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Neuropathological and cerebrospinal fluid correlates of choroid plexus inflammation in progressive multiple sclerosis

R. Magliozzi Orcid Logo, S. Hametner, M. Mastantuono, A. Mensi, M. Karimian, Lauren Griffiths, LEWIS WATKINS, A. Poli, G. M. Berti, E. Barusolo, B. Bellini, S. Rossi, D. Gveric, J. A. Stratton, K. Akassoglou, S. Magon, R. Nicholas, R. Reynolds, Owain Howell Orcid Logo, S. Monaco

Brain Pathology, Start page: e13322

Swansea University Authors: Lauren Griffiths, LEWIS WATKINS, Owain Howell Orcid Logo

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DOI (Published version): 10.1111/bpa.13322

Abstract

Among the intrathecal inflammatory niches where compartmentalized inflammation persists and plays a pivotal role in progressive multiple sclerosis (MS), choroid plexus (CP) has recently received renewed attention. To better characterize the neuropathological/molecular correlates of CP in progressive...

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Published in: Brain Pathology
ISSN: 1015-6305 1750-3639
Published: Wiley 2024
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URI: https://cronfa.swan.ac.uk/Record/cronfa68410
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To better characterize the neuropathological/molecular correlates of CP in progressive MS and its potential link with other brain inflammatory compartments, such as perivascular spaces and leptomeninges, the levels, composition and phenotype of CP immune infiltration in lateral ventricles of the hippocampus were examined in 40 post&#x2010;mortem pathologically confirmed MS and 10 healthy donors, using immunochemistry/immunofluorescence and in&#x2010;situ sequencing. Significant inflammation was detected in the CP of 21 out of the 40 MS cases (52%). The degree of CP inflammation was found correlated with: number of CP macrophages (R: 0.878, p = 1.012 x 10&#x2010;13) and high frequency of innate immune cells expressing the markers MHC&#x2010;class II, CD163, CD209, CD11c, TREM2 and TSPO; perivascular inflammation (R: 0.509, p = 7.921 x 10&#x2010;4), and less with meningeal inflammation (R: 0.365, p = 0.021); number of active lesions (R: 0.51, p: 3.524 x 10&#x2010;5). However, it did not significantly correlate with any clinical/demographic characteristics of the examined population. In&#x2010;situ sequencing analysis of gene expression in the CP of 3 representative MS cases and 3 controls revealed regulation of inflammatory pathways mainly related to &#x2018;type 2 immune response&#x2019;, &#x2018;defense to infections&#x2019;, &#x2018;antigen processing/presentation&#x2019;. Analysis of 78 inflammatory molecules in paired post&#x2010;mortem CSF, the levels of fibrinogen (R: 0.640, p = 8.752 x 10&#x2010;6), PDGF&#x2010;bb (R: 0.470, p = 0.002), CXCL13 (R: 0.428, p = 0.006) and IL15 (R: 0.327, p = 0.040) were correlated with extent of CP inflammation. Elevated fibrinogen and complement deposition were found in CP and in underlying subependymal periventricular areas, according to &#x201C;surface&#x2010;in&#x201D; gradient associated with concomitant prominent microglia activation. 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spelling 2025-03-31T16:08:51.0666123 v2 68410 2024-12-02 Neuropathological and cerebrospinal fluid correlates of choroid plexus inflammation in progressive multiple sclerosis 8811c280da03bf66352d97f756e91ae1 Lauren Griffiths Lauren Griffiths true false 97e10055a6937046ec3de94c0204e820 LEWIS WATKINS LEWIS WATKINS true false 58c995486fc93a242b987640b692db8c 0000-0003-2157-9157 Owain Howell Owain Howell true false 2024-12-02 MEDS Among the intrathecal inflammatory niches where compartmentalized inflammation persists and plays a pivotal role in progressive multiple sclerosis (MS), choroid plexus (CP) has recently received renewed attention. To better characterize the neuropathological/molecular correlates of CP in progressive MS and its potential link with other brain inflammatory compartments, such as perivascular spaces and leptomeninges, the levels, composition