Aicardi-Goutieres syndrome and related phenotypes: linking nucleic acid metabolism with autoimmunity

Abstract

Aicardi-Goutières syndrome (AGS) is a genetically determined encephalopathy demonstrating phenotypic overlap both with the sequelae of congenital infection and with systemic lupus erythematosus (SLE). Recent molecular advances have revealed that AGS can be caused by mutations in any one of five genes, most commonly on a recessive basis but occasionally as a dominant trait. Like AGS, SLE is associated with a perturbation of type I interferon metabolism. Interestingly then, heterozygous mutations in the AGS1 gene TREX1 underlie a cutaneous subtype of SLE-called familial chilblain lupus, and mutations in TREX1 represent the single most common cause of monogenic SLE identified to date. Evidence is emerging to show that the nucleases defective in AGS are involved in removing endogenously produced nucleic acid (NA) species, and that a failure of this removal results in activation of the immune system. This hypothesis explains the phenotypic overlap of AGS with congenital infection and some aspects of SLE, where an equivalent type I interferon-mediated innate immune response is triggered by viral and self NAs, respectively. The combined efforts of clinicians, geneticists, immunologists and cell biologists are producing rapid progress in the understanding of AGS and overlapping autoimmune disorders. These studies provide important insights into the pathogenesis of SLE and beg urgent questions about the development and use of immunosuppressive therapies in AGS and related phenotypes.

Figure 1.

Schematic of (selected) disease-associated TREX1 mutations. Mutations: black, recessive AGS; purple, dominant AGS; green, FCL; blue, SLE; red, RVCL. Exo1, 2, 3 domains; PII, polyproline II domain; TM, transmembrane domain.

Figure 2.

Model of disease pathogenesis in deficiency of TREX1, RNASEH2 and SAMHD1 activity. NA (ssDNA in TREX1 deficiency putatively derived from endogenous retroelements (12) and/or Okazaki fragments (11); possibly RNA:DNA hybrids in absence of RNASEH2 (17): unknown in SAMHD1 deficiency (18)) accumulate and are recognized by as yet undefined sensors leading to the TLR-independent induction of type I IFN via the transcription factor IRF3. At least in TREX1 deficiency, functional lymphocytes are necessary to propagate the disease phenotype (12).

Figure 3.

Stages in the pathogenesis of AGS which might be amenable to targeted interruption.