Autoimmunity against nucleosomes and lupus nephritis

Area of Science:

• Immunology
• Nephrology
• Rheumatology

Background:

• The role of anti-double-stranded DNA (anti-dsDNA) antibodies in lupus nephritis pathogenesis is traditionally assumed, based on elevated titers preceding renal disease and immune deposits in glomeruli.
• The classical hypothesis suggests DNA-anti-DNA complex deposition causes glomerular inflammation, but evidence for circulating DNA-anti-DNA complexes is questionable, and their glomerular localization is limited.
• Alternative concepts proposed cross-reactivity of anti-dsDNA with glomerular components like heparan sulfate (HS), but this was later attributed to nucleosomal antigens.

Purpose of the Study:

• To investigate the pathogenic role of nucleosomes and nucleosome-specific autoantibodies in lupus nephritis.
• To explore the mechanism of autoantibody binding to glomerular structures in systemic lupus erythematosus (SLE).
• To determine if nucleosomes are the primary autoantigen driving the autoimmune response in SLE.

Main Methods:

• Investigated cross-reactivity of anti-dsDNA antibodies with glomerular constituents, focusing on nucleosomes and heparan sulfate (HS).
• Examined in vivo binding of nucleosome-complexed antibodies to the glomerular basement membrane (GBM) and the effect of HS removal.
• Analyzed glomerular deposits for histones and nucleosomes, and eluted autoantibodies to identify specificities (anti-dsDNA, anti-nucleosome).
• Identified nucleosome-specific T helper cells in SLE patients and assessed their ability to induce various autoantibodies.
• Evaluated the role of aberrant apoptosis in systemic nucleosome release.

Main Results:

• Cross-reactivity of anti-dsDNA with HS is mediated by complexed histones, leading to cationic histone binding to anionic HS in glomeruli.
• Renal perfusion with nucleosome-complexed antibodies showed significant binding to the GBM, which was reduced by enzymatic HS removal; non-complexed antibodies did not bind.
• Glomerular deposits in lupus nephritis contain histones and nucleosomes, and eluted autoantibodies include anti-nucleosome specificities.
• Nucleosome-specific T helper cells in SLE patients induce anti-nucleosome, anti-dsDNA, and anti-histone antibodies.
• Formation of nucleosome-specific antibodies precedes anti-dsDNA or anti-histone antibodies, suggesting loss of tolerance to nucleosomes is an early event.
• Aberrant apoptosis is implicated in the systemic release of nucleosomes in lupus.

Conclusions:

• Nucleosomes, not DNA-anti-DNA complexes, are central to the induction and effector phases of lupus nephritis.
• The binding mechanism involves cationic histones within nucleosome complexes interacting with anionic heparan sulfate in the glomeruli.
• Loss of tolerance to nucleosomes, driven by aberrant apoptosis and nucleosome-specific T helper cells, is a primary event in SLE pathogenesis.