Pathogenesis of an experimental model of Goodpasture's hemorrhagic pneumonitis.

Abstract

The mechanisms that allow circulating basement membrane antibodies (Ab) to interact with the alveolar basement membrane (ABM) inducing Goodpasture's hemorrhagic pneumonitis are unknown. In laboratory animals the ABM is inaccessible to phlogogenic amounts of ABM Ab unless the permeability of the unfenestrated alveolar endothelium is increased. This study was designed to test the hypothesis that in the mouse polypeptide mediators, generated by activated lymphoid cells or cells infected by viruses, contribute to the pathogenesis of passive Goodpasture's hemorrhagic pneumonitis. In naive mice that received rabbit ABM Ab, these bound to the glomerular basement membrane but not to the ABM and their lungs were normal. In the lungs of mice injected with human recombinant IL-2 and IFN-a specific binding of ABM IgG, C3, and fibrinogen to the ABM, diffuse and severe erythrocyte extravasation, and accumulation of mononuclear and polymorphonuclear leukocytes were constantly observed. ABM Ab and IL-2 or ABM Ab and IFN-a did not produce comparable effects. Mice injected only with IL-2 and IFN-a had enlarged, edematous lungs without pulmonary hemorrhages. The results show that the synergism of IL-2 and IFN-a convert the lung into a preferential target for AMB Ab, suggesting that cytokines may have a role in the pathogenesis of human Goodpasture's pneumonitis. (J. Clin. Invest. 1990Invest. . 85:1507Invest. -1515 Goodpasture's pneumonitis * basement membrane antibodies.

Suppression of pulmonary injury in experimental ‘Goodpasture's syndrome’ by deoxyspergualin (DSP)

“…Reduction of rat IgG production and deposition on the ABM in this study suggest that inhibition of the secondary antibody response is one mechanism o\ DSP-nicdiated suppression of pulmonary injury. This is consistent with studies in which DSP inhibited allograft rejection due to secondary antibody responses [4] and DSP suppressed progressive splenomegaly, production of anti-DNA antibodies, and glomerular IgG and C3 deposition in spontaneous murine autoimmune lupus nephritis [41.42].…”

“…Pulmonary injury in Goodpasture's syndrome is dependent upon the deposition of antibodies on the ABM [3,4]. Reduction of rat IgG production and deposition on the ABM in this study suggest that inhibition of the secondary antibody response is one mechanism o\ DSP-nicdiated suppression of pulmonary injury.…”

Abolition of anti-glomerular basement membrane antibody-mediated glomerulonephritis in FcRγ-deficient mice

“…Goodpasture syndrome is one of the type II hypersensitivity diseases in which autoantibody reactive with GBM and alveolar basement membrane (ABM), especially the non-collagenous domain of type IV collagen § -3 chain, mediates glomerular injury with or without pulmonary hemorrhage [13][14][15]. The development of lung hemorrhage appears to require the presence of prior lung damage to allow antibody deposition on ABM [33][34][35][36]. Antibody binding to GBM and/or ABM is considered to mediate glomerular and/or pulmonary injury by mechanisms that involve complement activation and the participation of inflammatory cells.…”

Antiglomerular Basement Membrane Antibody-Mediated Glomerulonephritis after Intranasal Cocaine Use

“…Cocaine tissue damage may probably expose pulmonary basement membrane antigens with subsequent antibody formation or allow the binding of anti-GBM antibodies in the lung. Macrophages and cytokines may also play a role in the pathogenesis of lung lesions [29, 30]. …”