How does aberrant innate immune activation damage the microvasculature of the brain?

In lupus and Aicardi-Goutières syndrome, the body’s own immune system attacks the tiny blood vessels that feed the brain. These chronic autoimmune disorders cause severe neurological damage in both children and adults, yet no treatments exist for the brain symptoms. The problem is that doctors know a specific immune alarm signal—type I interferon—is overactive in these patients, but they do not understand exactly how it damages the brain’s microvasculature. This project will use genetically engineered mice that mimic human interferon dysregulation, alongside data from patients with neurolupus, to pinpoint which cells and molecules in the brain’s small blood vessels are targeted by interferon. The researchers also want to know whether different subtypes of interferon cause different types of damage, and how this process unfolds in a lupus model where interferon activation occurs spontaneously. This is fundamental science. It will not produce a drug tomorrow. But by identifying the precise immune pathways that drive brain damage in lupus and related disorders, it could reveal specific molecular targets for future therapies. Similar fundamental work on interferon pathways has already led to treatments for multiple sclerosis and certain rare inflammatory diseases—a deeper understanding here could eventually do the same for the neurological devastation of lupus.