Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0042384 (vasculitis)
 20,525 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Autoantibodies directed against polymorphonuclear neutrophils (PMN) have been observed in serum from patients with ulcerative colitis (UC), Crohn's disease (CD) and primary sclerosing cholangitis (PSC) using indirect immunofluorescence and fixed granulocyte ELISA. Our study demonstrates the presence in the serum of these patients of autoantibodies which bind to an azurophilic granule component distinct from proteinase 3, elastase and myeloperoxidase. These autoantibodies thus belong to the ANCA family, but their antigen specificity differs from the already characterized ANCA antigens. We have found that the same ANCA antigen target, named UC-antigen, was recognized by serum IgG from patients with UC, CD and PSC. It was purified by Matrex Gel Orange A dye affinity chromatography and subsequent immunoabsorption of contaminant proteinase 3 with immobilized anti-proteinase 3 MoAb. The identity between this UC antigen and cathepsin G was demonstrated by their coelution from Matrex Gel Orange A column and the parallel titration of cathepsin G-specific enzymatic activity and UC-ANCA binding, both in partially purified UC antigen and in highly pure cathepsin G. Furthermore, the use of cathepsin G ELISA confirmed that UC, CD and PSC patients' IgG did indeed bind to cathepsin G. Comparison of the results obtained with azurophilic granule- and cathepsin G-ELISA as well as inhibition of ANCA binding by anti-cathepsin G polyclonal antibodies, revealed that in some patients cathepsin G is the main azurophilic granule target of ANCA while others have other ANCA specificities. The fact that UC, CD and PSC are frequently associated with cathepsin G ANCA, while rarely occurring in other types of vasculitis, is intriguing but suggests that these diseases may have a common pathogenetic mechanism.
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PMID:Antineutrophil cytoplasmic antibodies (ANCA) directed against cathepsin G in ulcerative colitis, Crohn's disease and primary sclerosing cholangitis. 132 93

The specific antigens to antineutrophil cytoplasmic antibodies (ANCA) and their relations with renal diseases begin to be well-known. In patients with systemic vasculitis, two major antigens have been recognized: proteinase 3 and myoloperoxydase. These enzymes are located in the azurophilic granules of neutrophils and migrate to the surface of these cells when they are activated. Other antigens, such as elastase, lactoferrin, CAP57 and cathepsin G, have been identified, but they are less commonly encountered. The presence of ANCA is particularly frequent in Wegener's granulomatosis, microscopic periarteritis, crescentic necrotizing glomerulonephrites without immunoglobulin deposits; it is less frequent in periarteritis nodosa and in Churg-Strauss' syndrome. ANCA can now be considered as markers of vasculitis; they are related to disease activity and can be used to evaluate the effectiveness of treatments.
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PMID:[Anti-cytoplasmic antibodies of polynucle or "ANCA". A new class of autoantibodies]. 141 Nov 80

The antigenic specificity and clinical distribution of the antineutrophil cytoplasmic antibodies (ANCA) in kidney diseases have recently been extensively studied. In patients with systemic vasculitis, the great predominance of two major ANCA antigens, proteinase 3 (PR3) and myeloperoxidase (MPO), is now established. PR3 and MPO are colocalized in the azurophilic granules of neutrophils and translocated to the cell surface during activation, and thus are able to interact with autoantibodies after neutrophil preactivation. Furthermore, by comparison of amino acid and DNA sequences, it has been shown that PR3 is identical to myeloblastin, which has been described independently and is involved in the control of growth and differentiation of leukemic cells. Aside from the two major ANCA antigens, a number of neutrophil cytoplasmic antigens recognized by ANCA have been identified, including human leukocyte elastase, lactoferrin, CAP57, and cathepsin G. These rare ANCA specificities occur in a limited number of patients. The variety of ANCA antigen specificities contrasts, however, with the fact that the vast majority of ANCA-positive sera are monospecific for one single ANCA antigen. With regard to clinical distribution, ANCA have major diagnostic significance in the four conditions in which they are frequently detected: Wegener's granulomatosis (WG), Churg and Strauss Syndrome (CSS), microscopic periarteritis (MPA), and necrotic and crescentic glomerulonephritis (NCGN). However, the initial dichotomy between MPO-associated vasculitis (NCGN, MPA) and that associated with anti-PR3 antibodies (WG) appears far from absolute.
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PMID:Antigen specificities and clinical distribution of ANCA in kidney diseases. 172 65

