Introduction
Professor Richard Reynold's research laboratory at Imperial College focuses on the pathogenetic mechanisms underlying grey matter pathology in multiple sclerosis, in particular the link between inflammation and neurodegeneration via cytokine signaling. His laboratories house the UK MS and PD Tissue Bank that represents a worldwide resource for MS and PD research. His lab employ novel animal models of cortical pathology employing the chronic expression of cytokines and chemokines in the meningeal space alongside a detailed molecular analysis of the human tissues. This has led to the identification of alterations in TNF signaling pathways as a possible driver of progressive disease. His lab has demonstrated that chronic TNF and IFN-gamma expression in the meninges can give rise to progressive neuronal loss and demyelination, similar to that seen in MS. In addition, his research laboratory at LKC School of Medicine in Singapore is focusing on inflammatory signaling the AD and PD brain, by transferring knowledge gained from MS into the major neurodegenerative disorders.

Positions and Honors
1988-1994. Wellcome Trust Senior Research Fellow in Basic Biomedical Science, Dept Biochemistry, Imperial College London, UK

1994-2000. Associate Professor, Division of Neuroscience, Imperial College London, UK.

1998-2019. Director of the UK MS Tissue Bank, Imperial College London, UK.

2000-2020. Professor of Cellular Neurobiology, Faculty of Medicine, Division of Brain Sciences, Imperial College London, UK. Current position.

2013-2018. Deputy Head, Division of Brain Sciences, Imperial College London, UK.

2009-2020. Adjunct Professor, National Centre of Biomedical Engineering Sciences, National University of Ireland Galway.

2015-2020. Visiting Professor of Neuroscience, LKC School of Medicine, Nanyang Technological University, Singapore.

2016-2020. Director, Centre for Molecular Neuropathology, LKC School of Medicine, Nanyang Technological University, Singapore. Current position.

Contributions to Science
Pathogenetic mechanisms of multiple sclerosis

The Multiple Sclerosis research group at Imperial College is studying the cellular and molecular events that lead to these pathological changes, in particular the failure of remyelination and the progressive neurodegeneration, using a combination of human post-mortem tissues, experimental models and cell culture systems. Axonal damage and neuronal loss is now thought to be an early feature of MS pathology (Anderson et al, 2009; Kim et al, 2010) and evidence suggests that its accumulation may be the pathological correlate for the progression of disability. Recent evidence suggests a major role for neuronal loss in the cortical grey matter in MS (Magliozzi et al, 2007; Papadopoulos et al, 2009; Magliozzi et al, 2010; Nicholas et al, 2016). Our current work uses human tissues and novel experimental models of MS to investigate the mechanisms responsible for this neuronal loss. We have demonstrated the involvement of ectopic meningeal lymphoid structures in cortical pathology in MS, in particular in sub-pial demyelination and neurodegeneration. The presence of these structures and associated pathology is associated with a more rapid and aggressive disease course (Magliozzi et al, 2007; Magliozzi et al, 2010; Howell et al, 2011; Choi et al, 2012; Magliozzi et al, 2019). Our current studies are investigating the molecular nature of the mediators responsible for this pathology (Gardner et al, 2013; Calabrese et al, 2015; Watkins et al 2016; Farina et al, 2017; Magliozzi et al, 2018), particularly using lentiviral delivery of cytokine genes into the meningeal space to produce a chronic inflammatory state (James et al, 2020; Picon et al, 2021).

The role of neuroinflammation in neurodegeneration

Our recent studies have indicated that there is an interplay between innate and adaptive immunity, originating in the meningeal space, that can then regulate the level of microglial activation and neuronal damage in the underlying brain tissue (Magliozzi et al, 2010; Calabrese et al, 2015). Based on our findings in MS we have begun to extend these studies to other chronic neurodegenerative and neuropsychiatric conditions, using a gene expression profiling approach (Schmitt et al, 2011; 2012; Durrenberger et al, 2012a; 2012b; 2015). Of particular interest are the effects of chronic neuroinflammation on the structure and function of the nodes of Ranvier (Howell et al, 2006; Scheiermann et al, 2007; Zhang et al, 2015). Microglial activation is associated with a lengthening of the paranodes on the axon in both MS and PD and maybe responsible for some of the fatigue related symptoms (Howell et al, 2010). We have developed a computational model to understand the effects of these changes on action potential conduction and a slice culture system to study the molecular mediators involved (Gallego et al, 2020). My laboratory at LKC Medicine, Singapore, is focusing on inflammatory pathways in the brain in Alzheimer’s and Parkinson’s diseases, in particular TNF stimulated neurodegeneration via the necroptotic pathway. Our recent results have determined that neuronal cell death in Alzheimer’s is occurring via necroptosis rather than apoptosis and that TNF/TNFR1 signaling is highly upregulated in the entorhinal cortex. 

