KEY POINTS * The central nervous system mounts an innate immune response during systemic infection. This inflammatory response is characterized by the expression of Toll-like receptors

(TLRs) in structures that are devoid of blood–brain barrier. The response extends progressively to affect microglia across the brain parenchyma, and might lead to the onset of an adaptive

immune response. * Molecules of both innate and adaptive immune systems are induced in several neurological disorders, and it has been proposed that immunological challenges might act as

aetiological factors in sporadic cases of neurodegeneration, perhaps through the recognition of neuronal fingerprints, or after an inflammatory reaction that is elicited by peripheral

innate immune response can also have a beneficial effect. Indeed, this immune response can protect neurons by favouring remyelination and trophic support afforded by glial cells. ABSTRACT

Innate immunity was previously thought to be a nonspecific immunological programme that was engaged by peripheral organs to maintain homeostasis after stress and injury. Emerging evidence

indicates that this highly organized response also takes place in the central nervous system. Through the recognition of neuronal fingerprints, the long-term induction of the innate immune

response and its transition to an adaptive form might be central to the pathophysiology and aetiology of neurodegenerative disorders. Paradoxically, this response also protects neurons by

favouring remyelination and trophic support afforded by glial cells. Access through your institution Buy or subscribe This is a preview of subscription content, access via your institution

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OPPORTUNITIES AND PITFALLS Article 14 April 2021 IMMUNE CELL COMPARTMENTALIZATION FOR BRAIN SURVEILLANCE AND PROTECTION Article 24 August 2021 IMMUNOLOGICAL ASPECTS OF CENTRAL

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the Canadian Institutes of Health Research (CIHR) and the Neuromuscular Research Partnership. M.D.N. is a recipient of a K. M. Hunter–CIHR Ph.D. Scholarship. J.-P.J. holds a CIHR Senior

Investigator Award. S.R. is a CIHR Scientist and holds a Canadian Research Chair in Neuroimmunology. We thank G. Chabot, S. Nadeau and N. LaFlamme for assistance with the illustrations.

AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Centre for Research in Neurosciences, McGill University, The Montréal General Hospital Research Institute, Montréal, H3G 1A4, Québec, Canada

Minh Dang Nguyen & Jean-Pierre Julien * Laboratory of Molecular Endocrinology, CHUL Research Center and Laval University, 2705 Boulevard Laurier, Sainte-Foy, G1V 4G2, Québec, Canada

Serge Rivest Authors * Minh Dang Nguyen View author publications You can also search for this author inPubMed Google Scholar * Jean-Pierre Julien View author publications You can also search

for this author inPubMed Google Scholar * Serge Rivest View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to Serge

Rivest. RELATED LINKS RELATED LINKS DATABASES FLYBASE Toll  LOCUSLINK CD14 GABAA receptor γ2 GluR3 glycine receptor α2 Iba1 IFN-γ IKAP IκB IKK IL-1 IL-1R IL-12 IRAK Munc-18 MyD88 NFκB NIK

NOVA1 RIP TLRs TNF-α TNFR1 TNFR2 TRADD TRAF2 TRAF6  OMIM ALS-parkinsonism/dementia complex of Guam Alzheimer's disease amyotrophic lateral sclerosis frontotemporal dementia

Huntington's disease multiple sclerosis Parkinson's disease stiff-man syndrome  PROSITE TIR domain FURTHER INFORMATION antigen presentation to lymphocytes blood–brain barrier

microglia nervous and immune system interactions neuroimmunology GLOSSARY * INNATE IMMUNITY The early response of a host to infection. One of its main features is the pro-inflammatory

response induced by antigen-presenting cells — macrophages, dendritic cells and, in the brain, microglial cells. This response is followed by an adaptive response that is mediated by the

clonal selection of lymphocytes, which leads to long-term immune protection. * CIRCUMVENTRICULAR ORGANS Brain regions that have a rich vascular plexus with a specialized arrangement of the

