1/13. Allograft rejection and glomerular basement membrane antibodies in Alport's syndrome.BACKGROUND: Anti-glomerular basement membrane (GBM) antibodies occasionally occur in Alport patients after renal allograft transplantation. methods: We report a patient with Alport's syndrome who lost four transplants each within the first year post transplantation. We searched for the presence of anti-GBM antibodies using recombinant NC1 domains of type IV collagen. immunoblotting, enzyme linked immunosorbent assay (ELISA), and immunofluorescence were used to detect the presence of antibodies against the glomerular basement membrane. RESULTS: High antibody titers to the alpha3 chain (the Goodpasture antigen) and alpha5 chain of type IV collagen were detected. review of pathologic specimens showed features of vascular rejection in all specimens. CONCLUSION: The association of high titer anti-GBM antibodies and vascular rejection may be important. When vascular rejection occurs in Alport patients, the presence of anti-GBM antibodies should be sought. Recombinant anti-GBM assays should be used if standard anti-GBM testing is equivocal.- - - - - - - - - - ranking = 1keywords = antigen (Clic here for more details about this article) |
2/13. An unusual case of pulmonary-renal syndrome associated with defects in type IV collagen composition and anti-glomerular basement membrane autoantibodies.Commercial serological assays for the presence of anti-glomerular basement membrane (GBM) antibodies are thought to be indicative of Goodpasture's syndrome. We report a case in which commercial tests inaccurately suggested that a patient with a pulmonary-renal syndrome had Goodpasture's disease. Additional laboratory testing using recombinant type IV collagen NC1 domain proteins showed that the autoantibodies in question were not directed against the Goodpasture antigen (the alpha3NC1 domain), but against the alpha2NC1 domain of type IV collagen. Our findings represent the first known case of human autoantibodies to the alpha2NC1 domain. Further investigation showed that this patient has decreased alpha3 and alpha5 chain expression in the GBM and defects in type IV collagen, resembling abnormalities in patients with Alport's syndrome.- - - - - - - - - - ranking = 1keywords = antigen (Clic here for more details about this article) |
3/13. Distinct epitopes for anti-glomerular basement membrane alport alloantibodies and goodpasture autoantibodies within the noncollagenous domain of alpha3(IV) collagen: a janus-faced antigen.Alport posttransplantation anti-glomerular basement membrane (GBM) nephritis is mediated by alloantibodies against the noncollagenous (NC1) domains of the alpha3alpha4alpha5(IV) collagen network, which is present in the GBM of the allograft but absent from Alport kidneys. The specificity of kidney-bound anti-GBM alloantibodies from a patient who had autosomal recessive Alport syndrome (ARAS) and developed posttransplantation nephritis was compared with that of Goodpasture autoantibodies from patients with autoimmune anti-GBM disease. Allograft-eluted alloantibodies reacted specifically with alpha3alpha4alpha5 NC1 hexamers, targeting their alpha3NC1 and alpha4NC1 subunits, and recognized a noncontiguous alloepitope formed jointly by the E(A) and E(B) regions of alpha3NC1 domain. In contrast, human Goodpasture autoantibodies recognized the separate E(A) and E(B) autoepitopes of alpha3NC1 but not the composite alloepitope. Molecular modeling of alpha3NC1 revealed that the alloepitope is more accessible within the NC1 hexamers than the partially sequestered Goodpasture autoepitopes. overall, the specificity of alloantibodies indicated a selective lack of immune tolerance toward the alpha3 and alpha4(IV) collagen chains not expressed in patients with ARAS. Using COL4A3 knockout mice, a model of ARAS, it was shown further that acid-dissociated rather than native alpha3alpha4alpha5 NC1 hexamers elicited murine anti-GBM antibodies most closely resembling human ARAS alloantibodies. In contrast, alpha3NC1 monomers elicited Goodpasture-like murine antibodies, targeting the E(A) and E(B) autoepitopes. Thus, the identity of alpha3NC1 epitopes targeted by anti-GBM antibodies is strongly influenced by the molecular organization of the immunogen. These findings suggest that different isoforms of alpha3(IV) collagen may be implicated in the pathogenesis of ARAS posttransplantation anti-GBM nephritis and Goodpasture disease.- - - - - - - - - - ranking = 4keywords = antigen (Clic here for more details about this article) |
4/13. The pathogenesis of Alport syndrome involves type IV collagen molecules containing the alpha 3(IV) chain: evidence from anti-GBM nephritis after renal transplantation.Mutations in the COL4A5 collagen gene have been implicated as the primary defect in Alport syndrome, a heritable disorder characterized by sensorineural deafness and glomerulonephritis that progresses to end-stage renal failure. In the present study, the molecular nature of the defect in Alport glomerular basement membrane (GBM) was explored using anti-GBM alloantibodies (tissue-bound and circulating) produced in three Alport patients subsequent to renal transplantation. The alloantibodies bound to the alpha 3(IV)NC1 domain of type IV collagen and not to any other basement membrane component. In tissue sections, the alloantibodies bound specifically to peripheral GBM in normal kidney and the affected renal transplant but not to that of Alport kidney. These results establish that: the alpha 3 chain in type IV collagen molecules, the Goodpasture autoantigen, is the target alloantigen in post-transplant anti-GBM nephritis in patients with Alport syndrome, and that a molecular commonality exists in the pathogenesis of anti-GBM nephritis causing loss of renal allografts in patients with Alport syndrome and renal failure in patients with Goodpasture syndrome. These findings implicate: (1) defective assembly of type IV collagen molecules containing the alpha 3(IV) chain in Alport GBM; and (2) the existence of a mechanism linking the assembly of molecules containing the alpha 3(IV) chain with those containing the alpha 5(IV) chain.- - - - - - - - - - ranking = 2keywords = antigen (Clic here for more details about this article) |
