Neuroinflammation and multiple sclerosis
Professor Richard Reynolds
Multiple Sclerosis is characterised by the presence of inflammation, demyelination and axonal loss at multiple sites throughout the central nervous system. All these pathologies contribute to a loss of neurological function and the resulting symptoms are predominantly related to the site of the damage. Whereas focal areas of inflammation and demyelination are thought to be responsible for the acute symptoms that occur during relapses, the chronic progressive loss of neurological function is thought to be due to a combination of a failure of remyelination, axon loss and neurodegeneration. 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.
Mechanisms of demyelination and neuronal loss in multiple sclerosis
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). Therefore, we are using human tissues and experimental models of MS to investigate the mechanisms responsible for this neuronal loss. In collaboration with the group of Francesca Aloisi in Rome, we have demonstrated the involvement of ectopic meningeal lymphoid structures in cortical pathology in MS (fig 3A), in particular in sub-pial demyelination and neurodegeneration (fig 3B). 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). Our current studies are investigating the molecular nature of the mediators responsible for this pathology.
Remyelination in MS
Myelin repair in the adult CNS is thought to be brought about via the generation of new oligodendrocytes from quiescent progenitors, but very little is known about the signals that cause them to become reactivated in order to differentiate into oligodendrocytes for remyelination and to support their survival. We are investigating the characteristics of these cells in vitro using a combination of cellular and molecular techniques and are particularly interested in contact dependent signals from the axon that stimulate survival and process outgrowth (fig 1A). Recent studies in this laboratory (Palser et al, 2009) have demonstrated a role for the neural cell adhesion molecule (NCAM) in this process (fig 1B).
Remyelination in the MS brain is suggested to fail at an early stage, although very little is known about the natural history of this repair process in the human brain. Our recent studies have indicated that remyelination can be extensive in MS despite a long disease course (Patani et al, 2007) (fig 2).
The Multiple Sclerosis Society Tissue Bank
The Tissue Bank was set up at the beginning of 1998, funded by a 5-year grant from the UK MS Society, to provide a reliable source of post-mortem MS CNS material for researchers around the UK. 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). 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. 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. The MSS Tissue Bank is currently funded by a programme grant from the UK MS Society until 2014 and operates alongside the Parkinson’s Disease Society Tissue Bank.
http://www.ukmstissuebank.imperial.ac.uk/
Group members
Dr Djordje Gveric – Tissue Bank Manager (UK MS Tissue Bank)
Dr Roberta Magliozzi - Honorary Research Fellow
Dr Paolo Giannetti - Clinical Research Fellow
Dr Joel Raffel - Academic Foundation Clinical Fellow
Miss Renee Schalks - PhD Student (MRC)
Miss Eleanor Browne - PhD student (MRC)
Miss Julia Steele - Research Technician (UK MS Tissue Bank)
Miss Amanda Hajjawi - Research Technician (UK MS Tissue Bank)
Mrs Sue Fordham – Office manager (UK MS Tissue Bank)
The Neuroinflammation and Multiple Sclerosis group is part of MoS@IC - Multiple Sclerosis Research at Imperial College - which was formed in 2007 to translate insights gained from basic, experimental and clinical studies into the development of novel therapies for MS.
Recent publications
Papadopoulos D, Rundle J, Patel R, Marshall I, Stretton J, Eaton R, Richardson JC, Gonzalez MI, Philpott KL, Reynolds R (2010) FTY720 ameliorates MOG-EAE by suppressing both cellular and humoral immune responses. J Neurosci Res 88:346–359.
Durrenberger PF, Fernando S, Kashefi SN, Ferrer I, J-J Hauw, Seilhean D, Smith C, Walker R, Al-Sarraj S, Troakes C, Palkovits M, Kasztner M, I Huitinga, Arzberger T, Dexter DT, Kretzschmar H and Reynolds R (2010) Effects of antemortem and postmortem variables on human brain mRNA quality: a BrainNetEurope study. J Neuropathol Exp Neurol 69:70-81.
Anderson JM, Patani R, Reynolds R, Nicholas R, Compston A, Spillantini MG, Chandran S (2010) Abnormal tau phosphorylation in primary progressive multiple sclerosis. Acta Neuropathol. 119:591–600.
Amadio S, Montilli C, Magliozzi R, Bernardi G, Reynolds R, Volonte C (2010) P2Y12 receptor protein in cortical gray matter lesions in multiple sclerosis. Cerebral Cortex. 20:1263-1273.
Kim JY, Shen S, Dietz K, Seiser C, Howell O, Reynolds R, He Y, Casaccia-Bonnefil P (2010) Nuclear export of HDAC1 is induced by pathological conditions and is essential for the onset of axonal damage. Nature Neurosci. 13:180-189.
AndrodiasG, Reynolds R, ChanalM, Ritleng C, Confavreux C, Nataf S (2010) A link between meningeal T-cells and axonal loss in progressive multiple sclerosis spinal cords. Ann Neurol. 68:465-476.
