Nucleic Acid Sensors and Type I Interferon Production in Systemic Lupus Erythematosus

Abstract

The characteristic serologic feature of systemic lupus erythematosus (SLE) is autoantibodies against one’s own nucleic acid or nucleic acid-binding proteins – DNA and RNA-binding nuclear proteins. Circulating autoantibodies can deposit in the tissue, causing inflammation and production of cytokines such as type 1 interferon (IFN). Investigations in human patients and animal models have implicated environmental as well as genetic factors in the biology of the SLE autoimmune response. Viral/Bacterial nucleic acid is a potent stimulant of innate immunity by both toll-like receptor (TLR) and non-TLR signaling cascades. Additionally, foreign DNA may act as an immunogen to drive an antigen-specific antibody response. Self nucleic acid is normally restricted to the nucleus or the mitochondria, away from the DNA/RNA sensors, and mechanisms exist to differentiate between foreign and self nucleic acid. In normal immunity, a diverse range of DNA and RNA sensors in different cell types form a dynamic and integrated molecular network to prevent viral infection. In SLE, pathologic activation of these sensors occurs via immune complexes consisting of autoantibodies bound to DNA or to nucleic acid-protein complexes. In this review, we will discuss recent studies outlining how mismanaged nucleic acid sensing networks promote autoimmunity and result in the over-production of type I IFN. This information is critical for improving therapeutic strategies for SLE disease.

Epigenome profiling reveals significant DNA demethylation of interferon signature genes in lupus neutrophils

“…The role of components of the innate immune response in the pathogenesis of systemic autoimmune diseases, such as lupus, has been increasingly recognized [15,16]. Lupus is characterized by activation of plasmacytoid dendritic cells, a robust type-I interferon expression signature, and hyper-responsiveness of PBMCs to type-I interferon [17,18].…”

Advances in understanding the role of type I interferons in systemic lupus erythematosus

“…Important recent advances from studies addressing mechanisms of innate immune system activation, whether induced by viral infection or endogenous triggers, have extended the investigation of disease mechanisms in lupus beyond the activation of endosomal TLRs to address TLR-independent nucleic acid sensing pathways and their downstream consequences [26-28]*.…”

Advances in lupus genetics

“…The MAVS gene provides an example of an ancestry-specific coding-change functional polymorphism. MAVS is a mitochondrial protein which is involved in signaling downstream of cytosolic nucleic acid sensors which respond to virus infection with type I IFN and inflammatory cytokine production 72 . African-derived coding change polymorphisms in MAVS which were not found in other ancestral backgrounds were shown to be loss-of-function with respect to cytokine production after viral infection 20 , and these same polymorphisms were associated with a low IFN, autoantibody negative SLE phenotype in African-Americans 20 .…”