Experimental autoimmune anti-glomerular basement membrane glomerulonephritis: a protective role for IFN-gamma.
IL-12 and IFN-gamma play key roles in murine lupus and planted antigen models of glomerulonephritis. However, their roles in renal organ-specific autoimmunity are unknown. To establish the roles of endogenous IFN-gamma and IL-12 in experimental autoimmune anti-glomerular basement membrane (GBM) glomerulonephritis (EAG), EAG was induced in normal C57BL/6 mice (WT), IL-12p40-deficient (IL-12p40-/-) mice, and IFN-gamma-deficient (IFN-gamma-/-) mice by immunization with alpha3-alpha5(IV)NC1 heterodimers. At 13 wk, WT mice developed EAG with linear mouse anti-GBM antibody deposition, histologic injury, proteinuria, and mild tubulointerstitial disease. Compared with WT mice, IL-12p40-/- mice had decreased histologic injury and trends to decreased leukocyte infiltrates. In contrast, 40% (4 of 10) of IFN-gamma-/- mice developed significant crescent formation and focal or diffuse interstitial infiltrates (WT, 0 of 8). Compared with WT and/or IL-12p40-/- mice, IFN-gamma-/- mice developed increased injury: histologic injury, total glomerular cell numbers, leukocytes in glomeruli, and renal expression of P-selectin and intercellular adhesion molecule 1. All groups developed similar serum anti-alpha3-alpha5(IV)NC1 antibodies and glomerular Ig deposition, but IFN-gamma-/- mice had decreased anti-alpha3-alpha5(IV)NC1 IgG2a. Therefore, IFN-gamma-/- mice developed increased cellular reactants despite a potentially less damaging antibody response. Dermal delayed-type hypersensitivity was increased in alpha3-alpha5(IV)NC1 immunized IFN-gamma-/- mice and was suppressed by recombinant murine IFN-gamma. CD4+ cells from draining nodes of immunized IFN-gamma-/- mice showed increased proportions of proliferating CD4+ cells but similar numbers of apoptotic cells. These studies demonstrate that in renal organ-specific autoimmunity, IL-12 is pathogenetic but IFN-gamma is protective. They lend weight to the hypothesis that depending on the context/severity of the nephritogenic immune response IFN-gamma has different effects.
Kitching
A Richard
AR
Centre for Inflammatory Diseases, Monash University, Department of Medicine, Monash Medical Centre, Clayton, Victoria, Australia. richard.kitching@med.monash.edu.au
Turner
Amanda L
AL
Semple
Timothy
T
Li
Ming
M
Edgtton
Kristy L
KL
Wilson
Gabrielle R
GR
Timoshanko
Jennifer R
JR
Hudson
Billy G
BG
Holdsworth
Stephen R
SR
D000818:Animals; D019867:Anti-Glomerular Basement Membrane Disease / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis; D001327:Autoimmune Diseases / Q000473:pathology*; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D002448:Cell Adhesion; D002455:Cell Division; D003404:Creatinine / Q000097:blood; D019281:Dimerization; D004797:Enzyme-Linked Immunosorbent Assay; D005921:Glomerulonephritis / Q000276:immunology* / Q000378:metabolism; D006968:Hypersensitivity, Delayed / Q000473:pathology; D007074:Immunoglobulin G / Q000737:chemistry; D007150:Immunohistochemistry; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism / Q000502:physiology*; D018664:Interleukin-12 / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D007962:Leukocytes / Q000378:metabolism / Q000473:pathology; D008177:Lupus Vulgaris / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D019007:P-Selectin / Q000378:metabolism; D011507:Proteinuria / Q000097:blood; D013997:Time Factors
D007074:Immunoglobulin G; D019007:P-Selectin; D018799:Intercellular Adhesion Molecule-1; D018664:Interleukin-12; D007371:Interferon-gamma; D003404:Creatinine