Researchers at the Washington University School of Medicine have discovered that the immune cells that protect the brain and spinal cord come primarily from the skull. The finding opens up the possibility of developing therapies to target such cells as a way to prevent or treat brain conditions. The immune system is the brain's best frenemy. It protects the brain from infection and helps injured tissues heal, but it also causes autoimmune diseases and creates inflammation that drives neurodegeneration. Two new studies in mice suggest that the double-edged nature of the relationship between the immune system and the brain may come down to the origins of the immune cells that patrol the meninges, the tissues that surround the brain and spinal cord. In complementary studies published in the journal Science, two teams of researchers at Washington University School of Medicine in St. Louis unexpectedly found that many of the immune cells in the meninges come from bone marrow in the skull and migrate to the brain through special channels without passing through the blood. These skull-derived immune cells are peacekeepers, dedicated to maintaining a healthy status quo. It's the other immune cells, the ones that arrive from the bloodstream, that seem to be the troublemakers. They carry genetic signatures that mark them as likely to promote autoimmunity and inflammation, and they become more abundant with ageing or under conditions of disease or injury. Taken together, the findings reveal a key aspect of the connection between the brain and the immune system that could inform our understanding of a wide range of brain disorders.