BACKGROUND: Beginning in the early 19th century, the brain was considered a self-contained organ behind barriers and thus as "immune privileged." This assumption was supported by experiments showing that a dye injected into the circulation did not stain the brain and by evidence of prolonged survival of tissue grafts in the brain compared with transplants into peripheral tissues. These conclusions led to the axiomatic view that the brain cannot tolerate any immune activity. The identification of brain-resident immune cells, the microglia, was often used as an additional argument to support the immunological self-sufficiency of the brain. In addition, despite the early description of brain lymphatic drainage, which dates back to 1787, the supposed absence of lymphatic vessels within the brain was, until recently, among the most common rationales used to support the view of a complete separation between the brain and the immune system.
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