Why does the disease occur?


As long ago as 2003, Y. Crow and his collaborators noticed an overlap between the clinical manifestations of AGS, systemic lupus erythematosus (SLE) and some congenital viral infections (including HIV infection), and they suggested that the similarity in the symptoms of these conditions may be underlain by a common pathogenic process: dysregulation of the production of IFN. IFN is a protein belonging to the interferon family that, in physiological conditions, is produced both by immune system cells (white blood cells) and by tissue cells in response to the presence of fragments of nucleic acids (DNA and RNA) that can originate from exogenous agents (viruses or bacteria) or be of endogenous origin (i.e. the products of normal cell metabolism). 
Aicardi-Goutières syndrome is regarded as an interferonopathy, in other words, a pathological condition caused by overproduction of IFN. As a result of the discovery of the disease-causing genes and of the role they play, several key aspects of the pathogenetic process have been clarified: mutations in TREX1, RNASEH2, SAMHD1, ADAR1 and IFIH1 can disrupt the clearance of endogenous nucleic acids, causing them to  build up; mistaken by the organism for genetic material of viral origin, their presence triggers an activation of the immune system which leads to increased levels of  circulating IFN This leads to tissue damage with the release of new nucleic acids.
Thus, a self-sustaining vicious cycle is established: increase in nucleic acids » immune system activation » increase in IFN» increase in cell damage » release of new nucleic acids. 

Experimental studies supporting the role of IFN 

Murine model
The hypothesis that IFN plays a role in the pathogenesis of AGS has long been known: the cerebral calcification and vascular changes seen in the syndrome are very similar to those observed in transgenic mice with overproduction of IFN. 

Cell model
An in vitro cell model was recently created in order to assess the effects of chronic exposure of    brain cells (astrocytes) to IFN. The following were observed: reduced cell proliferation, abnormal vascular proliferation with the formation of immature and fragile vessels, and reactive gliosis. 
These changes appear to be permanent given that, following prolonged exposure to interferon, it was not possible, after elimination of the excess IFN, to restore the model to its initial condition. 

AGS and autoimmunity

The central role of IFN in the pathogenesis of AGS explains the presence of autoimmune symptoms in affected individuals. 
There has been extensive debate in the scientific literature  about the possible overlap between AGS and SLE, the latter being an autoimmune disease in which hypersecretion of IFN is recognised to be an essential pathogenic mechanism. 
Some studies, supporting the hypothesis of an overlap between the two conditions, have documented the presence of a lupus-like rash, chilblains, intermittent mouth ulcers, purpura-like skin lesions, chronic arthritis and SLE in individuals with AGS; in others, associated lupus-like symptoms were not reported. 
As regards laboratory tests, too, there are differences: some studies have reported increased levels of positive antinuclear antibodies, autoantibodies against nuclear antigens (dsDNA or ssDNA), C1q and cardiolipin, and reduced complement levels; in others there were only occasional abnormal antibody profiles.
At present, the most accepted interpretation is that the spectrum of clinical manifestations of AGS may have elements in common with SLE, given the common pathogenic mechanism underlying both conditions. The discrepancies that exist between the different studies can probably be ascribed to methodological errors in the recognition of autoimmune manifestations, partly due  to the lack of universal diagnostic criteria and to the difficulty in recognising the autoimmune nature of these symptoms (recurrent mouth ulcers, joint pain, epileptic seizures) arising in neurologically impaired children. This, therefore, is an aspect that needs to be further explored through more targeted assessments, carried out systematically in all patients with AGS.
In the light of the currently available data, it is considered that the autoimmune-like clinical manifestations should be interpreted as part of the collection of symptoms constituting the syndrome itself, in the framework of an interferonopathy.
This aspect is further demonstrated by the fact that other clinical conditions characterised by inappropriate activation of the interferon response, the so-called interferonopathies, have been described in individuals with mutations in genes responsible for AGS: TREX1 has been found to be mutated in some patients affected by SLE, while heterozygous mutations in  IFIH1/AGS7 have been described in cases with prominent autoimmune symptoms and a positive interferon signature.