Immunologic privilege in the central nervous system and the blood-brain barrier

Abstract

The brain is in many ways an immunologically and pharmacologically privileged site. The blood-brain barrier (BBB) of the cerebrovascular endothelium and its participation in the complex structure of the neurovascular unit (NVU) restrict access of immune cells and immune mediators to the central nervous system (CNS). In pathologic conditions, very well-organized immunologic responses can develop within the CNS, raising important questions about the real nature and the intrinsic and extrinsic regulation of this immune privilege. We assess the interactions of immune cells and immune mediators with the BBB and NVU in neurologic disease, cerebrovascular disease, and intracerebral tumors. The goals of this review are to outline key scientific advances and the status of the science central to both the neuroinflammation and CNS barriers fields, and highlight the opportunities and priorities in advancing brain barriers research in the context of the larger immunology and neuroscience disciplines. This review article was developed from reports presented at the 2011 Annual Blood-Brain Barrier Consortium Meeting.

Figure 1

The anatomical basis of the immune privilege of the central nervous system (CNS) resembles the architecture of a medieval castle. The CSF drained space (blue) resembles the castle moat, which is bordered at the outside by the BBB—the outer castle wall—and toward the inside by the glia limitans—the inner castle wall. In the cartoon, the outer castle wall is established by endothelial cells (ECs) (red bricks) protected toward the castle moat by the endothelial basement membrane (blue line), in which a high number of pericytes is embedded. The inner castle wall is mounted by astrocytic endfeet (green) protected toward the castle moat by the parenchymal basement membrane laid down by astrocytes (green line). Inside the castle, that is the CNS parenchyma, the royal family of sensitive neurons (black) resides with their servants, the glial cells. Immunosurveillance is restricted to the castle moat, where perivascular macrophages (brown cells) serve as guards that continuously collect information from within the castle, and present this information to the messengers, the immunosurveilling T cells that can cross the outer wall. If in their communication with the castle moat guards, T cells recognize their antigen they will get activated, clonally expand and open gates in the outer castle wall allowing the entry of more immune cells from the periphery. Within the castle moat, the immune cells then mount an invasion of the castle, breaching the inner castle wall and entering the castle with the aim to eliminate any intruders. If for reasons unknown, T cells turn their attack to the inhabitants of the castle; chronic immune cell invasion of the castle will eventually kill many of the castle inhabitants leading to neuronal deficits as observed in chronic neuroinflammatory diseases of the CNS.

Figure 2

Imaging inflammation. Ferumoxytol iron oxide nanoparticles are taken up by microglia in central nervous system (CNS) lesions and can be visualized on magnetic resonance imaging (MRI). (A) Delayed detection of inflammation in glioblastoma. MRI of 57-year-old woman with confusion, cognitive difficulties, and diagnosis of glioblastoma multiforme 9 months after chemoradiotherapy and on adjuvant temozolomide chemotherapy. Top: T1-weighted (T1w) MRI before contrast, after gadolinium contrast (Gd) or 24 hours after ferumoxytol (Fe). Ferumoxytol signal enhancement shows a larger tumor volume than gadoteridol because of uptake in inflammatory cells in the infiltrating edge of the tumor. Bottom: T2-weighted (T2w) MRI before contrast, 25 minutes after ferumoxytol, and 24 hours after ferumoxytol. Signal dropout is because of ferumoxytol uptake by inflammatory cells. (B) Imaging an inflammatory component of multiple sclerosis (MS) with ferumoxytol. MRI of 31-year-old woman with fatigue, confusion, and nondiagnostic biopsy. Presumptive diagnosis of primary CNS lymphoma was disproven at biopsy after ferumoxytol imaging and showed demyelination. Top: T1-weighted (T1w) MRI before contrast, after gadolinium contrast (Gd) or 24 hours after ferumoxytol (Fe) in a patient with MS. Bottom: T2-weighted (T2w) MRI before contrast, 25 minutes after ferumoxytol, and 24 hours after ferumoxytol. Arrow indicates signal dropout because of ferumoxytol uptake in inflammatory cells.