DNA as a self-antigen: nature and regulation

Abstract

High-affinity antibodies to double-stranded DNA are a hallmark of systemic lupus erythematosus (SLE) and are thought to contribute to disease flares and tissue inflammation such as nephritis. Notwithstanding their clinical importance, major questions remain about the development and regulation of these pathogenic anti- NA responses. These include the mechanisms that prevent anti-DNA responses in healthy subjects, despite the constant generation of self-DNA and the abundance of DNA-reactive B cells; the nature and physical form of antigenic DNA in SLE; the regulation of DNA availability as an antigen; and potential therapeutic strategies targeting the pathogenic DNA in SLE. This review summarizes current progress in these directions, focusing on the role of secreted DNases in the regulation of antigenic extracellular DNA.

Wiskott-Aldrich syndrome protein restricts cGAS/STING activation by dsDNA immune complexes

“…Notably, administration of STING inhibitors in vivo rescued chronic transcription of Isg15 in the spleen of WASp-null animals, indicat- ing that chronic systemic activation by circulating endogenous inducers depends on cytosolic sensing and can be modulated by inhibiting this pathway. Thus, as has been shown in monogenic disorders and in complex systemic diseases (4,5,(36)(37)(38), cytoskeletal defects can impact the threshold of self-NA sensing.…”

“…Pathogenic production of type I IFN was initially linked to binding of endogenous NA or antimicrobial peptides to endosomal Toll-like receptors (1)(2)(3). More recent evidence suggests that the cytosolic cGAS/STING sensing system plays a critical role in recognition of self-DNA in systemic autoimmunity (4)(5)(6). cGAS resides in the cytosol and binds to dsDNA, catalyzing the synthesis of a cyclic dinucleotide (cGAMP), which in turn binds the adaptor STING and recruits TBK1 to activate IRF3 and type I IFN transcription (7,8).…”

Autoantibody-dependent amplification of inflammation in SLE

“…Furthermore, the anti-dsDNA antibodies are only localised to kidneys of nephritic mice and not to healthy controls, suggesting that monoclonal antibodies identified in this study are more likely to exacerbate inflammatory immune responses and tissue damage but not to initiate it 55 – 57 . Rising evidence suggesting that both anti-dsDNA antibodies and NET are more likely to amplify rather than directly cause tissue pathology 6 , 12 , 46 , 48 , 49 , 57 – 59 . Anti-dsDNA antibodies deposit in the kidney of lupus nephritis patients but the mechanism is still controversial 5 , 60 , 61 .…”

Plasma DNA Profile Associated with DNASE1L3 Gene Mutations: Clinical Observations, Relationships to Nuclease Substrate Preference, and In Vivo Correction

“…Thus, DNASE1L3 shows a characteristic function and represents a critical mechanism of immune tolerance to DNA, and therefore is expected to play a major role in its regulation. 35 …”