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 α345NC1 hexamer, a critical structural domain of α345 collagen IV scaffolds. Hexamer disruption leads to a conformational changes that transitions α3 and α5NC1 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 α3 NC1 monomer of collagen IV and developed rapidly in patient serum reaching peak level within 5 weeks. Autoantibody binding to native α345NC1 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 α345NC1 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.
Highlights
Goodpasture’s (GP) disease is mediated by autoantibodies, commonly known as anti-GBM antibodies, that target α345 scaffold of collagen IV of the kidney glomerular (GBM) and lung alveolar basement membrane causing rapidly progressive glomerulonephritis and pulmonary hemorrhage
We previously reported the first patient with X-linked lymphoproliferative (XLP) disease-associated cerebral vasculitis to successfully undergo a hematopoietic stem cell transplant (HSCT) [5]
Recombinant human α1NC1 through α6NC1 domains of collagen IV in monomer form and α3/α1 chimeras were purified from culture medium of stably transfected human embryonic kidney (HEK) 293 cells using anti-FLAG agarose as previously described [6]. α3/α1NC1 chimeras corresponding to the EA and EB epitopes of the α3NC1 domain were constructed by PCR mutagenesis as previously described [7]
Summary
Goodpasture’s (GP) disease is mediated by autoantibodies, commonly known as anti-GBM antibodies, that target α345 scaffold of collagen IV of the kidney glomerular (GBM) and lung alveolar basement membrane causing rapidly progressive glomerulonephritis and pulmonary hemorrhage. In GP disease, the autoantibodies bind neoepitopes formed on α3 and α5 NC1 subunits upon disruption of the quaternary structure of native α345NC1 hexamer, a critical structural domain of α345 collagen IV scaffolds [1, 2]. Hexamer disruption leads to a conformational changes that transitions α3 and α5NC1 subunits into immunogens, 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)
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