Imperial College London

Professor Richard Reynolds, BSc AKC PhD

Faculty of MedicineDepartment of Brain Sciences

Professor of Cellular Neurobiology
 
 
 
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Contact

 

+44 (0)20 7594 6668r.reynolds

 
 
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Location

 

E414Burlington DanesHammersmith Campus

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Summary

 

Publications

Publication Type
Year
to

159 results found

Martin NA, Hyrlov KH, Elkjaer ML, Thygesen EK, Wlodarczyk A, Elbaek KJ, Aboo C, Okarmus J, Benedikz E, Reynolds R, Hegedus Z, Stensballe A, Svenningsen ÅF, Owens T, Illes Zet al., 2020, Absence of miRNA-146a Differentially Alters Microglia Function and Proteome, Frontiers in Immunology, Vol: 11, ISSN: 1664-3224

Background: MiR-146a is an important regulator of innate inflammatory responses and is also implicated in cell death and survival. Methods: By sorting CNS resident cells, microglia were the main cellular source of miR-146a. Therefore, we investigated microglia function and phenotype in miR-146a knock-out (KO) mice, analyzed the proteome of KO and wild-type (WT) microglia by LC-MS/MS, and examined miR-146a expression in different brain lesions of patients with multiple sclerosis (MS). Results: When stimulated with LPS or myelin in vitro, microglia from KO mice expressed higher levels of IL-1β, TNF, IL-6, IL-10, CCL3, and CCL2 compared to WT. Stimulation increased migration and phagocytosis of WT but not KO microglia. CD11c+ microglia were induced by cuprizone (CPZ) in the WT mice but less in the KO. The proteome of ex vivo microglia was not different in miR-146a KO compared to WT mice, but CPZ treatment induced differential and reduced protein responses in the KO: GOT1, COX5b, CRYL1, and cystatin-C were specifically changed in KO microglia. We explored discriminative features of microglia proteomes: sparse Partial Least Squares-Discriminant Analysis showed the best discrimination when control and CPZ-treated conditions were compared. Cluster of ten proteins separated WT and miR-146a KO microglia after CPZ: among them were sensomes allowing to perceive the environment, Atp1a3 that belongs to the signature of CD11c+ microglia, and proteins related to inflammatory responses (S100A9, Ppm1g). Finally, we examined the expression of miR-146a and its validated target genes in different brain lesions of MS patients. MiR-146 was upregulated in all lesion types, and the highest expression was in active lesions. Nineteen of 88 validated target genes were significantly changed in active lesions, while none were changed in NAWM. Conclusion: Our data indicated that microglia is the major source of miR-146a in the CNS. The absence of miR-146a differentially affected microglia f

Journal article

Magliozzi R, Scalfari A, Pisani AI, Ziccardi S, Marastoni D, Pizzini FB, Bajrami A, Tamanti A, Guandalini M, Bonomi S, Rossi S, Mazziotti V, Castellaro M, Montemezzi S, Rasia S, Capra R, Pitteri M, Romualdi C, Reynolds R, Calabrese Met al., 2020, The CSF profile linked to cortical damage predicts Multiple Sclerosis activity., Ann Neurol

OBJECTIVE: Intrathecal inflammation correlates with the grey matter damage since the early stages of Multiple Sclerosis (MS), but whether the cerebrospinal fluid (CSF) profile can help to identify patients at risk of disease activity is still unclear. METHODS: We evaluated the association between CSF levels of 18 cytokines, previously found to be associated to grey matter damage, and the disease activity, among 99 relapsing-remitting MS patients, who underwent blinded clinical and 3T-MRI evaluations for 4 years. Groups with (EDA) or without (NEDA) evidence of disease activity (occurrence of relapses, new white matter lesions, EDSS change) were identified. Cortical lesions and the annualized cortical thinning were also evaluated. RESULTS: Fortyone patients experienced EDA and, compared to the NEDA group, had at diagnosis higher CSF levels of CXCL13, CXCL12, IFNγ, TNF, sCD163, LIGHT and APRIL (p<0.001). In the multivariate analysis, CXCL13 (HR=1.35, p=0.0002), LIGHT (HR=1.22, p=0.005) and APRIL (HR=1.78, p=0.0001) were the CSF molecules more strongly associated with the risk of EDA. The model including CSF variables predicted more accurately the occurrence of disease activity than the model with only clinical/MRI parameters (C-index at 4 years= 71% vs 44%). Finally, higher CSF levels of CXCL13 (β=4.7*10-4 ,p<0.001), TNF (β=3.1*10-3 ,p=0.004), LIGHT (β=2.6*10-4 ,p=0.003), sCD163 (β=4.3*10-3 ,p=0.009) and TWEAK (β=3.4*10-3 ,p=0.024) were associated with more severe cortical thinning. INTERPRETATION: A specific CSF profile, mainly characterized by elevated levels of B-cell related cytokines, distinguishes patients at high risk of disease activity and severe cortical damage. The CSF analysis may allow stratifications of patients at diagnosis for optimizing therapeutic approaches. This article is protected by copyright. All rights reserved.

