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CNS infection and immune privilege

Abstract

Classically, the CNS is described as displaying immune privilege, as it shows attenuated responses to challenge by alloantigen. However, the CNS does show local inflammation in response to infection. Although pathogen access to the brain parenchyma and retina is generally restricted by physiological and immunological barriers, certain pathogens may breach these barriers. In the CNS, such pathogens may either cause devastating inflammation or benefit from immune privilege in the CNS, where they are largely protected from the peripheral immune system. Thus, some pathogens can persist as latent infections and later be reactivated. We review the consequences of immune privilege in the context of CNS infections and ask whether immune privilege may provide protection for certain pathogens and promote their latency.

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Fig. 1: Immune cell traffic through the CNS.
Fig. 2: Pathogen entry into the CNS parenchyma.
Fig. 3: Cells and sites of CNS latent infection.

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Acknowledgements

This Review is based on concepts developed and presented as part of the Ian Constable Lecture, University of Western Australia, 2013 (J.V.F.). J.V.F. acknowledges the generous support of Saving Sight in Grampian under the auspices of I. Fraser and the Development Trust of the University of Aberdeen, Scotland. In addition, J.V.F. thanks the many colleagues, students and associates who have contributed to the numerous discussions and debates surrounding this work, particularly A. Dick and L. Kuffova. P.G.M. acknowledges many past and present honours as well as Ph.D. students and research staff who have studied and worked with the author over the past 35 years, particularly D. Aitken, H. Chinnery and J. Kezic. P.G.M. acknowledges funding from the Australian National Health and Medical Research Council (APP1069979).

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Nature Reviews Neuroscience thanks C. Bergmann, G. Rall and the other, anonymous reviewer(s) for their contribution to the peer review of this work.

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J.V.F. conceived and researched data for the article and wrote the Review. P.G.M. and S.J.D. made substantial contributions to discussions of the content and writing of the article. All authors reviewed and edited the manuscript before submission.

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Correspondence to John V. Forrester.

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Glossary

Virulent

Describes pathogens that are extremely dangerous, are often lethal and spread rapidly.

Opportunistic

Describing fairly non-virulent pathogens, which may occur as commensal organisms and normally do not cause disease, but take advantage of a ‘weakened’ host, as in immunosuppressed patients, and cause life-threatening disease.

Latent infection

A dormant or non-replicative infection that does not elicit a host immune response; a mechanism of long-term microbial survival or persistence within the host.

Meninges

The non-parenchymal protective coverings of the brain, comprising the dura mater, arachnoid and pia mater.

Uveal tract

The middle covering layer of the eye, comprising the iris, ciliary body and choroid, the last of which is closely juxtaposed to the neural retina.

Ciliary body

The structure connecting the choroid layer of the uveal tract of the eye to the iris anteriorly. Its muscle tissue controls the ability to focus images, whereas its epithelial layers secrete aqueous humour to maintain intraocular pressure.

Delayed-type hypersensitivity

A T cell-mediated response to antigen, also known as type IV hypersensitivity. Pathological delayed-type hypersensitivity reactions present as granulomas, which contain predominantly T cells and macrophages.

Complement-fixing antibody

Antibody that binds to antigen, producing a complex that binds (fixes) surface complement and initiates the complement cascade.

Glia limitans

A thin but highly effective barrier layer formed by the foot processes of astroglial cells, covering the brain and accompanying vessels as they penetrate the CNS parenchyma, where it forms the limit of the neurovascular unit.

Dendritic cells

(DCs). Professional antigen-presenting cells that capture, process and present antigens to T cells.

Oncotic pressure

A measure of the ‘resistance’ of a tissue generated by its content of fluid (interstitial fluid).

Rostral migratory stream

A route along which neuronal precursors originating from the subventricular zone of the brain migrate to the olfactory bulbs.

Cribriform plate

The paired perforated, sieve-like parts of the ethmoid bone either side of the midline that separates the anterior cranial fossa from the nasal cavity.

Apicomplexan parasite

A phylum containing parasites such as Toxoplasma gondii and Plasmodium spp..

Tachyzoites

Rapidly proliferating, asexual, infectious stage of coccidia such as Toxoplasma gondii.

Melioidosis

An infectious life-threatening disease caused by the Gram-negative bacterium Burkholderia pseudomallei, which is found in soil and water. It is endemic in north-east Australia and southern regions of Asia.

Free fatty acid receptor 2

A G protein-coupled cell membrane receptor that binds free fatty acids (FFAs). The four FFA receptors are signalling receptors for FFAs and are involved in many cell physiological processes.

Type IV pili

Thin appendages found on the surface of many bacteria; they are frequently involved in adhesion to host cells, motility and bacterial conjugation.

Viral immune surveillance

A process in which T cells detect and respond to (for example, become activated by) virus. In doing so, T cells generate cytokines, which weaken the integrity of the blood–CNS barrier.

Lamina propria

The loose connective tissue located beneath mucosal epithelia and its supporting basement membrane.

Virchow-Robin space

Also known as perivascular space; small spaces between blood vessels and the pia mater.

Late genes

Genes produced by replicating virus after initial induction of immediate early and early genes.

Bradyzoites

The slowly replicating, latent form of Toxoplasma gondii that are located within tissue cysts.

Apoptosome

A large protein structure formed during cell death by the release of cytochrome c from mitochondria. It acts as a platform for activity of enzymes such as caspases.

Type I interferon response

Cytokine response of infected cells. Its function is to regulate immune activity by, for example, promoting virus clearance or, in the post-viral stage, promoting immunosuppression.

Plasmacytoid DCs

A rare subgroup of dendritic cells (DCs) that constitutively secrete large amounts of interferon-α and have strong antiviral properties.

Spirochaetes

Spiral-shaped bacteria, including Treponema pallidum.

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Forrester, J.V., McMenamin, P.G. & Dando, S.J. CNS infection and immune privilege. Nat Rev Neurosci 19, 655–671 (2018). https://doi.org/10.1038/s41583-018-0070-8

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