Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.11.1.7 (peroxidase)
 65,474 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Anti-proteinase 3 (PR3) and anti-myeloperoxidase (MPO) autoantibodies are present in many patients with Wegener's granulomatosis (WG) and microscopic polyarteritis. The aim of this study was to determine whether these antibodies bound to linear peptide sequences on their target antigens. If common linear epitopes were demonstrated, then these could be manufactured and used in diagnostic ELISAs for anti-PR3 and anti-MPO antibodies. In addition, any homology between these epitopes and bacterial or viral sequences might implicate those microorganisms in the development of these antibodies and the pathogenesis of the associated diseases. The presence of linear epitopes on PR3 and MPO was suggested by the binding of the corresponding autoantibodies to these proteins after they had been reduced with beta-mercaptoethanol (beta-ME) and denatured with SDS or boiling, and digested with proteases. Four of the 22 sera with anti-PR3 antibodies bound to PR3 in Western blots after treatment with SDS, beta-ME and boiling for 5 min. Thermal denaturation reduced the amount of binding more than other forms of denaturation. One serum with anti-PR3 antibodies bound to Lys-C and Glu-C-digested PR3 in dot blots. Linear epitopes could not be further defined by their binding in an ELISA using overlapping peptides corresponding to the PR3 molecule because of non-specific binding. Three of the five sera with anti-MPO antibodies bound to MPO in Western blots after treatment with SDS, beta-ME and boiling for 5 min. One serum with anti-MPO antibodies bound to Lys-C and Glu-C-digested MPO in dot blots. Again, linear epitopes could not be further defined using an ELISA with overlapping peptides because of non-specific binding. Some anti-PR3 and anti-MPO antibodies are likely to recognize linear epitopes, but these cannot be defined by use of a PIN ELISA system.
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PMID:Epitope mapping of anti-proteinase 3 and anti-myeloperoxidase antibodies. 755 77

Wegener's granulomatosis (WG) is a granulomatous necrotizing vasculitis associated with the presence of ANCA, predominantly directed against proteinase 3 (PR3). The titres of ANCA correlate with disease activity and titre increases may precede disease exacerbations. Previously, we have shown that it is possible to induce autoimmune disease (systemic lupus erythematosus (SLE) and anti-phospholipid syndrome) in naive mice following active immunization with human autoantibodies, namely anti-DNA and anti-cardiolipin, respectively. The mice developed first anti-autoantibodies and, after about 4 months anti-anti-autoantibodies (Ab3), simulating auto-antibodies (Ab1) in their binding activities, and their presence was associated with the development of disease manifestations, characteristic of the human disease. So far, there is no good animal model for WG. In the current study we have immunized mice with human ANCA with the aim of inducing experimental WG. In two separate studies 30 mice were immunized in their footpads with autoantigen-purified IgG fraction (ANCA) from the sera of two patients with untreated WG, emulsified in Freund's complete adjuvant, followed 3 weeks later by ANCA injection in PBS. In the first experiment mice immunized with ANCA developed sterile microabscesses in the lungs after 8 months, and died after 8-15 months. In the second experiment, mice immunized with ANCA developed after 4 months mouse ANCA, with specificity both to PR3 and to myeloperoxidase, as well as anti-endothelial autoantibodies (AECA), as shown by radioimmunoprecipitation. Pathologically, the immunized mice developed proteinuria but not haematuria, and histological sections of the lungs demonstrated mononuclear perivascular infiltration, while diffuse granular deposition of immunoglobulins was noted in the kidneys. Our results point to a pathogenic role of ANCA in WG, and confirm the importance of the idiotypic network in the etiopathogenesis of autoimmune conditions.
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PMID:Immunization with anti-neutrophil cytoplasmic antibody (ANCA) induces the production of mouse ANCA and perivascular lymphocyte infiltration. 755 78

Immunoprecipitation (IP) of radiolabeled PMN extracts was used as the gold standard for anti-proteinase 3 (PR-3) autoantibody detection to validate immunofluorescence (IF) and alpha granule (alpha) ELISA. A myeloperoxidase (MPO) ELISA was also used in parallel. We studied 48 patients with strictly defined vasculitic syndromes in the initial active phase of their disease. The 3 methods confirmed the high (> 90%) sensitivity and specificity of anti-PR-3 for patients with Wegener's granulomatosis (WG). Similarly, a high (86%) sensitivity of MPO-ELISA was found in microscopic polyarteritis as defined. Using alpha-ELISA, we could not improve the detection rate of anti-PR-3 obtained by IF-cANCA-pattern reading. Moreover, a small proportion (< 15%) of biopsy-proven WG patients had anti-MPO antibodies detected by IF, usually as pANCA but also, even if rarely, as bona fide cANCA (< 5%). Thus, IF would seem to be the most reliable screening method and alpha-ELISA should be used for confirmation. On the other hand, because MPO-ELISA detected twice as many anti-MPO positive sera as did pANCA pattern reading by IF, we suggest that in the clinical context of a vasculitis, MPO-ELISA should also be used as a screening test. Although IP is not designed for routine clinical use, it should be required when reporting the presence of anti-PR-3 in vasculitis-like diseases that are fertile grounds for false positive reactions.
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PMID:Detection of anti-neutrophil cytoplasmic antibodies by immunoprecipitation. 755 81