Journal article

James RE, Schalks R, Browne E, Eleftheriadou I, Munoz CP, Mazarakis ND, Reynolds Ret al., 2020, Persistent elevation of intrathecal pro-inflammatory cytokines leads to multiple sclerosis-like cortical demyelination and neurodegeneration., Acta Neuropathologica Communications, Vol: 8, Pages: 66-66, ISSN: 2051-5960

Analysis of isolated meninges and cerebrospinal fluid (CSF) of post-mortem MS cases has shown increased gene and protein expression for the pro-inflammatory cytokines: tumour necrosis factor (TNF) and interferon-γ (IFNγ). Here we tested the hypothesis that persistent production of these cytokines in the meningeal compartment and diffusion into underlying GM can drive chronic MS-like GM pathology. Lentiviral transfer vectors were injected into the sagittal sulcus of DA rats to deliver continuous expression of TNF + IFNγ transgenes in the meninges and the resulting neuropathology analysed after 1 and 2 months. Injection of TNF + IFNγ viral vectors, with or without prior MOG immunisation, induced extensive immune cell infiltration (CD4+ and CD8+ T-cells, CD79a + B-cells and macrophages) in the meninges by 28 dpi, which remained at 2 months. Control GFP viral vector did not induce infiltration. Subpial demyelination was seen underlying these infiltrates, which was partly dependant on prior myelin oligodendrocyte glycoprotein (MOG) immunisation. A significant decrease in neuronal numbers was seen at 28 and 56 days in cortical layers II-V that was independent of MOG immunisation. RNA analysis at 28 dpi showed an increase in expression of necroptotic pathway genes, including RIP3, MLKL, cIAP2 and Nox2. PhosphoRIP3+ and phosphoMLKL+ neurons were present in TNF + IFNγ vector injected animals, indicating activation of necroptosis. Our results suggest that persistent expression of TNF in the presence of IFNγ is a potent inducer of meningeal inflammation and can activate TNF signalling pathways in cortical cells leading to neuronal death and subpial demyelination and thus may contribute to clinical progression in MS.

Journal article

Donninelli G, Saraf-Sinik I, Mazziotti V, Capone A, Grasso MG, Battistini L, Reynolds R, Magliozzi R, Volpe Eet al., 2020, Interleukin-9 regulates macrophage activation in the progressive multiple sclerosis brain., Journal of Neuroinflammation, Vol: 17, Pages: 1-14, ISSN: 1742-2094

BACKGROUND: Multiple sclerosis (MS) is an immune-mediated, chronic inflammatory, and demyelinating disease of the central nervous system (CNS). Several cytokines are thought to be involved in the regulation of MS pathogenesis. We recently identified interleukin (IL)-9 as a cytokine reducing inflammation and protecting from neurodegeneration in relapsing-remitting MS patients. However, the expression of IL-9 in CNS, and the mechanisms underlying the effect of IL-9 on CNS infiltrating immune cells have never been investigated. METHODS: To address this question, we first analyzed the expression levels of IL-9 in post-mortem cerebrospinal fluid of MS patients and the in situ expression of IL-9 in post-mortem MS brain samples by immunohistochemistry. A complementary investigation focused on identifying which immune cells express IL-9 receptor (IL-9R) by flow cytometry, western blot, and immunohistochemistry. Finally, we explored the effect of IL-9 on IL-9-responsive cells, analyzing the induced signaling pathways and functional properties. RESULTS: We found that macrophages, microglia, and CD4 T lymphocytes were the cells expressing the highest levels of IL-9 in the MS brain. Of the immune cells circulating in the blood, monocytes/macrophages were the most responsive to IL-9. We validated the expression of IL-9R by macrophages/microglia in post-mortem brain sections of MS patients. IL-9 induced activation of signal transducer and activator of transcription (STAT)1, STAT3, and STAT5 and reduced the expression of activation markers, such as CD45, CD14, CD68, and CD11b in inflammatory macrophages stimulated in vitro with lipopolysaccharide and interferon (IFN)-γ. Similarly, in situ the number of activated CD68+ macrophages was significantly reduced in areas with high levels of IL-9. Moreover, in the same conditions, IL-9 increased the secretion of the anti-inflammatory cytokine, transforming growth factor (TGF)-β. CONCLUSIONS: These results reveal a new cytokine

