IFN-gamma mediates crescent formation and cell-mediated immune injury in murine glomerulonephritis.
Features of crescentic glomerulonephritis suggest that it results from a T helper 1 (Th1) nephritogenic immune response. Interferon-gamma (IFN-gamma), produced by Th1 cells, is involved in T cell-directed macrophage activation in effector Th1 responses. The hypothesis that endogenous IFN-gamma contributes to the development of crescentic glomerulonephritis was tested by comparing the development of glomerulonephritis (induced by a planted antigen) and immune responses in normal C57BL/6 mice (IFN-gamma +/+) and in mice genetically deficient in IFN-gamma (IFN-gamma -/-). Ten days after the initiation of glomerulonephritis, IFN-gamma -/- mice developed fewer glomerular crescents (5+/-1% versus 26+/-3%, P<0.005), less severe glomerular injury, and less renal impairment. Effectors of delayed-type hypersensitivity (CD4+ T cells, macrophages, and fibrin) in glomeruli were reduced in IFN-gamma -/- mice. Skin delayed-type hypersensitivity to sheep globulin was reduced. Total antigen-specific Ig and splenocyte interleukin-2 production were unchanged, but antigen-specific serum IgG2a was reduced. Markers of an antigen-specific Th2 response (serum IgG1, splenocyte interleukin-4) were unchanged. Studies 22 d after the initiation of glomerulonephritis showed that IFN-gamma -/- mice still had fewer crescents (11+/-2% versus 22+/-3%, P = 0.02) and glomerular CD4+ T cells and macrophages than IFN-gamma +/+ mice. These studies demonstrate that endogenous IFN-gamma mediates crescentic glomerulonephritis by promoting cell-mediated immune injury. They support the hypothesis that crescentic glomerulonephritis is a manifestation of a Th1 nephritogenic immune response.
Kitching
A R
AR
Department of Medicine, Monash Medical Centre, Clayton, Victoria, Australia. richard.kitching@med.monash.edu.au
Holdsworth
S R
SR
Tipping
P G
PG
D000818:Animals; D018791:CD4 Lymphocyte Count; D046508:Culture Techniques; D004195:Disease Models, Animal; D005921:Glomerulonephritis / Q000276:immunology* / Q000473:pathology*; D007111:Immunity, Cellular; D007136:Immunoglobulins / Q000032:analysis / Q000276:immunology; D007371:Interferon-gamma / Q000172:deficiency / Q000378:metabolism*; D007677:Kidney Function Tests; D007678:Kidney Glomerulus / Q000276:immunology* / Q000473:pathology; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000276:immunology / Q000473:pathology; D012016:Reference Values; D012756:Sheep; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*
D007136:Immunoglobulins; D007371:Interferon-gamma