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Immune responses to non-tumor antigens in the central nervous system.

Huber AK, Duncker PC, Irani DN - Front Oncol (2014)

Bottom Line: The central nervous system (CNS), once viewed as an immune-privileged site protected by the blood-brain barrier (BBB), is now known to be a dynamic immunological environment through which immune cells migrate to prevent and respond to events such as localized infection.During these responses, endogenous glial cells, including astrocytes and microglia, become highly reactive and may secrete inflammatory mediators that regulate BBB permeability and recruit additional circulating immune cells.Here, we discuss the various roles played by astrocytes, microglia, and infiltrating immune cells during host immunity to non-tumor antigens in the CNS, focusing first on bacterial and viral infections, and then turning to responses directed against self-antigens in the setting of CNS autoimmunity.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, University of Michigan Medical School , Ann Arbor, MI , USA.

ABSTRACT
The central nervous system (CNS), once viewed as an immune-privileged site protected by the blood-brain barrier (BBB), is now known to be a dynamic immunological environment through which immune cells migrate to prevent and respond to events such as localized infection. During these responses, endogenous glial cells, including astrocytes and microglia, become highly reactive and may secrete inflammatory mediators that regulate BBB permeability and recruit additional circulating immune cells. Here, we discuss the various roles played by astrocytes, microglia, and infiltrating immune cells during host immunity to non-tumor antigens in the CNS, focusing first on bacterial and viral infections, and then turning to responses directed against self-antigens in the setting of CNS autoimmunity.

No MeSH data available.


Related in: MedlinePlus

Orchestration of the immune response during viral infection of the CNS. With the BBB in a resting state (1), viruses can gain entry into the CNS by infecting peripheral nerves and traveling by anterograde axonal transport into the CNS, by infecting host immune cells in the periphery and using these cells as “Trojan horses” to carry them across the BBB, or by directly infecting BBB endothelial cells (2). Viral PAMPs then activate microglia, astrocytes, and oligodendrocytes (3). Microglia and astrocytes produce a range of anti-viral/pro-inflammatory cytokines, including type-I IFNs, IL-6, TNF-α, IL-12, IL-1α, and IL-1β (3). Astrocytes also produce MMP-3 and MMP-12 resulting in the up-regulation of adhesion molecules on endothelial cells (3). Interactions between adhesion molecules and neutrophils contribute to BBB breakdown via the production of MMP-9 and the disassembly of the tight junctions (4). DCs are seen in the CNS within several days and migrate to draining lymph nodes where they activate and expand virus-specific T cells (5). Chemokines produced by astrocytes are responsible for recruiting virus-specific CD4+ and CD8+ T cells as well as ASCs to the CNS (6). CD8+ T cells produce IFN-γ and lytic molecules, including granzyme B and perforin, to eliminate virus from astrocytes, while IFN-γ controls viral replication in oligodendrocytes (7). Virus-specific antibodies control virus replication in cells such as neurons via complement–independent, non-cytolytic mechanisms. These antibodies inhibit virus budding and replication, viral RNA transcription, and cell-to-cell virus spread.
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Figure 2: Orchestration of the immune response during viral infection of the CNS. With the BBB in a resting state (1), viruses can gain entry into the CNS by infecting peripheral nerves and traveling by anterograde axonal transport into the CNS, by infecting host immune cells in the periphery and using these cells as “Trojan horses” to carry them across the BBB, or by directly infecting BBB endothelial cells (2). Viral PAMPs then activate microglia, astrocytes, and oligodendrocytes (3). Microglia and astrocytes produce a range of anti-viral/pro-inflammatory cytokines, including type-I IFNs, IL-6, TNF-α, IL-12, IL-1α, and IL-1β (3). Astrocytes also produce MMP-3 and MMP-12 resulting in the up-regulation of adhesion molecules on endothelial cells (3). Interactions between adhesion molecules and neutrophils contribute to BBB breakdown via the production of MMP-9 and the disassembly of the tight junctions (4). DCs are seen in the CNS within several days and migrate to draining lymph nodes where they activate and expand virus-specific T cells (5). Chemokines produced by astrocytes are responsible for recruiting virus-specific CD4+ and CD8+ T cells as well as ASCs to the CNS (6). CD8+ T cells produce IFN-γ and lytic molecules, including granzyme B and perforin, to eliminate virus from astrocytes, while IFN-γ controls viral replication in oligodendrocytes (7). Virus-specific antibodies control virus replication in cells such as neurons via complement–independent, non-cytolytic mechanisms. These antibodies inhibit virus budding and replication, viral RNA transcription, and cell-to-cell virus spread.

Mentions: Because viruses can infect microglia, astrocytes, oligodendrocytes, as well as terminally differentiated and non-renewable cells such as neurons, the ensuing immune response within the CNS must avoid extensive cytolytic damage of virus-infected target cells (137). In general, innate anti-viral immunity such as the generation of type-I IFN occurs very rapidly, while the adaptive immune response is slower because it must first develop in the periphery (138). Important components of adaptive anti-viral immunity involve IFN-γ production by T cells as well as the expansion and migration of virus-specific antibody secreting cells (ASC) (138, 139) (Figure 2).


