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:3.4.24.3 (collagenase)
18,340 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Anti-basement membrane antibodies are now being associated with an increasing spectrum of disease, including Goodpasture's syndrome, rapidly progressive and occasionally milder forms of glomerulonephritis (GN), tubulointerstitial nephritis, pulmonary damage, and potentially other forms of tissue injury. We have developed a radioimmunoassay to detect circulating antiglomerular basement membrane (GBM) antibodies. The antigens for this assay are derived from the noncollagenous portion of the GBM remaining after collagenase digestion. After immunoabsorptive purification, the major antigens precipitated by human anti-GBM antibodies can be characterized by polyacrylamide gel electrophoresis (PAGE) into an unresolved high molecular weight fraction and two antigenic peaks of 54,000 and 27,000 daltons. The noncollagenous nature of the antigenic material has been confirmed by amino acid analysis. The radiolabelled antigen has proven useful in detecting circulating anti-GBM antibodies in over 500 patients. The assay is of use in monitoring the activity of disease and judging the patient's response to therapy. It is also useful in determining the timing of renal transplantation, if required. Differences in antigenic content of glomerular and tubular basement membranes (TBM) have been noted between individuals. These antigenic differences, under certain circumstances, can lead to the induction of anti-basement membrane antibody responses after transplantation.
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PMID:Anti-basement membrane antibodies in immunologic renal disease. 702 Jun 72

The immune nephritis antibody response against the collagen and glycoprotein portions of the glomerular basement membrane (GBM) has been monitored by using either type IV collagen prepared from pepsin digests or a collagenase digest of GBM. Sheep immunized with GBM, according to Steblay, respond by developing antibodies directed against the collagen and the glycoprotein portions, respectively. Circulating antibodies directed against sheep GBM structures were not demonstrated until overt clinical disease with high serum creatinine values and proteinuria. Such antibodies could, however, be eluted from the kidneys, where they adsorbed in a linear fashion as demonstrated by immunofluorescence microscopy. In spontaneous human nephritis in Goodpasture's syndrome, circulating antibodies were present at the time of diagnosis. These antibodies reacted only with the glycoprotein portion of the basement membrane, and not with the type IV collagen.
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PMID:Different antibody response in experimental and spontaneous glomerulonephritis. 732 28

The Goodpasture's epitope has been mapped to the alpha 3 non-collagenous chain (NC1) of type (IV) collagen [alpha 3col(IV)]. We have developed a model of experimental autoimmune glomerulonephritis (EAG) in rats immunized once with collagenase solubilized GBM (csGBM). Engelbreth-Holm-Swarm (EHS) tumor contains abundant col(IV) with little or no alpha 3col(IV). To test the hypothesis that antigens related to Goodpasture epitope are required to produce EAG in our model, we immunized rats once with 40 micrograms csEHS. Positive controls immunized with csGBM developed typical EAG with GBM bound antibody, proteinuria, and glomerulonephritis. EHS rats developed circulating and bound antibody to mesangium and tubular basement membrane with minimal GBM deposits, but did not develop proteinuria or glomerulonephritis. Although circulating antibody in EHS rats bound to csGBM by ELISA, there was no binding in ELISA to M2 antigen containing the Goodpasture epitope while EAG rat's serum did bind. By Western blot with antisera to Goodpasture epitope, EHS antigen was less complex than GBM in the monomer/dimer regions and appeared to lack NC1 corresponding to alpha 3col(IV). Blotting with sera from EHS rats demonstrated reactivity to various components of GBM but not to alpha 3col(IV). EAG sera and renal eluates bound to alpha 3col(IV). EAG rats evidenced cell mediated immunity while EHS rats did not (stimulation index EHS 1.1, EAG rats 8.0).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Study of EHS type IV collagen lacking Goodpasture's epitope in glomerulonephritis in rats. 753 54

Sera from patients with antiglomerular basement membrane (anti-GBM) antibodies associated with Goodpasture syndrome (GP) or glomerulonephritis were tested by ELISA and electroimmunoblot against whole basement membrane collagen (type IV) isolated from bovine anterior lens capsule (ALC) and bacterial collagenase resistant domains of the collagen molecule, that is, the NC-1 and 7-S domains isolated from either ALC or bovine and human glomerular basement membrane (GBM). Reactivity was high with the NC-1 domain by both the ELISA and the electroimmunoblot techniques. Some of the anti-GBM sera reacted with both the NC-1 and 7-S domains of both human and bovine type IV collagen. At a time when the patients' sera reacted weakly with a collagenase digest of human GBM using a radioimmunoassay, the reactivity with the NC-1 domain was also low, but some of the sera continued to react with the 7-S domain. The data suggest that there may be heterogeneity in the nature of autoantibodies with respect to collagen type IV domain reactivity in the sera of patients with anti-GBM antibody disease.
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PMID:Heterogeneity of antibodies in Goodpasture syndrome reacting with type IV collagen. 767 59

