The Blood-Brain Barrier

  1. Multiple Sclerosis Serum downregulates Occludin and VE-Cadherin expression in cultured Endothelial Cells
    Multiple Sclerosis, 1 June 2003, vol. 9, no. 3, pp. 235-238(4)

  2. Human Endothelial Cell presentation of Antigen and the homing of Memory/Effector T-Cells to skin
    Ann N Y Acad Sci 2001 Sep;941:12-25

  3. Growth Factors, Cytokines, Chemokines and NeuroPeptides in the modeling of T-Cells
    In Vivo 2002 Sep-Oct;16(5):365-86

  4. Ca2+ signaling and membrane potential in Descending Vasa Recta Pericytes and Endothelia
    Am J Physiol Renal Physiol 2002 Oct;283(4):F852-60

  5. Central Nervous System PeriVascular Cells are ImmunoRegulatory Cells that connect the CNS with the Peripheral Immune System
    Glia 2001 Nov;36(2):156-64

  6. AntiInflammatory mechanisms in the Vascular Wall
    Circ Res 2001 May 11;88(9):877-87

  7. Adhesion Receptors of Vascular Smooth Muscle Cells and their functions
    CardioVasc Res 2001 Dec;52(3):372-86

  8. IntraCerebral regulation of Immune responses
    Ann Med 2001 Nov;33(8):510-5

  9. Diversity within Pericytes
    Clin Exp Pharmacol Physiol 2000 Oct;27(10):842-6

  10. Leukocyte traffic in the Central Nervous System: the participants and their roles
    Semin Immunol 1999 Apr;11(2):125-37

  11. Interferon-beta (IFN-ß) -1a and IFN-ß-1b block IFN-gamma-induced disintegration of Endothelial junction integrity and barrier
    Endothelium 2003;10(6):299-307

  12. Persistent Endothelial abnormalities and Blood-Brain Barrier leak in Primary and Secondary/Progressive Multiple Sclerosis
    NeuroPathol Appl NeuroBiol 2007 Feb;33(1):86-98


Multiple Sclerosis Serum Downregulates Occludin And VE-Cadherin Expression In Cultured Endothelial Cells

Minagar A, Ostanin D, Long A.C, Jennings M, Kelley R.E, Sasaki M, Alexander J.S
Multiple Sclerosis, 1 June 2003, vol. 9, no. 3, pp. 235-238(4)
Louisiana State University Health Sciences Center, Departments of Neurology, Molecular and Cellular Physiology, Shreveport, LA, 71130-3932, USA
PMID# 12814168

Disruption of the Blood-Brain Barrier (BBB) and TransEndothelial Migration of Inflammatory Cells are crucial steps in the development of DeMyelinating lesions in Multiple Sclerosis (MS).

Occludin and Vascular Endothelial-Cadherin (VE-Cadherin) are two major components of the Tight Junctions (TJs) in the Brain MicroVasculature that help to create the BBB.

In the present study, we investigated the effect of Serum from MS patients on the expression of these two junctional markers and on the Endothelial integrity.

Serum from six MS patients in exacerbation, six in remission, and six normal controls (10% by volume) was incubated with cultured Endothelial Cells, and the expression of Occludin and VE-Cadherin was measured by ImmunoBlotting.

Serum from MS patients in exacerbation significantly reduced the expression of Occludin and VE-Cadherin compared with patients in remission and normal controls.

This disintegrating effect was more pronounced for Occludin than for VE-Cadherin.

We assume that the elevation in Cytokines or other Serum-soluble factors in MS patients in exacerbation likely provokes downregulation of Occludin and VE-Claudins.

This downregulation of TJs proteins may, therefore, contribute to the disruption of the BBB in this condition.


Human Endothelial Cell Presentation Of Antigen And The Homing Of Memory/Effector T-Cells To Skin

Pober JS, Kluger MS, Schechner JS
Ann N Y Acad Sci. 2001 Sep;941:12-25
Yale University School of Medicine, Department of Dermatology, New Haven, Connecticut 06510, USA
PMID# 11594565

Dermal MicroVascular Endothelial Cells (A HREF="gloss1-g.html#Ependymal">ECs) form a continuous lining that normally bars blood-borne T-Lymphocytes from entering the skin.