blood vessels. The junctions between the capillary endothelial cells are not tight in the blood vessels of these regions, allowing the diffusion of large molecules. These organs include the

organum vasculosum of the lamina terminalis, the subfornical organ, the median eminence and the area postrema. Although not included as circumventricular organs, the choroid plexus and

leptomeninges are also highly vascularized and are rapidly activated by circulating pathogens. * ADAPTIVE IMMUNITY Also known as acquired immunity, it describes the response of

antigen-specific lymphocytes to antigen and the development of immunological memory. It is mediated by the clonal selection of lymphocytes. * STIFF-MAN SYNDROME A neuromuscular disorder that

is characterized by progressive rigidity and a hyperactive startle reflex that results in the contraction of muscles, causing violent spasms. * RASMUSSEN ENCEPHALITIS A childhood disease

that is characterized by seizures, hemiparesis, inflammation and mental deterioration. * PATHOGEN-ASSOCIATED MOLECULAR PATTERNS Specific elements that are produced by microorganisms and can

induce innate immune responses. These elements are recognized by specific receptors that are expressed at the surface of macrophages, dendritic cells and microglia. * GRAM-NEGATIVE BACTERIA

Bacteria that do not retain a basic blue dye during the Gram-stain procedure. Their cell walls are thin, consisting of a layer of lipopolysaccharide outside a peptidoglycan layer. *

GRAM-POSITIVE BACTERIA Bacteria that retain a basic blue dye during the Gram-stain procedure. Their cell wall is thicker than that of Gram-negative bacteria, containing more peptidoglycan. *

NUCLEAR FACTOR κB A family of transcription factors that are important for pro-inflammatory and anti-apoptotic responses. * CYTOKINES In general terms, cytokines are proteins made by cells

that affect the behaviour of other cells. They are produced mainly by the immune system. * TOLL-LIKE RECEPTORS A large family of receptors that are expressed at the surface of leukocytes and

microglial cells. They are responsible for engaging the innate immune system in response to pathogens. * ANTIGEN-PRESENTING CELLS Specialized cells that present specific antigens to T

cells. Macrophages and dendritic cells are the main antigen-presenting cells; in the CNS, the antigen-presenting cells are the microglia. * DEATH DOMAIN A protein–protein interaction domain

found in many proteins that are involved in signalling and apoptosis. * CHEMOKINES Small, secreted proteins that stimulate the motile behaviour of leukocytes. * COMPLEMENT SYSTEM A set of

plasma proteins that attack extracellular pathogens. The pathogen becomes coated with complement proteins that facilitate pathogen removal by phagocytes. * CD14 The first lipopolysaccharide

receptor to be characterized. It exists two forms: membrane CD14 (mCD14) and soluble CD14 (sCD14). mCD14 is present at the surface of myeloid cells and acts as a glycosylphosphatidylinositol

(GPI)-anchored membrane glycoprotein, whereas sCD14 lacks the GPI anchor, but can bind LPS to activate cells that are devoid of mCD14, such as endothelial cells. * CHOROID PLEXUS A site of

production of cerebrospinal fluid in the adult brain. It is formed by the invagination of ependymal cells into the ventricles, which become richly vascularized. * DENDRITIC CELLS Also known

as interdigitating reticular cells because of their branched morphology, dendritic cells are the most potent stimulators of T-cell responses. * LEPTOMENINGES The pia mater and the arachnoid

considered together. * TNF-α Tumour necrosis factor-α. A cytokine produced by macrophages that has multiple functions in the immune response. * EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS A

rodent model of multiple sclerosis that is characterized by episodes of spasticity and tremor. * OPSONIZATION The alteration of the surface of a pathogen so that it can be ingested by a

phagocyte. * HELPER T CELLS At least two distinct subsets of activated CD4+ T lymphocytes have been described. TH1 cells produce IFN-γ, lymphotoxin and TNF-α, and support cell-mediated

