Figure 3

The role of extracellular chromatin fragments and anti-dsDNA antibodies in progressive lupus nephritis. Retention of chromatin is assumed to start with reduced clearance of apoptotic cells (station 1). Secondary to this, chromatin may be exposed in tissues (station 2) and is assumed to activate dendritic cells (station 3). These cells present chromatin-derived peptides in the context of MHC class II molecules to peptide-specific CD4⁺ T cells (station 4). When primed, the peptide-specific T cells recirculate and bind the same chromatin-derived peptides presented in the context of MHC class II by chromatin-specific B-cells (here recognizing dsDNA in chromatin; station 5). As a consequence of cognate interaction of dsDNA-specific B cells and peptide-specific CD4⁺ T cells, the B cells transform into plasma cells that secrete IgG anti-dsDNA antibodies (station 6), which bind chromatin fragments (station 7). Immune complexes that consist of IgG antibodies and chromatin fragments bind in the glomerular mesangial matrix and initiate mesangial lupus nephritis (station 8). This early inflammation is followed by silencing of renal DnaseI in tubular and glomerular cells (station 9) and accumulation of undigested chromatin fragments (station 10). These fragments promote upregulation of TLRs, proinflammatory cytokines and matrix metalloproteases (station 11). Finally, IgG autoantibodies recognize and bind the chromatin fragments, and these immune complexes deposit in the GBMs and aggravate renal inflammation (station 12). In this sense, chromatin fragments and anti-chromatin (here: anti-dsDNA) antibodies are the partners that impose the classic murine and human lupus nephritis. Thus, anti-chromatin antibodies are pathogenic only in the context of exposed chromatin structures. This model does not exclude other processes that can initiate and maintain lupus nephritis, as discussed in the text.