Goodpasture's disease is a rare form of glomerulonephritis characterized by the production of autoantibodies to the glomerular basement membrane (GBM). In order to understand the development of autoimmunity to the GBM, it is important to examine mechanisms underlying T cell responses to the autoantigen. A MoAb P1, with the same specificity as patients' autoantibodies, was used to affinity-purify the antigen from collagenase-digested human GBM. This material was enriched in the NC1 domain of the alpha 3 chain of type IV collagen (alpha 3(IV)NC1), known to be the principal target of anti-GBM antibodies, but also contained lower quantities of alpha 4(IV)NC1. In proliferation assays, T cells from 11/14 patients with Goodpasture's disease showed significant responses (SI > or = 2.0) to affinity-purified human GBM. Peak responses were demonstrated at 7 or 10 days at antigen concentrations of 10-30 micrograms/ml. As in other autoimmune disorders, the presence of autoantigen-reactive T cells was also demonstrated in 5/10 healthy volunteers. Tissue typing revealed that all patients possessed HLA-DR2 and/or -DR4 alleles, while normal individuals whose T cells responded possessed DR2 and/or DR7 alleles. The specificity of the T cell response in Goodpasture's disease was further investigated using monomeric components of human GBM purified by gel filtration and reverse phase high performance liquid chromatography (HPLC). Two antigenic monomer pools were obtained, which were shown by amino-terminal sequence analysis to contain alpha 3(IV)NC1 and alpha 4(IV)NC1, respectively. In all patients tested, significant T cell proliferation was observed in response to one or both of these alpha (IV)NC1 domains. These results demonstrate that patients with Goodpasture's disease possess T cells reactive with autoantigens known to be recognized by anti-GBM antibodies.
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PMID:Analysis of T cell responses to the autoantigen in Goodpasture's disease. 774 65

A high titre of antibodies to collagenase-solubilised human glomerular basement membrane (CS-GBM) is almost pathognomic of Goodpasture's (anti-GBM) disease. In order to develop an assay independent of scarce human material, a molecule of approximately 26 kD corresponding to the C-terminal NC1 domain of the alpha 3 chain of type IV collagen was purified from sheep GBM by gel filtration and reverse phase HPLC. This molecule was antigenic when assessed by inhibition studies, by immunoblotting, and as a ligand on ELISA plates. An ELISA using this sheep alpha 3(IV)NC1 preparation to detect circulating anti-GBM antibodies gave comparable results to the standard RIA using crude CS-GBM. Sera from patients with a variety of nephropathies other than Goodpasture's disease gave negative results. In a prospective study, 170 consecutive sera were analysed by both the ELISA and the RIA. Twenty seven specimens gave positive results in one or both of the assays. Eleven of these were confirmed as true positive results and all were correctly identified by the RIA. Two false negative results in the ELISA occurred in previously treated cases, and both sera were only weakly positive by RIA. The RIA gave 13 false positive results compared with five by ELISA. The ELISA using highly purified sheep antigen is a robust, reliable, and more specific alternative to immunoassays based on crude human antigen preparations.
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PMID:Development and application of an ELISA for Goodpasture's disease based on sheep alpha 3(IV)NC1 domains. 873 32

X-linked Alport syndrome (AS) is a heritable disorder which is associated with mutations in the type IV collagen alpha 5 (IV) chain gene (COL4A5) located on chromosome X. Following renal transplantation, an average of 6% of male AS patients develop anti-GBM nephritis. We studied the specificity of the antibodies against type IV collagen in the serum of a patient with COL4A5 partial deletion. The specificity of these alloantibodies was determined against collagenase-digested GBM, as well as against recombinant non-collagenous (NC1) domains of the type IV collagen alpha 1(IV)-alpha 6(IV) chains expressed in escherichia coli. Immunoblotting and ELISA demonstrated that these antibodies bound specifically to the NC1 domain of alpha 5(IV) collagen. There was no binding to the NC1 domain of the other chains, including the Goodpasture antigen. Competitive ELISA confirmed the results obtained by ELISA and immunoblotting. This patient developed alloantibodies directed against antigens present in the grafted kidney, but absent from his Alport kidney. The pathogenesis of post-transplantation glomerulonephritis in the Alport patient studied is thus similar to that of Goodpasture syndrome, with the exception that the pathogenic antibodies are targeted to another alpha chain of type IV collagen.
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PMID:Identification of post-transplant anti-alpha 5 (IV) collagen alloantibodies in X-linked Alport syndrome. 891 11

