Self-dsDNA in the pathogenesis of systemic lupus erythematosus

Abstract

Systemic lupus erythematosus (SLE) is a systemic and poly-aetiological autoimmune disease characterized by the production of antibodies to autologous double-stranded DNA (dsDNA) which serve as diagnostic and prognostic markers. The defective clearance of apoptotic material, together with neutrophil extracellular traps (NETs), provides abundant chromatin or self-dsDNA to trigger the production of anti-dsDNA antibodies, although the mechanisms remain to be elucidated. In SLE patients, the immune complex (IC) of dsDNA and its autoantibodies trigger the robust type I interferon (IFN-I) production through intracellular DNA sensors, which drives the adaptive immune system to break down self-tolerance. In this review, we will discuss the potential resources of self-dsDNA, the mechanisms of self-dsDNA-mediated inflammation through various DNA sensors and its functions in SLE pathogenesis.

Keywords: DNA sensors; IFN-I; SLE; autoantibody; self-dsDNA.

Figure 1

Self‐dsDNA involved in the pathogenesis of systemic lupus erythematosus (SLE). In SLE patients, the clearance of apoptosis, necrosis and neutrophil extracellular traps (NETs) is defective which is the major resource of self‐dsDNA to induce autoantibody production with unrevealed mechanism. Anti‐dsDNA antibodies are produced by autoreactive B cells with the help of autoreactive T cells. Immune complex of dsDNA and its autoantibody triggers the robust type I interferon (IFN‐I) production through various intercellular DNA sensors in phagocytes and plasmacytoid dendritic cells (pDC). IFN‐I is the driving force in SLE pathogenesis by participating in inflammatory reactions, tissue damage, DC maturation and activation of autoreactive T and B cells.

Figure 2

Cytosolic DNA sensors and their signalling pathways in systemic lupus erythematosus (SLE). Self‐dsDNA stimulates cytosolic DNA sensor‐dependent signal pathways for type I interferon (IFN‐I) and proinflammatory cytokines production. Many DNA sensors have been proven to be associated with the pathogenesis of SLE, mainly including Toll‐like receptor (TLR)‐9, cyclic growth arrest‐specific 6 (cGAS), DNA‐dependent activator of IFN‐regulatory factors (DAI), absent in melanoma 2 (AIM2), gamma‐interferon inducible protein‐16 (IFI16) and nucleotide‐binding domain leucine‐rich repeat containing protein family pyrin domain containing 3 (NLRP3) to activate different signal pathways: TLR‐9‐dependent, stimulator of IFN genes (STING)‐dependent and inflammasome‐dependent pathways.