Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.11.1.7 (peroxidase)
65,474 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Wegener's granulomatosis (WG), microscopic polyangiitis (MPA) and the Churg-Strauss syndrome (CSS) are small vessel vasculitides associated with anti-neutrophil cytoplasmic antibodies (ANCA). Cytoplasmic (c)-ANCA mainly target proteinase 3 (PR3) and are often observed in WG patients, while perinuclear (p)-ANCA predominantly bind to myeloperoxidase (MPO) and are common in patients with MPA and CSS. It is suspected that a genetic background contributes to disease formation since the diseases are more prevalent in Caucasian populations. This article provides a detailed review of the genetic impact of the pathogenesis and prognosis of ANCA-associated vasculitides. Alpha-1 anti-trypsin is the physiological inhibitor of PR3 and carriage of the defective allele PI*Z was observed as the first genetic risk factor for the development of PR3-ANCA-associated vasculitis. Expression analyses have revealed that PR3 surface expression is genetically determined. Elevated levels of PR3 expression have been observed in WG patients and high levels of PR3 expression corresponded to increased risk of disease relapses. Furthermore, the non-carriage of CTLA-4 allele 86 was associated with WG formation, while homocygotic carriage of the CCR5 allele delta 32 seemed to prevent ANCA-negative WG. MPO-ANCA vasculitides were associated with certain alleles of CD18 polymorphisms. Lack of or only weak allelic associations of ANCA-vasculitides with polymorphic cytokine, HLA, and Fcgamma receptor genes have been shown. Although, in practice, it is sometimes difficult to differentiate between WG and MPA, the diseases appear to be based on different genetic backgrounds.
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PMID:Genetic impact of pathogenesis and prognosis of ANCA-associated vasculitides. 1567 25

Antineutrophil cytoplasmic antibodies (ANCA) are a sensitive and specific marker for ANCA-associated systemic vasculitis. Using indirect immunofluorescence on ethanol-fixed neutrophils, two major fluoroscopic patterns can be recognised: a diffuse cytoplasmic staining (C-ANCA), and a perinuclear/nuclear staining (P-ANCA). In patients with vasculitis, more of 90% of C-ANCA are directed against proteinase 3 (PR3-ANCA) whereas approximately 80-90% of P-ANCA recognise myelperoxidase (MPO-ANCA). Although C-ANCA (PR3-ANCA) is preferentially associated with Wegener's granulomatosis (WG), and P-ANCA (MPO-ANCA) with microscopic polyangiitis (MPA), idiopathic necrotising crescentic glomerulonephritis (iNCGN) and Churg-Strauss syndrome (CSS), there is not absolute specificity. Between 10-20% of patients with classical WG show P-ANCA (MPO-ANCA), and even a larger percentage of patients with MPA or CSS have C-ANCA (PR3-ANCA). Furthermore, it should be stressed that approximately 10-20% of patients with WG or MPA (and 40-50% of cases of CSS) have negative assay for ANCA. The best diagnostic performance is obtained when indirect immunofluorescence is combined with PR3 and MPO-specific ELISAs. ANCA with different and unknown antigen specificity are found in a variety of conditions other than AASV, including inflammatory bowel diseases, other autoimmune diseases, and infections where their clinical significance is unclear. ANCA levels are useful to monitor disease activity but should not be used by themselves to guide treatment. A significant increase in ANCA titres, or the reappearance of ANCA, should alert the clinicians and lead to a stricter patient control.
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PMID:Antineutrophil cytoplasmic antibodies (ANCA). 1580 10

