Antibody independent crescentic glomerulonephritis in mu chain deficient mice

The hypothesis that crescent formation in glomerulonephritis (GN) is a delayed type hypersensitivity (DTH)-like lesion, not dependent on a humoral immune response, was addressed using mice with deletion of the mu immunoglobulin heavy chain gene (mu chain deficient mice). Homozygous mu chain deficient mice do not develop mature B cells or produce immunoglobulin, but have intact cell mediated immunity. GN was induced in sensitized mice by a subnephritogenic dose of sheep anti-mouse GBM globulin. Heterozygous mice (mu chain +/-) demonstrated normal antibody and DTH responses to sheep globulin and developed a proliferative GN with proteinuria (6.4 +/- 1.4 mg/24 hr), renal impairment (serum creatinine 32.6 +/- 3.3 mumol/liter) and crescents in 33 +/- 24% of glomeruli, when this antigen was planted in their glomeruli. This lesion was demonstrated to be T cell dependent by in vivo T cell depletion. Homozygous mu chain deficient mice (-/-) also developed proliferative GN, histologically indistinguishable from +/- mice. Proteinuria (3.8 +/- 1.0 mg/24 hr), renal impairment (serum creatinine 24.5 +/- 3.4 mumol/liter) and crescent formation (29 +/- 2% of glomeruli) were no different from =/- mice. Mouse immunoglobulin was absent in their serum and glomeruli, however, cutaneous DTH to sheep globulin was identical to heterozygous mice. These results demonstrate that glomerular crescent formation and injury can occur independent of a humoral immune response to planted glomerular antigen and without glomerular deposition of autologous antibody. This strongly supports the hypothesis that crescent formation is a manifestation of DTH.