How Does the Immune System Enter the Brain?

Abstract

Multiple Sclerosis (MS) is considered the most frequent inflammatory demyelinating disease of the central nervous system (CNS). It occurs with a variable prevalence across the world. A rich armamentarium of disease modifying therapies selectively targeting specific actions of the immune system is available for the treatment of MS. Understanding how and where immune cells are primed, how they access the CNS in MS and how immunomodulatory treatments affect neuroinflammation requires a proper knowledge on the mechanisms regulating immune cell trafficking and the special anatomy of the CNS. The brain barriers divide the CNS into different compartments that differ with respect to their accessibility to cells of the innate and adaptive immune system. In steady state, the blood-brain barrier (BBB) limits immune cell trafficking to activated T cells, which can reach the cerebrospinal fluid (CSF) filled compartments to ensure CNS immune surveillance. In MS immune cells breach a second barrier, the glia limitans to reach the CNS parenchyma. Here we will summarize the role of the endothelial, epithelial and glial brain barriers in regulating immune cell entry into the CNS and which immunomodulatory treatments for MS target the brain barriers. Finally, we will explore current knowledge on genetic and environmental factors that may influence immune cell entry into the CNS during neuroinflammation in Africa.

Keywords: arachnoid barrier; blood-brain barrier; blood-cerebrospinal fluid barrier; immune cell trafficking; multiple sclerosis.

Figure 1

The brain barriers. The schematic coronal brain section depicts the localization of the different brain barriers shown in (A–C). (A) Barriers at the surface of the human brain. 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. In humans, the dura mater is composed of three layers, the periosteal dura, the meningeal dura and the dural border cells. The dura mater has its own network of arteries (MA), veins (MV) and dural lymphatics (DL). The arachnoid barrier is formed by arachnoid fibroblasts which are connected by tight junctions and form a bona fide blood-cerebrospinal fluid barrier (BCSFB) – the arachnoid barrier – between the dura mater and the CSF filled subarachnoid space. Arachnoid trabeculae formed by a collagen core that is ensheathed by arachnoid and pial fibroblasts cross the SAS towards the pia mater and to the leptomeningeal blood vessels. The fibroblasts of the pia mater cover the veins and arteries in the SAS and separate the SAS from the subpial space filled with collagen bundles. The pia mater reflects of the surface where arteries dive into the brain parenchyma and at the same time ensheathes the arteries entering the brain. The glia limitans forms a barrier at all surfaces of the CNS parenchyma, this is the outer surface (glia limitians superficialis) and the perivascular surfaces (glia limitans perivascularis). (B) The blood–CSF barrier of the choroid plexus (ChP). The 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) The blood–brain barrier (BBB) is formed by highly specialized microvascular endothelial cells connected by complex tight junctions. The endothelial basement membrane harbors a high number of pericytes. At the level of capillaries the endothelial basement membrane and the parenchymal basement membrane of the glia limitans merge. However that the post-capillary venule level they leave a small gap where single antigen-presenting cells can be found. The microvessels are surrounded by the glia limitans, which is composed of the parenchymal basement membrane and astrocyte end-feet. The extravasation of immune cells into the CNS parenchyma occurs at the level of postcapillary venules and thus involves crossing two barriers, the endothelial BBB and after reaching the perivascular space subsequent crossing of the glia limitans. The shapes of the cell types were adapted from Servier Medical Art (http://smart.servier.com/), licensed under a Creative Common Attribution 3.0 Generic License.

Figure 2

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 of blood flow. High levels of endothelial 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, i.e. paracellular sites of diapedesis. 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 astrocyte 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. The shapes of the cell types were adapted from Servier Medical Art (http://smart.servier.com/), licensed under a Creative Common Attribution 3.0 Generic License.

Figure 3

Genetic and environmental factors influencing immune cell entry into the brain. Encounter of microbes takes place at the inner and outer surfaces of the body equipped with special barrier forming epithelia and innate immune cells residing behind these barriers. Priming of T cells in skin and gut-draining lymph nodes imprints their effector function, i.e. expression of trafficking molecules. Pale-skinned people have a higher risk of developing MS as compared to people with black skin. The schematic representation shows imprinting of trafficking properties in T-cells primed in the skin and the gut (adapted from (2), chapter 14). Experimental animal studies have shown that autoagressive T cells primed in skin-draining lymph nodes express CXCR6 and can enter the CNS white and grey matter, while when these T cells are primed in gut-draining lymph odes they express P2rx7 and only infiltrate CNS white matter. How skin color and the gut microbiome of the African population affects T cell priming and their CNS homing properties remains to be shown. The shapes of the cell types were adapted from Servier Medical Art (http://smart.servier.com/), licensed under a Creative Common Attribution 3.0 Generic License.