immunity. TH2 cells produce IL-4, IL-5 and IL-13, support humoural immunity, and downregulate TH1 responses. * FAS A transmembrane protein that mediates apoptosis and might be involved in

the negative selection of autoreactive T cells in the thymus. * CASPASES Cysteine proteases involved in apoptosis, which cleave at specific aspartate residues. * PROSTAGLANDINS Biologically

active metabolites of arachidonic acid and other lipids. Prostaglandins have many functions; for example, they are involved in vasodilation, bronchodilation, inflammatory reactions and the

regulation of cell proliferation. They are also involved in the control of endocrine functions. * CYCLIN-DEPENDENT KINASES Enzymes that phosphorylate proteins that are involved in DNA

synthesis and mitosis. They require a cyclin partner for activity and substrate specificity. * BCL PROTEINS Molecules that are associated with B-cell leukaemia and lymphoma. Bcl2 is a

mitochondrial protein of the inner membrane that can block apoptosis. * MAJOR HISTOCOMPATIBILITY COMPLEX There are two classes of MHC molecules. MHC class I molecules are found on the

surface of most cells and present proteins that are generated in the cytosol to T lymphocytes. MHC class II molecules are expressed only at the surface of activated antigen-presenting cells,

and they present peptides that have been degraded in cellular vesicles to T cells. * FINGERPRINT A distinct set of proteins expressed by a given population of neurons, which might account

for the specialized biochemical properties of these neurons, and make them vulnerable to an immune challenge by acting as antigens. * PARANEOPLASTIC NEUROLOGICAL DISEASES A set of

neurodegenerative disorders that arise in the context of cancer and are believed to be mediated by the immune system. Patients harbour autoantibodies that are targeted to specific tumour and

neuronal antigens (onconeural antigens). * ALTERNATIVE SPLICING During splicing, introns are excised from RNA after transcription and the cut ends are rejoined to form a continuous message.

Alternative splicing allows the production of different messages from the same DNA molecule. * GEPHYRIN A cytosolic protein that clusters glycine and GABAA receptors at synapses. *

AMPHIPHYSIN A molecule located at the presynaptic terminal that interacts with several proteins that are important in the synaptic-vesicle cycle. * SUPPRESSOR T CELLS Lymphocytes that can

suppress the activity of naive or effector T cells. They produce TGF-β, which inhibits T-cell proliferation. * CYTOTOXIC T CELLS Lymphocytes that can kill other cells and are important in

host defence against cytosolic pathogens. They are commonly MHC class I CD8 cells. * CD4/CD8 RATIO Most T lymphocytes express one of two antigens — CD4 and CD8. CD4 is expressed by helper

and inflammatory T cells and is a co-receptor for MHC class II molecules. CD8 is expressed by cytotoxic T cells and is a co-receptor for MHC class I molecules. An increased CD4/CD8 ratio

commonly indicates heightened immune function, whereas a decreased ratio is indicative of prevalent disease. * ISCHAEMIC PENUMBRA A term that is generally used to define ischaemic but still

viable cerebral tissue that surrounds a core ischaemic zone. * HAEMORRHAGIC TRANSFORMATION Secondary bleeding that can occur after an ischaemic episode. * PROGRESSIVE SUPRANUCLEAR PALSY A

brain disorder that affects the control of gait and balance. The most obvious sign of the disease is an inability to direct the eyes properly, reflecting lesions in brainstem regions that

coordinate eye movements. Patients often show alterations of mood and behaviour, including depression, apathy and mild dementia. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS

ARTICLE CITE THIS ARTICLE Nguyen, M., Julien, JP. & Rivest, S. Innate immunity: the missing link in neuroprotection and neurodegeneration?. _Nat Rev Neurosci_ 3, 216–227 (2002).

https://doi.org/10.1038/nrn752 Download citation * Issue Date: 01 March 2002 * DOI: https://doi.org/10.1038/nrn752 SHARE THIS ARTICLE Anyone you share the following link with will be able to

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