Intracellular Nucleic Acid Detection in Autoimmunity

Abstract

Protective immune responses to viral infection are initiated by innate immune sensors that survey extracellular and intracellular space for foreign nucleic acids. The existence of these sensors raises fundamental questions about self/nonself discrimination because of the abundance of self-DNA and self-RNA that occupy these same compartments. Recent advances have revealed that enzymes that metabolize or modify endogenous nucleic acids are essential for preventing inappropriate activation of the innate antiviral response. In this review, we discuss rare human diseases caused by dysregulated nucleic acid sensing, focusing primarily on intracellular sensors of nucleic acids. We summarize lessons learned from these disorders, we rationalize the existence of these diseases in the context of evolution, and we propose that this framework may also apply to a number of more common autoimmune diseases for which the underlying genetics and mechanisms are not yet fully understood.

Keywords: Aicardi-Goutières syndrome; RIG-I-like receptors; Toll-like receptors; cGAS-STING; systemic lupus erythematosus; type I interferons.

Figure 1:. Pathway-specific negative regulators of nucleic acid sensing.

Endosomal TLRs and sensors of cytosolic nucleic acids are depicted, together with key negative regulators. See text for details on each.

Figure 2:. Nucleic acid sensing and the host-virus conflict.

A: Two viruses are shown, each of which encodes a distinct antagonist of the same sensing pathway. An escape mutation in the sensor that overcomes antagonism by virus A does not impact continued antagonism by virus B. B: A mutation in a pathway-specific negative regulator increases the overall strength of the sensing pathway, conferring increased resistance to both viruses even in the presence of their antagonists.

Figure 3:. Pathway-specific and generic triggers of autoimmune disease.

A: In individuals with a sensitized cGAS-STING pathway, the enhanced response to DNA viruses might predispose to autoimmunity, but the normal response to infection with picornavirus, an RNA virus, might not. Conversely, individuals with a sensitized MDA5 pathway may be triggered by picornavirus infection, not DNA virus infection. B: In individuals with a sensitized MDA5 pathway, an infection that causes systemic type I IFN production may increase the abundance of MDA5 within cells, leading to autoreactivity against endogenous ligands.