DNA has emerged as a Pathogen Associated Molecular Pattern (PAMP), posing unique challenges in the discrimination between endogenous (self) and foreign DNA. This challenge is highlighted by certain autoinflammatory diseases that arise from monogenic mutations and result in periodic flares of inflammation, typically in the absence of autoantibodies or antigen-specific T lymphocytes. A number of autoinflammatory diseases arise due to mutations in genes that normally prevent the accrual of endogenous DNA or due to mutations that cause activation of intracellular DNA sensing pathway components. Experimental evidence from genetically-modified murine models further support the ability of endogenous DNA and DNA sensing to drive disease pathogenesis, prompting the question of whether endogenous DNA can also incite inflammation in human autoimmune diseases. Here we review the current understanding of intracellular DNA sensing and downstream signaling pathways as they pertain to autoinflammatory disease, including the development of monogenic disorders such as STING-associated vasculopathy with onset in infancy (SAVI) and Aicardi-Goutieres Syndrome (AGS). In addition, we discuss systemic rheumatic diseases, including certain forms of systemic lupus erythematosus, familial chilblain lupus and others with established links to intracellular DNA sensing pathways, and highlight the lessons learned from these examples as they apply to the development of therapies targeting these pathways.
