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Programmed cell death, an essential function in all cells, plays a central role in maintaining immune system homeostasis and controlling autoimmune reactions. Cell death may be an essential element in disseminated lupus erythematosus: defective cell death could lead to the development of autoreactive lymphocyte clones and degradation products of cell death could be implicated in autoimmunity induction and onset of renal lesions. Anomalies in programmed cell death have been demonstrated in murine models of lupus: mutations of the fas and fas-ligand genes, which play a known role in programmed cell death, produce the lpr and gld phenotypes associating lymphoproliferation and lupus. Transgenic mice which express Bcl-2 (the product of Bcl-2 inhibits programmed cell death) on B lymphocytes develop a lupus-type autoimmune disease. The role of these types of anomalies in human disease is not yet elucidated. However, cell death, via the degradation fragments of chromatin, could play a role in inducing antibody production and development of renal lesions. The anti-DNA antibodies, with characteristic antigen-induced immune response (clone expansion, class computation and somatic mutations) could be induced by nucleosomes released during cell death. Several arguments favor this mechanism including cation residues of histone nucleosomes which would bind to anionic residues of sulfate heparan and lead to deposit of autoantibodies in the glomerulus. The dual role of cell death is not really contradictory in autoimmune disease controlled by several independent genes, but would be compatible with several different genetic backgrounds.

Experimental studies on the NZBxNZW mouse lupus disease and on the development of immune complex (IC) glomerulonephritis in mouse infected with Escherichia coli lead us to state the following hypothesis: two types of factors are implicated in the development of immune complex glomerulonephritis: 1) specific factors leading to the production of IC involving antigens from the triggering agents; 2) non specific factors leading to the production of IC involving auto-antigens.

An accelerated model of the NZBxNZW mouse disease is described. The acceleration of the disease was induced by the simultaneous injections of DNA complexed to methylated bovine serum albumin and of bacterial lipopolysaccharide which allow for the production, early in life, of high levels of anti-DNA antibodies. This new model was found to be suitable for therapeutic studies in mice with accelerated disease treated with cyclophosphamide and heparin.

Anti-DNA antibodies play a pathogenic role in the development of lupus nephritis. The role of extracellular DNA in the pathophysiology of lupus diseases is still controversial. It is possible that anti-DNA antibodies are elicited by antigens which cross-react with DNA and that they play their pathogenic role through direct binding on cell membrane or tissue components. Alternatively, experimental and clinical studies suggest that extracellular DNA might be involved in the induction of anti-DNA antibodies and that they might be pathogenic through the formation of immune complexes. Recent studies done on circulating DNA led to propose the hypothesis that cell death phenomena might play a major pathogenic role in the induction of auto-immune reactions and/or in the development of kidney lesions in lupus diseases.