Journal article

Reali C, Magliozzi R, Roncaroli F, Nicholas R, Howell OW, Reynolds Ret al., 2020, B cell rich meningeal inflammation associates with increased spinal cord pathology in multiple sclerosis, Brain Pathology, ISSN: 1015-6305

Increased inflammation in the cerebral meninges is associated with extensive subpial cortical grey matter pathology in the forebrain and a more severe disease course in a substantial proportion of secondary progressive multiple sclerosis (SPMS) cases. It is not known whether this relationship extends to spinal cord pathology. We assessed the contribution of meningeal and parenchymal immune infiltrates to spinal cord pathology in SPMS cases characterised by the presence (F+) or absence (F‐) of lymphoid‐like structures in the forebrain meninges. Transverse cryosections of cervical, thoracic and lumbar cord of 22 SPMS and 5 control cases were analysed for CD20+ B cells, CD4+ and CD8+ T cells, microglia/macrophages (IBA‐1+), demyelination (myelin oligodendrocyte glycoprotein+) and axon density (neurofilament‐H+). Lymphoid‐like structures containing follicular dendritic cell networks and dividing B cells were seen in the spinal meninges of three out of 11 F+SPMS cases. CD4+ and CD20+ cell counts were increased in F+SPMS compared to F‐SPMS and controls, whilst axon loss was greatest in motor and sensory tracts of the F+SPMS cases (p<0.01). The density of CD20+ B cells of the spinal leptomeninges correlated with: CD4+ T cells and total B and T cells of the meninges; with the density of white matter perivascular CD20+ and CD4+ lymphocytes (p<0.05); with white matter lesion area (p<0.05); and the extent of axon loss (p<0.05) in F+SPMS cases only. We show that the presence of lymphoid‐like structures in the forebrain is associated with a profound spinal cord pathology, and local B cell rich meningeal inflammation associates with the extent of cord pathology. Our work supports a principal role for B cells in sustaining inflammation and tissue injury throughout the CNS in the progressive disease stage.

Journal article

Griffiths L, Reynolds R, Evans R, Bevan RJ, Rees MI, Gveric D, Neal JW, Howell OWet al., 2020, Substantial subpial cortical demyelination in progressive multiple sclerosis: have we underestimated the extent of cortical pathology?, Neuroimmunology and Neuroinflammation, Vol: 7, Pages: 51-67, ISSN: 2347-8659

Aim: Multiple sclerosis (MS) is an inflammatory demyelinating and neurodegenerative disease. Much of the complex symptomatology relates to pathology outside the classic white matter plaque, whereby lesions of the cortical grey matter, which are difficult to resolve by conventional clinical imaging, are in part predictive of outcome. We investigated the extent of grey matter pathology in whole coronal macrosections to reassess the contribution of cortical pathology to total demyelinating lesion area in progressive MS.Methods: Twenty-two cases of progressive MS were prepared as whole bi-hemispheric macrosections for histology, immunostaining and quantitative analysis of lesion number and relative area, leptomeningeal inflammation and microglial/macrophage activation.Results: Cortical grey matter demyelination was seen in all cases, which was more extensive than in white and deep grey matter (hippocampus, thalamus and basal ganglia) and accounted for 0.8%-60.2% of the entire measurable cortical ribbon. The pattern of cortical grey matter demyelination was predominantly subpial (mean 90.9%, range 60%-100%, of total cortical grey matter lesion area) and cases with the largest areas of subpial cortical lesions had more and larger deep grey matter lesions, greater numbers of activated microglia/macrophages, both in lesions as well as in normal cortical grey matter, together with elevated leptomeningeal inflammation and lymphoid-like structures. White matter lesion area was unchanged when compared with the progressive MS cases with little subpial cortical demyelination.Conclusion: Analysis of whole coronal macrosections reveals cortical demyelination is more extensive than reported by conventional histological methods. Cases of progressive MS with substantial subpial cortical demyelination that is independent of underlying white matter lesion area support the implications that these lesions may in-part arise through different pathogenetic mechanisms. Biomarkers and/or imagi

Journal article

Cooze B, Dickerson M, Loganathan R, Magliozzi R, Bevan R, Watkins L, Reynolds R, Neal JW, Howell OWet al., 2020, The contribution of thalamic pathology to progressive multiple sclerosis outcome, 121st Meeting of the British-Neuropathological-Society / Developmental Neuropathology Symposium, Publisher: WILEY, Pages: 30-30, ISSN: 0305-1846

Conference paper

Elkjaer ML, Frisch T, Reynolds R, Kacprowski T, Burton M, Kruse TA, Thomassen M, Baumbach J, Illes Zet al., 2019, Molecular signature of different lesion types in the brain white matter of patients with progressive multiple sclerosis, Acta Neuropathologica Communications, Vol: 7, ISSN: 2051-5960

