Deranged removal of apoptotic cells: its role in the genesis of lupus.

The formation of anti-nuclear autoantibodies is the main feature of the autoimmune disease systemic lupus erythematosus (SLE). We do not know why these nuclear components become autoantigens in the disease. Recently, evidence has emerged which points to an important connection with apoptosis and the removal of apoptotic cells. The process of apoptosis, or programmed cell death, contains a series of pathways leading to the regulated removal of unwanted cells, including the induction of tolerance for autoantigens. This process is strictly regulated. In particular, the adequate removal of early apoptotic cells is of great importance. Since nuclear autoantigens become clustered in apoptotic blebs [1], an impaired removal could lead to the release of nuclear structures, possibly also modified during apoptosis (Figure 1). The release of (modified) nuclear structures could then induce an immune response to these autoantigens leading to the production of autoantibodies. Chromatin, a complex of proteins and double-stranded (ds) DNA, is an autoantigen that is clustered in apoptotic blebs. Autoantibodies against chromatin (including antidsDNA, anti-histone and nucleosome-specific antibodies) are a hallmark of SLE [2]. Moreover, the formation of anti-chromatin/chromatin complexes can lead to the binding of these complexes to basement membranes, including the glomerular basement membrane (GBM). Here, the positively charged histone tails of chromatin bind to negatively charged molecules in the GBM, such as heparan sulphate proteoglycans [3]. This binding induces inflammation, which leads to lupus nephritis, the most serious manifestation of SLE. The evidence for dysregulation of the apoptotic process and removal of apoptotic cells for the development of SLE will be discussed in this Editorial Comment.