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(The FASEB Journal. 2003;17:860-868.)
© 2003 FASEB

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

HELMUT HOPFER, RUTH MARON*, ULRIKE BUTZMANN{dagger}, UDO HELMCHEN§, HOWARD L. WEINER* and RAGHU KALLURI1

Program in Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA;
* Center of Neurologic Diseases, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA;
{dagger} Cell Biology, Harvard Medical School, Boston, Massachusetts, USA; and
§ Department of Pathology, University of Hamburg, D-20246 Hamburg, Germany

1Correspondence: Program in Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center, 330 Brookline Ave., Dana 514, Boston MA 02215, USA. E-mail: rkalluri{at}bidmc.harvard.edu

Anti-glomerular basement membrane (GBM) disease is a rapidly progressive glomerulonephritis (GN) resulting from autoimmunity against the Goodpasture antigen {alpha}3(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 {alpha}3(IV)NC1 to investigate the involvement of humoral and cellular autoimmunity. DBA/1 mice had crescentic GN 11 wk postimmunization with {alpha}3(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 {alpha}3(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 {alpha}3(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.


Key Words: glomerulonephritis • Goodpasture syndrome • {alpha}3(IV) type IV collagen • autoimmunity




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