The brain's immune code: decoding antigen presentation at the meningeal-glymphatic interface in neurological disorders

The classical view of central nervous system (CNS) immune privilege has evolved from isolation to regulated crosstalk. Perivascular cerebrospinal fluid-interstitial fluid transport and meningeal lymphatic vessels (mLVs) move brain-derived molecules toward immune-rich border tissues and cervical lymph nodes, where antigen-presenting cells (APCs) decode this molecular drainage into adaptive immunity. We frame this sequence as a brain-immune code, wherein the identity, timing, route, and cellular presenter of exported antigens collectively dictate whether T-cell responses become suppressive, inflammatory, or ineffective. By comparing aging and Alzheimer's disease, multiple sclerosis, experimental autoimmune encephalomyelitis, and brain tumors, we illustrate why this same interface can mediate proteostatic clearance, pathogenic autoimmunity, or insufficient antitumor immunity. Accordingly, therapeutic strategies should tune drainage and antigen interpretation in a disease-, stage-, and compartment-specific manner, rather than uniformly enhance or suppress lymphatic function. Key priorities include integrated measurement of glymphatic and mLV function, time-resolved immunopeptidome mapping, definition of non-redundant APC roles, and validated human biomarkers linking drainage to immune status.