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Immune responses at brain barriers and implications for brain development and neurological function in later life.

Stolp HB, Liddelow SA, Sá-Pereira I, Dziegielewska KM, Saunders NR - Front Integr Neurosci (2013)

Bottom Line: This signaling system appears to change both with normal ageing, and during disease.Here we review the many elements that contribute to brain barrier functions and how they respond to inflammation, particularly during development and aging.The implications of inflammation-induced barrier dysfunction for brain development and subsequent neurological function are also discussed.

View Article: PubMed Central - PubMed

Affiliation: Department of Perinatal Imaging and Health, King's College London London, UK ; Department of Physiology, Anatomy and Genetics, University of Oxford Oxford, UK.

ABSTRACT
For a long time the brain has been considered an immune-privileged site due to a muted inflammatory response and the presence of protective brain barriers. It is now recognized that neuroinflammation may play an important role in almost all neurological disorders and that the brain barriers may be contributing through either normal immune signaling or disruption of their basic physiological mechanisms. The distinction between normal function and dysfunction at the barriers is difficult to dissect, partly due to a lack of understanding of normal barrier function and partly because of physiological changes that occur as part of normal development and ageing. Brain barriers consist of a number of interacting structural and physiological elements including tight junctions between adjacent barrier cells and an array of influx and efflux transporters. Despite these protective mechanisms, the capacity for immune-surveillance of the brain is maintained, and there is evidence of inflammatory signaling at the brain barriers that may be an important part of the body's response to damage or infection. This signaling system appears to change both with normal ageing, and during disease. Changes may affect diapedesis of immune cells and active molecular transfer, or cause rearrangement of the tight junctions and an increase in passive permeability across barrier interfaces. Here we review the many elements that contribute to brain barrier functions and how they respond to inflammation, particularly during development and aging. The implications of inflammation-induced barrier dysfunction for brain development and subsequent neurological function are also discussed.

No MeSH data available.


Related in: MedlinePlus

Protective barriers of the brain. The collective term “blood-brain barrier” is used to describe four main interfaces between the central nervous system and the periphery. (i) The blood-brain barrier proper formed by tight junctions between the endothelial cells of the cerebral vasculature. It is thought that pericytes (peri.) are sufficient to induce some barrier characteristics in endothelial cells, while astrocytes (astro.) are able to maintain the integrity of the blood-brain barrier postnatally. (ii) The blood-CSF barrier formed by tight junctions between epithelial cells of the choroid plexus epithelial cells (note the plexus vasculature is fenestrated). Resident epiplexus (epi.) immune cells are present on the CSF-surface of the plexus epithelium. (iii) The outer CSF-brain barrier and the level of the pia arachnoid, formed by tight junctions between endothelial cells of the arachnoid vessels. (iv) The inner CSF-brain barrier, present only in early development, formed by strap junctions between the neuroependymal cells lining the ventricular surfaces. In the adult this barrier is no longer present. Both the blood-brain and CSF-brain barriers extend down the spinal cord. The CSF-filled ventricular system is depicted in blue, while CNS brain tissue is in brown. The lateral ventricular choroid plexuses are shown in red. Abbreviations: astro, astrocyte; bv, blood vessel; cpec, choroid plexus epithelial cell; csf, cerebrospinal fluid; peri, pericytes.
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Figure 1: Protective barriers of the brain. The collective term “blood-brain barrier” is used to describe four main interfaces between the central nervous system and the periphery. (i) The blood-brain barrier proper formed by tight junctions between the endothelial cells of the cerebral vasculature. It is thought that pericytes (peri.) are sufficient to induce some barrier characteristics in endothelial cells, while astrocytes (astro.) are able to maintain the integrity of the blood-brain barrier postnatally. (ii) The blood-CSF barrier formed by tight junctions between epithelial cells of the choroid plexus epithelial cells (note the plexus vasculature is fenestrated). Resident epiplexus (epi.) immune cells are present on the CSF-surface of the plexus epithelium. (iii) The outer CSF-brain barrier and the level of the pia arachnoid, formed by tight junctions between endothelial cells of the arachnoid vessels. (iv) The inner CSF-brain barrier, present only in early development, formed by strap junctions between the neuroependymal cells lining the ventricular surfaces. In the adult this barrier is no longer present. Both the blood-brain and CSF-brain barriers extend down the spinal cord. The CSF-filled ventricular system is depicted in blue, while CNS brain tissue is in brown. The lateral ventricular choroid plexuses are shown in red. Abbreviations: astro, astrocyte; bv, blood vessel; cpec, choroid plexus epithelial cell; csf, cerebrospinal fluid; peri, pericytes.