But, as part of the response to foreign Antigen, Dermal ECs undergo alterations in their surface proteins so as to provide signals to circulating T-Cells that lead to their activation and recruitment.

Several observations suggest that human Dermal MicroVascular ECs may help initiate cutaneous Immune reactions by presentation of cognate Antigens to circulating T-Memory Cells:

  1. Antigen-specific inflammatory responses in the skin, as in other organs, involve accumulation of Memory and Effector T-Cell populations that are enriched in cells specific for the eliciting Antigen
  2. Recall responses to IntraDermal protein Antigens in the skin start very rapidly within two hours of challenge
  3. Dermal MicroVascular ECs in humans and other large mammals basally display high levels of Class I and Class II MHC molecules, the only known purpose of which is to present AntiGenic Peptides to Lymphocytes
  4. The Lumen of Dermal Capillaries are narrower than the diameter of circulating T-Cells, ensuring surface contact
  5. Cultured human ECs effectively present Antigens to resting Memory T-Cells isolated from the circulation

Upon contact with activated T-Cells or their secreted products (Cytokines), Dermal ECs themselves become activated, increasing their capacity to recruit Memory and Effector T-Cell populations in an Antigen-independent manner.

Specifically, activated ECs express inducible Leukocyte Adhesion Molecules such as E-Selectin, ICAM-1, and VCAM-1; and several lines of evidence, including Neutralizing AntiBody experiments and gene knockouts, have supported a role of these molecules in T-Cell recruitment.

Dermal ECs have unique expression patterns of Adhesion Molecules that can determine the subsets of Memory T-Cells that are recruited into the skin.

For example, slow internalization of E-Selectin allows more persistent expression of this protein on the surface of dermal ECs, favoring interactions with CLA-1+ T-Cells.

VCAM-1 expression, normally confined to Venular EC may extend to Capillaries within the Dermal Papillae and contribute to Epidermal inflammation, recruiting alpha4beta7 Integrin-expressing T-Cells that also express the Cadherin-binding Integrin alphaEbeta7.

New models involving transplantation of normal and genetically modified human dermal ECs into ImmunoDeficient mice may be used to further explore these properties.


Growth Factors, Cytokines, Chemokines And NeuroPeptides In The Modeling Of T-Cells

Krueger GR, Marshall GR, Junker U, Schroeder H, Buja LM, Wang G
In Vivo 2002 Sep-Oct;16(5):365-86
University of Texas Houston Medical School, Department of Internal Medicine, Department of Pathology & Laboratory Medicine, 6431 Fannin St., MSB 2.246, Houston, Texas 77030, USA
PMID# 12494879

The T-Lymphocyte lineage, from initial Stem Cells to peripheral mature T-Cells, are members of a highly reactive Cell System engaged in the control of internal homoeostasis and body intactness.

It fulfills its commitments in close communication with the Cellular and Non-Cellular MicroEnvironment and with NeuroEndocrine Regulatory mechanisms.

Tools of such communication are various substances and compounds identified as Cytokines, Chemokines, Hormones, Growth Factors and NeuroPeptides.

Any pathogenetical model of functional aberration and disease development in the T-Cell System must take into account the delicate Network Control exerted by the above mechanisms.

In the following we describe the major players in the network regulation of T-Cell development and function as a basis for a computational modeling study.


Ca2+ Signaling And Membrane Potential In Descending Vasa Recta Pericytes And Endothelia

Rhinehart K, Zhang Z, Pallone TL
Am J Physiol Renal Physiol 2002 Oct;283(4):F852-60
University of Maryland School of Medicine, Division of Nephrology, Baltimore 21201-1595, USA
PMID# 12217877

We devised a method for removal of Pericytes from isolated Descending Vasa Recta (DVR).

