Advances in how the peripheral immune system interacts with the brain in health and disease

The human body consists of various organs composed of many cells that form complex systems. The brain and immune system are especially interesting because they were once thought to operate independently, with little communication between them. However, the exact pathways connecting the brain and peripheral immune system, as well as their roles in maintaining brain balance or triggering neuropathologies, remain unclear. This review outlines the components of the immune system within the brain. Next, we elaborate on new evidence demonstrating that, in the brain, mast cells serve as neuroimmune sentinels, and that perivascular spaces, the skull's bone marrow, and meningeal lymphatic innervation coordinate brain immunity. This evidence uncovers a close interaction between the brain and the peripheral immune system. Additionally, recent findings on neurotransmitter-immune crosstalk and the role of miRNA-loaded exosomes in long-range peripheral signaling may outline potential regulatory pathways between the peripheral immune system and the brain. Finally, we highlight that changes in the mechanisms of interaction between the brain and the immune system are linked to the development and progression of various diseases. A deeper understanding of the connection between the immune and nervous systems could yield new insights into the causes of neuropathologies, neurodegenerative diseases, and immune-related disorders, potentially opening new avenues for treatment.