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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.

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Figure 1: Types of endogenous retroelements in the mammalian genome.
Figure 2: AGS-related enzymes restrict the replication of endogenous retroelements and exogenous retroviruses.
Figure 3: Model by which coevolution with endogenous retroelements shapes the DNA-sensing pathway.
Figure 4: Therapeutic strategies for mitigating cell-intrinsic activation of the ISD pathway.

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Acknowledgements

We thank members of the Stetson laboratory for discussions; R, Medzhitov for helpful comments on the manuscript; and Y. Crow for continued collaborations. Supported by the Jane Coffin Childs Fund (H.E.V.), the Rita Allen Foundation (D.B.S.), the National Institute of Allergy and Infectious Diseases (AI084914), the European Union Seventh Framework Programme 2007–2013 (241779; Nuclease Immune Mediated Brain and Lupus-like conditions) and the Lupus Research Institute.

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Correspondence to Daniel B Stetson.

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Volkman, H., Stetson, D. The enemy within: endogenous retroelements and autoimmune disease. Nat Immunol 15, 415–422 (2014). https://doi.org/10.1038/ni.2872

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