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| 2. |
- Csernok, E, et al.
(författare)
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Evaluation of capture ELISA for detection of antineutrophil cytoplasmic antibodies directed against proteinase 3 in Wegener's granulomatosis: first results from a multicentre study
- 2004
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Ingår i: Rheumatology. - : Oxford University Press (OUP). - 1462-0332 .- 1460-2172. ; 43:2, s. 174-180
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To evaluate the performance characteristics of direct and capture ELISA for the detection of PR3-ANCA in Wegener's granulomatosis (WG) in international ANCA reference laboratories. Methods: Serum samples were derived from patients with histological and clinical diagnosis of WG (n = 60), rheumatoid arthritis (RA) (n = 30) and healthy controls (n = 30). Each of them was tested for the presence of ANCA by indirect immunofluorescence technique (IFT), direct and capture ELISA in six international reference laboratories (Massachusetts General Hospital, Boston; Wieslab AB, Lund; University of Maastricht; University Hospital Groningen; Mayo Clinic, Rochester; Rheumaklinik Bad Bramstedt/University of Schleswig-Holstein Campus Lubeck). Each centre tested the sera according to their house protocols of IFT and ELISA. The diagnostic performance of each test was estimated by receiver operating characteristic curve analysis and sensitivity and specificity in detection of ANCA/PR3-ANCA were calculated for the respective methods. Results: In patients histologically and clinically known as WG, the detection of ANCA by IFT varied between 52 and 83% among the participating centres. PR3-ANCA positivity with the different ELISAs ranged from 53 to 80% in direct ELISA and from 72 to 76% in capture ELISA. While most capture ELISAs successfully detected PR3-ANCA, there were significant differences between IFT and direct ELISA results between laboratories. ROC curve analysis demonstrated that in five of six laboratories the overall diagnostic performance of capture ELISA was superior to IFT and direct ELISA, respectively. Conclusion: Capture ELISA is a highly sensitive assay for detection of PR3-ANCA in WG and should be used in conjunction with compatible clinical picture and histological evidence.
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| 3. |
- Gisslen, K, et al.
(författare)
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Relationship between anti-neutrophil cytoplasmic antibody determined with conventional binding and the capture assay, and long-term clinical course in vasculitis
- 2002
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Ingår i: Journal of Internal Medicine. - : Wiley. - 1365-2796 .- 0954-6820. ; 251:2, s. 129-135
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Tidskriftsartikel (refereegranskat)abstract
- Objectives. To evaluate the relationship between anti-neutrophil cytoplasmic antibody (ANCA) measured with two different methods and long-term clinical course in vasculitis. Design. Retrospective determination of ANCA with two different assays for detection of PR3-ANCA, conventional direct binding ELISA and capture ELISA using monoclonal antibodies against PR3. The 245 ANCA determinations were performed from frozen blood samples collected three to four times a year in each patient. Setting. Department of Nephrology at a Swedish University Hospital. Subjects. A total of 10 ANCA-positive patients with vasculitis caused by Wegener's granulomatosis (WG) or microscopic polyarteritis (MPA) and a very long follow-up time (mean 9 years, range 5-15.5 years). Results. The total number of episodes with active vasculitis was 29 and all of them (100%) were detected by the capture technique whilst the conventional technique detected 23 (79%). The mean number of episodes with active disease requiring treatment with steroids and cytotoxic drugs was three per patient (range 1-6). At the time of clinical relapse of the vasculitis disease. the ANCA titre using the capture technique was either increasing or showed a very high value in all cases. The pattern of capture ANCA response could be subdivided into three categories: a close (four patients), an intermediate (three patients), and no (three patients) relationship between capture ANCA level and long-term clinical course. Conclusion. Detection of PR3-ANCA by the capture ELISA showed a higher sensitivity than that obtained by the direct ELISA in diagnosing relapse during follow-up of patients with vasculitis. The specificity of the capture ANCA was, however, low. as high levels occurred in patients without clinical disease activity.
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| 4. |
- Gunnarsson, Andreas, et al.