Human nephritogenic antigen induces anti-glomerular basement membrane antibody glomerulonephritis in rats. This antigen was purified from collagenase-solubilized renal basement membrane by means of gel filtration and affinity chromatography using a rabbit antibody. Western blots of the purified nephritogenic antigen using epitope-defined monoclonal antibodies showed that it contains the NC1 domains of the a1 to a6 chains of type IV collagen. Nephritogenicity was thought to be a feature of the NC1 domains of the a3 to a5 chains, because the a6 chain is not located in the glomerular basement membrane, and because an NC1 fraction consisting of the NC1 domains of the a1 and a2 chains was poorly nephritogenic. Autoantibodies in the sera of patients with Goodpasture's syndrome were detected by ELISA using the purified nephritogenic antigen. These results indicate that the nephritogenic antigen contains the Goodpasture antigen, defined as the antigen reactive with sera from patients with Goodpasture's syndrome.
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PMID:Purification and characterization of human nephritogenic antigen that induces anti-GBM nephritis in rats. 927 35

A minority of patients with Alport syndrome develop anti-GBM disease in their allografts after renal transplantation. Clinically, the renal disease appears indistinguishable from Goodpasture's disease of native kidneys, in which the target of autoantibodies had been identified as the NC1 domain of the alpha 3 chain of type IV collagen, alpha 3(IV)NC1. However, in the majority of cases, Alport syndrome is due to mutations in the gene encoding the alpha 5 chain of type IV collagen, located on the X chromosome. Neither chain is detectable in the glomerular basement membrane (GBM) of most patients with Alport syndrome. We investigated the targets of the alloantibodies of 12 Alport patients who developed post-transplant anti-GBM disease by Western blotting onto recombinant NC1 domains made in insect cells. Binding to these antigens, for both typical Goodpasture and Alport anti-GBM antibodies, was strong and conformation-sensitive. Nine antibodies showed selective binding to alpha 5(IV)NC1. This specificity was confirmed by the demonstration of binding to a 26 kDa band of collagenase-solubilized human GBM, and/or binding to normal epidermal as well as renal basement membranes by indirect immunofluorescence. One antibody showed binding to alpha 5 and alpha 3(IV)NC1, while two showed predominant binding to alpha 3(IV)NC1. All seven patients whose pedigree or mutation analysis showed X-linked inheritance had predominant anti-alpha 5 reactivity. One with predominant anti-alpha 3 reactivity had a COL4A3 mutation. These findings show that human anti-GBM disease can be associated with antibodies directed towards different molecular targets. Alpha 5(IV)NC1 is the primary target in most patients with X-linked Alport syndrome who develop post-transplant anti-GBM disease.
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PMID:Targets of alloantibodies in Alport anti-glomerular basement membrane disease after renal transplantation. 950 24

Experimental autoimmune glomerulonephritis (EAG), an animal model of Goodpasture's disease, can be induced in Wistar Kyoto (WKY) rats by a single injection of collagenase-solubilized rat glomerular basement membrane (GBM) in adjuvant. EAG is characterized by circulating and deposited anti-GBM antibodies, accompanied by focal necrotizing glomerulonephritis with crescent formation. The inhibitory effect of orally administered antigens has been reported in various animal models of autoimmunity but not in EAG in the rat. The effects of feeding rat GBM by gavage, at total doses of 0.5, 2.5, or 5 mg, before immunization were examined. A dose-dependent effect was observed on the development of EAG. A dose of 0.5 mg of GBM had no effect on disease, 2.5 mg resulted in a moderate reduction in the severity of nephritis but no change in anti-GBM antibody production, and 5 mg resulted in a marked reduction in circulating and deposited anti-GBM antibodies, albuminuria, deposits of fibrin in the glomeruli, severity of glomerular abnormalities, and numbers of infiltrating T cells and macrophages. Animals that were fed 5 mg of GBM showed a significant reduction in IgG2a but not IgG1, anti-GBM antibody levels, suggesting downregulation of Th1 responses. There was also a dose-dependent reduction in the proliferative responses of splenic T cells from treated animals to GBM antigen in vitro. These results clearly demonstrate that mucosal tolerance can be induced by oral administration of GBM antigen and that this approach is effective in preventing EAG.
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PMID:Oral administration of glomerular basement membrane prevents the development of experimental autoimmune glomerulonephritis in the WKY rat. 1113 51


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