Experimental autoimmune anti-glomerular basement membrane glomerulonephritis: a protective role for IFN-gamma.

Kitching AR, Turner AL, Semple T, Li M, Edgtton KL, Wilson GR, Timoshanko JR, Hudson BG, Holdsworth SR
J Am Soc Nephrol. 2004 15 (7): 1764-74

PMID: 15213264 · DOI:10.1097/01.asn.0000128968.27705.5e

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.

MeSH Terms (26)

Animals Anti-Glomerular Basement Membrane Disease Apoptosis Autoimmune Diseases CD4-Positive T-Lymphocytes Cell Adhesion Cell Division Creatinine Dimerization Enzyme-Linked Immunosorbent Assay Glomerulonephritis Hypersensitivity, Delayed Immunoglobulin G Immunohistochemistry Intercellular Adhesion Molecule-1 Interferon-gamma Interleukin-12 Leukocytes Lupus Vulgaris Mice Mice, Inbred C57BL Mice, Transgenic Microscopy, Fluorescence P-Selectin Proteinuria Time Factors

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