Fingolimod (Gilenya), a sphingosine-1-phosphate modulator, has been described as accomplishing its beneficial immune effects in MS by sequestering inflammatory lymphocytes in lymph nodes and minimizing their crossing of the BBB. Nishihara et al. have reported that fingolimod also has a direct effect on claudin-5 (but apparently does not alter occludin), potentially stabilizing tight junctions against the influence of elevated inflammatory cytokines [113].

Cytokines and Chemokines in Endothelial Pathogenesis of MS

Th1, Th2, and Th17 cytokines have all been implicated in neuroinflammation and may influence brain EC functions in MS. Tumor necrosis factor-alpha (TNF-a) is one of the cytokines best investigated in the pathogenesis of MS, as well as with interferon gamma (IFN-y). Both TNF-a and IFN-y are overexpressed in MS and may increase endothelial activation and impair BBB junctional integrity [114, 115]. Indeed, MR measures have revealed a surge in TNF-a levels along with a decrease in anti-inflammatory cytokines (e.g. IL-10 and TGF-p) before MS relapses and inflammatory flares [116]. Of these anti-inflammatory cytokines, IL-10 has been reported to prevent MAdCAM-1 induction and junctional disruption [5, 117]. TNF-a is produced mainly by activated macrophages, but several cells in the CNS/ BBB may also contribute. TNF-a is a major immunomodulatory cytokine involved in many inflammatory diseases including AD [118], inflammatory bowel disease (IBD) [119], and MS [120]. The role of TNF-a in MS is complex with anti-TNF-a actually intensifying disease in some cases [121]. Anti-TNF-a therapy is not widely used in MS therapy, although TNF-a mRNA transcript levels have been reported to be significantly increased in active MS lesions compared to inactive ones [122].

Another study revealed abundant expression of ADAM metallopeptidase domain 17 (ADAM17) within MS lesions. [123] ADAM17 is a member of ADAM protein family of disintegrins and metalloproteases and is also known as tumor necrosis factor-alpha-converting enzyme (TACE), due to its role in cleavage of TNF-a at cell surface. The elevated levels of these proinflammatory cytokines may promote and amplify MS neuroinflammation. Proinflammatory cytokines activate macrophages by upregulating the expression of major histocompatibility complex II (MHC-II) and endothelial adhesion molecules as well as on glial cells, to further recruit Th1 immune cells. This ultimately results in an even greater demyelination [124]. Paradoxically, TNF-a inhibition has actually been reported to result in the induction of demyelination of the CNS and worsening of MS [125, 126].

Another cytokine that has received much attention regarding MS pathogenesis is IFN-y, which is involved in MS pathogenesis and in EAE. IFN-y is a dimeric soluble cytokine type 2 interferon and was originally described as a macrophageactivating factor [127-129]. Since then, many targets including endothelial cells have been described. IFN-y is crucial for both innate and adaptive immunity against viral and intracellular bacterial infections. It also plays an important role in tumor control and can cause autoimmune disease if expression is abnormally increased. IFN-y is involved in a feed-forward loop, where Th1 immune cells produce IFN-y that increases Th1 cells by differentiating CD4+ cells into Th1 cells. This positive cascade occurs concurrently with the decrease of differentiation into Th2 cell. IFN-y production is also reported to occur before clinical MS relapses [130, 131]. Elevated IFN-y levels correlate with inflammation within the CNS in MS [132]. A pilot study of 18 MS patients helped to understand IFN-y’s role in MS pathogenesis [133, 134]. Patients were treated with recombinant IFN-y to assess toxicity and dosage responses. IFN-y was given intravenously to three treatment groups. The group receiving “low dose” was given 1 microgram, “intermediate” was given 30 micrograms, and “high dose” was administered 1000 micrograms twice a week for 4 weeks. Although IFN-y was not detected in the CSF, levels in the serum correlated with administration. Interestingly, during this study, relapse rate significantly increased with seven patients experiencing relapses. Circulating monocyte bearing class II surface antigens also significantly increased, from which the investigators concluded that IFN-y intravenous administration to MS patients has a significant and negative impact on cellular immunity associated with elevated MS relapse rates. The investigators therefore recommended a study of specific inhibitors of IFN-y production or action, on immune cells as a treatment of MS.

An intriguing conclusion from murine-based MS models however is that interferon-y may be beneficial in these models [135, 136]. Studies in EAE suggest that IFN-y blockade intensified disease severity with poorer survival; these studies may reflect strain (JJL/J)-dependent effects. Conversely, the addition of IFN-y delayed the initiation of EAE. Thus, while EAE is an excellent model of some MS processes, not all pathomechanisms may be recapitulated by all MS models.

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