PATHOPHYSIOLOGY OF LUPUS NEPHRITIS - THE ROLE OF NUCLEOSOMES

Lupus nephritis is regarded as an immune complex mediated disease. Sin ce anti-DNA antibodies are present in the circulation and in diseased glomeruli of patients with lupus nephritis, these antibodies have been assigned a pivotal role in the initiation of lupus nephritis. It rema ins however unclear how these antibodies become localized in the glome rulus. Contrary td the classical concept of glomerular deposition of D NA/anti-DNA complexes, it has been suggested that anti-DNA antibodies can interact with intrinsic glomerular antigens. Some anti-DNA antibod ies can cross-react with heparan sulphate (HS), which is such an intri nsic constituent of the glomerular basement membrane (GBM). Serum HS r eactivity coincides with the occurrence of lupus nephritis. It was fou nd that this HS reactivity was exhibited by anti-DNA antibodies comple xed to nucleosomes and not by the antibody itself. Nucleosomes are DNA /histone complexes, present in the nucleus, which are released by dyin g cells. The histone part of the nucleosome is responsible for the bin ding to the GBM. Recently, it has become clear that also anti-nucleoso me antibodies can bind to HS in the GBM via nucleosomes. These nucleos ome-containing immune complexes exhibit anti-DNA reactivity in ELISA a nd Farr assay. It is now thought that nucleosomes released by dying ce lls bind to anti-DNA or anti-nucleosome antibodies in the circulation, giving rise to nephritogenic immune complexes. Alternatively, nucleos omes may bind to the GBM and serve then as planted antigen for subsequ ent binding of antibodies via an in situ mechanism. Binding of antibod ies via both mechanisms leads to complement activation and damage of t he GBM. The recent finding of histones and DNA in glomerular depositio ns in lupus nephritis is in line with this hypothesis.