Aicardi-Goutières Syndrome (AGS) is a rare and severe disorder that manifests in children and is linked to abnormal immune activation and excessive production of interferon-alpha (IFN-α). AGS leads to brain damage caused by vascular calcification and inflammation, resulting in severe neurological impairments.
AGS is caused by mutations in specific genes, most of which are associated with abnormalities in the processing of antiviral intracellular nucleic acids, resulting in excessive activation of the immune response, particularly an elevated level of IFN-α, which plays a crucial role in AGS, contributing to neuronal damage.
One of the critical questions is the source and target of neurotoxic IFN-α in the body. Interferon-alpha can activate various genes in cells via IFNAR receptors, but the harmfulness of this activation for different cell types depends on their characteristics and the source of interferon.
Scientists from the University of Sydney (Australia) have found that the primary source of neurotoxic IFN-α in AGS is the central nervous system (CNS), with IFN-α targeting the brain’s tiny blood vessels. IFN-α signaling in brain endothelial cells causes inflammation and neuronal damage in AGS.
The Central Nervous System – The Main Source of Elevated IFN-α Levels in Aicardi-Goutières Syndrome
To determine the location of abnormal IFN-α production in AGS, the researchers first measured its concentrations in the blood and cerebrospinal fluid (CSF) of healthy individuals and patients with multiple sclerosis (MS), another neuroinflammatory disease. In both groups, IFN-α levels in blood and CSF were deficient, not exceeding 2 fg/ml.
Next, the scientists compared IFN-α levels in healthy individuals and AGS patients. Unlike MS patients, AGS patients had significantly higher IFN-α concentrations in the CSF than in the blood, approximately 300 times higher than in healthy individuals.
The researchers then compared these results with data from patients with systemic lupus erythematosus (SLE), an autoimmune disease associated with elevated IFN-α levels. IFN-α levels in the blood of AGS and SLE patients were similar, but in the CSF of AGS patients, IFN-α levels were significantly higher.
These results indicate that in Aicardi-Goutières Syndrome, the primary source of neurotoxic IFN-α is in the central nervous system, distinguishing AGS from other conditions with increased interferon production.
Elevated IFN-α Levels in the Brain Cause Neuronal Damage in Aicardi-Goutières Syndrome
To verify if IFN-α causes neurotoxicity in AGS, researchers conducted studies on mice with elevated CNS levels of IFN-α. They compared brain changes in these mice with the pathologies observed in humans with AGS.
The study revealed that the primary source of IFN-α in AGS is astrocytes, cells that support and protect neurons.
Mice with elevated CNS IFN-α levels exhibited high IFN-α levels in cerebrospinal fluid but not in blood, similar to humans with AGS. These mice suffered severe brain issues from a young age, including intracerebral calcification, characteristic of humans with AGS. Besides calcification, these mice displayed microvascular abnormalities, glial cell activation, and neuronal death.
Brain Endothelial Cells – The Most Sensitive to IFN-α
In the brain cells of mice with elevated CNS IFN-α levels, the activity of genes associated with the IFN response was significantly higher than in the cells of healthy mice. The highest level of IFNAR receptors, responsible for IFN-α signal transmission, was found in brain microvascular cells, particularly endothelial cells. These cells line blood vessels and play a key role in barrier function.
Microglia (brain immune cells) and pericytes (vascular wall cells) also showed high activity of IFN-α-related genes but were less significant than endothelial cells.
These findings suggest that endothelial cells and microglia respond strongly to chronically elevated IFN-α levels, significantly affecting their functions. Specifically, brain microvascular endothelial cells may be responsible for the neurotoxic effect of IFN-α in AGS.
Chronic Activation of the IFN-α Response in Brain Endothelial Cells Causes Microvascular Damage
In mice with elevated levels of IFN-α in the CNS, there was a significant increase in the activity of genes related to endothelial cell function. The activated genes included:
- Cell adhesion molecules (Vcam1)
- Interferon-stimulated genes
- Genes involved in attracting immune cells (Cxcl10)
- Genes involved in antigen presentation (H2-K1)
These genetic changes preceded the development of severe microvascular disease, characterized by increased activity of cell adhesion molecules, lymphocyte infiltration, aneurysm formation in small vessels, and disruption of the blood-brain barrier, which protects the brain from harmful substances in the blood.
These results indicate that IFN-α induces changes in gene activity long before the overt development of small vessel disease in the brain.
The microvascular disease in mice exhibits many similarities with the disease in humans with Aicardi-Goutières Syndrome, including T-cell infiltration, vascular calcification, changes in vessel diameter, and aneurysm formation.
Microvascular Brain Disease in AGS is Caused by CNS-derived IFN-α, Not Peripheral Blood IFN-α
Studies on patients with Aicardi-Goutières Syndrome revealed that the higher the level of IFN-α in the cerebrospinal fluid, the earlier the symptoms appear.
Although AGS patients showed significantly elevated levels of IFN-α in the CNS, high concentrations of IFN-α were also observed in the blood, similar to systemic lupus erythematosus. However, the level of IFN-α in the blood was not associated with the development of microvascular disease.
Deletion of the Ifnar1 Gene in Endothelial Cells Prevents Microvascular Disease During Chronic Interferon Response Activation
Scientists engineered mice lacking the Ifnar1 gene in endothelial cells. These mice were almost entirely protected from brain vascular diseases. The levels of inflammatory markers and leukocyte infiltration were reduced. The structure of the capillaries remained standard, with no microaneurysms, and the blood-brain barrier retained its function.
Conclusion
Elevated levels of IFN-α in Aicardi-Goutières Syndrome play a crucial role in neuronal damage. The source of neurotoxic IFN-α is in the central nervous system, not the blood. IFN-α in the CNS activates endothelial cells and causes microvascular damage in the brain.
Deleting the Ifnar1 gene in endothelial cells prevents microvascular damage, preserving the integrity of the blood-brain barrier. Targeting the interferon response in endothelial cells could prevent microvascular damage and counteract the destructive effects of IFN-α in the brain in Aicardi-Goutières Syndrome and other cerebral interferonopathies.
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