Mentions: The brain develops and functions within a well-defined internal environment, which is determined by regulation of interchange between the main compartments of the CNS, brain, cerebrospinal fluid (CSF) and the blood, by a combination of physical and functional mechanisms. These mechanisms, often referred to by the generic term of “blood-brain barrier,” are present at three main interfaces in the brain, both in the adult and in the embryo, although there are some important age-related differences between them. These interfaces, illustrated in Figure 1, are: (i) the blood-brain barrier proper at the level of the cerebral endothelial cells, (ii) the blood-CSF barrier at the epithelial cells of the choroid plexuses within the four cerebral ventricles and (iii) the pia arachnoid. There is also an additional barrier interface (iv), present only in the early brain development, between the CSF and the brain interstitial fluid. In both the adult and developing brain the essential morphological feature of the blood-brain barrier proper (i) lies in the presence of tight junctions between the cerebral endothelial cells of the vasculature of the brain both within the parenchyma and over the surface in the pia-arachnoid. Compared with other blood vessels there is also a lack of pinocytotic vesicles in the cerebral endothelial cells, although there is some evidence that they may be more frequent in endothelial cells in the developing brain (Dziegielewska et al., 1979). In the choroid plexuses (ii), tight junctions are found between intimately apposed epithelial cells. The tight junctions prevent the intercellular (paracellular) passage of small molecules even in the very early stages of the developing brain (Ek et al., 2003, 2006). An important functional consequence of this is that the presence of tight intercellular junctions enables the cerebral endothelial cells and choroid plexus epithelial cells to have effective one-way transport mechanisms (Liddelow et al., 2009; Ek et al., 2010), which are essential for establishing and maintaining the internal environment of the brain separate from that of the rest of the organism. The morphology of the barrier interface over the surface of the brain (iii) is more complex during early development. Thus, in addition to the adult barrier of tight junctions linking the endothelial cells of blood vessels in the pia arachnoid, there is a wide array of specialized intercellular junctions over the pial surface of the brain, which has been described in the rat embryo (Balslev et al., 1997). From embryonic day 14 (E14), the progressive appearance of distinct junctional structures between the glial end feet was observed. Analysis of albumin distribution at the electron microscopic level suggested that these junctions may contribute to restriction of diffusion between the subarachnoid space and the brain interstitial space. However, at E12 and E14, the intercellular basis for this barrier appeared incomplete, so it was suggested that basement membrane may be an important component of this functionally effective barrier interface (Balslev et al., 1997). At the CSF-brain interface (iv) lining the cerebral ventricles, early in embryonic development, the cells of the neuroependyma (neuroepithelium) are linked by strap junctions (Møllgård et al., 1987), which are an effective limitation to intercellular diffusion at least for large molecules (Fossan et al., 1985). During brain development these strap junctions disappear, and in the adult the cells lining the ventricles (ependymal cells) are linked by gap junctions (Møllgård et al., 1987) that do not provide a significant restraint to diffusion of even large molecules from CSF to brain interstitial fluid (Fossan et al., 1985). Consequently, in the embryonic brain only, there appear to be barrier mechanisms that restrict entry of proteins from CSF into the brain interstitial fluid. These proteins may be contributing to some aspects of early brain development such as neurogenesis and cellular differentiation in the ventricular zone (VZ), either by uptake of individual proteins or ligands bound to them (see below).