To identify pathogenetic markers and potential drivers of different lesion types in the white matter (WM) of patients with progressive multiple sclerosis (PMS), we sequenced RNA from 73 different WM areas. Compared to 25 WM controls, 6713 out of 18,609 genes were significantly differentially expressed in MS tissues (FDR < 0.05). A computational systems medicine analysis was performed to describe the MS lesion endophenotypes. The cellular source of specific molecules was examined by RNAscope, immunohistochemistry, and immunofluorescence. To examine common lesion specific mechanisms, we performed de novo network enrichment based on shared differentially expressed genes (DEGs), and found TGFβ-R2 as a central hub. RNAscope revealed astrocytes as the cellular source of TGFβ-R2 in remyelinating lesions. Since lesion-specific unique DEGs were more common than shared signatures, we examined lesion-specific pathways and de novo networks enriched with unique DEGs. Such network analysis indicated classic inflammatory responses in active lesions; catabolic and heat shock protein responses in inactive lesions; neuronal/axonal specific processes in chronic active lesions. In remyelinating lesions, de novo analyses identified axonal transport responses and adaptive immune markers, which was also supported by the most heterogeneous immunoglobulin gene expression. The signature of the normal-appearing white matter (NAWM) was more similar to control WM than to lesions: only 465 DEGs differentiated NAWM from controls, and 16 were unique. The upregulated marker CD26/DPP4 was expressed by microglia in the NAWM but by mononuclear cells in active lesions, which may indicate a special subset of microglia before the lesion develops, but also emphasizes that omics related to MS lesions should be interpreted in the context of different lesions types. While chronic active lesions were the most distinct from control WM based on the highest number of unique DEGs (n&thi

Journal article

Magliozzi R, Howell OW, Durrenberger P, Arico E, James R, Cruciani C, Reeves C, Roncaroli F, Nicholas R, Reynolds Ret al., 2019, Meningeal inflammation changes the balance of TNF signalling in cortical grey matter in multiple sclerosis, Journal of Neuroinflammation, Vol: 16, Pages: 1-16, ISSN: 1742-2094

BackgroundRecent studies of cortical pathology in secondary progressive multiple sclerosis have shown that a more severe clinical course and the presence of extended subpial grey matter lesions with significant neuronal/glial loss and microglial activation are associated with meningeal inflammation, including the presence of lymphoid-like structures in the subarachnoid space in a proportion of cases.MethodsTo investigate the molecular consequences of pro-inflammatory and cytotoxic molecules diffusing from the meninges into the underlying grey matter, we carried out gene expression profiling analysis of the motor cortex from 20 post-mortem multiple sclerosis brains with and without substantial meningeal inflammation and 10 non-neurological controls.ResultsGene expression profiling of grey matter lesions and normal appearing grey matter not only confirmed the substantial pathological cell changes, which were greatest in multiple sclerosis cases with increased meningeal inflammation, but also demonstrated the upregulation of multiple genes/pathways associated with the inflammatory response. In particular, genes involved in tumour necrosis factor (TNF) signalling were significantly deregulated in MS cases compared with controls. Increased meningeal inflammation was found to be associated with a shift in the balance of TNF signalling away from TNFR1/TNFR2 and NFkB-mediated anti-apoptotic pathways towards TNFR1- and RIPK3-mediated pro-apoptotic/pro-necroptotic signalling in the grey matter, which was confirmed by RT-PCR analysis. TNFR1 was found expressed preferentially on neurons and oligodendrocytes in MS cortical grey matter, whereas TNFR2 was predominantly expressed by astrocytes and microglia.ConclusionsWe suggest that the inflammatory milieu generated in the subarachnoid space of the multiple sclerosis meninges by infiltrating immune cells leads to increased demyelinating and neurodegenerative pathology in the underlying grey matter due to changes in the balance of

Journal article

Magliozzi R, Hametner S, Facchiano F, Marastoni D, Rossi S, Castellaro M, Poli A, Lattanzi F, Visconti A, Nicholas R, Reynolds R, Monaco S, Lassmann H, Calabrese Met al., 2019, Iron homeostasis, complement, and coagulation cascade as CSF signature of cortical lesions in early multiple sclerosis, Annals of Clinical and Translational Neurology, Vol: 6, Pages: 2150-2163, ISSN: 2328-9503

