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Human glial cell regulation of immune response
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ABSTRACTS
Human glial cell regulation of immune response
Jack P. Antel and Voon Wee Yong (Montreal Neurological Institute, Montreal, Canada) Bi-directional interactions between glial cells and immune cells entering the central nervous system (CNS) may serve as an important regulatory mechanism which can influence the duration a n d / o r effector capability of a CNS target-directed immune response. To examine immuneregulatory properties of human adult glia, astrocytes and microglia were isolated from surgically resected tissue and established in dissociated cell cultures. An increased proportion of human adult astrocytcs under 'basal' culture conditions expressed immunoeytochemically detectable levels of major histocompatibility complex (MHC) class II molecules compared to rodent-derived astrocytes or to fetal human tissue-derived astrocytes. T-Interferon augmented both MHC expression and cell proliferation (BrdU incorporation) of all human astrocytes, whereas rodent cell proliferation was inhibited. The frequency and intensity of MHC expression by human adult astrocytes in vitro was, however, less than that observed for microglial cells contained within the same cultures. Mixed glial cell cultures (microglia, astrocytes) and enriched microglial cultures were able to stimulate allo-lymphocyte responses (mixed lymphocyte reaction), indicating the functional effect of the observed MHC class II expression. Our results suggest that MHC class II expression may occur more readily in human adult glial cells under the same conditions relative to younger donors and non-human-derived cells. These glial cells, particularly microglia, appear capable of functional interactions with T cells.
The role of microglia in 'bystander' injury in the central nervous system
Carol A. Co#on (Department of Physiology, Georgetown Uniz~ersity Medical School, Washington, DC, USA) Because neutrophils and macrophages have been described as the non-specific 'killers' in an inflammatory response, the possibility of 'bystander injury', i.e., damage to normal, adjacent cells, produced during the response, has been raised. Can the CNS macrophage, the microglia, produce injury as a result of its normal functioning? Certain microglial products may be damaging to adjacent glia and neurons. For example, cultured neonatal rat or mouse microglia produce reactive oxygen species (ROS) (i.e., superoxide anion) when stimulated. ROS induces lipid peroxidation and other damage to cellular and ECM components. However, abundant anti-oxidant mechanisms ordinarily limit the cellular changes. Under certain circumstances, microglia can produce greater quantities of ROS. Treatment with a//3 or ~, interferon or an increase in the extracellular K + concentration potentiates the stimulated production of ROS. Microglial superoxide anion production is also abnormally high in certain pathological conditions. Microglia cultured from the trisomy 16 mouse, a model for Down syndrome, produce a greater amount of ROS than normal littermates. Under these conditions, anti-oxidant defences may be unable to prevent oxidative damage, particularly with continued exposure. Microglia also produce metalloproteases and cytokines such as interleukin (IL)-I. An abnormally high production of both resting and stimulated IL-1 is seen in microglia cultured from the trisomy 16 mouse compared to their normal littermates. Continued exposure to abnormal levels of IL-1 could also produce injury, in that, inappropriate cellular responses are initiated. Thus, microglia do not necessarily have to kill
ABSTRACTS
Human glial cell regulation of immune response
Jack P. Antel and Voon Wee Yong (Montreal Neurological Institute, Montreal, Canada) Bi-directional interactions between glial cells and immune cells entering the central nervous system (CNS) may serve as an important regulatory mechanism which can influence the duration a n d / o r effector capability of a CNS target-directed immune response. To examine immuneregulatory properties of human adult glia, astrocytes and microglia were isolated from surgically resected tissue and established in dissociated cell cultures. An increased proportion of human adult astrocytcs under 'basal' culture conditions expressed immunoeytochemically detectable levels of major histocompatibility complex (MHC) class II molecules compared to rodent-derived astrocytes or to fetal human tissue-derived astrocytes. T-Interferon augmented both MHC expression and cell proliferation (BrdU incorporation) of all human astrocytes, whereas rodent cell proliferation was inhibited. The frequency and intensity of MHC expression by human adult astrocytes in vitro was, however, less than that observed for microglial cells contained within the same cultures. Mixed glial cell cultures (microglia, astrocytes) and enriched microglial cultures were able to stimulate allo-lymphocyte responses (mixed lymphocyte reaction), indicating the functional effect of the observed MHC class II expression. Our results suggest that MHC class II expression may occur more readily in human adult glial cells under the same conditions relative to younger donors and non-human-derived cells. These glial cells, particularly microglia, appear capable of functional interactions with T cells.
The role of microglia in 'bystander' injury in the central nervous system
Carol A. Co#on (Department of Physiology, Georgetown Uniz~ersity Medical School, Washington, DC, USA) Because neutrophils and macrophages have been described as the non-specific 'killers' in an inflammatory response, the possibility of 'bystander injury', i.e., damage to normal, adjacent cells, produced during the response, has been raised. Can the CNS macrophage, the microglia, produce injury as a result of its normal functioning? Certain microglial products may be damaging to adjacent glia and neurons. For example, cultured neonatal rat or mouse microglia produce reactive oxygen species (ROS) (i.e., superoxide anion) when stimulated. ROS induces lipid peroxidation and other damage to cellular and ECM components. However, abundant anti-oxidant mechanisms ordinarily limit the cellular changes. Under certain circumstances, microglia can produce greater quantities of ROS. Treatment with a//3 or ~, interferon or an increase in the extracellular K + concentration potentiates the stimulated production of ROS. Microglial superoxide anion production is also abnormally high in certain pathological conditions. Microglia cultured from the trisomy 16 mouse, a model for Down syndrome, produce a greater amount of ROS than normal littermates. Under these conditions, anti-oxidant defences may be unable to prevent oxidative damage, particularly with continued exposure. Microglia also produce metalloproteases and cytokines such as interleukin (IL)-I. An abnormally high production of both resting and stimulated IL-1 is seen in microglia cultured from the trisomy 16 mouse compared to their normal littermates. Continued exposure to abnormal levels of IL-1 could also produce injury, in that, inappropriate cellular responses are initiated. Thus, microglia do not necessarily have to kill