Goodpastures Syndrome

Goodpasture's syndrome, a prototypical autoantibody-mediated disease, is associated with antibodies specific for constituents of the GBM. The term Goodpasture's syndrome is applied to hemorrhagic lung involvement in the presence of anti-GBM antibodies. The term "anti-GBM disease" is now used to refer to the nephritic syndromes associated with the presence of these autoantibodies. Anti-GBM antibodies deposit linearly along the GBM and tubular basement membrane, but complement components are detected in only one third of the cases. The antibodies that form linear deposits on the glomerular and tubular basement membranes are essentially specific for the noncollagenous domains (NC1s) of collagen type IV Ubiquitary components of collagen IV are alpha 1 and 2 chains; in the kidney, lung, eye, ear, and choroids plexus alpha 3, 4, 5, and 6 chains are also expressed. Anti-GBM antibodies react with the alpha 3 NC1 domain, specifically with the conformational epitopes formed by adjacent molecules, which are cryptic in intact GBM (Borza and Hudson, 2003). Some sera also contain antibodies that are reactive with alpha 2, 4, and 6 chains (Dehan et al., 1996) or with the amino-terminal portion of alpha 3 (Ryan et al., 1998). Sera from patients with anti-GBM disease react with purified collagen IV or with recombinant alpha 3 chains, and a higher titer of antibodies is more frequent in patients with lung involvement. The severity of renal involvement, however, is not always proportional to the amount of circulating antibodies (Yamamoto and Wilson, 1987). Anti-GBM antibodies are characterized by a very high affinity for antigens, a high association rate, and a low dissociation rate. Therefore, these antibodies bind rapidly and remain bound to GBM, a property that probably explains the fulminant nature of the disease and its resistance to therapy (Rutgers et al., 2000).

The experimental model for Goodpasture's disease is experimental autoimmune glomerulonephritis (EAG), which can be induced in animals by immunization with GBM extracts or collagen type IV. EAG is characterized by circulating and deposited anti-GBM antibodies, accompanied by focal necrotizing glomeru-lonephritis with crescent formation. The observation that complement components are detectable in glomerular lesions and that the experimentally induced disease is milder in mice deficient in C3 or C4 (Sheerin et al., 1997) suggests that complement can contribute to tissue damage. However, higher amounts of anti-GBM antibodies induce renal damage even in the absence of complement. In contrast, mice are completely protected from disease in the absence of the y chain of the FcRs. After administration of anti-GBM antibodies, linear deposits of complement and immunoglobulins are observed in mice knockout for the y-chain of the FcRs, but no hypercellularity and inflammatory infiltrates can be detected (Park et al., 1998). On the contrary, mice lacking FcyRIIb on the nonpermissive H-2b haplotype develop pulmonary hemorrhage and crescentic glomerulonephritis with a "ribbon deposition" pattern of ICs in their glomeruli in response to immunization with bovine collagen type IV (Nakamura et al., 2000).

The role of T cells in the induction of anti-GBM disease is less clear. Initially, the therapeutic effects of cyclosporin A on anti-GBM antibody production and proteinuria in BN rats with EAG suggested that T cell help is required (Reynolds etal., 1991). Such a role has then been demonstrated in bursectomized chicks that, upon immunization with heterologous GBM, developed nephritis in the absence of autoantibodies. Oral tolerization of Wistar Kyoto rats (Reynolds and Pusey, 2001) and mice (Kalluri et al., 1997) leads to a significant reduction in circulating IgG2a but not IgG1, suggesting a downregulation of the Th1 response. Moreover, in rats that have been orally tolerized there is a dose-dependent reduction in the proliferative response of the splenic T cells to GBM antigens in vitro. Its in vivo counterpart probably is a significant reduction in the severity of the disease. In addition to indirect effects, a direct role of T cells in the induction of glomerular injury has also been investigated. In Wistar rats, rapidly progressive crescentic glomerulonephritis was elicited by a single immunization with denatured mouse collagen type IV alpha 3 chain NC1 (Wu et al., 2001) or with a peptide encompassing the amino acids 28-40 (Wu et al., 2004). Anti-GBM antibodies eluted from nephritic kidneys do not bind this epitope and the typical linear deposits appear days after proteinuria and the histological signs of cres-centic glomerulonephritis. These data, combined with the observation that T cells from immunized animals transfer the disease (Wu et al., 2002), suggest that anti-GBM antibodies are not the cause of the disease in this model, but are rather the consequence of T cell-mediated glomerular injury.

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