ObjectiveIntrathecal inflammation, compartmentalized in cerebrospinal fluid (CSF) and in meningeal infiltrates, has fundamental role in inflammation, demyelination, and neuronal injury in cerebral cortex in multiple sclerosis (MS). Since the exact link between intrathecal inflammation and mechanisms of cortical pathology remains unknown, we aimed to investigate a detailed proteomic CSF profiling which is able to reflect cortical damage in early MS.MethodsWe combined new proteomic method, TRIDENT, CSF analysis, and advanced 3T magnetic resonance imaging (MRI), in 64 MS patients at the time of diagnosis and 26 controls with other neurological disorders. MS patients were stratified according to cortical lesion (CL) load.ResultsWe identified 227 proteins differently expressed between the patients with high and low CL load. These were mainly related to complement and coagulation cascade as well as to iron homeostasis pathway (30 and 6% of all identified proteins, respectively). Accordingly, in the CSF of MS patients with high CL load at diagnosis, significantly higher levels of sCD163 (P < 0.0001), free hemoglobin (Hb) (P < 0.05), haptoglobin (P < 0.0001), and fibrinogen (P < 0.01) were detected. By contrast, CSF levels of sCD14 were significantly (P < 0.05) higher in MS patients with low CL load. Furthermore, CSF levels of sCD163 positively correlated (P < 0.01) with CSF levels of neurofilament, fibrinogen, and B cell‐related molecules, such as CXCL13, CXCL12, IL10, and BAFF.InterpretationIntrathecal dysregulation of iron homeostasis and coagulation pathway as well as B‐cell and monocyte activity are strictly correlated with cortical damage at early disease stages.

Journal article

Schirmer L, Velmeshev D, Holmqvist S, Kaufmann M, Werneburg S, Jung D, Vistnes S, Stockley J, Young A, Steindel M, Tung B, Goyal N, Bhaduri A, Mayer S, Engler JB, Bayraktar O, Franklin R, Haeussler M, Reynolds R, Schafer D, Friese M, Shiow L, Kriegstein A, Rowitch Det al., 2019, Single-cell genomics reveals neuron subtype vulnerability in multiple sclerosis, 35th Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS) / 24th Annual Conference of Rehabilitation in MS, Publisher: SAGE PUBLICATIONS LTD, Pages: 673-673, ISSN: 1352-4585

Conference paper

Calabrese M, Pisani A, Ziccardi S, Pizzini FB, Bajrami A, Tamanti A, Guandalini M, Bonomi S, Rossi S, Mazziotti V, Montemezzi S, Zuco C, Crescenzo F, Marastoni D, Pitteri M, Scalfari A, Romualdi C, Reynolds R, Magliozzi Ret al., 2019, Intrathecal inflammatory profile predicts disease course in multiple sclerosis: a 4-year longitudinal study, 35th Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS) / 24th Annual Conference of Rehabilitation in MS, Publisher: SAGE PUBLICATIONS LTD, Pages: 274-274, ISSN: 1352-4585

Conference paper

Poli A, Marastoni D, Nicholas R, Rossi S, Reynolds R, Calabrese M, Monaco S, Magliozzi Ret al., 2019, The extent and distribution of fibrinogen deposition in progressive MS correlate with meningeal and choroid plexus inflammation, 35th Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS) / 24th Annual Conference of Rehabilitation in MS, Publisher: SAGE PUBLICATIONS LTD, Pages: 10-11, ISSN: 1352-4585

Conference paper

Elkjaer ML, Frisch T, Reynolds R, Kacprowski T, Burton M, Kruse T, Thomassen M, Baumbach J, Illes Zet al., 2019, Molecular signatures of different lesions types in the white matter of SPMS, 35th Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS) / 24th Annual Conference of Rehabilitation in MS, Publisher: SAGE PUBLICATIONS LTD, Pages: 76-76, ISSN: 1352-4585

Conference paper

Magliozzi R, Montibiller L, Marastoni D, Mazziotti V, Rossi S, Tamanti A, Poli A, Ziccardi S, Pitteri M, Monaco S, Reynolds R, Calabrese Met al., 2019, Cerebrospinal fluid levels of parvalbumin predict cortical demyelination and atrophy in multiple sclerosis, 35th Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS) / 24th Annual Conference of Rehabilitation in MS, Publisher: SAGE PUBLICATIONS LTD, Pages: 672-672, ISSN: 1352-4585

Conference paper

Van Horssen J, Witte M, Reynolds R, 2019, Potential biological mechanisms behind MS progression, 35th Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS) / 24th Annual Conference of Rehabilitation in MS, Publisher: SAGE PUBLICATIONS LTD, Pages: 74-74, ISSN: 1352-4585

Conference paper

Howell O, Magliozzi R, Calabrese M, Reynolds Ret al., 2019, The spectrum of cortical pathology in the MS brain: when, where and why?, 35th Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS) / 24th Annual Conference of Rehabilitation in MS, Publisher: SAGE PUBLICATIONS LTD, Pages: 115-115, ISSN: 1352-4585