In a serological laboratory with a routine service for determining autoantibodies to human neutrophils, antibodies giving a selective or preferential reaction with the nucleus or perinuclear area of neutrophils are not uncommon. The aim of this study was to look for clinical correlates with the presence of such neutrophil-reactive autoantibodies. The specificity of such antibodies for nuclear or cytoplasmic antigens was studied in 65 consecutive sera displaying nuclear/perinuclear reactivity at a titre of at least 80 using the indirect immunofluorescence technique (IIF) on ethanol-fixed leucocytes. The sera were also investigated by IIF on formalin-acetone fixed leucocytes and on HEp-2 cells. ELISA techniques were used to measure antibodies to azurophil granule constituents (ANCA), purified myeloperoxidase (MPO-ANCA), and lactoferrin (LF-ANCA). Furthermore a qualitative spot immunoassay was used for the detection of antibodies to alpha, beta, and gamma fractions, and the nuclear fraction of neutrophils, purified proteinase 3 (PR3), MPO, enolase, lysozyme, elastase, lactoferrin, and cathepsin G. The diagnoses linked to such GS-ANA/pANCA positivity were arthritides, vasculitides, inflammatory bowel disease and chronic hepatic conditions. MPO was the main antigen recognized in the vasculitis group, but apart from that, rather limited antigen reactivity was demonstrable by these techniques, lysozyme being the most frequently recognized autoantigen in patients with arthritides. Human lymphocytes served as a suitable control substrate when distinguishing between GS-ANA/pANCA and ANA, whereas HEp-2 cells usually could not be used if both classes of antibodies were present in a sample. Furthermore, formalin-acetone fixation is not recommended for routine use.
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PMID:Clinical correlates and substrate specificities of antibodies exhibiting neutrophil nuclear reactivity--a methodological study. 749 88

Anti-cathepsin G antibodies have been detected by using three different methods. i) Binding to azurophilic granules constituents after separation of purified alpha-granules on Matrex gel Orange A chromatography according to Kao. ii) Binding to azurophilic granules freezed and thawed after coating on ELISA plates. iii) Binding to purified cathepsin G in ELISA assay. Anti-cathepsin G antibodies were observed patient's sera with ulcerative colitis, primary sclerosing cholangitis, primary biliary cirrhosis and autoimmune hepatitis but not in controls or patients with chronic viral hepatitis or vasculitis.
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PMID:Methods of detection of anti-cathepsin G autoantibodies in human. 829 15

Recently it has been demonstrated that human antibody fragments with binding activities against self antigens can be isolated from repertoires of rearranged V genes from non-immunized humans. We have applied phage display technology to study the B cell repertoire for antibody activity against neutrophil cytoplasmic antigens. These antibodies may play an important role in Wegener's granulomatosis (WG) and related forms of vasculitides. Autoantibodies in patients with WG are directed against proteinase 3. The immunodominant antigen in other forms of vasculitis is myeloperoxidase, but the B cell response can also be directed against other neutrophil enzymes, e.g. lysozyme, human neutrophil elastase, lactoferrin and cathepsin G. We show here that anti-self reactivity against neutrophil cytoplasmic antigens can be detected in the rearranged V gene repertoire of healthy individuals and that the reactivity can be directed against structural related epitopes which are present on different neutrophil cytoplasmic antigens. The scFv with binding activities were sequenced and the V gene usage, the level of somatic mutations and the immunoserological characteristics of the antibody fragments are discussed. Further evidence is presented that antibody fragments consisting only of a heavy chain variable domain can recognize neutrophil cytoplasmic antigens in a specific manner. These single-domain antibody fragments were used in experiments designed to establish the relative role of the light chain variable domains in antigen binding.
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PMID:Molecular characteristics of anti-self antibody fragments against neutrophil cytoplasmic antigens from human V gene phage display libraries. 853 74

