Role of Fcgamma receptors in glomerulonephritis.
Many forms of glomerulonephritis involve immune complex localization in the kidney. Fcgamma receptors (FcgammaR) expressed on the surface of leukocytes bind the Fc (constant) portion of IgG. They link immune complex deposition to innate immune responses, including phagocytosis, cytokine release, formation of reactive oxygen species, and antibody-dependent cytotoxicity. Activator and inhibitor FcgammaR co-exist on the surface of cells and set thresholds for immune responses. Inhibitor FcgammaR also have a specific role in the maintenance of B cell tolerance. Studies of gene-targeted mice lacking specific FcgammaR have demonstrated that animals lacking activator FcgammaR on circulating leukocytes were protected from immune complex induced glomerular injury, both in models of systemic lupus erythematosus (SLE) and anti-glomerular basement membrane antibody disease. In contrast, mice lacking inhibitor FcgammaR developed SLE-like auto-immunity on certain genetic backgrounds and were more susceptible to anti-glomerular basement membrane disease, with evidence of enhanced immune responses and dysregulated effector cells. There is also evidence for FcgammaR dysfunction in human SLE and for an association of 'low-binding' polymorphisms of FcgammaR with SLE. In the future, therapeutic possibilities may exist for the manipulation of the FcgammaR pathway in the treatment of glomerulonephritis.
Tarzi
Ruth M
RM
Rheumatology Section, Imperial College School of Medicine, Hammersmith Hospital, London, UK. rtarzi@hhnt.org.uk
Cook
H Terence
HT
D000818:Animals; D000936:Antigen-Antibody Complex / Q000378:metabolism; D001327:Autoimmune Diseases / Q000276:immunology; D004195:Disease Models, Animal; D005921:Glomerulonephritis / Q000276:immunology* / Q000378:metabolism*; D006801:Humans; D051379:Mice; D017452:Receptors, IgG / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
D000936:Antigen-Antibody Complex; D017452:Receptors, IgG