The Role of Extracellular DNA in Autoimmunity in SLE

Abstract

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterized by the expression of antibodies to DNA. These antibodies form immune complexes that can stimulate cytokine production as well as deposit in the tissues to incite inflammation and damage. For the formation of immune complexes, the availability of extracellular DNA in an immunologically relevant form is essential. While apoptosis has been implicated as the source of this nuclear material in SLE, as shown with in vitro or in vivo systems, extracellular DNA can originate from apoptotic as well as necrotic cells. In experimental models, the release of DNA occurs with the administration of cells induced to die, in vitro as well as the administration of agents to induce cell death in situ. This release can be influenced by the presence of inflammatory cells such as macrophages that can interact with dead and dying cells to modulate the translocation of DNA from the inside to the outside of cells. In vivo, both glucocorticoids and oestrogens can modify the extent of DNA release from the administration of dead and dying cells. Together, these findings indicate that the generation of extracellular DNA in SLE can result from cell death and that steps in this process represent potential targets for new therapies.

Complement C3a, CpG Oligos, and DNA/C3a Complex Stimulate IFN-α Production in a Receptor for Advanced Glycation End Product-Dependent Manner

“…Interestingly, TLR9 can be activated by DNA released from apoptotic and necrotic mammalian cells (2,23). When genomic DNA is released from necrotic cells and disassociated from histones in nucleosomes, it is subjected to demethylation and restriction cleavage (23,29) to form various demethylated DNA fragments which become effective ligands of TLR9 (30).…”

Plasma DNA aberrations in systemic lupus erythematosus revealed by genomic and methylomic sequencing

“…Cell death has been regarded as an important event in the pathogenesis of SLE, as it leads to the release of antigens, such as nucleic acids, for immune complex formation, which may trigger a cascade of immune responses against the bodily tissues of the SLE patients (5,6). Defects in the mechanism of cell death (7), impairment in the clearance of dead cells (8), and deficiency in DNase activity (9) have been implicated in SLE and suggested to be involved in the generation of autoantigens (5,6).…”

Annexin A5 and anti-annexin antibodies in patients with systemic lupus erythematosus

“…Through inhibiting prothrombin activation, ANX A5 prevents arterial and venous thrombus formation [1,7]. The anti-thrombotic effect of ANX A5 is mediated by its preferential binding to phosphatidylserine expressed on the surface during the destruction of the cells [15]. Phosphatidylserine exposure is the physiological signal for the processes of coagulation and apoptosis.…”

“…Apoptotic cells display characteristic morphological and surface changes related to a key functional phenomenon, which is the above-mentioned phosphatidylserine expression [15].…”

“…SLE is an autoimmune disease with disturbances in the process of clearance of apoptotic cells [8,17] and the dominant role of extracellular DNA in pathogenesis of disease [15]. Apoptotic cells display characteristic morphological and surface changes related to a key functional phenomenon, which is the above-mentioned phosphatidylserine expression [15].…”