The prototypical interferonopathy: Aicardi-Goutières syndrome from bedside to bench

Abstract

Aicardi-Goutières syndrome (AGS) is a progressive genetic encephalopathy caused by pathogenic mutations in genes controlling cellular anti-viral responses and nucleic acid metabolism. The mutations initiate autoinflammatory processes in the brain and systemically that are triggered by chronic overproduction of type I interferon (IFN), including IFN-alpha. Emerging disease-directed therapies aim to dampen autoinflammation and block cellular responses to IFN production, creating an urgent and unmet need to understand better which cells, compartments, and mechanisms underlying disease pathogenesis. In this review, we highlight existing pre-clinical models of AGS and our current understanding of how causative genetic mutations promote disease in AGS, to promote new model development and a continued focus on improving and directing future therapies.

Keywords: Aicardi‐Goutieres; Type I interferon; cytokines; inflammation; interferonopathy; leukodystrophy; neuroimmunology.

Figure 1.. Mutations in nine genes increase type I IFN expression in AGS.

A. Mutations in TREX1 cause cytoplasmic accumulation of dsDNA. B. Mutations of all three subunits of the RNaseH2 complex cause increased cytoplasmic levels of RNA:DNA hybrids. C. Without SAMHD1 activity, RNA and RNA:DNA hybrids accumulate in the cytoplasm. D. Inactive ADAR1 causes dsRNA sensing signaling pathway activation, which is enhanced by Z-RNA binding protein ZBP1. In addition, activating mutations in IFIH1, the gene encoding MDA5 have been identified in AGS patients. E. Mutations in LSM11 and RNU7–1 result in abnormal processing of histone pre-mRNAs. F. Ultimately, increased activation of the cGAS-STING or MDA5-MAVS pathways in AGS leads to TBK1-mediated activation of IRF3 and increased IFN-α production. IFN-α binds in an autocrine or paracrine fashion to the IFNAR1/IFNAR2 receptor resulting in JAK/STAT-mediated increased ISG expression.

Figure 2.. Systemic complications associated with AGS.

A. Most common symptomatology includes neurologic manifestation, skin involvement, hematologic/hepatic lab abnormalities, along with many others. B. Breakdown of pathophysiological manifestations on a microscopic level neurologically and for selected organs.

Figure 3.. Heat map revealing phenotypic spectrum of AGS mouse models.

Common AGS phenotypes are listed in rows, and summary AGS mouse models are shown in columns. Color depicts the approximate strength of the model for each phenotype. Grey shading shows areas to expand endophenotyping. Number code provides additional context. Models included are Adar1^−/− or CKO (including Adar1^F/F driven by CAGCre-ERT^–, K14-Cre, Cdh5-Cre, Meox2-Cre, Alb-Cre^,, Ubc-Cre, αMHC-Cre); ZD (Sox-Cre;Zα^F/F ; Zα^−/− ; Zα/Adar1^−/− ; Zα/MAVS^−/− ; Adar1^{P195A/P195A ,}; Adar1^{P150-/P150–} ; Adar1^P195A/− ; P195A/P150KO^,; W197A/W197A); or CD (K948N^,, E861A, D963H); IFIH1 GOF^–; Rnaseh2b^{−/− ,,} , A174T, and CKO (including Rnaseh2b^F/F driven by Nestin-Cre or GFAP-Cre); Rnaseh2c^−/− ; Rnaseh2a^RED or ^−/− or G73S^,; Samhd1^−/− or KOF^,; Trex1^{−/− –,} or CKO (including Nestin-Cre or CX3CR1-Cre) or D18N^–,; GFAP-IFNa^,,,,. Code: 1, hypothermia in Ubc-Cre; 2, due partly to significant cytopenia; 3, decreased RNA editing; 4, Full KO embryonically lethal; 5, especially with global KO or transplant with ADAR KO cells; 6, K14-Cre dependent KO; 7, in αMHC-Cre; 8, with postnatal Cre-deletion; 9, in Cdh5-Cre; 10, includes kidney deformity in some genotypes; 11, in W197/W197 showing thinned grey/white matter; 12, MAVS dependent; 13, Zα/Zα and P150/− embryonically lethal, P195A/P195A no effect; 14, in P195/− & W197A; 15, E861A; 16, E861A embryonically lethal; 17, K948N at 1 year; 18, G821S; 19, embryonically lethal; 20, in isolated cells from GFAP-Cre; 21, not in GFAP-Cre; 22, lymphoid infiltrate; 23, in Cx3cr1-Cre, not Nestin-Cre; 24, Not in not in αMHC-Cre. Abbreviations: CD, catalytic domain; CKO, conditional KO; CMP, cardiomyopathy; GOF, gain of function; KO, knockout; KOF, knockout first; N/A, not applicable as in embryonic lethal genotypes for later tissue phenotypes; RED, ribonucleotide excision defect.

Figure 4.. Expression of known AGS-causing genes in key cell types.

A. AGS gene expression heatmap across human primary^– and B. stem-cell derived cells^–. hES, human embryonic stem cell; iPSC, induced pluripotent stem cell; i, IPSC-derived; iEC, endothelial cells; iCM, cardiomyocyte; iVMSC, vascular smooth muscle cells; PN, postnatal; TPM, transcript per million.