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Review
. 2011 May;20(3):290-6.
doi: 10.1097/MNH.0b013e328344ff20.

Goodpasture's disease: molecular architecture of the autoantigen provides clues to etiology and pathogenesis

Vadim Pedchenko  1 , Roberto Vanacore, Billy Hudson
Affiliations
Review

Goodpasture's disease: molecular architecture of the autoantigen provides clues to etiology and pathogenesis

Vadim Pedchenko et al. Curr Opin Nephrol Hypertens. 2011 May.

Abstract

Purpose of review: Goodpasture's disease is an autoimmune disorder characterized by the deposition of pathogenic autoantibodies in basement membranes of kidney and lung, which induces rapidly progressive glomerulonephritis and pulmonary hemorrhage. The target antigen is the α3NC1 domain of collagen IV, which is expressed in target organs as an α345 network. Recent studies of specificity and epitopes of Goodpasture's autoantibodies and discovery of novel posttranslational modification of the antigen, a sulfilimine bond, provide further insight into mechanisms of initiation and progression of Goodpasture's disease.

Recent findings: Analysis of the specificity of Goodpasture's autoantibodies revealed a distinct subset of circulating and kidney-bound antiα5NC1 antibody, which is associated with loss of kidney function. Structural integrity of the α345NC1 hexamer is stabilized by the novel sulfilimine crosslinks conferring immune privilege to the Goodpasture's autoantigen. Native antibodies may contribute to establishment of immune tolerance to autoantigen. Structural analysis of epitopes for autoantibodies and alloantibodies indicates a critical role of conformational change in the α345NC1 hexamer in eliciting an autoimmune response in Goodpasture's disease.

Summary: Understanding of the quaternary structure of the Goodpasture's autoantigen continues to provide insights into autoimmune mechanisms that serve as a basis for development of novel diagnostic tools and therapies for Goodpasture's disease.

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Figures

Figure 1
Figure 1. Three-dimensional structure of the GP autoantigen, α345NC1 hexamer of collagen IV
The hexamer is composed of two trimeric caps each consisting of α3 (red), α4 (blue) and α5 (green) NC1 monomers, and stabilized by sulfilimine bonds (light yellow) as shown in center. The model depicts location of the homologous regions EA regions in α3NC1 (yellow) and inα5NC1 (magenta) domains, which become neoepitopes for GP autoantibodies upon hexamer dissociation concomitant with the exposure of residues and conformational change. The regions adopt a specific folding pattern of β-sheets stabilized by disulfide bonds as shown by ribbon diagrams (left and right top insets). Several critical residues are sequestered by lateral interactions with the α5NC1 and α4NC1 subunits in the α345NC1 hexamer as illustrated by removal of interacting NC1s (arrows on the bottom insets).
Figure 2
Figure 2. Potential role of conformational changes of α345NC1 hexamers in GP disease
The diagram represents a portion of the collagen IV network in which the α345NC1 hexamer is tethered to the triple-helical domain. Distinct conformational isoforms are shown: crosslinked form stabilized by sulfilimine bonds (C-1), non-crosslinked form (C-2), and form in which the NC1 hexamer is dissociated into trimers (C-3). In GP disease, C-3 may undergo a conformational change and exposure of critical residues resulting in the formation of neoepitopes in α3NC1 and α5NC1 subunits. This structural transition triggers formation of autoantibodies, which subsequently bind to C-3 and C-4. C-1 and C-2 could be potentially transformed into the pathogenic form C-4. GP autoantibodies in the immune complex are shown as Fab fragments.
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