Neuroimaging and biomarker discovery in multiple sclerosis

Our studies on post-mortem brains have led us to become involved in numerous collaborative studies investigating novel imaging modalities for MS and validating PET ligands for use in neuroinflammation studies (Owen et al, 2010a; 2010b; 2011; Kalk et al, 2013). The use of post-mortem tissues in validating MR imaging techniques is becoming increasingly important for developing improved imaging protocols and to understand the neuropathological substrates of changes on MR scans (Politis et al, 2012; Giannetti et al, 2014; 2015). Our more recent work, involving an ongoing very productive relationship with the University of Verona, is converting correlative studies on post-mortem and 3D DIR imaging at 3T with the development of new prognostic markers for the development of disability in MS (Calabrese et al, 2015; 2016; Farina, 2017; Castellaro et al, 2017; Magliozzi et al, 2018; 2020).

Human brain banking

We set up the UK MS Tissue Bank at the beginning of 1998 to provide a reliable source of post-mortem MS CNS material for researchers around the UK and the world. We have developed extensive protocols for collection, dissection and storage of brain, spinal cord and CSF, to ensure that the tissue is of maximum use for a wide variety of experimental techniques (Durrenberger et al, 2010; 2012). This has proven to be extremely successful and we are now supplying tissue for research projects throughout the world. All tissue collected by the bank is obtained via a prospective donor scheme and we now run the largest scheme in Europe. In addition to research into optimizing the efficiency of our tissue banking, we are carrying out a number of studies looking at the best ways to characterise the variety of pathologies within MS tissue using combinations of histology, immunohistochemistry and molecular studies. In 2004 we also incorporated the UK PD Brain Bank into our operation and this is now the largest live collection of PD brains in the world, with an annual retrieval rate of 120 brains and a total of 1,100 in the bank. In 2018 I pioneered the setting up of Brain Bank Singapore, which was finally launched in November 2019 and is operating a prospective donor scheme collecting brains from all neurological and psychiatric disorders. This has allowed us to build up an extensive knowledge of the use of human brain tissues for new generation technologies in multiple disorders.

Recent Publications (2018 - 2021)
Olst L, Rodriguez-Mogeda C, Kiljan S, Picon C, James RE, Kamermans A, Van der Pol S, Knoop L, Drost E, Franssen M, Schenk G, Geurts JJG, Amor S, Mazarakis ND, van Horssen J, De Vries, Reynolds R^*, Witte M^*. (2021) Cortical microglia become damaging over time in response to meningeal inflammation in progressive MS.  Acta Neuropathologica early on line.

Picon C, Jayaraman A, James R, Beck C, Gallego P, Witte ME, van Horssen J, Mazarakis ND, Reynolds R (2021) Neuron-specific activation of necroptosis signaling in multiple sclerosis cortical grey matter. Acta Neuropathologica 141, pages 585–604.

Wang Q, Luo Y, Chaudhuri KR, Reynolds R, Tan E-K, Pettersson S (2021) The role of gut dysbiosis in Parkinson's disease: mechanistic insights and therapeutic options. In press in Brain.

Padini M, Brown WL, Magliozzi R, Reynolds R, Chard DT (2021) Surface in pathology in multiple sclerosis: a new view on pathogenesis? In press in Brain.

Elkjaer ML, Nawrocki A, Kacprowski T, Lassen P, Simonsen AH, Marignier R, Sejbaek T, Nielsen HH, Wermuth L, Rashid AY, Hogh P, Sellebjerg F, Reynolds R, Baumbach J, Larssen MR, Illes Z (2021) CSF proteome in multiple sclerosis subtypes related to brain lesion transcriptomes. Sci Rep 11:4132.

Elkjaer M, Frisch T, Tonazzolli A, Roettger R, Reynolds R, Baumbach J, Illes Z (2021) Unbiased examination of genome-wide human endogenous retrovirus (HERV) transcripts in MS brain lesions. MS Journal, early on line. https://doi.org/10.1177/1352458520987269.

