Characterization of the renal CD4+ T-cell response in experimental autoimmune glomerulonephritis

Kidney Int. 2012 Jul;82(1):60-71. doi: 10.1038/ki.2012.73. Epub 2012 Mar 21.

Abstract

Autoimmunity against the Goodpasture antigen α3IV-NC1 results in antiglomerular basement membrane glomerulonephritis. Although antibodies are central to the pathogenesis, there is good evidence for the participation of T cells in this disease. To define the contribution of T cells, we used the model of experimental autoimmune glomerulonephritis. Immunization of DBA/1 mice with α3IV-NC1 resulted in proteinuria, a biphasic course of the disease, and an eventual loss of kidney function. In the initial phase, the mice developed an α3IV-NC1-specific IgG response, had IgG deposition along the glomerular basement membrane, and steadily increased proteinuria, but only marginal signs of inflammation with limited leukocyte infiltration. After 9-13 weeks, mice proceeded to develop crescentic glomerulonephritis, extensive tubulointerstitial damage, and massive macrophage infiltration. T-cell infiltration was less pronounced, mostly confined to the interstitium, and T cells displayed an activated phenotype with a significant fraction of Th1 or Th17 CD4(+) T cells. Close examination revealed the presence of autoreactive T cells producing IFNγ upon restimulation with α3IV-NC1. Thus, our results suggest that accumulation of effector T cells, including autoreactive T cells, represents a critical step in the progression from mild glomerulonephritis, with limited glomerular damage, to severe crescentic glomerulonephritis accompanied by tubulointerstitial inflammation and loss of kidney function.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Albuminuria / immunology
  • Animals
  • Anti-Glomerular Basement Membrane Disease / blood
  • Anti-Glomerular Basement Membrane Disease / immunology*
  • Anti-Glomerular Basement Membrane Disease / pathology
  • Anti-Glomerular Basement Membrane Disease / physiopathology
  • Antibodies / blood
  • Autoantigens
  • CD4-Positive T-Lymphocytes / immunology*
  • Chemotaxis
  • Collagen Type IV
  • Disease Models, Animal
  • Disease Progression
  • Humans
  • Interferon-gamma / metabolism
  • Kidney / immunology*
  • Kidney / pathology
  • Kidney / physiopathology
  • Lymphocyte Activation
  • Macrophages / immunology
  • Male
  • Mice
  • Mice, Inbred DBA
  • Phenotype
  • Th1 Cells / immunology
  • Th17 Cells / immunology
  • Time Factors

Substances

  • Antibodies
  • Autoantigens
  • Collagen Type IV
  • type IV collagen alpha3 chain
  • Interferon-gamma