Immune responses to non-tumor antigens in the central nervous system.

Huber AK, Duncker PC, Irani DN - Front Oncol (2014)

Orchestration of the immune response during viral infection of the CNS. With the BBB in a resting state (1), viruses can gain entry into the CNS by infecting peripheral nerves and traveling by anterograde axonal transport into the CNS, by infecting host immune cells in the periphery and using these cells as “Trojan horses” to carry them across the BBB, or by directly infecting BBB endothelial cells (2). Viral PAMPs then activate microglia, astrocytes, and oligodendrocytes (3). Microglia and astrocytes produce a range of anti-viral/pro-inflammatory cytokines, including type-I IFNs, IL-6, TNF-α, IL-12, IL-1α, and IL-1β (3). Astrocytes also produce MMP-3 and MMP-12 resulting in the up-regulation of adhesion molecules on endothelial cells (3). Interactions between adhesion molecules and neutrophils contribute to BBB breakdown via the production of MMP-9 and the disassembly of the tight junctions (4). DCs are seen in the CNS within several days and migrate to draining lymph nodes where they activate and expand virus-specific T cells (5). Chemokines produced by astrocytes are responsible for recruiting virus-specific CD4+ and CD8+ T cells as well as ASCs to the CNS (6). CD8+ T cells produce IFN-γ and lytic molecules, including granzyme B and perforin, to eliminate virus from astrocytes, while IFN-γ controls viral replication in oligodendrocytes (7). Virus-specific antibodies control virus replication in cells such as neurons via complement–independent, non-cytolytic mechanisms. These antibodies inhibit virus budding and replication, viral RNA transcription, and cell-to-cell virus spread.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4230036&req=5

Figure 2: Orchestration of the immune response during viral infection of the CNS. With the BBB in a resting state (1), viruses can gain entry into the CNS by infecting peripheral nerves and traveling by anterograde axonal transport into the CNS, by infecting host immune cells in the periphery and using these cells as “Trojan horses” to carry them across the BBB, or by directly infecting BBB endothelial cells (2). Viral PAMPs then activate microglia, astrocytes, and oligodendrocytes (3). Microglia and astrocytes produce a range of anti-viral/pro-inflammatory cytokines, including type-I IFNs, IL-6, TNF-α, IL-12, IL-1α, and IL-1β (3). Astrocytes also produce MMP-3 and MMP-12 resulting in the up-regulation of adhesion molecules on endothelial cells (3). Interactions between adhesion molecules and neutrophils contribute to BBB breakdown via the production of MMP-9 and the disassembly of the tight junctions (4). DCs are seen in the CNS within several days and migrate to draining lymph nodes where they activate and expand virus-specific T cells (5). Chemokines produced by astrocytes are responsible for recruiting virus-specific CD4+ and CD8+ T cells as well as ASCs to the CNS (6). CD8+ T cells produce IFN-γ and lytic molecules, including granzyme B and perforin, to eliminate virus from astrocytes, while IFN-γ controls viral replication in oligodendrocytes (7). Virus-specific antibodies control virus replication in cells such as neurons via complement–independent, non-cytolytic mechanisms. These antibodies inhibit virus budding and replication, viral RNA transcription, and cell-to-cell virus spread.
Mentions: Because viruses can infect microglia, astrocytes, oligodendrocytes, as well as terminally differentiated and non-renewable cells such as neurons, the ensuing immune response within the CNS must avoid extensive cytolytic damage of virus-infected target cells (137). In general, innate anti-viral immunity such as the generation of type-I IFN occurs very rapidly, while the adaptive immune response is slower because it must first develop in the periphery (138). Important components of adaptive anti-viral immunity involve IFN-γ production by T cells as well as the expansion and migration of virus-specific antibody secreting cells (ASC) (138, 139) (Figure 2).

Bottom Line: The central nervous system (CNS), once viewed as an immune-privileged site protected by the blood-brain barrier (BBB), is now known to be a dynamic immunological environment through which immune cells migrate to prevent and respond to events such as localized infection.During these responses, endogenous glial cells, including astrocytes and microglia, become highly reactive and may secrete inflammatory mediators that regulate BBB permeability and recruit additional circulating immune cells.Here, we discuss the various roles played by astrocytes, microglia, and infiltrating immune cells during host immunity to non-tumor antigens in the CNS, focusing first on bacterial and viral infections, and then turning to responses directed against self-antigens in the setting of CNS autoimmunity.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, University of Michigan Medical School , Ann Arbor, MI , USA.

ABSTRACT
The central nervous system (CNS), once viewed as an immune-privileged site protected by the blood-brain barrier (BBB), is now known to be a dynamic immunological environment through which immune cells migrate to prevent and respond to events such as localized infection. During these responses, endogenous glial cells, including astrocytes and microglia, become highly reactive and may secrete inflammatory mediators that regulate BBB permeability and recruit additional circulating immune cells. Here, we discuss the various roles played by astrocytes, microglia, and infiltrating immune cells during host immunity to non-tumor antigens in the CNS, focusing first on bacterial and viral infections, and then turning to responses directed against self-antigens in the setting of CNS autoimmunity.

No MeSH data available.


Related in: MedlinePlus