Role of nucleosomes for induction and glomerular binding of autoantibodies in lupus nephritis.
The cardinal feature of systemic lupus erythematosus is the formation of anti-nuclear antibodies. In recent years, it has become clear that the nucleosome is a major autoantigen that drives this T cell-dependent autoimmune response, as exemplified by the presence of nucleosome-specific T helper cells and the high prevalence of nucleosome-specific autoantibodies. The only way to generate nucleosomes in vivo is by the process of apoptosis. There is growing evidence that in systemic lupus erythematosus apoptosis is disturbed, leading to the release of nucleosomes. Moreover, apoptosis-induced modifications of these autoantigens may render them more immunogenic, especially if the removal of apoptotic cells is insufficient. The first indications for the impaired clearance of apoptotic cells in systemic lupus erythematosus are emerging. Nucleosomes are also important for mediating tissue lesions, especially glomerulonephritis. In lupus nephritis nucleosomes, nucleosome-specific antibodies and nucleosome/IgG complexes have been identified in the glomerular immune deposits. Via their cationic histone part nucleosomes mediate the binding of anti-nuclear antibodies to intrinsic constituents of the glomerular basement membrane, such as the anionic heparan sulfate and collagen IV. Appreciation of this binding mechanism may lead to new treatment strategies, as shown for non-coagulant heparinoids.
Berden
J H
JH
Division of Nephrology, University Hospital St Radboud, Nijmegen, The Netherlands. j.berden@nefro.azn.nl
Licht
R
R
van Bruggen
M C
MC
Tax
W J
WJ
D000818:Animals; D000974:Antibodies, Antinuclear / Q000378:metabolism; D017209:Apoptosis; D001323:Autoantibodies / Q000378:metabolism*; D003094:Collagen / Q000276:immunology; D003429:Cross Reactions; D006497:Heparan Sulfate / Q000276:immunology; D006801:Humans; D007678:Kidney Glomerulus / Q000276:immunology*; D008180:Lupus Erythematosus, Systemic / Q000276:immunology / Q000473:pathology; D008181:Lupus Nephritis / Q000276:immunology* / Q000473:pathology; D008213:Lymphocyte Activation; D009707:Nucleosomes / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology
D000974:Antibodies, Antinuclear; D001323:Autoantibodies; D003094:Collagen; D006497:Heparan Sulfate; D009707:Nucleosomes