Aicardi-Goutières syndrome: a model disease for systemic autoimmunity

Abstract

Systemic autoimmunity is a complex disease process that results from a loss of immunological tolerance characterized by the inability of the immune system to discriminate self from non-self. In patients with the prototypic autoimmune disease systemic lupus erythematosus (SLE), formation of autoantibodies targeting ubiquitous nuclear antigens and subsequent deposition of immune complexes in the vascular bed induces inflammatory tissue injury that can affect virtually any organ system. Given the extraordinary genetic and phenotypic heterogeneity of SLE, one approach to the genetic dissection of complex SLE is to study monogenic diseases, for which a single gene defect is responsible. Considerable success has been achieved from the analysis of the rare monogenic disorder Aicardi-Goutières syndrome (AGS), an inflammatory encephalopathy that clinically resembles in-utero-acquired viral infection and that also shares features with SLE. Progress in understanding the cellular and molecular functions of the AGS causing genes has revealed novel pathways of the metabolism of intracellular nucleic acids, the major targets of the autoimmune attack in patients with SLE. Induction of autoimmunity initiated by immune recognition of endogenous nucleic acids originating from processes such as DNA replication/repair or endogenous retro-elements represents novel paradigms of SLE pathogenesis. These findings illustrate how investigating rare monogenic diseases can also fuel discoveries that advance our understanding of complex disease. This will not only aid the development of improved tools for SLE diagnosis and disease classification, but also the development of novel targeted therapeutic approaches.

Keywords: Aicardi-Goutières syndrome; autoimmunity; nucleic acid sensing; systemic lupus erythematosus; type I interferon.

Figure 1

Functional properties of three prime repair exonuclease 1 (TREX1), ribonuclease H2 (RNase H2), SAM domain and HD domain-containing protein 1 (SAMHD1) and adenosine deaminase acting on RNA 1 (ADAR1) within the intracellular nucleic acid metabolism. TREX1 degrades cytosolic ssDNA arising during reverse transcription of endogenous retro-elements (1) and during replication stress (2). Loss of TREX1 function results in accumulation of cytosolic DNA. RNase H2 removes single ribonucleotides from DNA (3). RNase H2 deficiency induces genome instability associated with DNA damage signalling. The triphosphohydrolase SAMHD1 down-regulates the intracellular dNTP pool required for DNA synthesis. Absence of SAMHD1 may contribute to inappropriately increased DNA synthesis (4) or promote reverse transcription of endogenous retro-elements (5). The RNA-editing enzyme ADAR1 deaminates adenosine to inosine of RNA species that may derive from endogenous retro-elements (6) or microRNAs. This modification is thought to alter the immune-activating properties of the edited RNA species or to interfere with transcriptional control of type I interferon (IFN). Functional impairment of TREX1, RNase H2, SAMHD1 or ADAR1 results in quantitative or qualitative imbalances within the intracellular nucleic acid homeostasis. Inadequately accumulated nucleic acids are recognized as danger signals by innate immune sensors that activate type I IFN leading to inflammation and autoimmunity.