Key Points
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Decades of research in immunology has supported the view that the brain is an immunologically privileged site, in part because normal, uninfected neurons were not thought to express major histocompatibility complex (MHC) class I molecules. Recent evidence, however, indicates that neurons can and do normally express both classical and non-classical MHC class I mRNA and protein in vivo.
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MHC class I has been identified in multiple separate unbiased genetic screens for molecules expressed by distinct, anatomically and/or functionally defined populations of neurons. These studies subsequently revealed that MHC class I has functions outside the immune system in neuronal development, activity-dependent plasticity, and even behaviour.
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These novel neuronal functions of MHC class I might be mediated through classical immunoreceptors that are expressed in the CNS. Indeed, components of numerous MHC class I receptors and signalling components that were known from the immune system have been detected in adult and developing neurons.
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The neuronal functions of MHC class I might also be mediated by MHC class I interactions with non-immune proteins. There are numerous precedents for MHC class I-like proteins functioning in this way outside the immune system.
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The fact that MHC class I proteins are expressed in neurons indicates that this region might participate in neurological disorders in various ways. For example, it might render neurons vulnerable to autoimmune attack, it might be neuroprotective, or it might participate directly in the disruption of normal brain development, function and plasticity.
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The expression of MHC class I proteins in neurons indicates that we should re-examine its potential role in neurological disorders to which it has been genetically and/or symptomatically linked, including schizophrenia, dyslexia and autism.
Abstract
Research has long supported the view that the brain is immunologically privileged, in part because normal, uninfected neurons were not thought to express major histocompatibility complex (MHC) class I molecules. Recently, however, it has been shown that neurons normally express MHC class I molecules in vivo. Furthermore, accumulating evidence indicates that neuronal MHC class I does not simply function in an immune capacity, but is also crucial for normal brain development, neuronal differentiation, synaptic plasticity and even behaviour. These findings point to new directions for research, and imply that immune proteins could be involved in the origin and expression of neurological disorders.
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Acknowledgements
We are very grateful to N. Colaco and M. Majdan for critical reading of the manuscript. L.M.B. is supported by a Junior Fellowship from the Harvard Society of Fellows.
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major histocompatibility complex
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Glossary
- HISTOCOMPATIBILITY
-
The ability of tissues to be successfully grafted. Also refers to the genetic systems that determine tissue rejection through immune responses of histocompatibility antigens.
- ADAPTIVE IMMUNE SYSTEM
-
The system that coordinates the response of antigen-specific T cells to an antigen. The process is mediated by clonal selection of lymphocytes.
- CYTOTOXIC T LYMPHOCYTE
-
(CTL). An effector cell of the adaptive immune system that binds MHC class I and induces cytolysis of cells bearing non-self peptides derived from cytosolic pathogens. Most CTL express the co-receptor CD8.
- T CELLS
-
A subset of lymphocytes that are defined by their development in the thymus and by the expression of receptors associated with CD3 proteins. T cells mediate cellular adaptive immunity, whereas B lymphocytes (B cells) mediate humoral adaptive immunity.
- FLUORESCENCE-ACTIVATED CELL SORTING
-
A method that allows the separation of cells that express a specific protein by tagging them with a fluorescent antibody against the molecule of interest. A laser beam excites the fluorescent tag, and the emission of light triggers the cell sorting.
- EPITOPE
-
A site on an antigen that is recognized by an antibody or antigen receptor.
- POLYMORPHIC
-
Having multiple alleles at a single locus.
- RNASE PROTECTION
-
A technique that is used to measure the quantity of mRNA that corresponds to a given gene in an RNA sample. A labelled RNA probe that is complementary to the relevant sequence is hybridized with the RNA sample; any RNA that does not hybridize with the probe is then digested away using ribonuclease. The undigested mRNA can then be quantified on an electrophoresis gel.
- INNATE IMMUNE SYSTEM
-
The system that mediates the early phases of the host response to a group of related pathogens. Innate immune responses, unlike adaptive immune responses, do not increase with repeated exposure to a given pathogen.
- SOMATIC RECOMBINATION
-
Gene segment rearrangements during lymphocyte development that lead to the production of a wide variety of complete, variable regions for T-cell antigen receptors and immunoglobulins.
- AUTOIMMUNITY
-
Immune responses directed at self antigens.
- CELLULAR IMMUNE RESPONSE
-
An adaptive immune response that is dominated by antigen-specific T cells, as opposed to humoral immunity, which is primarily mediated by antibodies.
- CYTOKINES
-
Proteins that affect the behaviour of other cells through specific cytokine receptors. Cytokines that are made by lymphocytes are often called lymphokines or interleukins.
- HAPLOTYPE
-
The combination of alleles that is expressed by a given individual. The MHC genes are usually inherited as a haplotype from each parent.
- POLYGENIC
-
A term that refers to several loci that encodes proteins of similar function.
- MONOZYGOTIC
-
A term that refers to identical twins, which develop from a single egg.
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Boulanger, L., Shatz, C. Immune signalling in neural development, synaptic plasticity and disease. Nat Rev Neurosci 5, 521–531 (2004). https://doi.org/10.1038/nrn1428
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DOI: https://doi.org/10.1038/nrn1428
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Hypoimmunogenic human pluripotent stem cells are valid cell sources for cell therapeutics with normal self-renewal and multilineage differentiation capacity
Stem Cell Research & Therapy (2023)
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Neuronal MHC-I complex is destabilized by amyloid-β and its implications in Alzheimer’s disease
Cell & Bioscience (2023)
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Plasma β2-microglobulin and cerebrospinal fluid biomarkers of Alzheimer’s disease pathology in cognitively intact older adults: the CABLE study
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Cylindromatosis drives synapse pruning and weakening by promoting macroautophagy through Akt-mTOR signaling
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