Context-dependent effects of adaptive immunity on IFN-α-mediated neurotoxicity in Aicardi-Goutières syndrome.

Abstract

Aicardi-Goutières syndrome (AGS) is a severe neuroinflammatory disorder characterized by chronic overexpression of interferon-alpha (IFN-α) in the central nervous system (CNS), leading to progressive encephalopathy, developmental regression, and high mortality. Recent work has identified the brain microvasculature, particularly the blood-brain barrier (BBB) endothelial cells, as a central mediator of IFN-α-induced neurotoxicity. This microangiopathy is accompanied by the infiltration of B and T lymphocytes into the brain parenchyma, but their contribution to disease progression remains unclear. Here, we investigated the role of adaptive immune cells in AGS pathogenesis using a transgenic mouse model that overexpresses IFN-α in the brain, but lacks mature B and T cells. Loss of adaptive immune cells partially ameliorated IFN-α-driven neurotoxicity, improving neurological disease and reducing histopathological damage, without altering interferon or interferon-stimulated gene expression. These findings indicate that adaptive immunity is not essential but modulates specific aspects of disease. Together, our results support a model in which IFN-α primarily targets CNS-resident cells, such as endothelial cells, astrocytes, and microglia, while adaptive immune responses act as a secondary enhancer of pathology. This work provides new mechanistic insight into AGS and highlights therapeutic opportunities aimed at modulating IFN-α signalling or glial-driven neuroinflammation to slow disease progression.