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  • Review Article
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The anatomical and cellular basis of immune surveillance in the central nervous system

Nature Reviews Immunology volume 12, pages 623–635 (2012)Cite this article

Subjects

Key Points

  • Immune privilege of the central nervous system (CNS) is explained by the absence of dendritic cells or other resident antigen-presenting cells (APCs) that are capable of leaving the CNS parenchyma and conveying antigen to nearby lymph nodes. This feature makes the CNS virtually resistant to generating immune reactions to antigens locally deposited in the CNS parenchyma.

  • However, if antigen is instilled in the CNS parenchyma with subsequent peripheral immunization, a brisk immune reaction ensues. This observation implies that a mechanism for immune surveillance exists. Central memory T cells are found in abundance in human cerebrospinal fluid (CSF), suggesting that they provide a cellular basis for immune surveillance.

  • Extensive studies using neuroinflammation models, such as experimental autoimmune encephalomyelitis (EAE) and viral encephalitis, support this concept of CNS immune surveillance. In the EAE model, most lesions form in the subpial tissue of the spinal cord. Examination of biopsy material from the cerebral cortex of individuals with early-stage multiple sclerosis and remote from the target of biopsy also showed subpial lesions that were topographically related to meningeal inflammatory aggregates, affirming the relevance of the animal model studies.

  • Anatomical features of the CNS, including its vasculature and lining membranes, as well as the formation and circulation of CSF, help to clarify the mechanisms underpinning CNS immune–inflammatory reactions. These attributes are presented in the current Review, which integrates experimental and clinical findings to provide an account of immune surveillance of the CNS and the initiation of inflammatory demyelinating lesions.

Abstract

The central nervous system (CNS) comprises the brain, spinal cord, optic nerves and retina, and contains post-mitotic, delicate cells. As the rigid coverings of the CNS render swelling dangerous and destructive, inflammatory reactions must be carefully controlled in CNS tissues. Nevertheless, effector immune responses that protect the host during CNS infection still occur in the CNS. Here, we describe the anatomical and cellular basis of immune surveillance in the CNS, and explain how this shapes the unique immunology of these tissues. The Review focuses principally on insights gained from the study of autoimmune responses in the CNS and to a lesser extent on models of infectious disease. Furthermore, we propose a new model to explain how antigen-specific T cell responses occur in the CNS.

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Figure 1: CSF-mediated drainage of interstitial fluid and CNS antigens to deep cervical lymph nodes.
Figure 2: Pathogenic cascade in the periphery and CNS during experimental autoimmune encephalomyelitis.
Figure 3: Immune surveillance of the central nervous system: T cell–APC interactions and checkpoints for autoimmunity.

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Acknowledgements

Research in the Ransohoff laboratory is supported by the US National Institutes of Health, the National Multiple Sclerosis Society, the Alzheimer's Association, the Williams Family Foundation for MS Research and the Walker family. Research in the Engelhardt laboratory is supported by the Swiss National Science Foundation, the Swiss Multiple Sclerosis Society and the European Union. R.M.R. and B.E. thank their laboratory colleagues for their talent and commitment and are grateful to patients who participate in research programmes.

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Authors and Affiliations

  1. Neuroinflammation Research Center and Mellen Center for MS Treatment and Research, Cleveland Clinic, Cleveland, 44195, Ohio, USA

    Richard M. Ransohoff

  2. Theodor Kocher Institute, University of Bern, Bern, Switzerland

    Britta Engelhardt

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  1. Richard M. Ransohoff
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  2. Britta Engelhardt
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Correspondence to Richard M. Ransohoff.

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Glossary

Multiple sclerosis

A neurological disease that is characterized by focal demyelination in the central nervous system with leukocyte infiltration.

Neuromyelitis optica

An autoimmune disease of the central nervous system associated with antibodies to aquaporin 4, the astrocyte water channel.

Deep cervical lymph nodes

(DCLNs). A group of lymph nodes situated around or near the internal jugular vein.

Olfactory rootlets

Afferent input to the olfactory bulb neurons within the central nervous system (CNS) comes from olfactory rootlets, the sensory endings of which lie in the nasal epithelium in the nasal mucosa. These nerves enter the skull across the cribriform plate at the base of the skull below the frontal lobes. Because these rootlets are part of the CNS, they are covered by meninges containing cerebrospinal fluid, which percolates outwards to the nasal mucosa.

Experimental autoimmune encephalomyelitis

(EAE). An experimental model for the human disease multiple sclerosis. Autoimmune disease is induced in experimental animals by immunization with myelin or peptides derived from myelin. The animals develop a paralytic disease with inflammation and demyelination in the brain and spinal cord.

Exosomes

Small lipid-bilayer vesicles that are produced by various cell types and released into the extracellular space following the fusion of multivesicular bodies with the plasma membrane.

Pericytes

Cells embedded in the vascular basement membrane of microvessels that are related to mesenchymal stem cells. They make close cellular contact with endothelial cells, and this interaction is essential for the maintenance of vessel function, as well as for the regulation of angiogenesis and vascular remodelling.

Astrocyte

A type of glial cell that is found in the vertebrate brain and is named on the basis of its characteristic star-like shape. These cells provide both mechanical and metabolic support for neurons, thereby regulating the environment in which neurons function.

Leptomeningeal mesothelial cells

Mesothelial cells constitute the membranes lining body cavities, in this case the arachnoid and pia. These flattened polygonal cells also line the trabecular network in the subarachnoid space. They are capable of solute uptake and can present antigen to CD8+ T cells in an MHC class I-restricted fashion.

Weibel–Palade bodies

Specialized secretory vesicles that are present in resting endothelial cells and sequester molecules such as P-selectin and chemokines that facilitate leukocyte–endothelial cell interaction.

Cribriform plate

A portion of the ethmoid bone that separates the nasal cavity from the brain. The paper-thin cribriform plate is perforated by numerous openings that admit the olfactory rootlets.

Central memory T cells

(TCM cells). Antigen-experienced CD4+ or CD8+ T cells that lack immediate effector functions but are able to mediate rapid recall responses. These cells also rapidly develop the phenotype and function of effector memory T cells after re-stimulation with antigen. TCM cells possess the migratory properties of naive and memory T cells and therefore can circulate through tissues as well as secondary lymphoid organs.

Effector memory T cells

(TEM cells). Terminally differentiated T cells that lack lymph-node-homing receptors but express receptors that enable homing to inflamed tissues. TEM cells can exert immediate effector functions without the need for further differentiation.

Oligodendroglial cells

(Also known as oligodendrocytes). Glial cells that create and maintain the myelin sheath that nourishes and insulates axons as well as improving the speed and reliability of signal transmission by neurons.

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Ransohoff, R., Engelhardt, B. The anatomical and cellular basis of immune surveillance in the central nervous system. Nat Rev Immunol 12, 623–635 (2012). https://doi.org/10.1038/nri3265

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