CNS immune privilege: hiding in plain sight

Abstract

Central nervous system (CNS) immune privilege is an experimentally defined phenomenon. Tissues that are rapidly rejected by the immune system when grafted in sites, such as the skin, show prolonged survival when grafted into the CNS. Initially, CNS immune privilege was construed as CNS isolation from the immune system by the blood-brain barrier (BBB), the lack of draining lymphatics, and the apparent immunoincompetence of microglia, the resident CNS macrophage. CNS autoimmunity and neurodegeneration were presumed automatic consequences of immune cell encounter with CNS antigens. Recent data have dramatically altered this viewpoint by revealing that the CNS is neither isolated nor passive in its interactions with the immune system. Peripheral immune cells can cross the intact BBB, CNS neurons and glia actively regulate macrophage and lymphocyte responses, and microglia are immunocompetent but differ from other macrophage/dendritic cells in their ability to direct neuroprotective lymphocyte responses. This newer view of CNS immune privilege is opening the door for therapies designed to harness autoreactive lymphocyte responses and also implies (i) that CNS autoimmune diseases (i.e. multiple sclerosis) may result as much from neuronal and/or glial dysfunction as from immune system dysfunctions and (ii) that the severe neuronal and glial dysfunction associated with neurodegenerative disorders (i.e. Alzheimer's disease) likely alters CNS-specific regulation of lymphocyte responses affecting the utility of immune-based therapies (i.e. vaccines).

Fig. 1

Microglial morphology is an inaccurate predictor of juxtaposition with cerebrovasculature. (A) Three apparently stellate Iba-1⁺cells in the CNS of a healthy adult mouse are identified in green. (B) All nuclei in the same tissue section are identified in blue with DAPI. (C) All myeloid cells and blood vessels are identified in red with tomato lectin. (D) Merged images of all three panels illustrates close juxtaposition of cell 1 but not that of cells 2 and 3 with blood vessels. Confocal images were taken using a Zeiss. A rotating three-dimensional image is provided online as Supplemental Movie 1.

Fig. 2. The genotype of resident microglia and peripheral immune cells can be differentially manipulated using irradiation bone marrow chimeric methodology.

(A) Rodents receive whole-body irradiation sufficient to kill the adult bone marrow stem cell population. (B) To survive, irradiated rodents must receive bone marrow from a donor. The genotype of the donor and recipient can differ. (C) The donor bone marrow contributes to the repopulation of the peripheral immune system but not to that of most the CNS myeloid population (see text for discussion).