Chromatin as a target antigen in human and murine lupus nephritis

Abstract

The present review focuses on pathogenic molecular and transcriptional events in patients with lupus nephritis. These factors are renal DNaseI, exposed chromatin fragments and the corresponding chromatin-reactive autoantibodies. Lupus nephritis is the most serious complication in human systemic lupus erythematosus, and is characterised by deposition of chromatin fragment-IgG complexes in the mesangial matrix and glomerular basement membranes. The latter deposition defines end-stage disease. This event is stringently linked to a renal-restricted shutdown of expression of the DNaseI gene, as determined by loss of DNaseI mRNA level and DNaseI enzyme activity. The major aim of the present review is to generate new therapeutic strategies based on new insight into the disease pathogenesis.

Figure 1

Exposed, extracellular chromatin is a central factor in evolution of lupus nephritis - a model. In normal situations, chromatin is effectively removed in the context of apoptosis. When chromatin fragments are not appropriately cleared, they may be exposed in tissue or in circulation. Exposure of chromatin may have an impact on the immune system. Chromatin may recirculate as oligonucleosomes, and eventually activate dendritic cells (DC). These cells present chromatin-derived peptides and upregulated co-stimulatory molecules to naïve peptide-specific CD4⁺ T cells. Activated T cells may subsequently recirculate and provide help to DNA-specific or nucleosome-specific B cells to be transformed into antibody-secreting plasma cells. In this situation the antibodies are potentially pathogenic, but to exert this potential they must bind exposed chromatin fragments. This may happen in the kidneys when DNaseI is downregulated, and may have an immense impact on the pathogenic effect of the autoantibodies. Chromatin in cells dying from, for example, apoptosis may, due to loss of DNaseI, not be degraded, and instead of clearance they become exposed as secondary necrotic chromatin in, for example, glomerular basement membranes (GBMs), where they are targeted by induced anti-chromatin antibodies. Chromatin fragments may thus exert two effects with fatal consequences for the kidneys: they may induce autoimmunity (nucleosomes), and they represent targets for the induced autoantibodies (chromatin fragments). This identifies two hot points for therapy with chaperone molecules such as heparin: increased nuclease-mediated digestion of nucleosomal DNA, and thereby reduced load of immunogenic DNA; and prevention of binding of immunocomplexes containing chromatin fragments to GBMs and matrices (arrow to the left, surface plasmon resonance analysis of the effect of heparin, bottom right). Binding of nucleosomes to laminin was reduced by unfractionated heparin reaching approximately 75% and 100% inhibition at a nucleosome:heparin molar ratio of 1:1 and 1:10, respectively. For experimental details, see [73]. One single chaperone molecule may thus have a two-sided beneficial effect on lupus nephritis. KD, equilibrium dissociation constant; PC, plasma cell; TLR, Toll-like receptor; TUNEL IEM, terminal deoxynucleotidyltransferase biotin-dUTP nicked end-labelled immune electron microscopy. Modified with permission from [34], ^© 2010 Macmillan Publishers Ltd.