The importance of cell‐mediated immunity in the course and severity of autoimmune anti‐glomerular basement membrane disease in mice

ABSTRACT Anti‐glomerular basement membrane (GBM) disease is a rapidly progressive glomerulonephritis (GN) resulting from autoimmunity against the Goodpasture antigen α3(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 α3(IV)NC1 to investigate the involvement of humoral and cellular autoimmunity. DBA/1 mice had crescentic GN 11 wk postimmunization with α3(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 α3(IV)NC1 with Th1‐type isotypes, and 2) a strong proliferative response and high amounts of the inflammatory cytokine IFN‐γ, secreted by splenocytes stimulated in vitro with α3(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.—Hopfer, H., Maron, R., Butzmann, U., Helmchen, U., Weiner, H. L., Kalluri, R. The importance of cell‐mediated immunity in the course and severity of autoimmune anti‐glomerular basement membrane disease in mice. FASEB J. 17, 860–868 (2003)