Blood-brain barrier disruption in multiple sclerosis

Abstract

The blood-brain barrier (BBB) is a complex organization of cerebral endothelial cells (CEC), pericytes and their basal lamina, which are surrounded and supported by astrocytes and perivascular macrophages. Collectively these cells separate and form the compartments of the cerebral vascular space and the cerebral interstitium under normal conditions. Without the BBB, the 'interior milieu' of the central nervous system (CNS) would be flooded by humoral neurotransmitters and formed blood elements that upset normal CNS functions and lead to vascular/neural injury. Dysregulation of the BBB and transendothelial migration of activated leukocytes are among the earliest cerebrovascular abnormalities seen in multiple sclerosis (MS) brains and parallel the release of inflammatory cytokines/chemokines. Mechanisms for breakdown of the BBB in MS are incompletely understood, but appear to involve direct effects of these cytokines/ chemokines on endothelial regulation of BBB components, as well as indirect cytokine/chemokine-dependent leukocyte mediated injury. Unique endothelial structural features of the BBB include highly organized endothelial tight junctions, the absence of class II major histocompatibility complex, abundant mitochondria and a highly developed transport system in CEC. Exposure of endothelium to proinflammatory cytokines (IFN-gamma, TNF-alpha and IL-1beta) interrupts the BBB by disorganizing cell-cell junctions, decreases the brain solute barrier, enhances leukocyte endothelial adhesion and migration as well as increases expression of class II MHC and promotes shedding of endothelial 'microparticles' (EMP). In this review we examine interactions between cytokines/chemokines, activated leukocytes, adhesion molecules and activated CEC in the pathogenesis of BBB failure in MS.

T helper cell type 1 (Th1), Th2 and Th17 responses to myelin basic protein and disease activity in multiple sclerosis

“…7,15 The source of IL-17 production in wild-type mice with EAE appears to be almost exclusively Th17 cells, the presence of which has been demonstrated in the central nervous system as well as in the superficial lymph nodes. 16 IL-10 is thought to protect against disruption of the blood-brain barrier 17 and the development of EAE in mice. [18][19][20] In proteolipid protein-stimulated cultures, a higher production of IL-10 was observed in cultures from patients whose MS was in remission, compared with cultures from either patients undergoing acute MS attacks or control subjects.…”

Intravenous immunoglobulins contain naturally occurring antibodies that mimic antineutrophil cytoplasmic antibodies and activate neutrophils in a TNFα-dependent and Fc-receptor–independent way

“…Pre-existing alterations of the cerebral microvasculature or site-specific alterations of endothelial cells may contribute to the preferential recruitment of neutrophils to the meninges. Alterations of the vascular blood brain barrier (BBB) have been demonstrated in various neurologic conditions frequently treated with IVIg including multiple sclerosis, 59 GuillainBarré syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), and other polyneuropathies 60 but also in migraine, 60 which has previously been reported to be a risk factor for IVIg-associated aseptic meningitis 28 ; BBB dysfunction is also discussed in systemic lupus with central nervous system (CNS) involvement. 61 In addition, alterations of the chemokine and cytokine profiles linked to the underlying autoimmune condition or the IVIg therapy itself may be involved in priming and recruitment of neutrophils.…”

Resident Endothelial Cells Surrounding Damaged Arterial Endothelium Reendothelialize the Lesion

“…Although many diseases [1][2][3][4][5][6][7][8] involve endothelial damage in pathophysiological features, and new treatments of such diseases are already targeted at the endothelial repair, little is known about how the damaged endothelium is reconstructed at the cellular level. To our knowledge, this is the first study to clearly demonstrate that resident ECs adjacent to the lesion mostly, if not exclusively, restore the endothelium by elongation, migration, and proliferation.…”

“…Endothelial damage of the cerebral artery is a key mechanism involved in the pathophysiology of various brain diseases, including stroke, atherosclerosis, 1 diabetes mellitus, 2 dyslipidemia, 3 hypertension, 4 vasculitis, 5 multiple sclerosis, 6 radiation necrosis, 7 and drug adverse effects. 8 Some markers of endothelial damage are good indicators for the future incidence of cardiovascular events, including stroke.…”