Wegener's granulomatosis, microscopic polyangiitis, Churg-Strauss syndrome, and idiopathic pauci-immune necrotizing crescentic glomerulonephritis are associated with myeloperoxidase (MPO)-specific anti-neutrophil cytoplasmic autoantibodies (ANCAs). Clinical and experimental evidence indicates that ANCA and proinflammatory stimuli of infectious origin act synergistically to cause vasculitis. We tested this hypothesis in a recently developed mouse model of anti-MPO IgG-induced glomerulonephritis by using bacterial lipopolysaccharide (LPS) as the proinflammatory stimulus. Systemic administration of LPS dose dependently increased renal injury induced by anti-MPO IgG as demonstrated by increased glomerular crescent formation and glomerular necrosis. In the early phase, LPS enhanced anti-MPO IgG-induced glomerular neutrophil accumulation. Furthermore, a transient induction of circulating tumor necrosis factor (TNF)-alpha levels, followed by a marked increase in circulating MPO levels, was observed on administration of LPS. In vitro, anti-MPO IgG induced a respiratory burst in murine neutrophils only after priming with TNF-alpha. Finally, anti-TNF-alpha treatment attenuated, but did not prevent, the LPS-mediated aggravation of anti-MPO IgG-induced glomerulonephritis. In conclusion, our study demonstrates that ANCA and proinflammatory stimuli act synergistically to induce vasculitic disease and suggests potential benefits of inhibiting TNF-alpha bioactivity in treating human ANCA-associated necrotizing crescentic glomerulonephritis.
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PMID:Aggravation of anti-myeloperoxidase antibody-induced glomerulonephritis by bacterial lipopolysaccharide: role of tumor necrosis factor-alpha. 1597 51

There is substantial evidence that T-cells are off balance in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides. Genetic risk factors may influence shaping of the TCR repertoire and regulatory control of T-cells in predisposed individuals. T-cells are found in inflammatory lesions. Vigorous Th1-type responses are seen in Wegener's granulomatosis and microscopic angiitis, whereas a Th2-type response predominates in Churg-Strauss syndrome. Oligoclonality and shortened telomers indicate antigen-driven clonal expansion and replicative senescence of T-cells in ANCA-associated vasculitides. Potent CD28(-) Th1-type cells displaying an effector-memory/late differentiated, senescent phenotype are expanded in peripheral blood and are found in granulomatous lesions in Wegener's granulomatosis. Differences in proliferative peripheral blood T-cell responses to the autoantigens proteinase 3 (PR3)- and myeloperoxidase (MPO) have not consistently been detected between patients with ANCA-associated vasculitides and healthy controls in vitro. To recognize an autoantigen, break tolerance, and maintain autoimmune disease T- and B-cells require particular triggers and lymphoid structures. There is preliminary evidence of lymphoid-like structures and possible maturation of autoreactive PR3-ANCA-specific B-cells in granulomatous lesions in Wegener's granulomatosis. Alteration of the T-cell response and anomalous autoantigen-presentation in lymphoid-structures could facilitate development of autoimmune disease in ANCA-associated vasculitides.
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PMID:Off balance: T-cells in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides. 1599 83

The value of anti-neutrophil cytoplasmic antibody (ANCA) detection for monitoring disease activity in ANCA-associated systemic vasculitis (AASV) remains controversial. The aim of our work was to rate the performance of a new automated fluorescence PR3 and MPO-ANCA immunoassay (EliA) for monitoring disease activity in AASV. We evaluated 100 serum samples from 71 AASV patients (with Wegener's granulomatosis, microscopic polyangiitis, and Churg-Strauss syndrome) as well as sera from 58 pathological and 35 normal controls. In addition to PR3 and MPO-ANCA EliA, we performed indirect immunofluorescence and "homemade" PR3 and MPO-ANCA ELISA tests. In AASV patients, ANCA levels were correlated with disease activity, according to the Birmingham Vasculitis Activity Score (BVAS). We derived cutoff limits from receiver operating characteristic (ROC) curve analysis comparing AASV with pathological controls. Our results showed that EliA and ELISA had comparable sensitivity (76%) and specificity (95%). The analysis of active versus inactive status and correlation with ANCA levels showed a clear difference between BVAS Group I (score < or = 4) and BVAS Group II (scores > 4) (AUC = 0.86 vs. 0.72; relative risk [RR] = 2.4; P < 0.0001) for PR3-ANCA, but not for MPO-ANCA (AUC = 0.94 vs. 0.87; RR = 1.48; P = 0.46). Serial serum samples from 16 patients were examined in detail. For the majority of patients, for both PR3 and MPO-ANCA, change in titer was strongly associated with change in BVAS score. Our data showed a good correlation between ANCA titer (especially for PR3) and AASV disease activity. We recommend that ANCA titer be used to monitor AASV disease activity with the caveat that a few exceptions, in particular with MPO-ANCA, are possible.
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PMID:Value of a new automated fluorescence immunoassay (EliA) for PR3 and MPO-ANCA in monitoring disease activity in ANCA-associated systemic vasculitis. 1601 33

