Abnormal Endothelial Tight Junctions in Active Lesions and Normal‐appearing White Matter in Multiple Sclerosis

Abstract

Blood‐brain barrier (BBB) breakdown, demonstrable in vivo by enhanced MRI is characteristic of new and expanding inflammatory lesions in relapsing‐remitting and chronic progressive multiple sclerosis (MS). Subtle leakage may also occur in primary progressive MS. However, the anatomical route(s) of BBB leakage have not been demonstrated. We investigated the possible involvement of interendothelial tight junctions (TJ) by examining the expression of TJ proteins (occludin and ZO‐1) in blood vessels in active MS lesions from 8 cases of MS and in normal‐appearing white (NAWM) matter from 6 cases. Blood vessels (10–50 per frozen section) were scanned using confocal laser scanning microscopy to acquire datasets for analysis. TJ abnormalities manifested as beading, interruption, absence or diffuse cytoplasmic localization of fluorescence, or separation of junctions (putative opening) were frequent (affecting 40% of vessels) in oil‐red‐O‐positive active plaques but less frequent in NAWM (15%), and in normal (<2%) and neurological controls (6%). Putatively “open” junctions were seen in vessels in active lesions and in microscopically inflamed vessels in NAWM. Dual fluorescence revealed abnormal TJs in vessels with pre‐mortem serum protein leakage. Abnormal or open TJs, associated with inflammation may contribute to BBB leakage in enhancing MRI lesions and may also be involved in subtle leakage in non‐enhancing focal and diffuse lesions in NAWM. BBB disruption due to tight junctional pathology should be regarded as a significant form of tissue injury in MS, alongside demyelination and axonopathy.

Identification of an essential endogenous regulator of blood–brain barrier integrity, and its pathological and therapeutic implications

“…In particular, disrupted occludin expression and distribution have been reported within the microvascular endothelium of patients with MS (27), clearly paralleling our findings in AnxA1 −/− mice and AS hCMEC/D3 clones. It is important to note that endothelial ANXA1 down-regulation occurs in normal-appearing white matter, a finding that may inform the extensive discussion whether deficits in BBB permeability precede leukocyte extravasation or are a consequence of immune cell accumulation (28).…”

Effects of the Chemokine CCL2 on Blood–Brain Barrier Permeability during Ischemia–Reperfusion Injury

“…The inflammatory response involves rolling, firm adhesion and transendothelial migration of leukocytes on the level of postcapillary venules, BBB dysfunction and increased production of proinflammatory mediators including reactive oxygen species, nitric oxide, cytokines, adhesion molecules and chemokines (Peters et al, 1998;Schuerer et al, 1994;Lindauer et al, 1996;Okada et al, 1994;Che et al, 2001;Yang et al, 1999). All of these mediators have been suggested as being involved in BBB 'breakdown' during inflammation, causing a dysfunction of TJ structure (abnormality in occludin and ZO-1), greater influx of blood-borne cells and further amplification of inflammation and brain parenchymal damage (Plumb et al, 2002;Gloor et al, 2001). Most of these observations imply that reperfusion-induced BBB disruption might be caused by different mediators with different time frames, although so far there is no solid evidence to show this.…”

Cerebral Arterial Bolus Arrival Time is Prolonged in Multiple Sclerosis and Associated with Disability

“…1,3 Ongoing inflammatory processes in normal-appearing white and gray matter have been challenging to study using magnetic resonance imaging (MRI), as they are not associated with a frank breach of the blood-brain barrier that can be detected as a region of gadolinium contrast enhancement. 5 However, inflammation can cause more subtle microscopic alteration in vascular function, 6 and lead to increases in vasodilatory nitric oxide 7 and glutamate. 8 Using dynamic contrast-enhanced MRI, an increase in cerebral blood flow (CBF) has also been observed in prelesional normalappearing white matter (NAWM) for several weeks before the development of a focal white matter lesion, 9 and significant increase in cerebral blood volume is seen at the earliest stages of both new lesion development 10 and existing lesion reactivation 11,12 in animal models of MS.…”