After enzymatic digestion, aspiration of a Descending Vas Rectum into a MicroPipette strips the Pericytes from the Abluminal surface. Pericytes and denuded Endothelia can be recovered for separate study.

Using fura 2-loaded preparations, we demonstrated that 10 nM Angiotensin II (ANG II) elevates Pericyte IntraCellular Ca2+ concentration ([Ca2+](i)) and suppresses Endothelial [Ca2+](i).

The Anion transport blocker Probenecid helps retain fura 2 in the Pericyte cytoplasm.

DVR Endothelia were accessed for membrane potential measurement by perforated-patch whole cell recording by using the Pericyte-stripping technique and by turning nondigested vessels inside out with concentric MicroPipettes.

By either method of access, 10 nM ANG II depolarized (n = 20) and 100 nM Bradykinin hyperpolarized (n = 25) the Endothelia.

We conclude that isolated Endothelia and Pericytes remain functional for study of [Ca2+](i) responses and that ANG II and Bradykinin Receptors exist separately on each cell type.


Central Nervous System PeriVascular Cells Are ImmunoRegulatory Cells That Connect The CNS With The Peripheral Immune System

Williams K, Alvarez X, Lackner AA
Glia 2001 Nov;36(2):156-64
Harvard Medical School, Beth Israel Deaconess Medical Center, Division of Viral PathoGenesis, Department of Medicine, Boston, Massachusetts 02215, USA
PMID# 11596124

PeriVascular Cells are a heterogeneous population found in the Central Nervous System (CNS) and the Peripheral Nervous System (PNS).

Several terms are used for these cells, including PeriVascular Cells, PeriVascular Macrophages, PeriVascular Microglia, Fluorescent Granular Perithelial Cells (FGP), or Mato Cells.

Different terminology used may reflect subpopulations of PeriVascular Cells within different anatomic regions and experimental paradigms, NeuroPathological conditions, and species studied.

Different terminology also points to the lack of clear consensus of what cells are PeriVascular Cells in different disease states and models, especially with breakdown of the Blood-Brain Barrier (BBB).

Despite this, there is consensus that PeriVascular Cells, although a minor component of the CNS, are important ImmunoRegulatory Cells. PeriVascular Cells are bone marrow derived, continuously turn over in the CNS, and are found adjacent to CNS vessels.

Thus, they are potential sensors of CNS and Peripheral Immune System perturbations; are activated in models of CNS Inflammation, AutoImmune Disease, Neuronal Injury and Death; and are implicated as Phagocytic and PinoCytotic Cells in models of Stroke and Hypertension.

Recent evidence from our laboratory implicate PeriVascular Cells as primary targets of Human Immunodeficiency Virus (HIV) and Simian Immunodeficiency Virus (SIV) infection in the CNS of humans and macaques.

This article reviews current knowledge of PeriVascular Cells, including anatomic location and nomenclature and putative ImmunoRegulatory roles.

And, discusses new data on the infection of these cells by SIV, their accumulation after SIV infection, and a possible role of the Immune System in SIV Encephalitis.

Copyright 2001 Wiley-Liss, Inc.


AntiInflammatory Mechanisms In The Vascular Wall

Tedgui A, Mallat Z
Circ Res 2001 May 11;88(9):877-87
Institut National de la Sante et de la Recherche Medicale, INSERM U541 and Institut Federatif de Recherche "Circulation-Paris 7," Hopital Lariboisiere, Paris, France
PMID# 11348996

The role of Vascular Cells during inflammation is critical and is of particular importance in Inflammatory Diseases, including AtheroSclerosis, Ischemia/Reperfusion, and Septic Shock.

Research in Vascular Biology has progressed remarkably in the last decade, resulting in a better understanding of the Vascular Cell Responses to inflammatory stimuli.

Most of the Vascular Inflammatory Responses are mediated through the Ikappaß/Nuclear factor-kappaß System.

Much recent work shows that Vascular inflammation can be limited by AntInflammatory CounteRegulatory mechanisms that maintain the integrity and homeostasis of the Vascular Wall.

