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Immune environment of the brain in schizophrenia and during the psychotic episode: a human post-mortem study

Immune environment of the brain in schizophrenia and during the psychotic episode: a human post-mortem study
Immune environment of the brain in schizophrenia and during the psychotic episode: a human post-mortem study
A causal relationship between immune dysregulation and schizophrenia has been supported by genome-wide association studies and epidemiological evidence. It remains unclear to what extent the brain immune environment is implicated in this hypothesis. We investigated the immunophenotype of microglia and the presence of perivascular macrophages and T lymphocytes in post-mortem brain tissue. Dorsal prefrontal cortex of 40 controls (22F:18M) and 37 (10F:27M ) schizophrenia cases, of whom 16 had active psychotic symptoms at the time of death, was immunostained for seven markers of microglia (CD16, CD32a, CD32b, CD64, CD68, HLA-DR, Iba1 and P2RY12), two markers perivascular macrophages (CD163 and CD206) and T-lymphocytes (CD3). Automated quantification was blinded to the case designation and performed separately on the grey and white matter. 3D reconstruction of Iba1-positive microglia was performed in selected cases. An increased cortical expression of microglial Fc receptors (CD64 F=7.92 p=0.007; CD64/HLA-DR ratio F=5.02, p=0.029) highlights the importance of communication between the central and peripheral immune systems in schizophrenia. Patients in whom psychotic symptoms were present at death demonstrated an age-dependent increase of Iba1 and increased CD64/HLA-DR ratios relative to patients without psychotic symptoms. Microglia in schizophrenia demonstrated a primed/reactive morphology. A potential role for T-lymphocytes was observed, but we did not confirm the presence of recruited macrophages in the brains of schizophrenia patients. Taking in account the limitations of a post-mortem study, our findings support the hypothesis of an alteration of the brain immune environment in schizophrenia, with symptomatic state- and age-dependent effects.
Schizophrenia, psychosis, microglia, perivascular macrophages, T lymphocytes, human brain
0889-1591
De Picker, Livia
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Mendez-Victoriano, Gerardo
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Richards, Rhys
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Gorvett, Alexander
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Lyons, Simeon
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Buckland, George
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Tofani, Tommaso
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Norman, Jeanette
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Chatelet, David
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Nicoll, James
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Boche, Delphine
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De Picker, Livia
8646e4e2-34c9-4156-98ec-fed01231d8ab
Mendez-Victoriano, Gerardo
efcde084-e732-4b7c-8176-49ac18472f89
Richards, Rhys
d5e04d52-3a2b-4f4a-b45b-72a81e25c94b
Gorvett, Alexander
9304250e-4b34-4969-bb6b-f88dfdc61c1c
Lyons, Simeon
a5e1003a-ef51-4664-813e-2872489c9af2
Buckland, George
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Tofani, Tommaso
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Norman, Jeanette
b4fa0e8e-3b6e-458b-af1e-2f55c651639a
Chatelet, David
6371fd7a-e274-4738-9ccb-3dd4dab32928
Nicoll, James
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Boche, Delphine
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De Picker, Livia, Mendez-Victoriano, Gerardo, Richards, Rhys, Gorvett, Alexander, Lyons, Simeon, Buckland, George, Tofani, Tommaso, Norman, Jeanette, Chatelet, David, Nicoll, James and Boche, Delphine (2021) Immune environment of the brain in schizophrenia and during the psychotic episode: a human post-mortem study. Brain, Behavior and Immunity, [BBI-D-21-00220R2]. (doi:10.1016/j.bbi.2021.07.017).

Record type: Article

Abstract

A causal relationship between immune dysregulation and schizophrenia has been supported by genome-wide association studies and epidemiological evidence. It remains unclear to what extent the brain immune environment is implicated in this hypothesis. We investigated the immunophenotype of microglia and the presence of perivascular macrophages and T lymphocytes in post-mortem brain tissue. Dorsal prefrontal cortex of 40 controls (22F:18M) and 37 (10F:27M ) schizophrenia cases, of whom 16 had active psychotic symptoms at the time of death, was immunostained for seven markers of microglia (CD16, CD32a, CD32b, CD64, CD68, HLA-DR, Iba1 and P2RY12), two markers perivascular macrophages (CD163 and CD206) and T-lymphocytes (CD3). Automated quantification was blinded to the case designation and performed separately on the grey and white matter. 3D reconstruction of Iba1-positive microglia was performed in selected cases. An increased cortical expression of microglial Fc receptors (CD64 F=7.92 p=0.007; CD64/HLA-DR ratio F=5.02, p=0.029) highlights the importance of communication between the central and peripheral immune systems in schizophrenia. Patients in whom psychotic symptoms were present at death demonstrated an age-dependent increase of Iba1 and increased CD64/HLA-DR ratios relative to patients without psychotic symptoms. Microglia in schizophrenia demonstrated a primed/reactive morphology. A potential role for T-lymphocytes was observed, but we did not confirm the presence of recruited macrophages in the brains of schizophrenia patients. Taking in account the limitations of a post-mortem study, our findings support the hypothesis of an alteration of the brain immune environment in schizophrenia, with symptomatic state- and age-dependent effects.

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Accepted/In Press date: 24 July 2021
e-pub ahead of print date: 30 July 2021
Keywords: Schizophrenia, psychosis, microglia, perivascular macrophages, T lymphocytes, human brain

Identifiers

Local EPrints ID: 450535
URI: http://eprints.soton.ac.uk/id/eprint/450535
ISSN: 0889-1591
PURE UUID: b4a5486e-cbba-4303-b116-f26351036770
ORCID for James Nicoll: ORCID iD orcid.org/0000-0002-9444-7246
ORCID for Delphine Boche: ORCID iD orcid.org/0000-0002-5884-130X

Catalogue record

Date deposited: 03 Aug 2021 16:31
Last modified: 04 Aug 2021 01:37

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Contributors

Author: Livia De Picker
Author: Gerardo Mendez-Victoriano
Author: Rhys Richards
Author: Alexander Gorvett
Author: Simeon Lyons
Author: George Buckland
Author: Tommaso Tofani
Author: Jeanette Norman
Author: David Chatelet
Author: James Nicoll ORCID iD
Author: Delphine Boche ORCID iD

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