Conference paper

Marastoni D, Magliozzi R, Howell O, Roncaroli F, Muraro P, Friede T, Calabrese M, Reynolds R, Nicholas Ret al., 2019, High levels of perivascular inflammation and active white matter lesions at time of death are associated with rapidly progressive multiple sclerosis, 35th Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS) / 24th Annual Conference of Rehabilitation in MS, Publisher: SAGE PUBLICATIONS LTD, Pages: 76-77, ISSN: 1352-4585

Conference paper

Smith AM, Khozoie C, Fancy N, Srivastava P, Matthews PM, Owen D, Reynolds Ret al., 2019, Single nucleus RNA sequencing of post-mortem multiple sclerosis cortical grey matter, 35th Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS) / 24th Annual Conference of Rehabilitation in MS, Publisher: SAGE PUBLICATIONS LTD, Pages: 233-233, ISSN: 1352-4585

Conference paper

Frisch T, Elkjaer ML, Reynolds R, Michel TM, Kacprowski T, Burton M, Kruse TA, Thomassen M, Baumbach J, Illes Zet al., 2019, The MS Atlas - A molecular map of brain lesion stages in secondary progressive MS, 35th Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS) / 24th Annual Conference of Rehabilitation in MS, Publisher: SAGE PUBLICATIONS LTD, Pages: 379-380, ISSN: 1352-4585

Conference paper

Schirmer L, Velmeshev D, Holmqvist S, Kaufmann M, Werneburg S, Jung D, Vistnes S, Stockley JH, Young A, Steindel M, Tung B, Goyal N, Bhaduri A, Mayer S, Engler JB, Bayraktar OA, Franklin RJM, Haeussler M, Reynolds R, Schafer DP, Friese MA, Shiow LR, Kriegstein AR, Rowitch DHet al., 2019, Neuronal vulnerability and multilineage diversity in multiple sclerosis, Nature, Vol: 573, Pages: 75-82, ISSN: 0028-0836

Multiple sclerosis (MS) is a neuroinflammatory disease with a relapsing–remitting disease course at early stages, distinct lesion characteristics in cortical grey versus subcortical white matter and neurodegeneration at chronic stages. Here we used single-nucleus RNA sequencing to assess changes in expression in multiple cell lineages in MS lesions and validated the results using multiplex in situ hybridization. We found selective vulnerability and loss of excitatory CUX2-expressing projection neurons in upper-cortical layers underlying meningeal inflammation; such MS neuron populations exhibited upregulation of stress pathway genes and long non-coding RNAs. Signatures of stressed oligodendrocytes, reactive astrocytes and activated microglia mapped most strongly to the rim of MS plaques. Notably, single-nucleus RNA sequencing identified phagocytosing microglia and/or macrophages by their ingestion and perinuclear import of myelin transcripts, confirmed by functional mouse and human culture assays. Our findings indicate lineage- and region-specific transcriptomic changes associated with selective cortical neuron damage and glial activation contributing to progression of MS lesions.

Journal article

Bartoletti-Stella A, Corrado P, Mometto N, Baiardi S, Durrenberger PF, Arzberger T, Reynolds R, Kretzschmar H, Capellari S, Parchi Pet al., 2019, Analysis of RNA Expression Profiles Identifies Dysregulated Vesicle Trafficking Pathways in Creutzfeldt-Jakob Disease, MOLECULAR NEUROBIOLOGY, Vol: 56, Pages: 5009-5024, ISSN: 0893-7648

Journal article

Bevan RJ, Evans R, Griffiths L, Watkins LM, Rees MI, Magliozzi R, Allen I, McDonnell G, Kee R, Naughton M, Fitzgerald DC, Reynolds R, Neal JW, Howell OWet al., 2018, Meningeal inflammation and cortical demyelination in acute multiple sclerosis, Annals of Neurology, Vol: 84, Pages: 829-842, ISSN: 0364-5134

ObjectiveCortical gray matter (GM) pathology, involving demyelination and neurodegeneration, associated with meningeal inflammation, could be important in determining disability progression in multiple sclerosis (MS). However, we need to know more about how cortical demyelination, neurodegeneration, and meningeal inflammation contribute to pathology at early stages of MS to better predict long‐term outcome.MethodsTissue blocks from short disease duration MS (n = 12, median disease duration = 2 years), progressive MS (n = 21, disease duration = 25 years), non‐diseased controls (n = 11), and other neurological inflammatory disease controls (n = 6) were quantitatively analyzed by immunohistochemistry, immunofluorescence, and in situ hybridization.ResultsCortical GM demyelination was extensive in some cases of acute MS (range = 1–48% of total cortical GM), and subpial lesions were the most common type (62%). The numbers of activated (CD68+) microglia/macrophages were increased in cases with subpial lesions, and the density of neurons was significantly reduced in acute MS normal appearing and lesion GM, compared to controls (p < 0.005). Significant meningeal inflammation and lymphoid‐like structures were seen in 4 of 12 acute MS cases. The extent of meningeal inflammation correlated with microglial/macrophage activation (p < 0.05), but not the area of cortical demyelination, reflecting the finding that lymphoid‐like structures were seen adjacent to GM lesions as well as areas of partially demyelinated/remyelinated, cortical GM.InterpretationOur findings demonstrate that cortical demyelination, neuronal loss, and meningeal inflammation are notable pathological hallmarks of acute MS and support the need to identify early biomarkers of this pathology to better predict outcome. Ann Neurol 2018;84:829–842

