Redefining CNS immune privilege
Abstract
The central nervous system (CNS) has a unique relationship with the immune system, referred to as immune privilege. For many years it was thought that immune privilege was due to isolation of the CNS from the immune system, but recent findings have shown that this theory is flawed and that there is substantial neuroimmune communication, particularly at border sites that encase the CNS. These border sites include perivascular and subarachnoid spaces, the choroid plexus, the meninges and the vasculature, including the recently discovered meningeal lymphatic vessels. CNS border tissues have extensive interaction with the cerebrospinal fluid, which acts as an immune mediator, allowing the immune system at the CNS borders to respond to challenges within the CNS parenchyma. Together, CNS border tissues enable immune surveillance and protection against infections while preventing inflammatory damage to the parenchyma. A better understanding of the mechanisms of immune privilege as an accord, as opposed to isolation, between the two systems would help us obtain effective immunotherapies for neurological diseases.
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During neurodegeneration, blood-brain barrier integrity declines, which may facilitate peripheral monocytes to infiltrate the CNS and differentiate into microglia-like cells.
“during neurodegeneration, the integrity of the blood–brain barrier declines. This may facilitate debated levels of peripheral monocytes to infiltrate the central nervous system and differentiate into microglia-like cells.”
From Clonal Hematopoiesis of Indeterminate Potential as an Emerging Interdisciplinary Risk Factor in Alzheimer’s Disease: Current Evidence and Future Directions (2026) · cites this paper as [26]
Somatic mutations present in the peripheral hematopoietic system could theoretically be imported into the brain's immune environment, posing a mechanistic link between systemic aging and local neuroinflammation.
“any somatic mutations present in the peripheral hematopoietic system could theoretically be imported into the brain’s immune environment, posing a mechanistic link between systemic aging and local neuroinflammation [10,24,25,26].”
From Clonal Hematopoiesis of Indeterminate Potential as an Emerging Interdisciplinary Risk Factor in Alzheimer’s Disease: Current Evidence and Future Directions (2026) · cites this paper as [26]
Differences in blood-brain barrier integrity, vascular pathology, and immune trafficking across cohorts may further modulate the extent to which peripheral CHIP influences central neuroimmune processes.
“Differences in blood–brain barrier integrity, vascular pathology, and immune trafficking across cohorts may further modulate the extent to which peripheral CHIP influences central neuroimmune processes [26].”
From Clonal Hematopoiesis of Indeterminate Potential as an Emerging Interdisciplinary Risk Factor in Alzheimer’s Disease: Current Evidence and Future Directions (2026) · cites this paper as [26]
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Kopp, K., Silva, P., Damm, F., & Cosma, N. C. (2026) · Biomedicines · doi:10.3390/biomedicines14051012
- Authors
- Smyth, L. C. D., & Kipnis, J.
- Affiliations
- Washington University in St. Louis (US)
- Corresponding author
- Kipnis, Jonathan
- Venue
- Nature Reviews Immunology
- Published
- 2025-05-02
- Volume
- 25
- Issue
- 10
- Pages
- 766-775
- ISSN
- 1474-1733 (ISSN-L)
- 1474-1741
- OpenAlex
- W4410034576
- Cited by
- 80
- References
- 15
- Citations by year
- 2026: 70 · 2025: 10
- FWCI
- 7.68
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Nature reviews. Immunology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Cerebrospinal fluid and hydrocephalus
- Keywords
- immune privilege, central nervous system, neuroimmune interactions, cerebrospinal fluid, meningeal lymphatic vessels, choroid plexus, meninges, perivascular spaces, subarachnoid space, immune surveillance, neuroinflammation
- MeSH terms
- Immune Privilege, Animals, Central Nervous System, Humans, Meninges, Neuroimmunomodulation
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