Glomerulonephritis induced by recombinant collagen IV alpha 3 chain noncollagen domain 1 is not associated with glomerular basement membrane antibody: A potential T cell-mediated mechanism

Glomerulonephritis is believed to result commonly from Ab-mediated glomerul ar injury. However, Ab-associated mechanisms alone cannot explain many case s of human glomerulonephritis. We developed a rat model of human anti-glome rular basement membrane (GBM) disease to investigate T cell and Ab response , and their associations with the disease. A single immunization of highly denatured recombinant mouse collagen IV alpha3 chain noncollagen domain I ( rCol4 alpha 3NC1) induced severe glomerulonephritis in 100% of Wistar Kyoto rats, 33% of which died of this disease around day 35 postimmunization. Th e renal pathology demonstrated widespread glomerular damage and a mononucle ar cell infiltration within the interstitial tissue. T cells from immunized rats responded not only to rCol4 alpha 3NC1, but also to isolated rat GBM. Sera Abs to rCol4 alpha 3NC1 were detectable in 100% of the rats, but only 20% of the rats had low levels of Ab to isolated rat GBM by Western blot, and none by immunofluorescence. Furthermore, IgG/M binding to or C3 deposit ion on endogenous GBM in immunized rats were not detected in most of the ex perimental rats, and showed no statistical correlation with disease severit y. Additionally, no electronic dense deposition in the glomeruli was detect ed in all rats. Those data revealed a disassociation between the disease an d anti-GBM Ab. T cell-mediated mechanisms, which are currently under our in vestigation, may be responsible for the glomerular disease.