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Simon Rinaldi was a medical undergraduate and postgraduate general medical trainee in Manchester. He moved to the University of Glasgow in 2007 to undertake a PhD looking into the neuroimmunology of inflammatory peripheral nerve disease, supervised by Professor Hugh Willison. Following 2 years of clinical neurology training in the East of Scotland, he was appointed as an NIHR Clinical Lecturer in Neurology at the University of Oxford in March 2012. During his lectureship he developed models of immune mediated axonal injury and demyelination using human induced pluripotent stem cells. He has now been awarded an MRC Clinician Scientist Fellowship to identify the specific antibodies responsible for the acute and chronic inflammatory neuropathies and to delineate their pathogenic mechanisms.
Immune mediated axonal injury
In this model system, human axons (neurofilament, green) in myelinating co-culture (myelin basic protein, red) develop pathological blebbing and degenerate after exposure to an inflammatory neuropathy associated antibody plus a source of complement (lower panel).
Training and Qualifications
BSc (Hons) - University of Manchester (2002)
MBChB - University of Manchester (2003)
MRCP (UK) - Royal College of Physicians, London (2006)
PhD - University of Glasgow (2011)
MRCP (Neuro) - Royal College of Physicians and Surgeons of Glasgow (2011)
CCT (Neurology) - Joint Royal Colleges of Physicians Training Board (2015)
- