A pathogenetic role for mast cells in experimental crescentic glomerulonephritis.
Mast cells infiltrate kidneys of humans with crescentic glomerulonephritis (GN), and the degree of infiltrate correlates with outcome. However, a functional role for mast cells in the pathogenesis of GN remains speculative. GN was induced by intravenous administration of sheep anti-mouse glomerular basement membrane globulin. After 21 d, systemic immune responses and disease severity were analyzed in wild-type, mast cell-deficient (W/Wv), and bone marrow-derived mast cell-reconstituted W/Wv mice (BMMC-->W/Wv). There were no significant differences in the humoral response toward the nephritogenic antigen or in memory T cell number among the three groups; however, antigen-stimulated T cell IFN-gamma production was significantly elevated in BMMC-->W/Wv mice. Dermal delayed-type hypersensitivity in W/Wv mice was reduced compared with wild-type and BMMC-->W/Wv mice. No mast cells were detected in kidneys of W/Wv mice with GN, whereas in BMMC-->W/Wv mice, the numbers of renal mast cells were similar to wild-type mice with GN. W/Wv mice were protected from the development of crescentic GN, exhibiting reduced crescent formation (10 +/- 1% c.f. 36 +/- 2% in wild type), glomerular influx of T cells/macrophages, and interstitial infiltrate compared with wild-type mice. In contrast, BMMC-->W/Wv demonstrated a similar severity of GN as wild-type mice (35 +/- 2% crescentic glomeruli), accompanied by a prominent inflammatory cell infiltrate into glomeruli and interstitial areas. Glomerular expression of intercellular adhesion molecule-1 and P-selectin were reduced in W/Wv mice but restored to wild-type levels in BMMC-->W/Wv mice. These findings suggest that renal mast cells mediate crescentic GN by facilitating effector cell recruitment into glomeruli via augmentation of adhesion molecule expression.
Timoshanko
Jennifer R
JR
Center for Inflammatory Diseases, Monash University, Department of Medicine, Monash Medical Center, 246 Clayton Road, Melbourne, Victoria 3168, Australia. jennifer.timoshanko@med.monash.edu
Kitching
A Richard
AR
Semple
Timothy J
TJ
Tipping
Peter G
PG
Holdsworth
Stephen R
SR
D000818:Animals; D018925:Chemokines / Q000096:biosynthesis; D005921:Glomerulonephritis / Q000209:etiology* / Q000276:immunology; D006968:Hypersensitivity, Delayed / Q000209:etiology; D007074:Immunoglobulin G / Q000097:blood / Q000145:classification; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis; D007668:Kidney / Q000276:immunology; D008297:Male; D008407:Mast Cells / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL
D018925:Chemokines; D007074:Immunoglobulin G; D018799:Intercellular Adhesion Molecule-1