title: Autoimmunity against nucleosomes and lupus nephritis.
abstract: It is generally assumed that anti-dsDNA antibodies play an important role in the pathogenesis of lupus nephritis. This is mainly based on the facts that an increase in anti-dsDNA titer often precedes onset of renal disease, that immune deposits are present in glomeruli and that eluates of glomeruli are enriched for anti-dsDNA. This led to the classical concept that deposition of DNA-anti-DNA complexes incites the glomerular inflammation. However, important pieces of evidence are lacking to support this hypothesis. Free, naked, DNA is not present in the circulation. The existence of DNA/anti-DNA complexes is highly questionable and injection of these complexes hardly leads to glomerular localization. As an alternative concept cross-reactivity of anti-dsDNA with glomerular constituents like heparan sulfate (HS) and laminin has been proposed. However, subsequent research has indicated that this cross-reactivity is due to nucleosomal antigens (histones and DNA) complexed to the auto-antibodies. The cationic histone part of the complex is responsible for the binding to the anionic HS. This binding also occurs in vivo since renal perfusion of nucleosome complexed antibodies leads to abundant binding of auto-antibodies to the GBM, while enzymatic removal of HS from the GBM, decreases this binding considerably. Non-complexed antibodies did not bind at all. This mechanism of binding is also consistent with the decrease of HS staining in the GBM in human and murine lupus due to masking of HS with nucleosome-complexed auto-antibodies. Furthermore the presence of histones and nucleosomes in glomerular deposits in lupus nephritis was recently shown. Elution of auto-antibodies from glomeruli not only showed anti-dsDNA but also anti-nucleosome specificities. Nucleosomes are not only important for the induction of glomerular lesions, but there is now also increasing evidence that the nucleosome is the auto-antigen that drives the auto-immune response in SLE. There is ample evidence that this response is antigen-driven and T cell dependent. However immunization with DNA in general fails to induce pathogenic anti-dsDNA antibodies. Recently, in SLE T helper cells were identified specific for nucleosomes. These nucleosome specific T helper cells were not only able to induce anti-nucleosome antibodies but also anti-dsDNA and anti-histone antibodies. This is in line with the finding that in SLE nucleosome specific antibodies are formed. These antibodies react exclusively with nucleosomes and not with its constituents DNA or histones. The formation of these nucleosome specific antibodies precedes the development of anti-dsDNA or anti-histone suggesting that the loss of tolerance for nucleosomes is a primary event. The systemic release of nucleosomes is due to an aberrant apoptosis. There is now growing evidence that apoptosis is disturbed both in certain murine lupus models as well as in human lupus. In conclusion, nucleosomes seem to play a central role in the induction and the effector phase of SLE.
authors.affiliation: Div. of Nephrology, University Hospital St. Radboud, Nijmegen, The Netherlands.
authors.forename: M C
authors.initials: MC
authors.lastname: Van Bruggen
authors.forename: C
authors.initials: C
authors.lastname: Kramers
authors.forename: J H
authors.initials: JH
authors.lastname: Berden
mesh_terms: D000974:Antibodies, Antinuclear / Q000502:physiology*; D000936:Antigen-Antibody Complex / Q000276:immunology; D006801:Humans; D008181:Lupus Nephritis / Q000276:immunology / Q000503:physiopathology*; D009707:Nucleosomes / Q000276:immunology*
chemical_list: D000974:Antibodies, Antinuclear; D000936:Antigen-Antibody Complex; D009707:Nucleosomes