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.

Engineered Wnt7a ligands rescue blood brain barrier and neurobehavioral deficits in a mouse model of COVID-19

“…Reactive microglial and macrophages present antigen and restimulate T cells in CNS in COVID-19 (Schwabenland et al ., 2021). CNS-infiltrating T cells directly damage neurons, axons, and myelin to cause neurological impairment (Ai and Klein, 2020; Mapunda et al ., 2022; Prasad and Lokensgard, 2019). Concordantly, T-cell mediated neuroinflammation is exacerbated in middle-aged mice(Atkinson et al ., 2022; Peferoen et al ., 2016).…”

“…The BBB selectively restricts permeability of CNS blood vessels to macromolecules and immune cells from the blood. BBB damage occurs from loss of endothelial tight junctions, which normally suppress inter-cellular diffusion, and from increased rates of vesicular traffic across the endothelial cytoplasm(Knowland et al, 2014; Lutz et al, 2017; Mapunda et al, 2022). Importantly, Wnt/β-catenin signaling promotes BBB function in an age-dependent pattern.…”

“…We found parenchymal accumulation of fibrinogen was significantly greater in infected mice as compared to age--old infected mice had more brainstem fibrinogen than age-matched vehicle (p<0.001, one-way ANOVA and Sidak's multiple comparisons test). Thus, age exacerbates BBB leakage caused by SARS-CoV-2 infection.BBB permeability occurs through two pathways: movement through the spaces in between adjacent endothelial cells through disrupted tight junctions, and through the cytoplasm of the endothelial cell (transcytosis)(Mapunda et al, 2022). Caveolin-1 is a signaling and scaffolding molecule that can promote transcellular BBB permeability(Knowland et al., 2014; Lengfeld et al, 2017; Lutz et al, 2017; Martin et al, 2022) and that increases BBB permeability with age(Guérit et al, 2020;Yang et al, 2020).…”

Unveiling the gut-brain axis: structural and functional analogies between the gut and the choroid plexus vascular and immune barriers

“…Meninges, BBB, and BCSFB control the exchange of nutrients, metabolic solutes, hormones, metabolites, infectious agents, toxins, and waste, from and to the brain interstitium, the cerebrospinal fluid, and the bloodstream [ 100 , 101 ]. The intrinsic nature of cellular composition and permeability of the endothelium differs drastically between these three barriers, reflecting the different degrees of freedom necessary to balance the exchange and the protection needed to maintain the milieu of the CNS [ 102 ]. Here, we will describe only the blood-cerebrospinal fluid barrier which is the barrier that seems to play a role in both immune surveillance and protection of the brain [ 18 ].…”

Relevance of Pathogenetic Mechanisms to Clinical Effectiveness of B-Cell-Depleting Monoclonal Antibodies in Multiple Sclerosis

“…In the absence of neuroinflammation, T cells patrol the CNS crossing the BBB at the level of CNS post-capillary venules and reaching perivascular or subarachnoid spaces [ 36 ]. In such areas, putative cross-reactive T-cell clones may be further activated by CNS antigens (sharing structural motifs with their cognate antigen) which, after being drained from the parenchyma, are processed and presented by tissue-resident APCs.…”