The enemy within: endogenous retroelements and autoimmune disease

Abstract

Inappropriate or chronic detection of self nucleic acids by the innate immune system underlies many human autoimmune diseases. We discuss here an unexpected source of endogenous immunostimulatory nucleic acids: the reverse-transcribed cDNA of endogenous retroelements. The interplay between innate immune sensing and clearance of retroelement cDNA has important implications for the understanding of immune responses to infectious retroviruses such as human immunodeficiency virus (HIV). Furthermore, the detection of cDNA by the innate immune system reveals an evolutionary tradeoff: selection for a vigorous, sensitive response to infectious retroviruses may predispose the inappropriate detection of endogenous retroelements. We propose that this tradeoff has placed unique constraints on the sensitivity of the DNA-activated antiviral response, with implications for the interactions of DNA viruses and retroviruses with their hosts. Finally, we discuss how better understanding of the intersection of retroelement biology and innate immunity can guide the way to novel therapies for specific autoimmune diseases.

Figure 1. Types of Endogenous Retroelements in the Mammalian Genome

Autonomous retroelements encode all the proteins necessary for replication. These include LTR type endogenous retroviruses and LINE elements. Nonautonomous retroelements include SINEs, and require LINEs for their mobility. (LTR, Long terminal repeat; GAG, group-specific antigen; PRT, protease; Pol, polymerase; ENV, envelope)

Figure 2. Model: Coevolution with Endogenous Retroelements Shapes the DNA Sensing Pathway

Low levels of nucleic acids arising from reverse transcription of endogenous retroelements are kept in check by AGS genes. We predict that the sensitivity of DNA sensors must be above this level to prevent inappropriate activation of the DNA sensing pathway and autoimmune disease. This level of detection would aid DNA viruses to maintain their genome in the nucleus during latent infection. We predict that some DNA viruses during latency would act to inhibit the DNA sensing pathway, thereby raising the threshold needed to initiate an immune response. During AGS the burden of nucleic acids from endogenous retroelements reaches a level now detectable by the DNA sensors and initiates a chronic immune response leading to autoimmune disease. The threshold of sensitivity for RNA sensors can be much lower because of a lack of endogenous RNA ligands.

Figure 3. AGS Genes Restrict Replication of Endogenous Retroelements and Exogenous Retroviruses

Schematic of LINE and Retrovirus Replication. AGS genes act throughout the steps of replication to restrict products of reverse transcriptase. SAMHD1 inhibits reverse transcription through degradation of cellular dNTPs. TREX1 metabolizes DNA products of reverse transcription, and can block retrotransposition of endogenous retroelements. RNASEH2 can degrade RNA of RNA/DNA hybrids and can also block retrotransposition of endogenous retroelements, and we hypothesize that it acts by degrading viral RNA in the context of reverse transcription.

Figure 4. Therapeutic Strategies to Mitigate Cell Intrinsic Activation of the ISD Pathway

Failure to metabolize reverse transcribed products causes inappropriate activation of the DNA sensing pathway, chronic type I IFN production, and autoimmune disease. Disease intervention strategies include blockade of type I IFNs, preventing signaling through the ISD pathway through TBK1 specific inhibitors, and elimination of reverse transcribed products through the use of reverse transcriptase inhibitors (RTIs).