In this article new informations about systemic vasculitis were reviewed. Evaluation of ANCA and their antigen specificity is of a great help in classification of systemic vasculitis. Among idiopathic systemic vasculitis anti-serine proteinase antibodies are found in Wegener granuloma, anti-MPO antibodies in Churg-Strauss syndrome and in polyarteritis nodosa. Antibodies against other components of PMNL granules still remain unknown. The main purpose of this review was to underline incidence of systemic vasculitis and the meaning of ANCA in the diagnosis and classification of these diseases.
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PMID:[Autoantibodies against neutrophil cytoplasm and their significance in the classification of systemic vasculitis]. 756 88

Antineutrophil cytoplasmic autoantibodies (ANCA) have been described in sera of patients with several forms of systemic vasculitis, including Wegener's granulomatosis and microscopic polyarteritis. The two main targets of ANCA in vasculitis are proteinase 3 (PR3) and myeloperoxidase (MPO). ANCA are capable of activating neutrophils primed by tumor necrosis factor-alpha (TNF-alpha) in vitro, which may be relevant for the induction of the vascular inflammation observed in vivo. Recently, it has been suggested that engagement of Fc gamma receptor IIa (Fc gamma RIIa) on the neutrophils is involved in the activation by ANCA. In the present study, we show that activation of the neutrophil respiratory burst by anti-PR3 and anti-MPO is strongly enhanced after TNF priming and lost on removal of the Fc parts of the antibodies. Similar results were obtained when the neutrophils were activated with antibodies against known membrane antigens without major changes in the expression of the target antigens. The TNF-induced enhancement of the neutrophil activation was not observed when adherence of the cells was prevented by continuous stirring of the suspension or by the addition of CD18 antibodies before TNF exposure. Hence, our results indicate that engagement of both Fc gamma RIIa and beta 2 integrins is instrumental in neutrophil activation induced by ANCA.
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PMID:Effect of tumor necrosis factor-induced integrin activation on Fc gamma receptor II-mediated signal transduction: relevance for activation of neutrophils by anti-proteinase 3 or anti-myeloperoxidase antibodies. 757 14

Antineutrophil cytoplasmic antibodies (ANCA) are well described in Wegener's granulomatosis and some forms of vasculitis. They have also been described in patients with arthritis, but the specificity of these ANCA and their relationship to the presence of vasculitis, antinuclear antibodies (ANA) and granulocyte-specific ANA (GS-ANA), and to disease activity are uncertain. We studied 101 patients with forms of inflammatory arthritis and detected four cytoplasmic ANCA, eight perinuclear ANCA and 16 atypical ANCA. There was no association between the presence of ANCA and ANA or rheumatoid factor. No anti-PR3 antibodies were found and no strong anti-myeloperoxidase antibodies were detected. Four GS-ANA were detected and were distinct from ANCA. There was no association between rheumatoid arthritis disease activity or disability and ANCA status. ANCA did not predict vasculitis over a 3 yr follow-up. These ANCA appear to be epiphenomena. Their importance lies in their potential to mislead physicians towards a misdiagnosis of vasculitis.
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PMID:Antineutrophil cytoplasmic antibodies in inflammatory arthritis--potential for misdiagnosis? 758 20

A 42-year-old housewife was admitted to our hospital because of an asthma attack, fever, severe eosinophilia, mononeuritis-multiplex, arthralgia, skin-eruptions, transient pulmonary infiltration, and other symptoms. Chung-Strauss syndrome was diagnosed. When there were signs and symptoms of vasculitis, chest radiography revealed that pulmonary infiltrates had decreased, but her chest CT showed ground glass opacities of both lung fields and fine granular shadows. Differential cell count of bronchoalveolar lavage fluid revealed a high level of eosinophils, and transbronchial lung biopsy specimens showed vasculitis and marked infiltration of eosinophils. When signs and symptoms of vasculitis were prominent, antineutrophil cytoplasmic antibodies (ANCA) in the serum were examined. PR3-ANCA (antibodies to serine-protease, nearly equal to c-ANCA), which is specific to Wegener's granulomatosis, was negative, but MPO-ANCA (antibodies to myeloperoxidase, nearly equal to p-ANCA) was positive and the level was very high (478 EU/ml). After corticosteroid therapy, her symptoms markedly improved, and MPO-ANCA became negative. MPO-ANCA appeared to reflect the disease activity in this case.
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PMID:[A case of Churg-Strauss syndrome in which MPO-ANCA (antibodies to myeloperoxidase) appeared to reflect the disease activity]. 760 41