The AntiInflammatory mechanisms in the Vascular Wall involve AntiInflammatory external signals and IntraCellular Mediators.

The AntiInflammatory external signals include the AntiInflammatory Cytokines, Transforming Growth Factor-ß, InterLeukin-10 and InterLeukin-1 Receptor Antagonist, HDL, as well as some angiogenic and Growth Factors.

Physiological laminar shear stress is of particular importance in protecting Endothelial Cells against inflammatory activation. Its effects are partly mediated through NO production.

Finally, endogenous cytoprotective genes or Nuclear Receptors, such as the Peroxisome proliferator-activated Receptors, can be expressed by Vascular Cells in response to ProInflammatory stimuli to limit the inflammatory process and the injury.


Adhesion Receptors Of Vascular Smooth Muscle Cells And Their Functions

Moiseeva EP
CardioVasc Res 2001 Dec;52(3):372-86
University of Leicester, Department of Medicine, Division of Cardiology, Clinical Sciences Wing, Glenfield General Hospital, LE3 9QP, Leicester, UK
PMID# 11738054

Vascular Smooth Muscle Cells (SMCs) are present in several phenotypic states in blood vessels. They show a high degree of plasticity, undergoing rapid and reversible phenotypic changes in response to environmental stresses and Vascular Injury.

Thereby, SMCs play an important role in development of AtheroSclerosis and Restenosis after Angioplasty and Coronary Bypass grafting.

Many functions of SMCs, such as Adhesion, Migration, Proliferation, Contraction, Differentiation and Apoptosis are determined by surface Adhesion Receptors involved in cell-cell binding and interactions between cells and ExtraCellular Matrix (ECM) proteins.

Some cell Adhesion Receptors are involved in IntraCellular Signalling and participate in Cellular Response to different stimuli.

The Adhesion Receptors of Vascular SMCs discussed here include the ECM Adhesion Receptors Integrins, alpha-DystroGlycan and Syndecans, as well as the Cell-Cell Adhesion Receptors Cadherins and cell Adhesion Molecules.

This review is intended to provide a generalized overview of the receptors expressed in Vascular SMCs in relation to their functions and implications for Vascular pathology.


IntraCerebral Regulation Of Immune Responses

Aloisi F, Ambrosini E, Columba-Cabezas S, Magliozzi R, Serafini B
Ann Med 2001 Nov;33(8):510-5
Istituto Superiore di Sanita, Laboratory of Organ and System PathoPhysiology, Rome, Italy
PMID# 11730157

Major progress has been made over the last years in our understanding of the mechanisms underlying Immune privilege and Immune surveillance of the Central Nervous System (CNS).

Once considered a passive process relying only on physical barriers, Immune privilege is now viewed as a more complex phenomenon, which involves active regulation of Immune reactivity by the CNS MicroEnvironment.

Evidence has also emerged that the Immune System continuously and effectively patrols the CNS and that dysregulated Immune Responses against CNS-associated (Exogenous or Self) Antigens are involved in the pathogenesis of various Neurological Diseases.

In this article we shall briefly review current knowledge of how the Immune Response is regulated locally in the CNS and which cell types and molecular mechanisms are involved in shaping IntraCerebral Immune Responses.


Diversity Within Pericytes

Sims DE
Clin Exp Pharmacol Physiol. 2000 Oct;27(10):842-6
University of Prince Edward Island, College of Veterinary Medicine, Department of Anatomy and Physiology, Charlottetown, Canada
PMID# 11022980

Pericytes are cells of MicroVessels (Arterioles, Capillaries and Venules) that wrap around Endothelial Cells. They are most abundant on Venules and are common on Capillaries.

The Pericyte population is highly variable between different tissues and organs, probably in a manner reflecting PostArteriolar Hydrostatic pressures.

Pericytes are more abundant in the distal legs and feet, again suggesting a hydrostatic pressure-driven mechanical role for Pericytes as protectors of MicroVessel Wall integrity.

Pericyte alteration or degeneration is linked directly with MicroAngiopathy in Diabetes, Scleroderma, Hypertension, Dementias and, possibly, inappropriate calcification of blood vessels.

