Hierarchy of immune responses to antigen in the normal brain.

For approximately 100 years the brain has been classified as an “immunologically privileged organ” based on the observations that tissue transplants into cerebral cortex survive longer than tissue transplants into conventional peripheral sites (Shirai 1921; Murphy and Sturm 1923; Medawar 1948; Scheinberg et al. 1966). Various conclusions and presumptions were attributed to these studies, including two predominant beliefs that: (1) there is no lymphatic drainage to alert the immune system to the presence of antigen in the brain (afferent arm of immunity), and (2) the tight endothelial junctions of the cerebral vasculature (blood-brain barrier; BBB) prevent blood lymphocytes from facilitating antigen elimination in the brain (efferent arm of immunity; for reviews see Barker and Billingham 1977; Brent 1990; Waksman 1998).