Immune responses at brain barriers and implications for brain development and neurological function in later life.

Stolp HB, Liddelow SA, Sá-Pereira I, Dziegielewska KM, Saunders NR - Front Integr Neurosci (2013)

Protective barriers of the brain. The collective term “blood-brain barrier” is used to describe four main interfaces between the central nervous system and the periphery. (i) The blood-brain barrier proper formed by tight junctions between the endothelial cells of the cerebral vasculature. It is thought that pericytes (peri.) are sufficient to induce some barrier characteristics in endothelial cells, while astrocytes (astro.) are able to maintain the integrity of the blood-brain barrier postnatally. (ii) The blood-CSF barrier formed by tight junctions between epithelial cells of the choroid plexus epithelial cells (note the plexus vasculature is fenestrated). Resident epiplexus (epi.) immune cells are present on the CSF-surface of the plexus epithelium. (iii) The outer CSF-brain barrier and the level of the pia arachnoid, formed by tight junctions between endothelial cells of the arachnoid vessels. (iv) The inner CSF-brain barrier, present only in early development, formed by strap junctions between the neuroependymal cells lining the ventricular surfaces. In the adult this barrier is no longer present. Both the blood-brain and CSF-brain barriers extend down the spinal cord. The CSF-filled ventricular system is depicted in blue, while CNS brain tissue is in brown. The lateral ventricular choroid plexuses are shown in red. Abbreviations: astro, astrocyte; bv, blood vessel; cpec, choroid plexus epithelial cell; csf, cerebrospinal fluid; peri, pericytes.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3750212&req=5

Figure 1: Protective barriers of the brain. The collective term “blood-brain barrier” is used to describe four main interfaces between the central nervous system and the periphery. (i) The blood-brain barrier proper formed by tight junctions between the endothelial cells of the cerebral vasculature. It is thought that pericytes (peri.) are sufficient to induce some barrier characteristics in endothelial cells, while astrocytes (astro.) are able to maintain the integrity of the blood-brain barrier postnatally. (ii) The blood-CSF barrier formed by tight junctions between epithelial cells of the choroid plexus epithelial cells (note the plexus vasculature is fenestrated). Resident epiplexus (epi.) immune cells are present on the CSF-surface of the plexus epithelium. (iii) The outer CSF-brain barrier and the level of the pia arachnoid, formed by tight junctions between endothelial cells of the arachnoid vessels. (iv) The inner CSF-brain barrier, present only in early development, formed by strap junctions between the neuroependymal cells lining the ventricular surfaces. In the adult this barrier is no longer present. Both the blood-brain and CSF-brain barriers extend down the spinal cord. The CSF-filled ventricular system is depicted in blue, while CNS brain tissue is in brown. The lateral ventricular choroid plexuses are shown in red. Abbreviations: astro, astrocyte; bv, blood vessel; cpec, choroid plexus epithelial cell; csf, cerebrospinal fluid; peri, pericytes.
Mentions: The brain develops and functions within a well-defined internal environment, which is determined by regulation of interchange between the main compartments of the CNS, brain, cerebrospinal fluid (CSF) and the blood, by a combination of physical and functional mechanisms. These mechanisms, often referred to by the generic term of “blood-brain barrier,” are present at three main interfaces in the brain, both in the adult and in the embryo, although there are some important age-related differences between them. These interfaces, illustrated in Figure 1, are: (i) the blood-brain barrier proper at the level of the cerebral endothelial cells, (ii) the blood-CSF barrier at the epithelial cells of the choroid plexuses within the four cerebral ventricles and (iii) the pia arachnoid. There is also an additional barrier interface (iv), present only in the early brain development, between the CSF and the brain interstitial fluid. In both the adult and developing brain the essential morphological feature of the blood-brain barrier proper (i) lies in the presence of tight junctions between the cerebral endothelial cells of the vasculature of the brain both within the parenchyma and over the surface in the pia-arachnoid. Compared with other blood vessels there is also a lack of pinocytotic vesicles in the cerebral endothelial cells, although there is some evidence that they may be more frequent in endothelial cells in the developing brain (Dziegielewska et al., 1979). In the choroid plexuses (ii), tight junctions are found between intimately apposed epithelial cells. The tight junctions prevent the intercellular (paracellular) passage of small molecules even in the very early stages of the developing brain (Ek et al., 2003, 2006). An important functional consequence of this is that the presence of tight intercellular junctions enables the cerebral endothelial cells and choroid plexus epithelial cells to have effective one-way transport mechanisms (Liddelow et al., 2009; Ek et al., 2010), which are essential for establishing and maintaining the internal environment of the brain separate from that of the rest of the organism. The morphology of the barrier interface over the surface of the brain (iii) is more complex during early development. Thus, in addition to the adult barrier of tight junctions linking the endothelial cells of blood vessels in the pia arachnoid, there is a wide array of specialized intercellular junctions over the pial surface of the brain, which has been described in the rat embryo (Balslev et al., 1997). From embryonic day 14 (E14), the progressive appearance of distinct junctional structures between the glial end feet was observed. Analysis of albumin distribution at the electron microscopic level suggested that these junctions may contribute to restriction of diffusion between the subarachnoid space and the brain interstitial space. However, at E12 and E14, the intercellular basis for this barrier appeared incomplete, so it was suggested that basement membrane may be an important component of this functionally effective barrier interface (Balslev et al., 1997). At the CSF-brain interface (iv) lining the cerebral ventricles, early in embryonic development, the cells of the neuroependyma (neuroepithelium) are linked by strap junctions (Møllgård et al., 1987), which are an effective limitation to intercellular diffusion at least for large molecules (Fossan et al., 1985). During brain development these strap junctions disappear, and in the adult the cells lining the ventricles (ependymal cells) are linked by gap junctions (Møllgård et al., 1987) that do not provide a significant restraint to diffusion of even large molecules from CSF to brain interstitial fluid (Fossan et al., 1985). Consequently, in the embryonic brain only, there appear to be barrier mechanisms that restrict entry of proteins from CSF into the brain interstitial fluid. These proteins may be contributing to some aspects of early brain development such as neurogenesis and cellular differentiation in the ventricular zone (VZ), either by uptake of individual proteins or ligands bound to them (see below).