(författare)
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Molecular properties of the Goodpasture epitope
- 2000
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Ingår i: Journal of Biological Chemistry. - 1083-351X. ; 275:40, s. 30844-30848
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Tidskriftsartikel (refereegranskat)abstract
- Goodpasture disease fulfils all criteria for a classical autoimmune disease, where autoantibodies targeted against the non-collagenous domain of the alpha3-chain of collagen IV initiates an inflammatory destruction of the basement membrane in kidney glomeruli and lung alveoli. This leads to a rapidly progressive glomerulonephritis and severe pulmonary hemorrhage. Previous studies have indicated a limited epitope for the toxic antibodies in the N-terminal part of the non-collagenous domain. The epitope has been partially characterized by recreating the epitope in the non-reactive alpha1-chain by exchanging nine residues to the corresponding ones of alpha3. In this study we have investigated to what extent each of these amino acids contribute to the antibody binding in different patient sera. The results show that seven of the nine substitutions are enough to get an epitope that is recognized equally well as the native alpha3-chain by all sera from 20 clinically verified Goodpasture patients. Furthermore, the patient sera reactivity against the different recombinant chains used in the study are very similar, with some minor exceptions, strongly supporting a highly defined and restricted epitope. We are convinced that the restriction of the epitope is of significant importance for the understanding of the etiology of the disease. Thereby also making every step on the way to characterization of the epitope a crucial step on the way to specific therapy for the disease.
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| 5. |
- Jais, JP, et al.
(författare)
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X-linked Alport syndrome: Natural history and genotype-phenotype correlations in girls and women belonging to 195 families: A "European community Alport syndrome concerted action" study
- 2003
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Ingår i: Journal of the American Society of Nephrology. - 1046-6673. ; 14:10, s. 2603-2610
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Tidskriftsartikel (refereegranskat)abstract
- Alport syndrome (AS) is a type IV collagen hereditary disease characterized by progressive hematuric nephritis, hearing loss, and ocular changes. Mutations in the COL4A5 collagen gene are responsible for the more common X-linked dominant form of the disease characterized by much less severe disease in girls and women. A "European Community Alport Syndrome Concerted Action" (ECASCA) group was established to delineate the Alport syndrome phenotype in each gender and to determine genotype-phenotype correlations in a large number of families. Data concerning 329 families, 250 of them with an X-linked transmission, were collected. Characteristics of heterozygous girls and women belonging to the 195 families with proven COL4A5 mutation are compared with those of hemizygous boys and men. Hematuria was observed in 95% of carriers and consistently absent in the others. Proteinuria, hearing loss, and ocular defects developed in 75%, 28%, and 15%, respectively. The probability of developing end-stage renal disease or deafness before the age of 40 yr was 12% and 10%, respectively, in girls and women versus 90 and 80%, respectively, in boys and men. The risk of progression to end-stage renal disease appears to increase after the age of 60 yr in women. Because of the absence of genotype-phenotype correlation and the large intrafamilial phenotypic heterogeneity, early prognosis of the disease in X-linked Alport syndrome carriers remains moot. Risk factors for developing renal failure have been identified: the occurrence and progressive increase in proteinuria, and the development of a hearing defect.
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| 6. |
- Ohlsson, Sophie, et al.
(författare)
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Circulating cytokine profile in anti-neutrophilic cytoplasmatic autoantibody-associated vasculitis: prediction of outcome?
- 2004
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Ingår i: Mediators of Inflammation. - : Hindawi Limited. - 0962-9351 .- 1466-1861. ; 13:4, s. 275-283
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: The anti-neutrophilic cytoplasmatic autoantibody-associated vasculitides (AASV) are diseases of relapsing-remitting inflammation. Here we explore the cytokine profile in different phases of disease, looking for pathogenic clues of possible prognostic value. Results: Interleukin (IL)-6, IL-8 and IL-10 were significantly elevated in plasma. Patients in the stable phase who subsequently developed adverse events had higher IL-8 values. Patients in the stable phase who relapsed within 3 months had lower IL-10 values and higher IL-6 levels. Conclusions: Patients with AASV have raised circulating cytokine levels compared with healthy controls, even during remission. Raised IL-8 seems associated with poor prognosis. Lower levels of IL-10 and higher levels of IL-6 herald a greater risk of relapse. Patients with systemic vasculitis in clinical remission have persistent disease activity, kept under control by inhibitory cytokines.
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| 7. |
- Ohlsson, Sophie, et al.