Journal article

Jelcic I, Al Nimer F, Wang J, Lentsch V, Planas R, Jelcic I, Madjovski A, Ruhrmann S, Faigle W, Frauenknecht K, Pinilla C, Santos R, Hammer C, Ortiz Y, Opitz L, Gronlund H, Rogler G, Boyman O, Reynolds R, Lutterotti A, Khademi M, Olsson T, Piehl F, Sospedra M, Martin Ret al., 2018, Memory B cells activate brain-homing, autoreactive CD4(+) T cells in multiple sclerosis, Cell, Vol: 175, Pages: 85-100.e23, ISSN: 0092-8674

Multiple sclerosis is an autoimmune disease that is caused by the interplay of genetic, particularly the HLA-DR15 haplotype, and environmental risk factors. How these etiologic factors contribute to generating an autoreactive CD4+ T cell repertoire is not clear. Here, we demonstrate that self-reactivity, defined as “autoproliferation” of peripheral Th1 cells, is elevated in patients carrying the HLA-DR15 haplotype. Autoproliferation is mediated by memory B cells in a HLA-DR-dependent manner. Depletion of B cells in vitro and therapeutically in vivo by anti-CD20 effectively reduces T cell autoproliferation. T cell receptor deep sequencing showed that in vitro autoproliferating T cells are enriched for brain-homing T cells. Using an unbiased epitope discovery approach, we identified RASGRP2 as target autoantigen that is expressed in the brain and B cells. These findings will be instrumental to address important questions regarding pathogenic B-T cell interactions in multiple sclerosis and possibly also to develop novel therapies.

Journal article

Magliozzi R, Reynolds R, Calabrese M, 2018, MRI of cortical lesions and its use in studying their role in MS pathogenesis and disease course, BRAIN PATHOLOGY, Vol: 28, Pages: 735-742, ISSN: 1015-6305

Journal article

Zeis T, Howell OW, Reynolds R, Schaeren-Wiemers Net al., 2018, Molecular pathology of Multiple Sclerosis lesions reveals a heterogeneous expression pattern of genes involved in oligodendrogliogenesis, EXPERIMENTAL NEUROLOGY, Vol: 305, Pages: 76-88, ISSN: 0014-4886

Journal article

Elson JL, Kochaj R, Reynolds R, Pienaar ISet al., 2018, Temporal-Spatial Profiling of Pedunculopontine Galanin-Cholinergic Neurons in the Lactacystin Rat Model of Parkinson's Disease, NEUROTOXICITY RESEARCH, Vol: 34, Pages: 16-31, ISSN: 1029-8428

Journal article

Magliozzi R, Howell OW, Nicholas R, Cruciani C, Castellaro M, Romualdi C, Rossi S, Pitteri M, Benedetti MD, Gajofatto A, Pizzini FB, Montemezzi S, Rasia S, Capra R, Bertoldo A, Facchiano F, Monaco S, Reynolds R, Calabrese Met al., 2018, Inflammatory intrathecal profiles and cortical damage in multiple sclerosis, Annals of Neurology, Vol: 83, Pages: 739-755, ISSN: 0364-5134

OBJECTIVE: Grey matter (GM) damage and meningeal inflammation have been associated with early disease onset and a more aggressive disease course in Multiple Sclerosis (MS), but can these changes be identified in the patient early in the disease course? METHODS: To identify possible biomarkers linking meningeal inflammation, GM damage and disease severity, gene and protein expression were analysed in meninges and CSF from 27 post-mortem secondary progressive MS (SPMS) and 14 control cases. Combined cytokine/chemokine CSF profiling and 3T-MRI were performed at diagnosis in two independent cohorts of MS patients (35 and 38 subjects) and in 26 non-MS patients. RESULTS: Increased expression of pro-inflammatory cytokines (IFNγ, TNF, IL2 and IL22) and molecules related to sustained B-cell activity and lymphoid-neogenesis (CXCL13, CXCL10, LTα, IL6, IL10) was detected in the meninges and CSF of post-mortem MS cases with high levels of meningeal inflammation and GM demyelination. Similar pro-inflammatory patterns, including increased levels of CXCL13, TNF, IFNγ, CXCL12, IL6, IL8 and IL10, together with high levels of BAFF, APRIL, LIGHT, TWEAK, sTNFR1, sCD163, MMP2 and pentraxin III, were detected in the CSF of MS patients with higher levels of GM damage at diagnosis. INTERPRETATION: A common pattern of intrathecal (meninges and CSF) inflammatory profile strongly correlates with increased cortical pathology, both at time of the diagnosis and of death. These results suggest a role for detailed CSF analysis combined with MRI, as a prognostic marker for more aggressive MS. This article is protected by copyright. All rights reserved.

