Vascular pathology in multiple sclerosis: reframing pathogenesis around the blood-brain barrier

Abstract

Blood-brain barrier (BBB) disruption has long been recognised as an important early feature of multiple sclerosis (MS) pathology. Traditionally, this has been seen as a by-product of the myelin-specific immune response. Here, we consider whether vascular changes instead play a central role in disease pathogenesis, rather than representing a secondary effect of neuroinflammation or neurodegeneration. Importantly, this is not necessarily mutually exclusive from current hypotheses. Vascular pathology in a genetically predisposed individual, influenced by environmental factors such as pathogens, hypovitaminosis D and smoking, may be a critical initiator of a series of events including hypoxia, protein deposition and immune cell egress that allows the development of a CNS-specific immune response and the classical pathological and clinical hallmarks of disease. We review the changes that occur in BBB function and cerebral perfusion in patients with MS and highlight genetic and environmental risk factors that, in addition to modulating immune function, may also converge to act on the vasculature. Further context is provided by contrasting these changes with other neurological diseases in which there is also BBB malfunction, and highlighting current disease-modifying therapies that may also have an effect on the BBB. Indeed, in reframing current evidence in this model, the vasculature could become an important therapeutic target in MS.

A case of disseminated microscopic demyelination with multifocal dystrophic calcification

“…In these patients, demyelination is accompanied by oligodendroglial cell loss . Additionally, microvascular brain pathologies and blood–brain barrier abnormalities have been suggested as etiologies for MS lesions . Similarly, it is possible for the demyelinating lesions in this case to have been caused by blood vessel abnormalities.…”

Gastrointestinal influences in multiple sclerosis: Focus on the role of the microbiome

“…MS is characterized by disruption of the BBB with compromised tight junctions and increased chemokine levels . Expression of junctional proteins, claudin‐5 and occludin, by endothelial cells of the BBB is reduced in germ‐free mice, associated with disruption of tight junctions and increased permeability.…”

“…Levels of LPS in the circulation (a marker of intestinal permeability) are associated with increased serum IL‐6 and IL‐17 levels, and correlate with Expanded Disability Status Scale scores . LPS can reduce BBB integrity by inducing expression of leukocyte adhesion molecules that bind to receptors upregulated in CNS inflammation, and can activate phagocytes in the parenchyma . Microbe associated molecular patterns (MAMPs) can induce expression of inflammatory cytokines by the endothelial cells of the BBB .…”

“…51 MS is characterized by disruption of the BBB with compromised tight junctions and increased chemokine levels. 52 Expression of junctional proteins, claudin-5 and occludin, by endothelial cells of the BBB is reduced in germ-free mice, associated with disruption of tight junctions and increased permeability. These changes are reversed by intestinal colonization with Clostridium tyrobutyricum, (a producer of the SCFA butyrate), Bacteroides thetaiotaomicron (a producer of acetate and propionate) or oral administration of butyrate.…”

“…23 LPS can reduce BBB integrity by inducing expression of leukocyte adhesion molecules that bind to receptors upregulated in CNS inflammation, and can activate phagocytes in the parenchyma. 52 Microbe associated molecular patterns (MAMPs) can induce expression of inflammatory cytokines by the endothelial cells of the BBB. 56 Therefore, alterations in intestinal permeability, which could itself arise as a result of dysbiosis, might increase bacterial products in the circulation.…”