We isolated a 27-kD protein using cation exchange chromatography from an acid extract of neutrophil granules. N-terminal amino acid sequence analysis of the first 10 residues showed that this protein is azurocidin, a member of the family of neutral serine proteinase found in the neutrophil, which shares amino acid sequence homology with the three other neutral serine proteinases, elastase, proteinase 3 (PR3) and cathepsin G, but unlike them is without proteolytic activity. To test whether, in addition to these proteases, azurocidin might be a target for the humoral autoimmune responses associated with human vasculitis, 185 indirect immunofluorescence (IIF)-positive ANCA sera, made up of four groups of sera with specificities for PR3 (n=37), myeloperoxidase (MPO; n=50), bactericidal/permeability-increasing protein (BPI; n=41) and sera that recognized none of them (triple negative, n=57), and 46 normal sera were screened for IgG anti-azurocidin antibodies using an ELISA incorporating purified azurocidin. Twenty of the 185 IIF-positive sera and 2/46 normal sera displayed reactivity with azurocidin. Positive sera could blot the 27-kD band by Western blot analysis. Further study of the 20 positive sera revealed that: (i) 10 also had autoreactivity for MPO, of which six additionally recognized lactoferrin; (ii) two had reactivity with BPI; (iii) the remaining eight sera were positive only for azurocidin. All 20 sera were from patients with systemic vasculitis, and four of the six sera with triple reactivity (for azurocidin, MPO and lactoferrin) were from patients with hydralazine-induced vasculitis. We concluded that: (i) azurocidin is a novel ANCA antigen; (ii) anti-azurocidin antibodies from a subgroup of patients might represent the consequence of a drug-induced multi-clone activation.
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PMID:Azurocidin is a novel antigen for anti-neutrophil cytoplasmic autoantibodies (ANCA) in systemic vasculitis. 860 37

We determined the occurrence of antineutrophil cytoplasmic antibodies (ANCAs) and their specificities in 77 rheumatoid arthritis (RA) patients and compared them with 25 patients with psoriatic arthritis (Pso), 19 with drug-induced lupus erythematosus (DI-LE) and 11 with systemic lupus erythematosus (SLE). Thirty-two percent of RA patients had positive indirect immunofluorescence (IIF) stains (P or atypical ANCA). Twenty-nine per cent of patients with rheumatoid vasculitis (RAV), 48% with long-standing RA (LSRA) and 20% with early RA (Ely RA) had positive ANCAs compared with 4% of Pso patients, 47% of DI-LE patients and 45% of SLE patients. Western blotting (with polymorphonuclear cell extracts or alpha-granules) and alpha-granule enzyme-linked immunosorbent assay (ELISA) yielded variable results and proved unhelpful for characterizing the specificities of ANCAs. ELISAs based on commercial purified lactoferrin (LF), myeloperoxidase (MPO), human elastase (HLE) and cathepsin G (CG) showed that anti-HLE antibody was the most prevalent (14%) antibody in RA, followed by anti-MPO antibody and anti-LF antibody (10% each). Statistical analysis of antibody prevalence by clinical presentation showed that LSRA patients were more likely to have anti-HLE antibody and that DI-LE patients were more likely to have anti-CG antibody compared with the other patient groups. In lupus patients serial ELISA titration of ANCAs (LF and MPO) was found to be reliable for predicting the outcome. The overall incidence of ANCAs in RA patients was 33% by IIF.
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PMID:Antineutrophil cytoplasmic antibodies in rheumatoid arthritis patients. 862 21