and phenotype of CP immune infiltration in lateral ventricles of the hippocampus were examined in 40 post‐mortem pathologically confirmed MS and 10 healthy donors, using immunochemistry/immunofluorescence and in‐situ sequencing. Significant inflammation was detected in the CP of 21 out of the 40 MS cases (52%). The degree of CP inflammation was found correlated with: number of CP macrophages (R: 0.878, p = 1.012 x 10‐13) and high frequency of innate immune cells expressing the markers MHC‐class II, CD163, CD209, CD11c, TREM2 and TSPO; perivascular inflammation (R: 0.509, p = 7.921 x 10‐4), and less with meningeal inflammation (R: 0.365, p = 0.021); number of active lesions (R: 0.51, p: 3.524 x 10‐5). However, it did not significantly correlate with any clinical/demographic characteristics of the examined population. In‐situ sequencing analysis of gene expression in the CP of 3 representative MS cases and 3 controls revealed regulation of inflammatory pathways mainly related to ‘type 2 immune response’, ‘defense to infections’, ‘antigen processing/presentation’. Analysis of 78 inflammatory molecules in paired post‐mortem CSF, the levels of fibrinogen (R: 0.640, p = 8.752 x 10‐6), PDGF‐bb (R: 0.470, p = 0.002), CXCL13 (R: 0.428, p = 0.006) and IL15 (R: 0.327, p = 0.040) were correlated with extent of CP inflammation. Elevated fibrinogen and complement deposition were found in CP and in underlying subependymal periventricular areas, according to “surface‐in” gradient associated with concomitant prominent microglia activation. CP inflammation, predominantly characterized by innate immunity, represents another key determinant of intrathecal, compartmentalised inflammation persisting in progressive MS, which may be possibly activated by fibrinogen and influence periventricular pathology, even without substantial association with clinical features. Journal Article Brain Pathology 0 e13322 Wiley 1015-6305 1750-3639 Choroid plexus, gradient, inflammation, multiple sclerosis 1 12 2024 2024-12-01 10.1111/bpa.13322 COLLEGE NANME Medical School COLLEGE CODE MEDS Swansea University Another institution paid the OA fee We thank: the UK MS Society Tissue Bank at Imperial College and Dr. Djordje Gveric (funding from the MS Society of Great Britain, grant 007/14 to RR and RN) for the supply of post-mortem MS samples; the Laboratory of Neuropathology at LURM (University Laboratory of Medical Research), University of Verona; the National Recovery and Resilience Plan (NRRP), project MNESYS (PE0000006); the Excellence Project 2023–2027, funded by MUR, of the Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona; RM wish to acknowledge support from Italian MS Foundation (FISM 2023/R-Single/038). LG, LW, OWH wish to acknowledge support from the Research Wales Innovation Fund and the BRAIN Unit Infrastructure Award (Grant no: UA05; funded by Welsh Government through Health and Care Research Wales). 2025-03-31T16:08:51.0666123 2024-12-02T13:02:37.4567768 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Biomedical Science R. Magliozzi 0000-0001-8284-7763 1 S. Hametner 2 M. Mastantuono 3 A. Mensi 4 M. Karimian 5 Lauren Griffiths 6 LEWIS WATKINS 7 A. Poli 8 G. M. Berti 9 E. Barusolo 10 B. Bellini 11 S. Rossi 12 D. Gveric 13 J. A. Stratton 14 K. Akassoglou 15 S. Magon 16 R. Nicholas 17 R. Reynolds 18 Owain Howell 0000-0003-2157-9157 19 S. Monaco 20 68410__33015__438a75b0debf41b382164910fe8b949f.pdf bpa.13322.pdf 2024-12-02T13:02:37.4363313 Output 11727752 application/pdf Version of Record true © 2024 The Author(s). This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License (CC BY-NC 4.0). true eng http://creativecommons.org/licenses/by-nc/4.0/
title Neuropathological and cerebrospinal fluid correlates of choroid plexus inflammation in progressive multiple sclerosis
spellingShingle Neuropathological and cerebrospinal fluid correlates of choroid plexus inflammation in progressive multiple sclerosis
Lauren Griffiths
LEWIS WATKINS
Owain Howell
title_short Neuropathological and cerebrospinal fluid correlates of choroid plexus inflammation in progressive multiple sclerosis
