The importance of cell-mediated immunity in the course and severity of autoimmune anti-glomerular basement membrane disease in mice.
Anti-glomerular basement membrane (GBM) disease is a rapidly progressive glomerulonephritis (GN) resulting from autoimmunity against the Goodpasture antigen alpha3(IV)NC1. In addition to the well-characterized antibody contribution, a T helper 1 (Th1) response has been suspected as the culprit for glomerular injury. We induced anti-GBM disease in DBA/1, C57BL/6, AKR, and NOD mice with recombinant human alpha3(IV)NC1 to investigate the involvement of humoral and cellular autoimmunity. DBA/1 mice had crescentic GN 11 wk postimmunization with alpha3(IV)NC1. C57BL/6 and AKR mice developed a chronic disease course resulting in comparable kidney injury to DBA/1 mice within 6 months. NOD revealed only minor glomerular changes. The rapid course and the severity of the disease in DBA/1 mice can be explained by our immunological findings in their sera and splenocytes: 1) high antibody titers specific for the putative clinically relevant epitope of alpha3(IV)NC1 with Th1-type isotypes, and 2) a strong proliferative response and high amounts of the inflammatory cytokine IFN-gamma, secreted by splenocytes stimulated in vitro with alpha3(IV)NC1, with only low amounts of the anti-inflammatory cytokine IL-10. Our in vivo and in vitro results provide direct evidence that the balance between Th1 and Th2 responses associates with the outcome of anti-GBM disease in mice.
Program in Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, 330 Brookline Ave., Dana 514, Boston Massachusetts 02215, USA.
Helmut
H
Hopfer
Ruth
R
Maron
Ulrike
U
Butzmann
Udo
U
Helmchen
Howard L
HL
Weiner
Raghu
R
Kalluri
D000818:Animals; D019867:Anti-Glomerular Basement Membrane Disease / Q000276:immunology* / Q000473:pathology; D015153:Blotting, Western; D002460:Cell Line; D024141:Collagen Type IV / Q000235:genetics / Q000276:immunology; D006801:Humans; D007111:Immunity, Cellular / Q000276:immunology*; D007678:Kidney Glomerulus / Q000276:immunology / Q000473:pathology / Q000648:ultrastructure; D008297:Male; D051379:Mice; D008806:Mice, Inbred AKR; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D016688:Mice, Inbred NOD; D008854:Microscopy, Electron; D011994:Recombinant Proteins / Q000235:genetics / Q000276:immunology; D012598:Sclerosis; D012720:Severity of Illness Index; D013045:Species Specificity; D013997:Time Factors
D024141:Collagen Type IV; D011994:Recombinant Proteins