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Guardians of the brain: The brain’s immune system

Figure 1: The immune system of the brain includes a network of transport vessels (blue) and its own immune cells made in bone marrow (green)

The brain is the body’s sovereign, and receives protection in keeping with its high status. Its cells are long-lived and shelter inside a fearsome fortification called the blood–brain barrier. For a long time, scientists thought that the brain was completely cut off from the chaos of the rest of the body — especially its eager defence system, a mass of immune cells that battle infections and whose actions could threaten a ruler caught in the crossfire. The brain had its own resident immune cells, called microglia; recent discoveries are painting more-detailed pictures of their functions and revealing the characteristics of the other immune warriors housed in the regions around the brain. Some of these cells come from elsewhere in the body; others are produced locally, in the bone marrow of the skull (Kwon, 2022).

The anatomical location of the CNS within the skull and vertebral column provides robust protection from injury from the outside. Unless there is a penetrating injury, pathogens are thus unlikely to directly reach the CNS, unless they have escaped the innate and adaptive immune defence mechanisms at the outer surfaces of the body. However, the CNS resides behind blood-brain barriers that restrict pathogen and immune cell entry from the periphery into the CNS parenchyma and lacks lymphatic system that differs from that of thus has a unique relationship with the immune system that differs from that of peripheral organs and is referred to as CNS immune privilege. The discovery of CNS immune privilege is based on the observation that foreign tissues, when grafted to peripheral sites like the skin, are readily rejected, but when grafted into the brain parenchyma, they survive for prolonged durations.

CNS immune privilege was originally thought to be based on “immune ignorance” where lack of lymphatic vessels and the endothelial blood-brain barrier (BBB) would inhibit the afferent and efferent arm of the CNS immunity respectively (Engelhardt B, Vajkoczy P, Weller RO., 2017 ). However, the observation that tissue grafts when transplanted into the cerebral ventricles were readily rejected (Murphy JB, Sturm E., 1923) and that foreign tissue grafts transplanted into the brain parenchyma of animals that had previously rejected a skin graft of the same donor were readily destroyed. (PB., 1948) Observations demonstrating that activated circulating T cells can cross the BBB in the absence of neuroinflammation and that tracers injected into the cerebrospinal fluid (CSF) drain into the deep cervical lymph nodes (Bradbury MW, Cole DF., 1980) finally provided direct evidence for afferent and efferent connections of the CNS with the immune system and asked for revisiting the concept of CNS immune privilege.

Bottom line, it was proposed that CNS immune privilege does not exist but requires proper consideration of the special anatomy of the CNS and especially of the localization and function of the different brain barriers, which divide the CNS into compartments that differ with respect to their accessibility to mediators and cells of the innate and adaptive immune system (Engelhardt B, Vajkoczy P, Weller RO., 2017). In this concept, the CNS parenchyma is immune privileged, allowing it to prioritize the proper function of neurons over eliciting an immune response, while the CNS ventricular spaces and border compartments (subarachnoid and perivascular spaces) are dedicated to CNS and thus lack full CNS immune privilege.

Under physiological conditions, the meningeal, endothelial, epithelial and glial brain barriers maintain CNS homeostasis by protecting the CNS parenchyma from the constantly changing milieu of the bloodstream (Kwon, 2022).

Figure 2: (A) Barriers at the surface of the human brain, (B) Leptomeningeal Blood-Cerebrospinal Fluid (CSF) Barrier and (C) Endothelial Blood-Brain Barrier (BBB)

Based on the above figure (A), the meninges are composed of three layers, the dura mater, the arachnoid barrier, and the pia mater. The dura mater is directly connected to the skull bone. (B), ChPs are localized in all four ventricles of the brain. The ChP epithelial cells are connected by unique parallel running tight junction stands and establish a BCSFB. The ChP stroma harbors dendritic cells and macrophages and the blood vessels of the ChP are fenestrated. (C), is formed highly specialised microvascular endothelial cells connected by complex tight junctions (Kwon, 2022).

The Role of the Individual Brain Barriers in Regulating Immune Cell Entry Into the CNS

CNS immune surveillance has been shown to be ensured by peripherally activated circulating T cells that have the specific ability to cross the BBB to reach perivascular or subarachnoid spaces in the absence of neuroinflammation (Engelhardt B, Vajkoczy P, Weller RO., 2017). While immune cells trafficking occurs at the level of CNS post-capillary venules, transport of nutrients occurs at the level of CNS capillaries (Ransohoff RM, Engelhardt B., 2012). This allows immune cells to reach perivascular or subarachnoid space, where they can encounter tissue resident antigen-presenting cells (APCs), like border associated macrophages (BAMs). Recognition of their cognate antigen on these CNS border associated APCs leads to local reactivation of T cells and is the prerequisite for subsequent T cell migration across the glia limitans into the CNS parenchyma (Angiari S, Rossi B, Piccio L, Zinselmeyer BH, Budui S, Zenaro E, et al., 2013).

Figure 3: Multi-step T cell extravasation across the BBB during neuroinflammation.

Multi-step T cell extravasation across the BBB occurs at the level of CNS post capillary venules. During inflammation, the rolling of activated T-cells on the BBB endothelial cells is mediated by P-selectin and a4-integrins. After their GPCR-dependent arrest, T cells crawl on the BBB endothelium against the direction ICAM-1 and de novo expression of ACKR1 that can shuttle CNS chemokines across the BBB promote transcellular diapedesis of T cells while low levels of endothelial ICAM-1 direct T cells mainly to tricellular and bicellular junctions. Once T cells have crossed the BBB endothelium, they reach the perivascular space. The CNS-antigen-specific T cells may recognize their cognate antigens on perivascular APCs and become reactivated and start to proliferate. The change in local cytokine milieu leads to induction of matrix metalloproteinases – 2 and -9 which cleave extracellular matrix receptors on astrocytes endfeet, allowing for T cell passage across the glia limitans. Once in the CNS parenchyma, T cells induce tissue injury and clinical disease symptoms start to appear (Kwon, 2022).


  1. Angiari S, Rossi B, Piccio L, Zinselmeyer BH, Budui S, Zenaro E, et al. (2013 , December 01). Regulatory T Cells Suppress the Late Phase of the Immune Response in Lymph Nodes Through P-Selectin Glycoprotein Ligand-1. Retrieved from The Journal of Immunology :

  2. Bradbury MW, Cole DF. (1980 , February 01). The Role of the Lymphatic System in Drainage of Cerebrospinal Fluid and Aqueous Humour. Retrieved from The Physiological Society :

  3. Engelhardt B, Vajkoczy P, Weller RO. (2017 , January 16). The Movers and Shapers in Immune Privilege of the CNS. Retrieved from PubMed :

  4. Kwon, D. (2022, June 01). Guardians of the brain: how a special immune system protects our grey matter. Retrieved from nature :

  5. Murphy JB, Sturm E. (1923, July 31). Conditions Determining the Transplantability Of Tissues In The Brain. Retrieved from PubMed:

  6. PB., M. (1948, February 29). Immunity to Homologous Grafted Skin; the Fate of Skin Homografts Transplanted to the Brain, to Subcutaneous Tissue, and to the Anterior Chamber of the Eye. Retrieved from PubMed :

  7. Ransohoff RM, Engelhardt B. (2012, August 20). The Anatomical and Cellular Basis of Immune Surveillance in the Central Nervous System. Retrieved from nature reviews immunology :


This article was prepared by Emeralda Erna Nordin


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