Endogenous retroelements and autoimmune disease

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Innate immune sensors of foreign nucleic acids are essential for antiviral immunity, but these same sensors can cause autoimmune disease through inappropriate detection of self-nucleic acids. The sources of the endogenous RNA and DNA that trigger autoreactive responses include chromatin and ribonucleoproteins that are the targets of autoantibodies in numerous autoimmune diseases, including systemic lupus erythematosus. In this review, I discuss recent data implicating endogenous retroelements  viruses that make up a substantial fraction of our genomes  as an important source of endogenous nucleic acids that can cause autoimmune disease. Understanding this potentially pathologic role for retroelements and the precise mechanisms by which their genomes are sensed and metabolized has important implications for the diagnosis and treatment of numerous autoimmune disorders.

Highlights

► Endogenous retroelements are a source of viral nucleic acids within our own genomes. ► Aicardi–Goutieres Syndrome genes encode antiretroviral enzymes. ► Failure to metabolize retroelement cDNAs can drive IFN-mediated autoimmunity.

Introduction

After over a decade of remarkable progress in our understanding of innate immunity, it is now clear that the primary mechanism for detection of viral infection is the sensing of nucleic acids by a variety of innate immune receptors [1]. Viral genomes are composed of either RNA or DNA, and the numerous sensors that detect each of these nucleic acids can be broadly categorized into two categories. First, several Toll-like receptors are expressed largely by hematopoietic cells and couple nucleic acid detection to a number of essential immune functions: inducible cytokine responses, antigen presentation to lymphocytes, and enhancement of virus-specific antibody responses. Second, intracellular receptors for RNA and DNA are broadly expressed by all nucleated cells and detect the presence of foreign nucleic acids within the infected cell itself. These cell-intrinsic sensors activate a type I interferon (IFN) response, which alerts neighboring cells to the presence of infection and drives the induction of hundreds of antiviral genes that serve to prevent viral replication and spread. The two classes of nucleic acid receptors communicate with each other to coordinate the protective antiviral response, although the nature of this crosstalk is only beginning to be understood. In the case of viral infection of nonhematopoietic cells, the cell-intrinsic sensors are the first receptors to be triggered. These activate the IFN response, as well as other signals that recruit professional antigen presenting like dendritic cells and monocytes to the site of infection. The recruited cells phagocytose local dead cells and debris, and use TLRs to sample this cargo for foreign nucleic acids. The activated APCs then migrate to the draining lymphoid organs, where they present antigens from infected cells to T cells and B cells. Finally, B cells use nucleic acid-sensing TLRs to synergize with their antigen receptors to drive robust antibody responses to particles containing both foreign antigen and nucleic acids  the hallmarks of viral particles [2]. In parallel, the IFN response in the context of foreign antigens augments the differentiation of effector and memory T cells [3].

The events described above illustrate the stepwise progression of productive antiviral responses, with each step under the control of innate immune nucleic acid receptors. This allows for the continued ‘quality control’ of the adaptive immune response such that the most robust and long-lived antiviral responses require both foreign antigens and foreign nucleic acids. However, it is now clear that endogenous (noninfectious) nucleic acids can feed into this coordinated response. Chronic detection of these nucleic acids can overcome lymphocyte tolerance and drive T and B cell responses to abundant self-antigens, particularly those like chromatin and ribonucleoproteins that contain T cell epitopes, B cell epitopes, and TLR ligands. Indeed, autoantibody responses to these nucleic acid–protein complexes are diagnostic for and underlie the pathology of a number of IFN-associated autoimmune diseases, including systemic lupus erythematosus (SLE) and Sjogrens syndrome.

The contribution of TLRs to SLE and related autoimmune disorders was first recognized a decade ago [4], and this realization has led to the development of new classes of therapeutics that aim to eliminate the early events of disease through inhibition of TLRs or type I IFNs. However, if we draw parallels to the coordinated model summarized above, we can envision a scenario in which accumulation of endogenous nucleic acids within cells could trigger an inappropriate cell-intrinsic antiviral response that would lead to autoimmunity by precisely the same stepwise program that protects us from infection. Indeed, the recent confluence of numerous independent lines of inquiry  the genetics of rare human diseases, basic innate immunity research, and study of the interaction between host cells and human immunodeficiency virus (HIV)  has revealed a remarkable example of cell-intrinsic initiation of autoimmunity. In this case, the nucleic acids are of viral origin, but they are derived from the endogenous retroelements that comprise over a third of the nucleotide content of the human genome.

Section snippets

Retroelements and autoimmunity

Endogenous retroelements are so-called because they replicate through a ‘copy and paste’ mechanism that involves reverse-transcription of a viral RNA transcript into a double-stranded DNA molecule that can insert into a unique genomic site. Retroelements come in three flavors, two of which are autonomous in that an individual, functional element encodes all of the activities required for its own retrotransposition. First, the long terminal repeat (LTR) retrotransposons are derived from ancient,

AGS genes are antiretroviral enzymes

In line with the antiretroviral role of Trex1 described in the context of retroelements [17], Lieberman and colleagues found that Trex1 also metabolizes the reverse-transcribed cDNA of HIV [24]. In the absence of Trex1, HIV cDNA accumulates within infected cells, and this triggers a STING-dependent innate immune response [24]. Thus, Trex1 sets a threshold for the innate immune response to retroviral infection. Interestingly, HIV encodes its own antagonists of antiviral immunity that target

Implications for tissue-specific autoimmunity

If retroelements are involved in AGS and related diseases, then reverse transcriptase inhibitors may hold promise as a potential therapy to ameliorate disease. Indeed, Wabl and colleagues have found that treatment of Trex1-deficient mice from conception with a cocktail of three FDA-approved antiretroviral drugs dramatically reduces mortality and ameliorates tissue inflammation [43••]. This fascinating study immediately suggests that similar drugs may be of therapeutic value in humans, and it

Conclusions

The potential involvement of endogenous retroelements in autoimmune disease has recently gained support from a confluence of independent lines of investigation, suggesting that an approach integrating retroelement biology, innate immunity, and host defense against retroviruses may yield important new insights into the origins and pathological progression of certain autoimmune diseases. In the future, if the relevant RT activities can be unequivocally identified and inhibited in a safe and

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

I apologize to colleagues whose work I was unable to cite because of space considerations. I am grateful to all the members of my lab for discussions, and to Hannah Volkman for help with the figure. We are supported by the National Institute of Allergy and Infectious Disease (AI084914, 5U54AI057141-08), the European Union (FP7/2007-2013) grant agreement number 241779 (NIMBL: http://www.NIMBL.eu), the Lupus Research Institute, and the Rita Allen Foundation.

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