Blood circulating microparticle species in relapsing–remitting and secondary progressive multiple sclerosis. A case–control, cross sectional study with conventional MRI and advanced iron content imaging outcomes

Abstract

Background Although multiple sclerosis (MS) is thought to represent an excessive and inappropriate immune response to several central nervous system (CNS) autoantigens, increasing evidence also suggests that MS may also be a neurovascular inflammatory disease, characterized by endothelial activation and shedding of cell membrane microdomains known as ‘microparticles’ into the circulation. Objective To investigate the relationships between these endothelial biomarkers and MS. Methods We examined the relative abundance of CD31+/PECAM-1, CD51+CD61+ (αV–β3) and CD54+ (ICAM-1) bearing microparticles in sera of healthy individuals, patients with relapsing–remitting MS, and secondary-progressive MS. We also investigated the correlation among circulating levels of different microparticle species in MS with conventional MRI (T2- and T1-lesion volumes and brain atrophy), as well as novel MR modalities [assessment of iron content on susceptibility-weighted imaging (SWI)-filtered phase]. Results Differences in circulating microparticle levels were found among MS groups, and several microparticle species (CD31+/CD51+/CD61+/CD54+) were found to correlate with conventional MRI and SWI features of MS. Conclusion These results indicate that circulating microparticles’ profiles in MS may support mechanistic roles for microvascular stress and injury which is an underlying contributor not only to MS initiation and progression, but also to pro-inflammatory responses.

Brain Endothelial Cells Release Apical and Basolateral Microparticles in Response to Inflammatory Cytokine Stimulation: Relevance to Neuroinflammatory Stress?

“…Research in the field of MP biology has gained tremendous attention over the past decade with MPs being found to be significantly increased in several diseases including MS (10), AD (27), stroke (28), coronary artery disease (29), and type 2 diabetes (4) to name only a few. Consequently, MPs have become useful biomarkers of many diseases, which not only have diagnostic and prognostic value, but also provide mechanistic insights (1, 30).…”

“…EC-derived microparticles (“EMPs”) are constitutively released at low levels under normal physiological conditions, with the rate and magnitude of EMP release increasing during endothelial inflammatory activation or apoptosis (8). Several recent studies analyzing circulating MPs in plasma and serum samples have implicated MPs in the pathology of neurodegenerative, neurovascular and inflammatory diseases including stroke (9), multiple sclerosis (MS) (10) and Alzheimer's disease (AD) (11, 12). Apically released EMPs have widely been reported, both in in vitro and in vivo studies as well as in clinical studies (1, 10).…”

“…Several recent studies analyzing circulating MPs in plasma and serum samples have implicated MPs in the pathology of neurodegenerative, neurovascular and inflammatory diseases including stroke (9), multiple sclerosis (MS) (10) and Alzheimer's disease (AD) (11, 12). Apically released EMPs have widely been reported, both in in vitro and in vivo studies as well as in clinical studies (1, 10). Such MPs accumulate in the plasma and serum in vivo , and in cell culture media in vitro .…”

Emerging Role of Extracellular Vesicles in the Pathophysiology of Multiple Sclerosis

“…Conversely, endothelial EVs CD51+ (integrin alpha-V) remained elevated during both exacerbation and remission, thus appearing to be a marker of chronic damage more than endothelial disruption [ 40 ]. Other clinical studies showed that endothelial EVs were significantly increased in the serum of both SPMS and RRMS patients, with higher levels in relapsing–remitting than progressive forms, thus reflecting a status of active peripheral inflammation rather than chronic neurodegeneration [ 42 , 45 , 50 ]. Interestingly, elevated plasma levels of conjugates between endothelial EVs and monocytes directly correlated with MRI gad+ lesions in a court of RRMS patients [ 41 ].…”

“…Pro-inflammatory microenvironment has been also associated to EVs shedding from platelets (glycoprotein Ib alpha chain/CD42b+), significantly increased in plasma of MS patients [ 42 , 47 , 70 ]. Marcos-Ramiro and colleagues isolated platelet EVs and endothelial EVs from the serum of CIS, RRMS and PMS patients and verified their effects on the permeability of a monolayer model of BBB by using trans-endothelial electric resistance (TEER; a measure inversely proportional with barrier permeability) and by confocal analysis.…”