Anti-DNA autoantibodies initiate experimental lupus nephritis by binding directly to the glomerular basement membrane in mice.
The strongest serological correlate for lupus nephritis is antibody to double-stranded DNA, although the mechanism by which anti-DNA antibodies initiate lupus nephritis is unresolved. Most recent reports indicate that anti-DNA must bind chromatin in the glomerular basement membrane or mesangial matrix to form glomerular deposits. Here we determined whether direct binding of anti-DNA antibody to glomerular basement membrane is critical to initiate glomerular binding of anti-DNA in experimental lupus nephritis. Mice were co-injected with IgG monoclonal antibodies or hybridomas with similar specificity for DNA and chromatin but different IgG subclass and different relative affinity for basement membrane. Only anti-DNA antibodies that bound basement membrane bound to glomeruli, activated complement, and induced proteinuria whether injected alone or co-injected with a non-basement-membrane-binding anti-DNA antibody. Basement membrane-binding anti-DNA antibodies co-localized with heparan sulfate proteoglycan in glomerular basement membrane and mesangial matrix but not with chromatin. Thus, direct binding of anti-DNA antibody to antigens in the glomerular basement membrane or mesangial matrix may be critical to initiate glomerular inflammation. This may accelerate and exacerbate glomerular immune complex formation in human and murine lupus nephritis.
Department of Microbiology, Immunology, and Biochemistry, The University of Tennessee Health Science Center, Memphis, TN 38163, USA.
Meera R
MR
Krishnan
Congmiao
C
Wang
Tony N
TN
Marion
D000818:Animals; D000974:Antibodies, Antinuclear / Q000008:administration & dosage* / Q000378:metabolism; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000378:metabolism; D000915:Antibody Affinity; D001666:Binding Sites, Antibody; D002843:Chromatin / Q000276:immunology; D003167:Complement Activation; D004247:DNA / Q000276:immunology*; D004195:Disease Models, Animal; D050533:Glomerular Basement Membrane / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism; D006825:Hybridomas; D007275:Injections, Intravenous; D008181:Lupus Nephritis / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D011507:Proteinuria / Q000276:immunology
D000974:Antibodies, Antinuclear; D000911:Antibodies, Monoclonal; D002843:Chromatin; D019812:Heparan Sulfate Proteoglycans; D004247:DNA