title_full Neuropathological and cerebrospinal fluid correlates of choroid plexus inflammation in progressive multiple sclerosis
title_fullStr Neuropathological and cerebrospinal fluid correlates of choroid plexus inflammation in progressive multiple sclerosis
title_full_unstemmed Neuropathological and cerebrospinal fluid correlates of choroid plexus inflammation in progressive multiple sclerosis
title_sort Neuropathological and cerebrospinal fluid correlates of choroid plexus inflammation in progressive multiple sclerosis
author_id_str_mv 8811c280da03bf66352d97f756e91ae1
97e10055a6937046ec3de94c0204e820
58c995486fc93a242b987640b692db8c
author_id_fullname_str_mv 8811c280da03bf66352d97f756e91ae1_***_Lauren Griffiths
97e10055a6937046ec3de94c0204e820_***_LEWIS WATKINS
58c995486fc93a242b987640b692db8c_***_Owain Howell
author Lauren Griffiths
LEWIS WATKINS
Owain Howell
author2 R. Magliozzi
S. Hametner
M. Mastantuono
A. Mensi
M. Karimian
Lauren Griffiths
LEWIS WATKINS
A. Poli
G. M. Berti
E. Barusolo
B. Bellini
S. Rossi
D. Gveric
J. A. Stratton
K. Akassoglou
S. Magon
R. Nicholas
R. Reynolds
Owain Howell
S. Monaco
format Journal article
container_title Brain Pathology
container_volume 0
container_start_page e13322
publishDate 2024
institution Swansea University
issn 1015-6305
1750-3639
doi_str_mv 10.1111/bpa.13322
publisher Wiley
college_str Faculty of Medicine, Health and Life Sciences
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hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Biomedical Science{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Biomedical Science
document_store_str 1
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description Among the intrathecal inflammatory niches where compartmentalized inflammation persists and plays a pivotal role in progressive multiple sclerosis (MS), choroid plexus (CP) has recently received renewed attention. To better characterize the neuropathological/molecular correlates of CP in progressive MS and its potential link with other brain inflammatory compartments, such as perivascular spaces and leptomeninges, the levels, composition and phenotype of CP immune infiltration in lateral ventricles of the hippocampus were examined in 40 post‐mortem pathologically confirmed MS and 10 healthy donors, using immunochemistry/immunofluorescence and in‐situ sequencing. Significant inflammation was detected in the CP of 21 out of the 40 MS cases (52%). The degree of CP inflammation was found correlated with: number of CP macrophages (R: 0.878, p = 1.012 x 10‐13) and high frequency of innate immune cells expressing the markers MHC‐class II, CD163, CD209, CD11c, TREM2 and TSPO; perivascular inflammation (R: 0.509, p = 7.921 x 10‐4), and less with meningeal inflammation (R: 0.365, p = 0.021); number of active lesions (R: 0.51, p: 3.524 x 10‐5). However, it did not significantly correlate with any clinical/demographic characteristics of the examined population. In‐situ sequencing analysis of gene expression in the CP of 3 representative MS cases and 3 controls revealed regulation of inflammatory pathways mainly related to ‘type 2 immune response’, ‘defense to infections’, ‘antigen processing/presentation’. Analysis of 78 inflammatory molecules in paired post‐mortem CSF, the levels of fibrinogen (R: 0.640, p = 8.752 x 10‐6), PDGF‐bb (R: 0.470, p = 0.002), CXCL13 (R: 0.428, p = 0.006) and IL15 (R: 0.327, p = 0.040) were correlated with extent of CP inflammation. Elevated fibrinogen and complement deposition were found in CP and in underlying subependymal periventricular areas, according to “surface‐in” gradient associated with concomitant prominent microglia activation. CP inflammation, predominantly characterized by innate immunity, represents another key determinant of intrathecal, compartmentalised inflammation persisting in progressive MS, which may be possibly activated by fibrinogen and influence periventricular pathology, even without substantial association with clinical features.
published_date 2024-12-01T09:38:38Z
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