Therapies in Aicardi-Goutières syndrome

Abstract

Aicardi-Goutières syndrome (AGS) is a genetically determined disorder, affecting most particularly the brain and the skin, characterized by the inappropriate induction of a type I interferon-mediated immune response. In most, but not all, cases the condition is severe, with a high associated morbidity and mortality. A number of important recent advances have helped to elucidate the biology of the AGS-related proteins, thus providing considerable insight into disease pathology. In this study, we outline the clinical phenotype of AGS, paying particular attention to factors relevant to therapeutic intervention. We then discuss the pathogenesis of AGS from a molecular and cell biology perspective. Finally, we suggest possible treatment strategies in light of these emerging insights.

Keywords: Aicardi-Goutières syndrome; anti-interferon antibodies; interferonopathy; reverse transcriptase inhibitors; type I interferon.

© 2013 British Society for Immunology.

Figures

Figure 1

Schematic representation of possible disease activity profiles observed in patients with Aicardi–Goutières syndrome. (a) Disease-associated damage already accrued at birth (i.e. beginning in utero), with abatement of pathological process some months after birth (illustrated arbitrarily as 12 months). Seen frequently with mutations in TREX1. (b) Apparently normal period of early development followed by subacute encephalopathic period, with abatement of pathological process some months after disease onset (illustrated arbitrarily as 12 months). Seen most typically with mutations in RNASEH2B. (c) Ongoing, possibly intermittent, disease ‘flares’ – most obvious in the context of chilblains. Note the significant, although currently unquantified, risk of intracerebral vascular disease associated with mutations in SAMHD1.

Figure 2

Proposed model of immune system stimulation by nucleic acids accumulating as a consequence of Aicardi–Goutières syndrome (AGS)-related protein dysfunction. AGS-related protein dysfunction is proposed to result in an aberrant accumulation of intracellular nucleic acids which are sensed by the innate immune system, triggering the output of interferon-stimulated genes, and recruitment of the adaptive immune system.

Figure 3

Hypothesized model suggesting a role for TREX1, the RNase H2 complex, SAMHD1 and ADAR1 in endogenous retro-element metabolism. A schematic representation of the retro-element reverse transcription process is given. TREX1 can block retrotransposition by metabolizing retro-element-derived reverse-transcribed DNA. SAMHD1 might prevent the initiation of reverse transcription by controlling the pool of dNTPs necessary for reverse transcription. ADAR1 editing of dsRNA derived from Alu sequences may prevent these sequences accumulating/being sensed. A speculative role for RNase H2 in degrading the RNA strand of RNA/DNA hybrids is suggested. A loss of Aicardi–Goutières syndrome-associated enzymatic activity could lead to an accumulation of retro-element-derived nucleic acid, which is then sensed by the innate immune system machinery.