Bottom Line: This signaling system appears to change both with normal ageing, and during disease.Here we review the many elements that contribute to brain barrier functions and how they respond to inflammation, particularly during development and aging.The implications of inflammation-induced barrier dysfunction for brain development and subsequent neurological function are also discussed.

View Article: PubMed Central - PubMed

Affiliation: Department of Perinatal Imaging and Health, King's College London London, UK ; Department of Physiology, Anatomy and Genetics, University of Oxford Oxford, UK.

ABSTRACT
For a long time the brain has been considered an immune-privileged site due to a muted inflammatory response and the presence of protective brain barriers. It is now recognized that neuroinflammation may play an important role in almost all neurological disorders and that the brain barriers may be contributing through either normal immune signaling or disruption of their basic physiological mechanisms. The distinction between normal function and dysfunction at the barriers is difficult to dissect, partly due to a lack of understanding of normal barrier function and partly because of physiological changes that occur as part of normal development and ageing. Brain barriers consist of a number of interacting structural and physiological elements including tight junctions between adjacent barrier cells and an array of influx and efflux transporters. Despite these protective mechanisms, the capacity for immune-surveillance of the brain is maintained, and there is evidence of inflammatory signaling at the brain barriers that may be an important part of the body's response to damage or infection. This signaling system appears to change both with normal ageing, and during disease. Changes may affect diapedesis of immune cells and active molecular transfer, or cause rearrangement of the tight junctions and an increase in passive permeability across barrier interfaces. Here we review the many elements that contribute to brain barrier functions and how they respond to inflammation, particularly during development and aging. The implications of inflammation-induced barrier dysfunction for brain development and subsequent neurological function are also discussed.

No MeSH data available.


Related in: MedlinePlus