Vasculitis is inflammation of blood vessels and can affect any type of vessel in any organ. Pulmonary vasculitis usually is a component of a systemic small vessel vasculitis. Three major forms of small vessel vasculitis that often affect the lungs are Wegener's granulomatosis, microscopic polyangiitis, and Churg-Strauss syndrome. These forms of vasculitis are strongly associated with antineutrophil cytoplasmic autoantibodies (ANCA) directed against enzymes contained in the primary granules of neutrophils and peroxidase-positive lysosomes of monocytes. This review discusses the evidence for a pathogenic role of ANCA. In vitro, ANCAs can activate cytokine-primed neutrophils and monocytes resulting in oxygen radical formation and release of lysosomal enzymes. In vivo, antimyeloperoxidase ANCA has been shown to induce crescentic glomerulonephritis and systemic vasculitis. Overall, the available data suggest that ANCA are indeed a pathogenic factor in the development of small-vessel vasculitis. Antiglomerular basement membrane (anti-GBM) disease also causes pulmonary vasculitis through immune attack on alveolar capillaries and glomerulonephritis through antibody mediated injury to glomerular capillaries. Thus, there is evidence that antibodies are important pathogenic factors in both ANCA disease and anti-GBM disease, however, there are also indications that T cells may play important pathogenic roles in both categories of disease as well.
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PMID:Pathogenesis of pulmonary vasculitis. 1608 92

First described in 1951 as an allergic and granulomatous angiitis, Churg-Strauss syndrome (CSS) is a small-vessel vasculitis. Mean age at the time of diagnosis is approximately 50 years, with a sex ratio around 1. Asthma is the central feature of CSS and precedes the systemic manifestations in almost all cases, whereas 70% of the patients have maxillary sinusitis, allergic rhinitis, and/or sinus polyposis. General symptoms are frequent, and associated with pulmonary infiltrates in 38 to 77% of the patients; peripheral neuropathy, usually mononeuritis multiplex, in 64 to 75%; skin involvement in 40 to 70%; and gastrointestinal tract symptoms in 37 to 62%. Cardiac involvement is common, with pericarditis in 23% of the patients and myocarditis in 13%, and represents the primary cause of mortality. Hypereosinophilia is the main biological feature of CSS, whereas antineutrophil cytoplasm antibodies (ANCA), especially anti-myeloperoxidase (MPO), are found in one third to one half of the patients. Triggering factors, such as vaccination, desensitization, or exposure to leukotriene-receptor antagonists, have been suspected as contributing to the development of CSS, but its etiology has not yet been fully elucidated. T-helper type 2 (Th2) lymphocytes, by analogy with the pathogenesis of asthma, eosinophils infiltrating tissues, and anti-MPO ANCA are probably implicated in the pathogenesis of vasculitic lesions. CSS usually responds rapidly to corticosteroids. Adjunction of cyclophosphamide is indicated when at least one factor of poor prognosis is present. With treatment, remission is obtained in more than 80% of the patients, but it is often impossible to withdraw corticosteroids completely because of residual asthma. Relapses occur in 25% of the patients, half during the first year. The 10-year survival rate was 79% for our patients, with 73% of them requiring low-dose prednisone maintenance therapy for persistent asthma.
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PMID:Churg-strauss syndrome. 1608 97