5/13. Failure of two subsequent renal grafts by anti-GBM glomerulonephritis in Alport's syndrome: case report and review of the literature.We describe a patient with Alport's syndrome who developed severe crescentic glomerulonephritis after each of two successive transplantations, leading to accelerated graft failure on both occasions. This complication occurred in the 7th postoperative month for the first transplant and in the immediate postoperative period for the second. Immunopathological studies of the second transplant demonstrated that the glomerular lesions were mediated by antiglomerular basement membrane (GBM) antibodies displaying the same pattern of reactivity as the MCA-Pl monoclonal antibody directed against the Good-pasture antigen. This observation indicates that the anti-GBM immunization induced by renal transplantation in some patients with Alport's syndrome may be responsible for recurrent graft failure.- - - - - - - - - - ranking = 1keywords = antigen (Clic here for more details about this article) |
6/13. Posttransplant anti-glomerular basement membrane nephritis in related males with Alport syndrome.This report describes the development of anti-glomerular basement membrane (GBM) glomerulonephritis after kidney transplantation in related males with Alport syndrome. Antibodies in sera from one of these patients stained normal GBM, Bowman's capsule, tubular basement membranes, and epidermal basement membranes but did not stain tissues from an unrelated Alport male. The target antigen was found to be a 26 kd peptide of the noncollagenous domain of basement membrane collagen. This study provides further evidence of the importance of abnormalities of basement membrane collagen in the pathogenesis of the Alport nephropathy. We speculate that certain mutations at the Alport locus, such as large intragenic deletions or frame-shift mutations, may be associated with failure to develop immune tolerance to epitopes on this 26kd peptide. In the setting of permissive immune response and regulation, transplantation of a normal kidney may result in the generation of anti-GBM antibodies.- - - - - - - - - - ranking = 1keywords = antigen (Clic here for more details about this article) |
7/13. Chronic nephritis, sensorineural deafness, growth and developmental retardation, hyperkinesis, and cleft soft palate in a 5-year-old boy. A new combination?A 5-year-old Japanese boy showed nephritis similar to, but distinct from, that in Alport syndrome. nephrotic syndrome without hematuria was noticed at age 2, although renal biopsy at age 4 revealed widespread irregular thickening of the glomerular basement membrane with splitting of the lamina densa on electron microscopy, characteristic of nephritis in Alport syndrome. Sensorineural deafness was noticed at age 4 weeks by no auditory brain stem response, unusually early for Alport syndrome. Goodpasture antigen and amyloid P component were found in the glomerular basement membrane. Thus, the antigenicity of the glomerular basement membrane was different from that in male patients with X-linked Alport syndrome. In addition, growth and developmental retardation, hyperkinesis, and cleft soft palate were seen. These features are a hitherto undescribed combination. The family history was negative for any of the features of the boy.- - - - - - - - - - ranking = 2keywords = antigen (Clic here for more details about this article) |
8/13. The development of anti-glomerular basement membrane nephritis in two children with Alport's syndrome after renal transplantation: characterization of the antibody target.Two children with Alport's syndrome are described, who developed anti-glomerular basement membrane (GMB) antibody-mediated nephritis after renal transplantation. The reactivity of antibodies in their serum with collagenase-solubilized normal GBM was examined by SDS-PAGE with one- and two-dimensional immunoblotting. The specificity was compared with that of antibodies present in serum from a patient with Goodpasture's syndrome, and a mouse monoclonal antibody (MCA-P1), directed against the Goodpasture antigen. All reacted in a similar way with collagenase-solubilized GBM. Since abnormalities in the composition of the GBM are present in Alport's syndrome, it is proposed that differing antigen composition of GBM in the host compared with the donor kidney, together with transplant rejection, may have provoked the development of post-transplant anti-GBM antibodies.- - - - - - - - - - ranking = 2keywords = antigen (Clic here for more details about this article) |
9/13. Anti-glomerular basement membrane antibody-mediated nephritis complicating transplantation in a patient with Alport's syndrome.Loss of an allograft caused by anti-GBM antibody-mediated nephritis is a rare complication of renal transplantation in Alport's syndrome. We describe a patient in whom this occurred. He belongs to the subgroup of patients with hereditary nephritis and deafness with an abnormal Goodpasture antigen, and he developed a high level of circulating anti-GBM antibodies within 20 days of transplantation of a kidney with a presumably normal Goodpasture antigen. The antibody titer fell, only to rise again when he developed evidence of acute infection with CMV. Coincident with this second rise in antibody titer he developed an anti-GBM antibody-mediated crescentic nephritis with resultant loss of graft function and transplant nephrectomy. This case provides support for the hypothesis that the abnormality in the basement membrane in some patients with Alport's syndrome involves the Goodpasture antigen, and raises the possibility that viral infection may have triggered autoantibody production.- - - - - - - - - - ranking = 3keywords = antigen (Clic here for more details about this article) |
10/13. Allograft antiglomerular basement membrane glomerulonephritis in a patient with Alport's syndrome.A patient with Alport's syndrome and chronic renal failure received a cadaver kidney graft. Six months after the transplantation he developed 'de novo' crescentic glomerulonephritis mediated by antiglomerular basement membrane antibodies. This rare complication may be attributed to sensitization against usual antigenic determinants of the graft glomerular basement membrane.- - - - - - - - - - ranking = 1keywords = antigen (Clic here for more details about this article) |
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