ANTI-dsDNA ANTIBODIES AND LUPUS NEPHRITIS

NEPHRITIS Antibodies against DNA were described in 1957 by four independent research groups (1–4). Scientists at that time could not foresee that the discovery of antibodies to double-stranded DNA (dsDNA) would have an immense impact on our understanding of origin and regulation of autoimmunity in general, and more specifically on autoimmunemediated inflammation. Soon after their discovery, it was shown that anti-dsDNA autoantibodies were associated with lupus nephritis. This finding was supported by three facts: (i) DNA bound glomerular collagen (5,6); (ii) the nephritogenic antibodies were specific for DNA (7,8); and (iii) anti-dsDNA antibodies could be eluted from the nephritic kidneys (7,9–14; reviewed in [15]). Despite several decades of research, there is no consensus on the basic mechanisms that promote lupus nephritis. Data on cross-reactivity of anti-dsDNA antibodies led to the interpretation that renal structures bound nephritogenic autoantibodies in vivo (reviewed in [15,16]; for details, see below). However, renal targets for anti-dsDNA antibodies can also be their homologous antigens (dsDNA or chromatin fragments) generated during apoptosis (reviewed in [15,17]). The release and accumulation of apoptotic chromatin fragments under normal physiological conditions is prevented by the rapid and silent clearance of apoptotic cells by macrophages. Pathological processes in systemic lupus erythematosus (SLE) that lead to accumulation and exposure of immunogenic chromatin fragments may include aberrant apoptosis, impaired clearance of apoptotic cells and reduced chromatin fragmentation (18–20). Early mesangial nephritis is characterized by mesangial deposits of chromatin fragments in complex with antibodies to dsDNA, whereas advanced stages of lupus nephritis are characterized by deposition of immune complexes in both the mesangial matrix and the glomerular basement membrane (GBM) (21). Moreover, we have demonstrated that advanced stages of lupus nephritis are associated in time with an almost complete and selective silencing of the renal DNaseI gene (22–24), the major