Unknown

Dataset Information

0

Molecular Analysis of Goodpasture's Disease Following Hematopoietic Stem Cell Transplant in a Pediatric Patient, Recalls the Conformeropathy of Wild-Type Anti-GBM Disease.


ABSTRACT: Background: Goodpasture's disease (GP) is mediated by autoantibodies that bind the glomerular and alveolar basement membrane, causing rapidly progressive glomerulonephritis with or without pulmonary hemorrhage. The autoantibodies bind neoepitopes formed upon disruption of the quaternary structure of ?345NC1 hexamer, a critical structural domain of ?345 collagen IV scaffolds. Hexamer disruption leads to a conformational changes that transitions ?3 and ?5NC1 subunits into immunogens, however, the trigger remains unknown. This contrasts with another anti-GBM disease, Alports' post-transplant nephritis (APTN), where the pathogenic alloantibody binds directly to native NC1 hexamer. The current report includes the first study of antigenic specificity and allo-incompatability in anti-GBM disease occurring after allogeneic haematopoietic stem cell transplant (HSCT). Results: The anti-GBM antibodies were found to be directed predominantly against the EA epitope of the ?3 NC1 monomer of collagen IV and developed rapidly in patient serum reaching peak level within 5 weeks. Autoantibody binding to native ?345NC1 hexamer was minimal; however, binding was greatly increased upon dissociation of the native hexamer. There were no polymorphic genetic differences between donor and recipient collagen IV genes which would be predicted to cause a significant NC1 conformational change or to provide a target for antibody binding. Both patient and donor possessed the Goodpasture's susceptibility HLA-allele DRB1 * 1501. Conclusions: The current report includes the first in-depth study of allo-incompatability and antigenic specificity in anti-GBM disease occurring after allogeneic haematopoietic stem cell transplant (HSCT). No polymorphic genetic differences were identified between donor and recipient collagen IV genes which would be predicted to provide a target for antibody binding. Furthermore, autoantibody binding to native ?345NC1 hexamer was minimal, increasing greatly upon dissociation of the native hexamer, resembling wild-type GP diseases and marking this as the first example of a post-HSCT conformeropathy.

SUBMITTER: Gray PE 

PROVIDER: S-EPMC6868084 | BioStudies | 2019-01-01

SECONDARY ACCESSION(S): 1NC1

REPOSITORIES: biostudies

Similar Datasets

2010-01-01 | S-EPMC4144421 | BioStudies
2019-01-01 | S-EPMC6527180 | BioStudies
2018-01-01 | S-EPMC6136232 | BioStudies
2016-01-01 | S-EPMC5600521 | BioStudies
2011-01-01 | S-EPMC3159420 | BioStudies
2008-01-01 | S-EPMC2596392 | BioStudies
2008-01-01 | S-EPMC2597645 | BioStudies
2010-01-01 | S-EPMC3009915 | BioStudies
2010-01-01 | S-EPMC2951005 | BioStudies
1000-01-01 | S-EPMC5571546 | BioStudies