anti-MPO. IgG fractions from anti-PR3-positive patients induced more oxygen radical release from tumor necrosis factor-alpha-primed neutrophils compared with IgG fractions from anti-MPO-positive patients, as assessed by ferricytochrome c reduction (P < 0.05) and dihydrorhodamine 123 oxidation (P < 0.01). In addition, IgG fractions from anti-PR3-positive patients generated more neutrophil degranulation of beta-glucuronidase (P < 0.01) than IgG fractions from anti-MPO-positive patients. In conclusion, IgG fractions from anti-PR3-positive patients with NCGN are more potent activators of the respiratory burst and degranulation in vitro than IgG fractions from anti-MPO-positive patients. These observations may be relevant in view of the clinical differences between anti-PR3- and anti-MPO-positive patients with NCGN.

Adult↗
PubMed1999

Outcome analysis of patients with vasculitis associated with antineutrophil cytoplasmic antibodies.

BACKGROUND: Objective scoring systems of disease activity and disease-associated damage have proven useful in the management of patients with systemic vasculitis. PATIENTS AND METHODS: We used the recently designed Birmingham vasculitis activity score (BVAS; maximum score 63) and vasculitis damage index (VDI; maximum score 59) to assess initial activity and long-term damage, respectively, in ANCA positive patients from one center over a 3-year period. Thirty-two patients with ANCA vasculitis were identified and analyzed as an historic cohort. The median BVAS for all vasculitis patients at first presentation was 19 (range 6 - 36). Patients with Wegener's granulomatosis had a significantly higher total score and respiratory BVAS score compared to the 15 with microscopic polyangiitis. The majority of patients received standard cyclophosphamide/steroid treatment. RESULTS: At the end of follow-up (mean 24.9 months), 4 patients had died; all patients had evidence of permanent organ damage. The median total VDI score at last follow-up was 4.0 (range 0-11), with no differences between patients with Wegener's granulomatosis and microscopic polyangiitis. The VDI was not associated with the number of relapses. A high initial BVAS was found to correlate with a later high vasculitis damage index (r = 0.56). Initial renal or respiratory involvement was also associated with longterm damage in the same organ system. CONCLUSION: Although mortality from ANCA-associated vasculitis has decreased, morbidity remains a common problem. High early-disease activity may identify patients at high risk of long-term organ damage, allowing more effective individualized therapy. This hypothesis requires validation in a prospective, controlled study.

Antibodies, Antineutrophil Cytoplasmic↗
PubMed1998

[Immunology in clinical practice IX. Systemic vasculitis].

A diagnosis of vasculitis generally requires histopathological proof of vasculitis, particularly because many other disease entities may mimic vasculitis ('vasculitis-look-alikes'). Vasculitis can be primary (idiopathic) or secondary to other diseases, especially infectious diseases. The primary vasculitides are classified according to the size of the vessels involved and the nature of the inflammation, in combination with clinical symptoms. The detection of autoantibodies, particularly the antineutrophil cytoplasmic antibodies (ANCA), in some of the primary vasculitides, has facilitated the diagnosis of those diseases and has given more insight into their pathophysiology. Treatment of primary vasculitis still consists of corticosteroids whether or not in combination with immunosuppression. New insights in pathophysiology may provide more specific and less toxic treatment modalities.

Adrenal Cortex Hormones↗
PubMed1998

Antineutrophil cytoplasmic antibodies in primary sclerosing cholangitis: defined specificities may be associated with distinct clinical features.

PURPOSE: The clinical significance of antineutrophil cytoplasmic autoantibodies (ANCA) in primary sclerosing cholangitis has not been established. We investigated whether analysis of the antigenic specificities of ANCA is useful for delineating clinical subsets of the disease. METHODS: Sixty-nine patients with primary sclerosing cholangitis were studied. The presence of ANCA was analyzed by indirect immunofluorescence. Antibodies directed against specific antigens--proteinase 3, myeloperoxidase, elastase, bactericidal/permeability-increasing protein, cathepsin G, and lactoferrin--were identified by enzyme-linked immunosorbent assay. RESULTS: ANCA were detected by indirect immunofluorescence in 46 (67%) patients. In antigen-specific enzyme-linked immunosorbent assays, 37 (55%) of the 69 patients had antibodies to one or more antigens: 32 (46%) had antibodies to bactericidal/permeability-increasing protein, 16 (23%) had antibodies to cathepsin G, and 15 (22%) had antibodies to lactoferrin. Only 3 patients had antibodies to proteinase 3. Antibodies to myeloperoxidase or elastase were not detected. Twenty (29%) patients had antibodies to different antigens simultaneously. ANCA as detected by indirect immunofluorescence were not significantly associated with the presence of cirrhosis nor with the coexistence of inflammatory bowel disease. However, antibodies to bactericidal/permeability-increasing protein and cathepsin G were both associated with the presence of cirrhosis, and antibodies to lactoferrin were more frequently detected in patients with primary sclerosing cholangitis in conjunction with ulcerative colitis than in those without inflammatory bowel disease. CONCLUSION: Defined specificities of ANCA in primary sclerosing cholangitis may be related to particular clinical features of the disease.

Adult↗