Th1 responsiveness to nephritogenic antigens determines susceptibility to crescentic glomerulonephritis in mice.
The pattern of glomerulonephritis (GN) developing in response to a planted antigen (sheep anti-mouse GBM globulin) was compared in two strains of mice which demonstrated either a predominant Th1 (C57BL/6) or Th2 (BALB/c) response to this antigen. GN was induced with a subnephritogenic i.v. dose of sheep anti-mouse GBM globulin in mice presensitized to sheep globulin. Sensitized C57BL/6 mice showed pronounced cutaneous delayed-type hypersensitivity (DTH) following the challenge with sheep globulin, low titers of circulating anti-sheep globulin antibody and high interferon gamma (IFN-gamma) and low interleukin 4 (IL-4) production by splenic T cells, consistent with a predominant Th1 pattern of immune response. Sensitized BALB/c mice did not develop DTH following cutaneous challenge with sheep globulin, had higher circulating anti-sheep globulin antibody titers, and showed high IL-4 and low IFN gamma production by splenic T cells compared with C57BL/6 mice, consistent with a predominant Th2 response. In C57BL/6 mice, GN developing in response to sheep globulin exhibited a severe crescentic pattern with prominent glomerular T cell and macrophage influx and fibrin deposition. In vivo depletion with a monoclonal anti-CD4 antibody demonstrated that this injury was T helper cell dependent. Treatment with monoclonal anti-mouse IFN gamma antibody significantly reduced glomerular injury and crescent formation and attenuated the cutaneous DTH response. GN induced by the same protocol in BALB/c mice exhibited pronounced glomerular IgG and complement deposition. Crescent formation, fibrin deposition, and glomerular T cell and macrophage infiltration were significantly less than observed in C57BL/6 mice, and injury was not T cell dependent in the effector phase. These data suggest that the pattern of glomerular injury induced by a planted antigen can be determined by the balance of T helper cell subset activation. A Th1 response induces a severe crescentic pattern of GN, which like cutaneous DTH, is T helper cell and IFN gamma dependent.
Huang
X R
XR
Monash University, Department of Medicine, Monash Medical Centre, Clayton, Victoria, Australia.
Tipping
P G
PG
Shuo
L
L
Holdsworth
S R
SR
D000818:Animals; D000941:Antigens / Q000276:immunology / Q000494:pharmacology; D001323:Autoantibodies / Q000276:immunology; D015704:CD4 Antigens / Q000276:immunology; D003165:Complement System Proteins / Q000032:analysis; D003404:Creatinine / Q000097:blood / Q000652:urine; D005337:Fibrin / Q000276:immunology; D005916:Globulins / Q000276:immunology; D005921:Glomerulonephritis / Q000276:immunology* / Q000473:pathology; D006968:Hypersensitivity, Delayed / Q000276:immunology; D007074:Immunoglobulin G / Q000276:immunology / Q000494:pharmacology; D016756:Immunoglobulins, Intravenous; D007371:Interferon-gamma / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011507:Proteinuria; D012756:Sheep; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*
D000941:Antigens; D001323:Autoantibodies; D015704:CD4 Antigens; D005916:Globulins; D007074:Immunoglobulin G; D016756:Immunoglobulins, Intravenous; D007371:Interferon-gamma; D005337:Fibrin; D003165:Complement System Proteins; D003404:Creatinine