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

ABSTRACT: 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 ?3NC1 domain of collagen IV, which is expressed in target organs as an ?345 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.Analysis of the specificity of Goodpasture's autoantibodies revealed a distinct subset of circulating and kidney-bound anti?5NC1 antibody, which is associated with loss of kidney function. Structural integrity of the ?345NC1 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 ?345NC1 hexamer in eliciting an autoimmune response in Goodpasture's disease.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.

SUBMITTER: Pedchenko V

PROVIDER: S-EPMC3159420 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature

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

Pedchenko Vadim V Vanacore Roberto R Hudson Billy B

Current opinion in nephrology and hypertension 20110501 3

<h4>Purpose of review</h4>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 t ...[more]

PMID: 21378566

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Project description:BackgroundIn Goodpasture's disease, circulating autoantibodies bind to the noncollagenous-1 (NC1) domain of type IV collagen in the glomerular basement membrane (GBM). The specificity and molecular architecture of epitopes of tissue-bound autoantibodies are unknown. Alport's post-transplantation nephritis, which is mediated by alloantibodies against the GBM, occurs after kidney transplantation in some patients with Alport's syndrome. We compared the conformations of the antibody epitopes in Goodpasture's disease and Alport's post-transplantation nephritis with the intention of finding clues to the pathogenesis of anti-GBM glomerulonephritis.MethodsWe used an enzyme-linked immunosorbent assay to determine the specificity of circulating autoantibodies and kidney-bound antibodies to NC1 domains. Circulating antibodies were analyzed in 57 patients with Goodpasture's disease, and kidney-bound antibodies were analyzed in 14 patients with Goodpasture's disease and 2 patients with Alport's post-transplantation nephritis. The molecular architecture of key epitope regions was deduced with the use of chimeric molecules and a three-dimensional model of the alpha345NC1 hexamer.ResultsIn patients with Goodpasture's disease, both autoantibodies to the alpha3NC1 monomer and antibodies to the alpha5NC1 monomer (and fewer to the alpha4NC1 monomer) were bound in the kidneys and lungs, indicating roles for the alpha3NC1 and alpha5NC1 monomers as autoantigens. High antibody titers at diagnosis of anti-GBM disease were associated with ultimate loss of renal function. The antibodies bound to distinct epitopes encompassing region E(A) in the alpha5NC1 monomer and regions E(A) and E(B) in the alpha3NC1 monomer, but they did not bind to the native cross-linked alpha345NC1 hexamer. In contrast, in patients with Alport's post-transplantation nephritis, alloantibodies bound to the E(A) region of the alpha5NC1 subunit in the intact hexamer, and binding decreased on dissociation.ConclusionsThe development of Goodpasture's disease may be considered an autoimmune "conformeropathy" that involves perturbation of the quaternary structure of the alpha345NC1 hexamer, inducing a pathogenic conformational change in the alpha3NC1 and alpha5NC1 subunits, which in turn elicits an autoimmune response. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases.)

Project description:Animal tuberculosis (TB), caused by Mycobacterium bovis, is maintained in Portugal in a multi-host system, with cattle, red deer and wild boar, playing a central role. However, the ecological processes driving transmission are not understood. The main aim of this study was thus to contribute to the reconstruction of the spatiotemporal history of animal TB and to refine knowledge on M. bovis population structure in order to inform novel intervention strategies. A collection of 948 M. bovis isolates obtained during long-term surveillance (2002-2016, 15 years) of cattle (n = 384), red deer (n = 303) and wild boar (n = 261), from the main TB hotspot areas, was characterized by spoligotyping and 8 to 12-loci MIRU-VNTR. Spoligotyping identified 64 profiles and MIRU-VNTR distinguished 2 to 36 subtypes within each spoligotype, enabling differentiation of mixed or clonal populations. Common genotypic profiles within and among livestock and wildlife in the same spatiotemporal context highlighted epidemiological links across hosts and regions, as for example the SB0119-M205 genotype shared by cattle in Beja district or SB0121-M34 shared by the three hosts in Castelo Branco and Beja districts. These genomic data, together with metadata, were integrated in a Bayesian inference framework, identifying five ancestral M. bovis populations. The phylogeographic segregation of M. bovis in specific areas of Portugal where the disease persists locally is postulated. Concurrently, robust statistics indicates an association of the most probable ancient population with cattle and Beja, providing a clue on the origin of animal TB epidemics. This relationship was further confirmed through a multinomial probability model that assessed the influence of host species on spatiotemporal clustering. Two significant clusters were identified, one that persisted between 2004 and 2010, in Beja district, with Barrancos county at the centre, overlapping the central TB core area of the Iberian Peninsula, and highlighting a significant higher risk associated to cattle. The second cluster was predominant in the 2012-2016 period, holding the county Rosmaninhal at the centre, in Castelo Branco district, for which wild boar contributed the most in relative risk. These results provide novel quantitative insights beyond empirical perceptions, that may inform adaptive TB control choices in different regions.

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

Publications

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

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