AUTOIMMUNITY AGAINST NUCLEOSOMES AND LUPUS NEPHRITIS

It is generally assumed that anti-dsDNA antibodies play an important r ole in the pathogenesis of lupus nephritis. This is mainly based on th e facts that an increase in anti-dsDNA titer often precedes onset of r enal disease, that immune deposits are present in glomeruli and that e luates of glomeruli are enriched for anti-dsDNA. This led to the class ical concept that deposition of DNA-anti-DNA complexes incites the glo merular inflammation. However, important pieces of evidence are lackin g to support this hypothesis. Free, naked, DNA is not present in the c irculation. The existence of DNA/anti-DNA complexes is highly question able and injection of these complexes hardly leads to glomerular local ization. As an alternative concept cross-reactivity of anti-dsDNA with glomerular constituents like heparan sulfate (HS) and laminin has bee n proposed. However, subsequent research has indicated that this cross -reactivity is due to nucleosomal antigens (histones and DNA) complexe d to the auto-antibodies, The cationic histone part of the complex is responsible for the binding to the anionic HS. This binding also occur s in vivo since renal perfusion of nucleosome complexed antibodies lea ds to abundant binding of auto-antibodies to the GEM, while enzymatic removal of HS from the GEM, decreases this binding considerably. Non-c omplexed antibodies did not bind at all. This mechanism of binding is also consistent with the decrease of HS staining in the GEM in human a nd murine lupus due to masking of HS with nucleosome-complexed auto-an tibodies. Furthermore the presence of histones and nucleosomes in glom erular deposits in lupus nephritis was recently shown. Elution of auto antibodies from glomeruli not only showed anti-dsDNA but also anti-nuc leosome specificities. Nucleosomes are not only important for the indu ction of glomerular lesions, but there is now also increasing evidence that the nucleosome is the auto-antigen that drives the auto-immune r esponse 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 h elper 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-histon antibodies. This is in line with the finding that in SLE nucleosome specific antibodies are f ormed. These antibodies react exclusively with nucleosomes and not wit h its constituents DNA or histones. The formation of these nucleosome specific antibodies precedes the development of anti-dsDNA or anti-his ton suggesting that the loss of tolerance for nucleosomes is a primary event. The systemic release of nucleosomes is due to an aberant apopt osis. There is now growing evidence that apoptosis is disturbed both i n certain murine lupus models as well as in human lupus. In conclusion , nucleosomes seem to play a central role in the induction and the eff ector phase of SLE.