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, CD64, CD68, HLA-DR, Iba1 and P2RY12), two markers for 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 Fcγ 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
319-327
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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October 2021
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
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, 97, , [BBI-D-21-00220R2].
(doi:10.1016/j.bbi.2021.07.017).
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, CD64, CD68, HLA-DR, Iba1 and P2RY12), two markers for 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 Fcγ 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.
Text
Revised_Sz paper (BBI)v3clean
- Accepted Manuscript
More information
Accepted/In Press date: 24 July 2021
e-pub ahead of print date: 30 July 2021
Published date: October 2021
Additional Information:
Funding Information:
We would like to thank Professor Steve Gentleman from the Corsellis collection who facilitated the access to the tissue under the UK Brain Archive Information Network (BRAIN UK) which is funded by the Medical Research Council and Brain Tumour Research. We acknowledge the Histochemistry Research Unit and the Biomedical Imaging Unit of the Faculty of Medicine, University of Southampton that facilitated tissue processing, staining and analysis.
Funding Information:
We would like to thank Professor Steve Gentleman from the Corsellis collection who facilitated the access to the tissue under the UK Brain Archive Information Network (BRAIN UK) which is funded by the Medical Research Council and Brain Tumour Research. We acknowledge the Histochemistry Research Unit and the Biomedical Imaging Unit of the Faculty of Medicine, University of Southampton that facilitated tissue processing, staining and analysis.
Funding Information:
This work was supported by the the Medical Research Council (UKRI, G1100578) and Alzheimer’s Research UK (grant number ARUK-EG2015A-4); the Mexican National Council of Science and Technology (CONACyT reference 899569) to GMV and the Flemish Agency for Innovation by Science and Technology (IWT-SB reference 121373) to LDP.
Publisher Copyright:
© 2021 The Author(s)
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
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Date deposited: 03 Aug 2021 16:31
Last modified: 17 Mar 2024 02:55
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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
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