Anti-neutrophil cytoplasmic autoantibodies (ANCA) occur in a subset of patients with systemic small vessel vasculitis, including patients with Wegener's granulomatosis, microscopic polyangiitis (microscopic polyarteritis), and Churg-Strauss syndrome. Pulmonary disease appears at some time during the course in many patients with ANCA-associated vasculitis. The histologic features of 25 open lung biopsies and two autopsy cases were studied from 27 patients with ANCA. Patients' ages ranged from 8 to 79 years with a mean of 52.6 years. There were 12 females and 15 males. Autoantibodies were characterized as C-ANCA in 13 patients and as P-ANCA in 14 patients. Anti-proteinase 3 antibodies were documented in 12 of 13 patients with C-ANCA. Anti-myeloperoxidase antibodies were documented in all 14 patients with P-ANCA. Vascular lesions were present in 21 patients (78%) and 11 patients (41%) had bronchial lesions. Capillaritis was the most common vascular lesion (17 patients, 63%), and was found with similar frequency in patients with C-ANCA and those with P-ANCA. Extravascular structures were a common site of tissue injury. Airway lesions including bronchiolitis obliterans organizing pneumonia (4 patients, 19%), necrotizing granulomatous inflammation (4 patients, 15%), and non-granulomatous inflammation (3 patients, 11%) were more commonly associated with patients with C-ANCA. Interstitial lesions were found in 20 patients (74%), and included necrotizing granulomatous inflammation (8 patients, 30%), fibrosis (13 patients, 48%), and chronic inflammation (12 patients, 44%). No histologic lesion were found that were specific for C-ANCA or P-ANCA. This series demonstrates the wide variety of pulmonary lesions found in patients with ANCA-associated pulmonary disease, and shows that extravascular structures are a common site of injury in ANCA-associated vasculitis.
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PMID:The pathologic spectrum of pulmonary lesions in patients with anti-neutrophil cytoplasmic autoantibodies specific for anti-proteinase 3 and anti-myeloperoxidase. 761 Nov 70

A retrospective analysis of the authors' own findings and foreign authors' data has demonstrated that neutrophilic cytoplasm antibodies (NCAs) play a definite pathogenetic role in the activation of neutrophils, a central link in the pathogenesis of vascular wall damage in necrotizing vasculitides. The clinical value of NCAs varies with their specificity. Proteinase 3 antibodies whose detection allows one to suppose Wegener's granulomatosis are of greater diagnostic value. Myeloperoxidase antibodies are revealed in various necrotizing vasculitides and promptly progressive glomerulonephritis and more infrequently in other diseases. Thus, the detection of antibodies to proteinase-3 and myeloperoxidase in the presence of appropriate clinical signs is most likely to diagnose primary necrotizing vasculitis. The changes in the levels of NCA reflect the activity of a renal processes and the progression of the whole disease.
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PMID:[Clinical and pathogenetic aspects of kidney damage associated with neutrophilic cytoplasm antibodies]. 762 83

Detection of circulating antineutrophil cytoplasmic antibodies (ANCA) to the neutrophil serine proteinase, proteinase 3 (PR3), has proven valuable for the diagnosis of Wegener's granulomatosis (WG). However, the importance of these autoantibodies in the pathogenesis of WG remains unknown. It was recently reported that anti-PR3 autoantibodies (PR3-ANCA) from some patients with WG inhibit the proteolytic activity of PR3 and interfere with the inactivation of PR3 by the physiologic inhibitor, alpha 1-proteinase inhibitor (alpha 1-PI). We have studied the effect of PR3-ANCA on the enzymatic activity of PR3 and its correlation with disease activity in patients with WG. We purified IgG from 21 PR3-ANCA positive sera obtained from 17 patients with WG, and determined its effect on the esterolytic and proteolytic activity of purified human PR3 using Boc-Ala-O-Nitrophenyl ester and fluoresceinated-elastin as enzyme substrates. Controls included seven sera containing anti-MPO autoantibodies (MPO-ANCA) from patients with systemic vasculitis and seven ANCA-negative sera obtained from healthy individuals. We found that PR3-ANCA from 9 of the 17 patients significantly inhibited the activity of PR3. There was no correlation between the titers of PR3-ANCA and their inhibitory activity. For one extensively characterized autoantibody, the inhibition reached 70 to 95% at 20-fold molar excess of IgG to enzyme, with an apparent Kiapp of 56.5 microM. This inhibition was non-competitive in nature, and was additive to that produced by alpha 1-PI. A review of the clinical histories of the patients revealed a strong association between active WG and inhibitory autoantibodies.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Inhibition of proteinase 3 by ANCA and its correlation with disease activity in Wegener's granulomatosis. 764 21


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