Counteracting roles of MHCI and CD8+T cells in the peripheral and central nervous system of ALS SOD1G93Amice

G Nardo, MC Trolese, Mattia Verderio, A. Mariani, M De Paola, N Riva, G Dina, N Panini, E Erba, A Quattrini, C Bendotti

Research output: Contribution to journalArticle

Abstract

Background: The major histocompatibility complex I (MHCI) is a key molecule for the interaction of mononucleated cells with CD8+T lymphocytes. We previously showed that MHCI is upregulated in the spinal cord microglia and motor axons of transgenic SOD1G93Amice. Methods: To assess the role of MHCI in the disease, we examined transgenic SOD1G93Amice crossbred with β2 microglobulin-deficient mice, which express little if any MHCI on the cell surface and are defective for CD8+T cells. Results: The lack of MHCI and CD8+T cells in the sciatic nerve affects the motor axon stability, anticipating the muscle atrophy and the disease onset. In contrast, MHCI depletion in resident microglia and the lack of CD8+T cell infiltration in the spinal cord protect the cervical motor neurons delaying the paralysis of forelimbs and prolonging the survival of SOD1G93Amice. Conclusions: We provided straightforward evidence for a dual role of MHCI in the peripheral nervous system (PNS) compared to the CNS, pointing out regional and temporal differences in the clinical responses of ALS mice. These findings offer a possible explanation for the failure of systemic immunomodulatory treatments and suggest new potential strategies to prevent the progression of ALS. © 2018 The Author(s).
Original languageEnglish
Article number42
JournalMolecular Neurodegeneration
Volume13
DOIs
Publication statusPublished - 2018

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Peripheral Nervous System
Major Histocompatibility Complex
Central Nervous System
T-Lymphocytes
Microglia
Axons
Muscular Atrophy
Forelimb
Motor Neurons
Sciatic Nerve
Cell Communication
Paralysis
Spinal Cord

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Counteracting roles of MHCI and CD8+T cells in the peripheral and central nervous system of ALS SOD1G93Amice. / Nardo, G; Trolese, MC; Verderio, Mattia; Mariani, A.; De Paola, M; Riva, N; Dina, G; Panini, N; Erba, E; Quattrini, A; Bendotti, C.

In: Molecular Neurodegeneration, Vol. 13, 42, 2018.

Research output: Contribution to journalArticle

Nardo, G ; Trolese, MC ; Verderio, Mattia ; Mariani, A. ; De Paola, M ; Riva, N ; Dina, G ; Panini, N ; Erba, E ; Quattrini, A ; Bendotti, C. / Counteracting roles of MHCI and CD8+T cells in the peripheral and central nervous system of ALS SOD1G93Amice. In: Molecular Neurodegeneration. 2018 ; Vol. 13.
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abstract = "Background: The major histocompatibility complex I (MHCI) is a key molecule for the interaction of mononucleated cells with CD8+T lymphocytes. We previously showed that MHCI is upregulated in the spinal cord microglia and motor axons of transgenic SOD1G93Amice. Methods: To assess the role of MHCI in the disease, we examined transgenic SOD1G93Amice crossbred with β2 microglobulin-deficient mice, which express little if any MHCI on the cell surface and are defective for CD8+T cells. Results: The lack of MHCI and CD8+T cells in the sciatic nerve affects the motor axon stability, anticipating the muscle atrophy and the disease onset. In contrast, MHCI depletion in resident microglia and the lack of CD8+T cell infiltration in the spinal cord protect the cervical motor neurons delaying the paralysis of forelimbs and prolonging the survival of SOD1G93Amice. Conclusions: We provided straightforward evidence for a dual role of MHCI in the peripheral nervous system (PNS) compared to the CNS, pointing out regional and temporal differences in the clinical responses of ALS mice. These findings offer a possible explanation for the failure of systemic immunomodulatory treatments and suggest new potential strategies to prevent the progression of ALS. {\circledC} 2018 The Author(s).",
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T1 - Counteracting roles of MHCI and CD8+T cells in the peripheral and central nervous system of ALS SOD1G93Amice

AU - Nardo, G

AU - Trolese, MC

AU - Verderio, Mattia

AU - Mariani, A.

AU - De Paola, M

AU - Riva, N

AU - Dina, G

AU - Panini, N

AU - Erba, E

AU - Quattrini, A

AU - Bendotti, C

PY - 2018

Y1 - 2018

N2 - Background: The major histocompatibility complex I (MHCI) is a key molecule for the interaction of mononucleated cells with CD8+T lymphocytes. We previously showed that MHCI is upregulated in the spinal cord microglia and motor axons of transgenic SOD1G93Amice. Methods: To assess the role of MHCI in the disease, we examined transgenic SOD1G93Amice crossbred with β2 microglobulin-deficient mice, which express little if any MHCI on the cell surface and are defective for CD8+T cells. Results: The lack of MHCI and CD8+T cells in the sciatic nerve affects the motor axon stability, anticipating the muscle atrophy and the disease onset. In contrast, MHCI depletion in resident microglia and the lack of CD8+T cell infiltration in the spinal cord protect the cervical motor neurons delaying the paralysis of forelimbs and prolonging the survival of SOD1G93Amice. Conclusions: We provided straightforward evidence for a dual role of MHCI in the peripheral nervous system (PNS) compared to the CNS, pointing out regional and temporal differences in the clinical responses of ALS mice. These findings offer a possible explanation for the failure of systemic immunomodulatory treatments and suggest new potential strategies to prevent the progression of ALS. © 2018 The Author(s).

AB - Background: The major histocompatibility complex I (MHCI) is a key molecule for the interaction of mononucleated cells with CD8+T lymphocytes. We previously showed that MHCI is upregulated in the spinal cord microglia and motor axons of transgenic SOD1G93Amice. Methods: To assess the role of MHCI in the disease, we examined transgenic SOD1G93Amice crossbred with β2 microglobulin-deficient mice, which express little if any MHCI on the cell surface and are defective for CD8+T cells. Results: The lack of MHCI and CD8+T cells in the sciatic nerve affects the motor axon stability, anticipating the muscle atrophy and the disease onset. In contrast, MHCI depletion in resident microglia and the lack of CD8+T cell infiltration in the spinal cord protect the cervical motor neurons delaying the paralysis of forelimbs and prolonging the survival of SOD1G93Amice. Conclusions: We provided straightforward evidence for a dual role of MHCI in the peripheral nervous system (PNS) compared to the CNS, pointing out regional and temporal differences in the clinical responses of ALS mice. These findings offer a possible explanation for the failure of systemic immunomodulatory treatments and suggest new potential strategies to prevent the progression of ALS. © 2018 The Author(s).

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JO - Molecular Neurodegeneration

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