Owen DR, Howell OW, Tang SP, Wells LA, Bennacef I, Bergstrom M, Gunn RN, Rabiner EA, Wilkins MR, Reynolds R, Matthews PM, Parker CA (2010) Two binding sites for [3H]PBR28 in human brain: implications for TSPO PET imaging of neuroinflammation. Journal of Cerebral Blood Flow & Metabolism. 30:1608-1618.
Serafini B, Severa M, Columba-Cabezas S, Rosicarelli B, Veroni C, Chiappetta G, Magliozzi R, Reynolds R, Coccia EM, Aloisi F (2010) Epstein-Barr virus latent infection and BAFF expression in B cells in the multiple sclerosis brain: implications for viral persistence and intrathecal B-cell activation. J Neuropath Exp Neurol. 69:677-693.
Howell OW, Rundle JL, Garg A, Komada M, Brophy PJ, Reynolds R (2010) Activated microglia mediate axo-glial disruption that contributes to axonal injury in multiple sclerosis. J Neuropath Exp Neurol. 69:1017-1033.
Aloisi F, Serafini B, Magliozzi R, Howell O, Reynolds R (2010) Detection of Epstein-Barr virus and B-cell follicles in the multiple sclerosis brain: what you find depends on how and where you look. Brain epub Aug 25.
Magliozzi R, Howell OW, Reeves C, Roncaroli F, Nicholas R, Serafini B, Aloisi F and Reynolds R (2010) A gradient of neuronal loss and meningeal inflammation in multiple sclerosis. Ann Neurol. 68:477-493.
Owen DR, Gunn RN, Rabiner EA, Bennacef I, Fujita M, Kreisl WC, Innis RB, Pike VW, Reynolds R, Matthews PM, Parker CA (2010) Mixed affinity binding in humans with 18 kDa translocator protein (TSPO) ligands. J Nuc Med. 52:24-32.
Campbell GR, Ziabreva I, Reeve AK, Krishnan KJ, Reynolds R, Howell O, Lassmann H, Turnbull DM, Mahad DJ (2011) Mitochondrial deletions within neurons in multiple sclerosis. Ann Neurol 69:481-492.
Sun G, Reynolds R, Leclerc I, Rutter G (2011) LKB1 deletion causes axon degeneration in the spinal cord and hid-limb paralysis. Disease Models & Mechanisms 4:193-202.
Schmitt A, Leonardi-Essmann F, Durrenberger PF, Parlapani E, Spanagel R, Herrera-Marschitz M, Reynolds R, Falkai P, Gebicke-Haeter PJ. (2011) Regulation of immune-modulatory genes in left superior temporal cortex of schizophrenia patients. World J Biol Psych 12:201-215.
Lovato L, Willis SN, Rodig SJ, Caron T, Almendinger S, Howell O, Reynolds R, O’Connor KC, Hafler DA (2011) A network of B-cells populates the meninges and parenchyma of patients with MS. Brain 134:534-541.
Owen DRJ, Lewis AJM, Reynolds R, Rupprecht R, Eser D, Wilkins MR, Nutt DJ, Parker CA (2011) Variation in binding affinity of the novel anxiolytic XBD172 for the 18kDa translocator protein in human brain. Synapse. 65:257-259.
Reynolds R, Roncaroli F, Nicholas R, Radotra B, Gveric D, Howell O (2011) The neuropathological basis of clinical progression in multiple sclerosis. Acta Neuropathol 122:155-170.
Howell OW, Reeves CA, Carassiti D, Nicholas R, Radotra B, Gentleman S, Roncaroli F, Gveric D, Serafini B, Aloisi A, Magliozzi R, Reynolds R (2011) Meningeal inflammation is widespread and linked to cortical pathology in multiple sclerosis. Brain 134:2755-2771.
The International Multiple Sclerosis Genetics Consortium (IMSGC) (2011) Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 476:214-219.
Politis M, Giannetti P, Su P, Turkheimer F, Keihaninejad S, Wu K, Waldman A, Reynolds R, Nicholas R, Piccini P (2012) Microglial activation in the cortical grey matter of patients with multiple sclerosis correlates with measures of impairment. In press in Neurology.
Durrenberger PF, Grünblatt E, Fernando FS, Monoranu CM, Evans J, Riederer P, Reynolds R, Dexter DT (2012) Inflammatory pathways in Parkinson’s disease – a BNE microarray study. In press in Parkinson’s Disease.
Durrenberger PF, Ettorre A, Kamel F, Webb LV, Sim M, Nicholas RS, Malik O, Reynolds R, Boyton RJ, Altmann DM (2012) Innate immunity in multiple sclerosis white matter lesions: expression of natural cytotoxicity triggering receptor 1 (NCR1). J Neuroinflammation on line.
McMahon JM, McQuaid S, Reynolds R, Fitzgerald U (2012) Expression of ER stress and hypoxia associated molecules in grey matter lesions in multiple sclerosis. Multiple Sclerosis J , early access.
