Glomerular expression of CD80 and CD86 is required for leukocyte accumulation and injury in crescentic glomerulonephritis.
The participation of renal expression of CD80 and CD86 in the immunopathogenesis of crescentic Th1-mediated anti-glomerular basement membrane (anti-GBM) glomerulonephritis (GN) has not been assessed. Immunohistochemical staining demonstrated prominent upregulation of both molecules in glomeruli of mice with anti-GBM GN, suggesting a potential role for the local expression of CD80 and CD86 in nephritogenic effector T cell responses. For testing this hypothesis, control or inhibitory anti-CD80 and/or anti-CD86 mAb were administered to mice during the effector phase of the disease but after the establishment of a systemic immune response. Anti-CD80 or anti-CD86 mAb treatment had no effect on the development of GN or infiltration of leukocytes into glomeruli; however, administration of anti-CD80/86 mAb attenuated glomerular accumulation of CD4+ T cells and macrophages, crescent formation, and proteinuria, correlating with reduced antigen-specific skin delayed-type hypersensitivity. Attenuated glomerular infiltration of leukocytes in mice that were treated with anti-CD80/86 mAb was associated with decreased intraglomerular expression of adhesion molecules P-selectin and intercellular adhesion molecule-1, as well as attenuated renal mRNA levels of proinflammatory cytokines IFN-gamma and migration inhibitory factor, without reducing chemokine and chemokine receptor expression in the kidney or intraglomerular apoptosis and proliferation. The systemic Th1/Th2 balance (assessed by splenocyte production of IFN-gamma and IL-4 and circulating levels of IgG1 and IgG2a) was not affected by the inhibition of CD80 and CD86. These studies show that CD80 and CD86 are expressed in glomeruli of mice with crescentic anti-GBM GN, in which they play a critical role in facilitating accumulation of Th1 effectors and macrophages, thus exacerbating renal injury.
Odobasic
Dragana
D
Monash University, Department of Medicine, Monash Medical Centre, 246 Clayton Road, Clayton, Victoria 3168, Australia.
Kitching
A Richard
AR
Semple
Timothy J
TJ
Timoshanko
Jennifer R
JR
Tipping
Peter G
PG
Holdsworth
Stephen R
SR
D000818:Animals; D019867:Anti-Glomerular Basement Membrane Disease / Q000276:immunology*; D015703:Antigens, CD / Q000096:biosynthesis*; D018122:B7-1 Antigen / Q000096:biosynthesis*; D051940:B7-2 Antigen; D002634:Chemotaxis, Leukocyte / Q000276:immunology*; D007678:Kidney Glomerulus / Q000276:immunology*; D008264:Macrophages / Q000502:physiology; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis*; D051379:Mice; D018417:Th1 Cells / Q000502:physiology
D015703:Antigens, CD; D018122:B7-1 Antigen; D051940:B7-2 Antigen; C497965:Cd86 protein, mouse; D008562:Membrane Glycoproteins