Clinical and serological profiles of idiopathic and drug-induced autoimmune diseases can be very similar. We compared data from idiopathic and antithyroid drug (ATD)-induced antineutrophil cytoplasmic antibody (ANCA)-positive patients. From 1993 to 2003, 2474 patients were tested for ANCA in the Laboratory for Allergy and Clinical Immunology in Belgrade. Out of 2474 patients, 72 (2.9%) were anti-proteinase 3 (PR3)- or anti-myeloperoxidase (MPO)-positive and their clinical and serological data were analyzed. The first group consisted of ANCA-associated idiopathic systemic vasculitis (ISV) diagnosed in 56/72 patients: 29 Wegener's granulomatosis (WG), 23 microscopic polyangiitis (MPA) and four Churg-Strauss syndrome. The second group consisted of 16/72 patients who became ANCA-positive during ATD therapy (12 receiving propylthiouracil and four receiving methimazole). We determined ANCA and antinuclear (ANA) antibodies by indirect immunofluorescence; PR3-ANCA, MPO-ANCA, anticardiolipin (aCL) and antihistone antibodies (AHA) by ELISA; and cryoglobulins by precipitation. Complement components C3 and C4, alpha-1 antitrypsin (alpha1 AT) and C reactive protein (CR-P) were measured by nephelometry. Renal lesions were present in 3/16 (18.8%) ATD-treated patients and in 42/56 (75%) ISV patients (p <0.001). Skin lesions occurred in 10/16 (62.5%) ATD-treated patients and 14/56 (25%) ISV patients (p <0.01). ATD-treated patients more frequently had MPO-ANCA, ANA, AHA, aCL, cryoglobulins and low C4 (p <0.01). ISV patients more frequently had low alpha1 AT (p = 0.059) and high CR-P (p <0.001). Of 16 ATD-treated patients, four had drug-induced ANCA vasculitis (three MPA and one WG), while 12 had lupus-like disease (LLD). Of 56 ISV patients, 13 died and eight developed terminal renal failure (TRF). There was no lethality in the ATD-treated group, but 1/16 with methimazole-induced MPA developed pulmonary-renal syndrome with progression to TRF. ANCA-positive ISV had a more severe course in comparison with ATD-induced ANCA-positive diseases. Clinically and serologically ANCA-positive ATD-treated patients can be divided into two groups: the first consisting of patients with drug-induced WG or MPA which resemble ISV and the second consisting of patients with LLD. Different serological profiles could help in the differential diagnosis and adequate therapeutic approach to ANCA-positive ATD-treated patients with symptoms of systemic disease.
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PMID:Antineutrophil cytoplasmic antibody (ANCA)-associated autoimmune diseases induced by antithyroid drugs: comparison with idiopathic ANCA vasculitides. 1620 47

The pathogenesis of different types of systemic vasculitis positive for antineutrophil cytoplasmic antibodies (ANCA) remains incompletely understood. ANCA constitute a heterogeneous group of antibodies that are associated with different types of small-vessel vasculitis, including Wegener's granulomatosis (WG), microscopic polyangiitis (MPA) and Churg-Strauss syndrome (CSS). Anti-proteinase 3 ANCA are present in more than 90% of patients with systemic WG, and anti-myeloperoxidase (MPO) ANCA in 50-75% of those with MPA and 40-60 % of those with CSS. The pathogenic role of ANCA has been well documented in vivo: passive transfer of anti-MPO ANCA in an MPO knockout mouse model immunized with MPO is sufficient to induce the disease. In vitro, mouse and human anti-proteinase 3 ANCA can activate neutrophils primed with TNF-a and contribute to vasculitic lesions. T-cells are also involved: type 1 helper cytokines have been detected in tissue lesions of limited forms of WG, while type 2 helper cytokines have been identified in its systemic forms. Eosinophils may play a key role in the development of vasculitic lesions in CSS, although this remains to be proved.
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PMID:[Pathogenesis of primary systemic vasculitides (I): ANCA-positive vasculitides]. 1622 57

Churg-Strauss syndrome was originally called "allergic granulomatosis and angiitis," describing the combination of eosinophilic inflammation, extravascular granulomas, and necrotizing vasculitis occurring in patients with severe asthma. It is now classified as a small-vessel vasculitis and, together with Wegener's granulomatosis and microscopic polyangiitis, as one of the vasculitides associated with antineutrophil cytoplasmic autoantibodies (ANCA). Glucocorticoid-sparing agents used in the treatment of asthma, such as leukotriene receptor antagonists, may unmask this particular form of vasculitis as oral glucocorticoids are withdrawn. ANCA occur in 40-75% of patients with active disease and typically react with myeloperoxidase. Patients' symptoms are defined by various degrees of eosinophilic inflammation and necrotizing vasculitis, which may affect any organ. On presentation, Churg-Strauss syndrome needs to be differentiated from other eosinophilic pneumonias, idiopathic hypereosinophilic syndrome, and Wegener's granulomatosis and microscopic polyangiitis. Churg-Strauss syndrome remains a rare disease with a poorly understood pathogenesis. Treatment consists primarily of glucocorticoids. Patients who have ANCA at the time of presentation should be treated according to the treatment principles for ANCA-associated vasculitides. However, the exact role of glucocorticoid-sparing immunosuppressive agents and treatment options for refractory disease remain poorly studied.
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PMID:Churg-Strauss syndrome. 1661 66


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