Gallego P, James R, Browne E, Meng J, Umashankar S, Picon P, Mazarakis ND, Faisal AA, Howell OW, Reynolds R (2020) Neuroinflammation in the normal appearing white matter of multiple sclerosis brain causes abnormalities at the node of Ranvier. PLoS Biology, 18:e3001008.

Monaco S, Nicholas R, Reynolds R, Magliozzi R (2020) Intrathecal inflammation in progressive multiple sclerosis. Int J Mol Sci 21:8217.

Magliozzi R, Pitteri M, Ziccardi S, Pisani AI, Marastoni D, Montibeller L, Rossi S, Mazziotti V, Guandalini M, Dapor C, Schiavi GM, Tamanti A, Nicholas R, Reynolds R^*, Calabrese M^* (2020) Cerebrospinal fluid levels of parvalbumin reflect interneuron damage associated with cortical demyelination and atrophy in MS. Ann Clin Trans Neurol. 8:534-547.

Wang J, Jelcic I, Mühlenbruch L, Haunerdinger V, Toussaint NC, Zhao Y, Cruciani C, Faigle W Naghavian R, Foege M, Binder TMC, Eiermann T, Opitz L, Fuentes-Font L, Reynolds R, Kwok WW, Nguyen J, Lee JH, Lutterotti A, Münz C, Rammensee HG, Hauri-Hohl M, Sospedra M, Stevanovic S, Martin R (2020) Tightly Linked HLA-DR15 Molecules Jointly Shape an Autoreactive T Cell Repertoire in Multiple Sclerosis. Cell 183:1-18.

Donninelli G, Saraf-Sinik I, Mazziotti V, capone A, Grasso MG, Battistini L, Reynolds R, Magliozzi R, Volpe E (2020) Interleukin-9 regulates macrophage activation in the progressive multiple sclerosis brain. J Neuroinflammation 17:149.

Reali C, Magliozzi R, Roncaroli, F, Nicholas R, Howell OW, Reynolds R (2020) The influence of parenchymal and meningeal inflammation on spinal cord pathology in multiple sclerosis. Brain Pathology, 30:779-793.

Magliozzi R, Scalfari A, Pisani AI, Ziccardi S, Marastoni D, Pizzini FB, Bajrami A, Tamanti A, Guansdalini M, Bonomi S, Rossi S, Mazziotti V, Castellaro M, Montemezzi S, Rasia S, Cara R, Pitteri M, Romualdi C, Reynolds R, Calabrese M (2020). Intrathecal inflammatory profile predicts disease course in multiple sclerosis. Annals Neurology, 88:562-573.

James RE, Schalks R, Browne E, Eleftheriadou I, Mazarakis ND, Reynolds R (2020) Persistent elevation of intrathecal pro-inflammatory cytokines leads to multiple sclerosis-like cortical demyelination and neurodegeneration. Acta Neuropathol Comm, 8:66.

Magliozzi R, Howell O, Durrenberger P, Arico E, James R, Cruciani C, Reeves C, Roncaroli F, Nicholas R, Reynolds R (2019) Meningeal inflammation changes the balance of TNF signalling in cortical grey matter in multiple sclerosis. J Neuroinflammation, 16:259.

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 M (2019) Iron homeostasis, complement, and coagulation cascade as CSF signature of cortical lesions in early multiple sclerosis. Ann Clin Trans Neurol 6:2150-2163.

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 DH (2019) Neuronal vulnerability and multilineage diversity in multiple sclerosis. Nature 573:75-82.

Bevan RJ, Evans R, Griffiths L, Watkins L, Rees MI, Magliozzi R, Allen I, McDonnell G, Kee R, Naughton M, Fitzgerald DC, Reynolds R, Neal JW, Howell OW (2018) Meningeal inflammation and cortical demyelination in acute multiple sclerosis. Ann Neurol 27:305-311.

Jelcic I, Nimer FA, Wang J, Lentsch V, Planas R, Jelcic I, Madjovski A, Ruhrmann S, Faigle W, Frauenknecht K, Pinilla C, Santos R, Hammer C, Ortiz Y, Optiz L, Gronland H, Rogler G, Boyman O, Reynolds R, Lutterotti A, Khademi M, Olsson T, Piehl F, Sospedra M, Martin R (2018) Memory B cells activate brain-homing, autoreactive CD4⁺ T cells in multiple sclerosis. Cell 175:1-16.

Magliozzi R, Howell O, 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 M. (2018) Inflammatory intrathecal profiles and cortical pathology stratify multiple sclerosis patients. Ann Neurol 83:739-755.