Proteinase 3 is the major target antigen of antineutrophil cytoplasmic autoantibodies (ANCA) in Wegener's granulomatosis and is contained in the azurophilic granules of polymorphonuclear neutrophils, the dominant cell type in vascular lesions during the early stages of systemic vasculitis. This study questioned whether neutrophil lysosomal enzymes, once released at the site of inflammation, are able to potentiate the influx of additional neutrophils by enhancing the production of the chemotactic cytokine interleukin-8 (IL-8) by endothelial cells. Therefore, human umbilical vein endothelial cells in culture were incubated with varying concentrations of highly purified proteinase 3, human neutrophil elastase, and cathepsin G for different time periods. The supernatants were subsequently assessed for IL-8 antigen by using a sandwich ELISA. The presence of both proteinase 3 and elastase resulted in an increased production of IL-8, up to 15.6- and 4.2-fold, respectively, in a dose- and time-dependent fashion. Cathepsin G did not influence IL-8 production. Although the addition of an alpha 1-proteinase inhibitor completely abrogated elastase-mediated IL-8 production, it did not significantly influence the effect of proteinase 3. Both proteinase 3-and elastase-mediated production of IL-8 was inhibited by cycloheximide, indicating de novo synthesis. This was supported by the finding of increased IL-8 mRNA levels in proteinase 3-treated human umbilical vein endothelial cells by using Northern blot analysis. Taken together, the neutrophil lysosomal enzymes proteinase 3 and human neutrophil elastase may contribute to a self-perpetuating process of neutrophil recruitment in acute inflammation by increasing de novo synthesis of IL-8 by endothelial cells. The studies presented here also show that proteinase 3 mediates its effect independently of its enzymatic activity, indicating a hitherto unknown mode of action on endothelial cells.
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PMID:Proteinase 3, the major autoantigen of Wegener's granulomatosis, enhances IL-8 production by endothelial cells in vitro. 873 4

In this study of antineutrophil cytoplasmic antibody (ANCA)-associated diseases, we determined the prevalence of other autoantibodies and the antigen specificities of ANCA. ANA were common, occurring in 7 of 36 (19%) patients with Wegener's granulomatosis, in 16 of 34 (47%) patients with microscopic polyarteritis, in 6 of 11 (55%) patients with segmental necrotising glomerulonephritis and in 8 of 18 (44%) of those with ANCA-associated systemic vasculitis without renal involvement. ANA were associated more often with pANCA and microscopic polyarteritis than with cANCA (P < 0.05). Patterns were speckled (n = 23), homogeneous (n = 10) or nucleolar (n = 4). Anticardiolipin antibodies were also common, occurring in 10 of 25 (40%) patients with Wegener's granulomatosis, in 8 of 14 (57%) patients with microscopic polyarteritis and in 6 of 18 (33%) of those with a systemic vasculitis. However, anticardiolipin antibodies did not correlate with the presence of ANCA in any of the disease groups. Anti-GBM antibodies were demonstrated in only 2 of 25 (8%) patients with Wegener's granulomatosis, in 1 patient with microscopic polyarteritis (1/14, 7%) and in 1 with segmental necrotising glomerulonephritis (1/11, 9%). All four patients with anti-GBM antibodies had either cANCA or pANCA. In the second part of the study, the target antigens of ANCA were determined in Wegener's granulomatosis, microscopic polyarteritis, systemic vasculitis, inflammatory bowel disease, rheumatoid arthritis and systemic lupus erythematosus (SLE). Of the 19 sera with cANCA, 13 (68%) were directed against proteinase 3; other antigens were myeloperoxidase (1/19, 5%), elastase and lactoferrin together (1/19, 5%), lysozyme (1/19, 5%) or unknown (3/19, 16%). Of the 12 (58%) sera from patients with Wegener's granulomatosis who had cANCA, 7 bound to proteinase 3. Antimyeloperoxidase antibodies were present in 14 of 45 (31%) sera with pANCA; other antigens were proteinase 3 (5/45, 11%), elastase (3/45, 78%), lactoferrin (1/45, 2%), cathepsin G (5/45, 11%) or unknown (17/45, 38%). Antimyeloperoxidase antibodies were common in microscopic polyarteritis (6/14, 43%) and systemic vasculitis (5/16, 31%). However, the majority of target antigens in systemic vasculitis and rheumatoid arthritis with pANCA were not determined. "Atypical" ANCA were present in four patients, one with inflammatory bowel disease (1/8, 13%) and three with SLE (3/15, 20%). The specificities were cathepsin G, cathepsin G plus lactoferrin, or unknown in two sera. A recent report has suggested that bactericidal/permeability-increasing protein may be the target in patients with inflammatory bowel disease.
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PMID:Autoantibodies and target antigens in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides. 889 75


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