CD4(+) T cells specific to a glomerular basement membrane antigen mediate glomerulonephritis

J Clin Invest. 2002 Feb;109(4):517-24. doi: 10.1172/JCI13876.

Abstract

Ab-mediated mechanisms have been considered the major causes of glomerulonephritis (GN). However, recent studies suggest that T cells may be more important in mediating GN. To investigate the effects of antigen-specific CD4(+) T cells, we generated Th1 cell lines specific for this antigen from rats that had been immunized with a recombinant form of the glomerular basement membrane (GBM) antigen, Col4alpha3NC1. Upon the transfer of in vitro-activated T cell lines to pertussis toxin-primed, naive syngeneic rats, the recipients developed severe proteinuria/albuminuria, which plateaued after approximately 35 days. Although no IgG binding to GBM or C3 deposition could be detected by immunofluorescence, five out of eleven rats exhibited severe GN, as judged by the formation of characteristic crescent-shaped lesions in the glomeruli, whereas the others exhibited modest GN. Thus Col4alpha3NC1-specific T cells directly initiated glomerular injury in the recipients. One notable difference from GN induced by active immunization was a T cell infiltration in the renal interstitium, which affected some tubules. We therefore injected fluorescence-labeled Col4alpha3NC1-specific into naive rats, and we found that they were enriched 4.5-fold in the kidney cortex relative to nonspecific control T cells 24 hours later. Many of the T cells were located in the Bowman's space and had a flattened shape, suggesting that the primary target for the T cells was in or adjacent to the Bowman's capsule.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Autoantigens / administration & dosage
  • Basement Membrane / immunology
  • CD4-Positive T-Lymphocytes / immunology*
  • Cell Line
  • Collagen Type IV / immunology*
  • Cytokines / metabolism
  • Female
  • Glomerulonephritis / etiology*
  • Glomerulonephritis / immunology*
  • Glomerulonephritis / pathology
  • Immunization
  • Kidney Glomerulus / immunology*
  • Kidney Glomerulus / pathology
  • Lymphocyte Activation
  • Rats
  • Rats, Inbred WKY

Substances

  • Autoantigens
  • Collagen Type IV
  • Cytokines