(författare)
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Novel distribution of the secretory leucocyte proteinase inhibitor in kidney
- 2001
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Ingår i: Mediators of Inflammation. - : Hindawi Limited. - 0962-9351 .- 1466-1861. ; 10:6, s. 347-350
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Tidskriftsartikel (refereegranskat)abstract
- The secretory leucocyte proteinase inhibitor (SLPI) is a low molecular weight, tissue-specific inhibitor of, for example, elastase and cathepsin G, which also have antimicrobial capacity. SLPI has been localised to the respiratory, gastrointestinal and genital tracts, but so far not to the kidney. The presence of SLPI in renal tubuli cells was demonstrated using immunohistochemistry and, by means of in situ hybridisation on human renal biopsies, we were able to demonstrate SLPI production. In various inflammatory conditions in the kidneys, the protease-antiprotease balance is disturbed. For this reason, as well as the possible role in the defence against ascending urinary tract infections, it is interesting to establish a source of SLPI in renal tubuli cells.
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| 8. |
- Persson, Ulf, et al.
(författare)
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Patients with Goodpasture's disease have two normal COL4A3 alleles encoding the NC1 domain of the type IV collagen {alpha}3 chain.
- 2004
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Ingår i: Nephrology Dialysis Transplantation. - : Oxford University Press (OUP). - 1460-2385 .- 0931-0509. ; 19:8, s. 2030-2035
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Tidskriftsartikel (refereegranskat)abstract
- Background. Goodpasture's disease (GP) is a rare but severe disease characterized by anti-glomerular basement membrane antibodies, rapidly progressive glomerulonephritis and lung haemorrhage. The autoantibodies are restricted to a narrow epitope region on the NC1 domain of the alpha3 chain of type IV collagen. GP is strongly associated with major histocompatibility complex (MHC) allele HLA DRB1-15. Recent research, however, has failed to identify a T-cell epitope with molecular characteristics that explain the relationship between the MHC class II molecule and the autoantibody generation. We hypothesized that an as yet unidentified sequence variant in exons 48-52 of the COL4A3 gene that encodes the NC1 domain of the type IV collagen alpha3 chain could generate a new peptide sequence that, through interaction with specific MHC class II molecules, would increase the risk of developing GP. Methods. All patients previously treated for GP at the Lund and Malmo University Hospitals, who were alive at the time of the study, were asked to participate. DNA was extracted from leukocytes and subjected to genomic tissue typing and sequencing of the COL4A3 gene exons 48-52. Results. All 15 patients in the study had a nucleotide sequence in the COL4A3 gene encoding a protein identical to GenBank entry NM_000091. HLA D allele distribution was in line with previous publications, showing a strong positive association between HLA DRB1-15, HLA DQB1-6 and GP (P < 0.02). Of the 15 GP patients, 73% carried HLA DRB1-15 and 87% carried the HLA DQB1-6 antigen. Corresponding figures for the controls were 27 and 50%. Conclusion. This study effectively falsifies the hypothesis that a minor alteration in the COL4A3 gene could be a major factor in the aetiology of GP. Scandinavian GP patients have an MHC distribution similar to that which has been described previously for Anglo-Saxon patients.
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| 9. |
- Segelmark, Mårten, et al.
(författare)
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The prognostic significance in Goodpasture's disease of specificity, titre and affinity of anti-glomerular-basement-membrane antibodies.
- 2003
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Ingår i: Nephron Clinical Practice. - : S. Karger AG. - 1660-2110. ; 94:3, s. 59-68
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Tidskriftsartikel (refereegranskat)abstract
- Background: The nephrotoxic potential of anti-glomerular-basement-membrane (GBM) antibodies has been demonstrated in numerous animal experiments. However, it is not known to what extent the properties of circulating anti-GBM antibodies in human disease reflect the severity of the disease and predict the outcome. Methods: Clinical data were collected for 79 Swedish patients for whom a positive result had previously been obtained with anti-GBM ELISA. In stored sera from the patients, we measured antibody concentration, specificity and affinity together with antineutrophil cytoplasmic antibodies and alpha(1)-antitrypsin phenotype. Results: Six months after diagnosis, 27 (34%) were dead, 32 (41%) were on dialysis treatment and only 20 (25%) were alive with a functioning native kidney. The best predictor for renal survival was renal function at diagnosis. In patients who were not dialysis dependent at diagnosis however, renal survival was associated with a lower concentration of anti-GBM antibodies, a lower proportion of antibodies specific for the immunodominant epitope and the histological severity of the renal lesion. The only factor that correlated with patient survival was age. Conclusions: Immunochemical properties of autoantibodies do not affect patient survival in anti-GBM disease but seem to be a factor in renal survival in patients detected before renal damage is too advanced. Copyright (C) 2003 S. Karger AG, Basel.
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