Goodpasture Syndrome

Clinical Features

Goodpasture syndrome is an autoimmune disease of lung and kidney. Viral and streptococcal infections and exposure to hydrocarbon fumes have been suggested as possible causes. Three familial instances (Gossain et al., 1972; Maddock et al., 1967), including a pair of identical twins (D'Apice et al., 1978), have been reported. One twin had pumped gasoline in a filling station for 2 weeks before onset; the other twin had, 5 days before onset, started a job spraying ball-bearings with a fine mist of mineral turpentine. The host factor might be immune response genes. Maddock et al. (1967) described the Goodpasture syndrome in 2 male first cousins.

Pathogenesis

Turner et al. (1992) demonstrated that the Goodpasture antigen is the alpha-3 chain of type IV collagen (COL4A3; 120070).

Hudson et al. (2003) reviewed extensively the biology of type IV collagen and its relation to Goodpasture syndrome. They pointed to the existence of 2 forms: the antineutrophil cytoplasmic autoantibody (ANCA)-negative form, present in 75% of cases, and the ANCA-positive form, present in 25% of cases. Both have autoantibodies to the NC1 domain of the alpha-3 chain of type IV collagen, but the ANCA-positive form also has antibodies to myeloperoxidase. The Goodpasture syndrome occurring posttransplantation in cases of Alport syndrome shows alloantibodies to NC1 domains of alpha-3, alpha-4, and alpha-5 chains of type IV collagen.

Pedchenko et al. (2010) analyzed circulating autoantibodies in 57 patients with Goodpasture disease and kidney-bound antibodies in 14 patients. Autoantibodies to both the COL4A3 and COL4A5 (303630) NC1 monomers were bound in the kidneys and lungs, indicating roles for those monomers as autoantigens. The antibodies bound to distinct epitopes encompassing region E(A) in the COL4A5 NC1 monomer and regions E(A) and E(B) in the COL4A3 NC1 monomer, but they did not bind to the native crosslinked COL4A3-COL4A4 (120131)-COL4A5 NC1 hexamer. Pedchenko et al. (2010) concluded that the development of Goodpasture disease may be considered an autoimmune 'conformeropathy' that involves perturbation of the quaternary structures of the COL4A3-COL4A4-COL4A5 NC1 hexamer, inducing a pathogenic conformational change in the COL4A3 NC1 and COL4A5 NC1 subunits, which in turn elicits an autoimmune response.

Ooi et al. (2017) showed that autoreactive alpha-3(135-145)-specific T cells expand in patients with Goodpasture disease and, in alpha-3(135-145)-immunized HLA-DR15 transgenic mice, alpha-3(135-145)-specific T cells infiltrate the kidney and mice develop Goodpasture disease. HLA-DR15 and HLA-DR1 exhibit distinct peptide repertoires and binding preferences and present the Goodpasture epitope in different binding registers. HLA-DR15-alpha-3(135-145) tetramer-positive T cells in HLA-DR15 transgenic mice exhibit a conventional T-cell phenotype that secretes pro-inflammatory cytokines. In contrast, HLA-DR1-alpha-3(135-145) tetramer-positive T cells in HLA-DR1 and HLA-DR15/DR1 transgenic mice are predominantly CD4+Foxp3+ regulatory T cells (Treg cells) expressing tolerogenic cytokines. HLA-DR1-induced Treg cells confer resistance to disease in HLA-DR15/DR1 transgenic mice. HLA-DR15+ and HLA-DR1+ healthy human donors display altered alpha-3(135-145)-specific T-cell antigen receptor usage. Moreover, patients with Goodpasture disease display a clonally expanded alpha-3(135-145)-specific CD4+ T-cell repertoire. Ooi et al. (2017) concluded that they provided a mechanistic basis for the dominantly protective effect of HLA in autoimmune diseases, whereby HLA polymorphism shapes the relative abundance of self-epitope-specific Treg cells that leads to protection or causation of autoimmunity.

Animal Model

Kalluri et al. (1997) developed a new mouse model of human anti-glomerular basement disease (GBM) to characterize better the genetic determinants of cell-mediated injury. The findings in studies of the model suggested that anti-GBM antibodies in mice facilitate disease only in MHC haplotypes capable of generating nephritogenic lymphocytes with special T-cell repertoires.