Pericytes are functionally codependent on Endothelial Cells. Each cell type influences each others' Mitotic rate and probably phenotypic expression.

Pericytes are not randomly located around MicroVessels. Instead, they are located adjacent to or over Endothelial Cell Junctions of Venules and especially over gaps between Endothelial Cells during inflammation.

Pericytes are emerging as essential components of the MicroVessel Wall, with metabolic, signalling and mechanical roles to support the Endothelia Cell.


Leukocyte Traffic In The Central Nervous System: The Participants And Their Roles

Hickey WF
Semin Immunol 1999 Apr;11(2):125-37
Dartmouth Medical School, Department of Pathology, DHMC, Lebanon, NH 03756, USA
PMID# 10329499

While the Central Nervous System has long been considered Immunologically privileged, over the past decade it has become evident that a wide variety of Leukocyte types traffic through the Nervous System.

It is also apparent that the rules governing the trafficking of these disparate cell types are different for each. Some arrive, and probably depart, continuously as part of normal physiology.

Others only appear to seek a specific Antigen or in response to tissue damage.

In this review the nature and function of individual cell types are discussed and our current knowledge regarding the parameters governing their entry into the CNS is examined.

Copyright 1999 Academic Press.


Interferon-beta (IFN-ß) -1a And IFN-ß-1b Block IFN-gamma-Induced Disintegration Of Endothelial Junction Integrity And Barrier

Minagar A, Long A, Ma T, Jackson TH, Kelley RE, Ostanin DV, Sasaki M, Warren AC, Jawahar A, Cappell B, Alexander JS
Endothelium 2003;10(6):299-307
Louisiana State University Health Sciences Center, Department of Neurology, Shreveport, Louisiana 71130, USA
PMID# 14741845

Recent clinical trials indicate the efficacy of Interferon-beta (IFN-ß) -1b in reducing relapse rate in Relapsing/Remitting Multiple Sclerosis (MS), whereas a surge of IFN-γ precedes and provokes acute relapses.

Disruption of the Cerebral Endothelial barrier and TransEndothelial migration of inflammatory cell migration into the Brain play a significant role in pathogenesis of MS and may be driven by this surge in IFN-γ.

However, the molecular mechanisms underlying the beneficial effects of IFN-ß 1b against the deleterious effects of IFN-γ on the barrier formed by the junctional proteins remain to be characterized.

The authors investigated the effects of IFN-ß-1b, IFN-ß-1a, and IFN-γ on the integrity of two Endothelial junctional proteins, Occludin and Vascular Endothelial-Cadherin (VE-Cadherin).

Human Umbilical Vein Endothelial Cell (HUVEC) layers were treated with IFN-ß-1b, IFN-ß-1a, IFN-γ, IFN-ß-1b plus IFN-γ, or IFN-ß-1a plus IFN-γ.

IFN-ß-1b, IFN-ß-1a, and IFN-γ effects on Occludin and VE-Cadherin integrity and electrical resistance were assessed by Western blotting and immunofluorescence.

IFN-γ significantly reduced Occludin expression and produced gaps in Endothelial Monolayers. VE-Cadherin expression was decreased to a lesser extent in Endothelia Cells exposed to IFN-γ.

IFN-ß-1b significantly attenuated the IFN-γ-induced decrease in Occludin and VE-Cadherin expression. The protective effects of IFN-ß-1a on IFN-γ-treated Endothelial Cells were similar to those of IFN-ß-1b.

IFN-γ also significantly reduced Endothelial Monolayer electrical resistance; this effect was blocked by either IFN-ß-1a or IFN-ß-1b.

IFN-ß-1a and IFN-ß-1b effectively prevent the IFN-γ-induced disintegration of the Endothelial tight junctions and sustain barrier against the effects of IFN-γ.

The protective effects of IFN-ß on Occludin and VE-Cadherin stability appear to represent molecular mechanisms for the therapeutic effects of the IFN-ß on Blood-Brain Barrier in MS.

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