Role of the Blood–Brain Barrier in Multiple Sclerosis

Ortíz, Genaro Gabriel; Pacheco-Moisés, Fermín Paul; Macías-Islas, Miguel Ángel; Flores-Alvarado, Luis Javier; Mireles-Ramírez, Mario Alberto; González-Renovato, Erika Daniela; Hernández-Navarro, Vanessa Elizabeth; Sánchez-López, Angélica Lizeth; Alatorre-Jiménez, Moisés Alejandro

doi:10.1016/j.arcmed.2014.11.013

Cited by 309 publications

(232 citation statements)

References 77 publications

Supporting

Mentioning

230

Contrasting

Unclassified

Order By: Relevance

“…However, this increase should be distinguished from that observed in progressive diseases, such as MS, where sustained S100B, as detected herein in the chronic MS lesions, might have different roles by modulating the inflammatory response [35,36] and consequently modify the disease progression by yet unknown mechanisms. Although there are other sources of S100B than the CNS, such as adipose tissue, testis and skin [15,37,38], the elevation of S100B in serum has been associated with blood-brain barrier (BBB) disruption [39], which is in line with the presence of signs of BBB breakdown in the very early stages of MS [40].…”

Section: Discussionmentioning

confidence: 98%

S100B as a Potential Biomarker and Therapeutic Target in Multiple Sclerosis

et al. 2015

View full text Add to dashboard Cite

Multiple sclerosis (MS) pathology is characterized by neuroinflammation and demyelination. Recently, the inflammatory molecule S100B was identified in cerebrospinal fluid (CSF) and serum of MS patients. Although seen as an astrogliosis marker, lower/physiological levels of S100B are involved in oligodendrocyte differentiation/maturation. Nevertheless, increased S100B levels released upon injury may induce glial reactivity and oligodendrocyte demise, exacerbating tissue damage during an MS episode or delaying the following remyelination. Here, we aimed to unravel the functional role of S100B in the pathogenesis of MS. Elevated S100B levels were detected in the CSF of relapsing-remitting MS patients at diagnosis. Active demyelinating MS lesions showed increased expression of S100B and its receptor, the receptor for advanced glycation end products (RAGE), in the lesion area, while chronic active lesions displayed increased S100B in demyelinated areas with lower expression of RAGE in the rim. Interestingly, reactive astrocytes were identified as the predominant cellular source of S100B, whereas RAGE was expressed by activated microglia/macrophages. Using an ex vivo demyelinating model, cerebral organotypic slice cultures treated with lysophosphatidylcholine (LPC), we observed a marked elevation of S100B upon demyelination, which co-localized mostly with astrocytes. Inhibition of S100B action using a directed antibody reduced LPC-induced demyelination, prevented astrocyte reactivity and abrogated the expression of inflammatory and inflammasome-related molecules. Overall, high S100B expression in MS patient samples suggests its usefulness as a diagnostic biomarker for MS, while the beneficial outcome of its inhibition in our demyelinating model indicates S100B as an emerging therapeutic target in MS.

show abstract

Section: Discussionmentioning

confidence: 98%

S100B as a Potential Biomarker and Therapeutic Target in Multiple Sclerosis

et al. 2015

View full text Add to dashboard Cite

show abstract

“…Astrocyte dysfunction is shown to induce neurotoxic effects in neurological disorders (Ben Haim et al 2015;Carmignoto and Haydon 2012;Gallardo et al 2014;Ortiz et al 2014;Seifert et al 2006;Vincent et al 2010). When astrocytes are activated in the pathologic conditions, their roles in CNS change by a manner of acquiring new functions or losing several physiological effects, which results in their heterogeneous influence on CNS injury and diseases (Table 2).…”

Section: Diverse Roles In Neurological Disordersmentioning

confidence: 97%

Heterogeneous astrocytes: Active players in CNS

Yuan

Wang

et al. 2016

Brain Research Bulletin

View full text Add to dashboard Cite

“…Peripheral anergic autoreactive lymphocytes (mainly T cells) undergo activation with microbial superantigens or with self-antigens with enhanced immunogenicity, particularly due to chronic inflammation (Tauber et al 2007). The next step is penetration of these cells through blood-brain barrier (BBB), a complex organization of cerebral endothelial cells, pericytes and their basal lamina, which are surrounded and supported by astrocytes and perivascular macrophages (Ortiz et al 2014). Cytokine imbalance toward the increased production of pro-inflammatory cytokines by T-helpers 1 (Th1) and 17 (Th17) (Hedegaard et al 2008) promotes the expression of adhesion molecules and HLA class II molecules on endothelial cells of BBB (Dore-Duffy et al 1993).…”

Section: Genes Carrying Gwas-identified Polymorphisms: Possible Biolomentioning

confidence: 99%

A review of genome-wide association studies for multiple sclerosis: classical and hypothesis-driven approaches

et al. 2015

View full text Add to dashboard Cite

Multiple sclerosis (MS) is a common complex neurodegenerative disease of the central nervous system. It develops with autoimmune inflammation and demyelination. Genome-wide association studies (GWASs) serve as a powerful tool for investigating the genetic architecture of MS and are generally used to identify the genetic factors of disease susceptibility, clinical phenotypes, and treatment response. This review considers the main achievements and challenges of using GWAS to identify the genes involved in MS. It also describes hypothesis-driven studies with extensive genome coverage of the selected regions, complementary to GWASs. To date, over 100 MS risk loci have been identified by the combination of both approaches; 40 of them were found in at least two GWASs and meet genome-wide significance threshold (p ≤ 5 × 10(-8)) in at least one GWAS, whereas the threshold for the rest of GWASs was set in our review at p < 1 × 10(-5). Yet, MS risk loci identified to date explain only a part of the total heritability, and the reasons of "missing heritability" are discussed. The functions of MS-associated genes are described briefly; the majority of them encode immune-response proteins involved in the main stages of MS pathogenesis.

show abstract

Role of the Blood–Brain Barrier in Multiple Sclerosis

Cited by 309 publications

References 77 publications

S100B as a Potential Biomarker and Therapeutic Target in Multiple Sclerosis

S100B as a Potential Biomarker and Therapeutic Target in Multiple Sclerosis

Heterogeneous astrocytes: Active players in CNS

A review of genome-wide association studies for multiple sclerosis: classical and hypothesis-driven approaches

Contact Info

Product

Resources

About