Multiple sclerosis ( MS ) is increasingly being viewed and studied not only as an immune-mediated demyelinating and neurodegenerative disease of the human central nervous system ( CNS ) but as a vascular-based form of neuroinflammation.
Irrespective of the type of multiple sclerosis ( relapsing-remitting [ RRMS, 85% ], secondary progressive [ SPMS, 12% ], primary progressive [ PPMS, 3% ], or progressive-relapsing [ PRMS, less than 1% ] ), the complex pathogenesis of multiple sclerosis can only be appreciated when and if vascular contributions are recognized as a significant part of the etiology of multiple sclerosis.
Indeed, many novel therapies for multiple sclerosis target the mechanistically relevant vascular inflammatory features of these conditions and implicate cerebrovascular endothelial cells ( CECs ) as the failing gatekeeper of the blood-brain barrier ( BBB ).
Cerebrovascular endothelial cells and their metabolically and biochemically coupled cells ( astrocytes, glia and neurons ) establish and regulate several types of intercellular junctions which isolate the circulation from the brain as the functional neuro- and gliovascular units of the blood-brain barrier.
In health, the blood-brain barrier generally isolates the brain parenchyma from immune cells and blood-borne neurotransmitters ( glutamate, norepinephrine, serotonin ) controlling solute exchange into and out of the CNS by a system of pumps, channels, and pores, requiring a continuous and significant energy expenditure.
Binding interactions between leukocytes and activated CEC ( like non-BBB endothelial cells ) can initiate and regulate trans-BBB immune cell penetration of the CNS during routine immune reconnaissance.
The inappropriate intensification of these responses appears to be central to multiple sclerosis pathogenesis ( and contributes to other neuroinflammatory diseases, acute demyelinating encephalomyelitis [ ADEM ], optic neuritis / Devic’s disease ).
Extravasation of activated and committed leukocytes across the CEC into the protected environment of the brain is the first step in generating multiple sclerosis lesions.
All forms of multiple sclerosis show propagation of immune cascades culminating in the white matter demyelination and expansion of scar tissue ( hence the term sclerosis ).
These regions of tissue destruction are revealed diagnostically by magnetic resonance imaging ( MRI ) of the brain and spinal cord as T1 and T2 hypointensities reflecting demyelination and gray matter injury, respectively.
Basic scientific and clinical studies now support contributions of vascular and endothelial cell stress and apoptosis as significant features of multiple sclerosis and help explain how blockade of leukocyte binding and transendothelial extravasation of activated immune cells across the multiple sclerosis-inflamed cerebral microvasculature and restitution of endothelial barrier function represent important goals of the treatment of multiple sclerosis.
Such approaches can achieve significant reductions in MS disease activity and progression, but carry risks from interference with immune surveillance.
Endothelial stress in the forms of endothelial cell-derived microparticles ( EMPs ) is also becoming increasingly recognized, with EMPs acting as both markers and mediators of the pathology of multiple sclerosis. ( Xagena )
Source: Inflammatory Disorders of the Nervous System, 2017