Journal article

Cencioni MT, Magliozzi R, Nicholas R, Ali R, Malik O, Reynolds R, Borsellino G, Battistini L, Muraro PAet al., 2017, Programmed death 1 is highly expressed on CD8(+) CD57(+) T cells in patients with stable multiple sclerosis and inhibits their cytotoxic response to Epstein-Barr virus., Immunology, Vol: 152, Pages: 660-676, ISSN: 0019-2805

Growing evidence points to a deregulated response to Epstein-Barr virus (EBV) in the central nervous system of patients with multiple sclerosis (MS) as a possible cause of disease. We have investigated the response of a subpopulation of effector CD8(+) T cells to EBV in 36 healthy donors and in 35 patients with MS in active and inactive disease. We have measured the expression of markers of degranulation, the release of cytokines, cytotoxicity and the regulation of effector functions by inhibitory receptors, such as programmed death 1 (PD-1) and human inhibitor receptor immunoglobulin-like transcript 2 (ILT2). We demonstrate that polyfunctional cytotoxic CD8(+) CD57(+) T cells are able to kill EBV-infected cells in healthy donors. In contrast, an anergic exhaustion-like phenotype of CD8(+) CD57(+) T cells with high expression of PD-1 was observed in inactive patients with MS compared with active patients with MS or healthy donors. Detection of CD8(+) CD57(+) T cells in meningeal inflammatory infiltrates from post-mortem MS tissue confirmed the association of this cell phenotype with the disease pathological process. The overall results suggest that ineffective immune control of EBV in patietns with MS during remission may be one factor preceding and enabling the reactivation of the virus in the central nervous system and may cause exacerbation of the disease.

Journal article

Raffel J, Wallace A, Gveric D, Reynolds R, Friede T, Nicholas Ret al., 2017, Patient-reported outcomes and survival in multiple sclerosis: a 10-year retrospective cohort study using the Multiple Sclerosis Impact Scale-29, PLOS Medicine, Vol: 14, ISSN: 1549-1277

BackgroundThere is increasing emphasis on using patient-reported outcomes (PROs) to complement traditional clinical outcomes in medical research, including in multiple sclerosis (MS). Research, particularly in oncology and heart failure, has shown that PROs can be prognostic of hard clinical endpoints such as survival time (time from study entry until death). However, unlike in oncology or cardiology, it is unknown whether PROs are associated with survival time in neurological diseases. The Multiple Sclerosis Impact Scale–29 (MSIS-29) is a PRO sensitive to short-term change in MS, with questions covering both physical and psychological quality of life. This study aimed to investigate whether MSIS-29 scores can be prognostic for survival time in MS, using a large observational cohort of people with MS.Methods and findingsFrom 15 July 2004 onwards, MSIS-29 questionnaires were completed by people with MS registered with the MS Society Tissue Bank (n = 2,126, repeated 1 year later with n = 872 of the original respondents). By 2014, 264 participants (12.4%) had died. Higher baseline MSIS-29 physical (MSIS-29-PHYS) score was associated with reduced survival time (subgroup with highest scores versus subgroup with lowest scores: hazard ratio [HR] 5.7, 95% CI 3.1–10.5, p < 0.001). Higher baseline MSIS-29 psychological score was also associated with reduced survival time (subgroup with highest scores versus subgroup with lowest scores: HR 2.8, 95% CI 1.8–4.4, p < 0.001). In those with high baseline MSIS-29 scores, mortality risk was even greater if the MSIS-29 score worsened over 1 year (HR 2.3, 95% CI 1.2–4.4, p = 0.02). MSIS-29-PHYS scores were associated with survival time independent of age, sex, and patient-reported Expanded Disability Status Scale score in a Cox regression analysis (per 1-SD increase in MSIS-29-PHYS score: HR 1.8, 95% CI 1.1–2.9, p = 0.03). A limitation of the study is that this cohort had high baseline age and disabi

Journal article

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