The Blood–Brain Barrier—A Key Player in Multiple Sclerosis Disease Mechanisms

Abstract

Over the past decade, multiple sclerosis (MS), a chronic neuroinflammatory disease with severe personal and social consequences, has undergone a steady increase in incidence and prevalence rates worldwide. Despite ongoing research and the development of several novel therapies, MS pathology remains incompletely understood, and the prospect for a curative treatment continues to be unpromising in the near future. A sustained research effort, however, should contribute to a deeper understanding of underlying disease mechanisms, which will undoubtedly yield improved results in drug development. In recent years, the blood–brain barrier (BBB) has increasingly become the focus of many studies as it appears to be involved in both MS disease onset and progression. More specifically, neurovascular unit damage is believed to be involved in the critical process of CNS immune cell penetration, which subsequently favors the development of a CNS-specific immune response, leading to the classical pathological and clinical hallmarks of MS. The aim of the current narrative review is to merge the relevant evidence on the role of the BBB in MS pathology in a comprehensive and succinct manner. Firstly, the physiological structure and functions of the BBB as a component of the more complex neurovascular unit are presented. Subsequently, the authors review the specific alteration of the BBB encountered in different stages of MS, focusing on both the modifications of BBB cells in neuroinflammation and the CNS penetration of immune cells. Finally, the currently accepted theories on neurodegeneration in MS are summarized.

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“…The BBB, a unique structure in the human body [ 75 ], is a crucial structure in the maintenance of brain homeostasis [ 76 ]. Structural and functional dysfunctions of this structure may lead to many neurological disorders [ 77 ]. One of the BBB’s primary roles is to prevent the penetration of toxins and exogenous pathogens into the sensitive brain parenchyma.…”

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“…Lymphocyte transmigration through the blood–brain barrier constitutes an important step in MS pathogenesis [ 42 ]. The importance of the blood–brain barrier has been recently thoroughly reviewed by Schreiner et al [ 43 ]. Indeed, two modern and highly effective drugs (natalizumab and fingolimod) target the transmigration of lymphocytes [ 44 , 45 ].…”

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“…Some of them can induce neuroinflammatory and neurodegenerative processes in the CNS, which occur when the integrity of the BBB is compromised ( Zlokovic, 2008 ; Bennett et al, 2010 ). The BBB is considered a highly selective barrier between the cerebral capillary blood and interstitial fluid of the CNS ( Kadry et al, 2020 ; Schreiner et al, 2022 ), and helps keep harmful substances from reaching the brain as pathogens, toxins, and some drugs, as well as prevents the entry of IS components ( Daneman, 2012 ; Kadry et al, 2020 ; Knudsen et al, 2022 ). The principal constituent of the BBB is the endothelial cells, which provide protection and structural stability to the blood vessels on tight junctions (the liner sheets pericytes, and astrocytes that ensheath the blood vessels and restrict the substances entering the brain) ( Daneman, 2012 ).…”

“…These cells are associated with the breakdown and increase in the permeability of the BBB through the secretion of Th1 cells of interferon gamma (INF-γ), IL-2, TNF-α, and lymphotoxin. These CD4 + T cells express α4 integrin (VLA-4) on their surface, which is required for their entry across the BBB ( Baron et al, 1993 ; Schreiner et al, 2022 ). Activated reactive CD4 + T cells can be found in the cerebrospinal fluid (CSF) of patients with MS in contrast to healthy individuals.…”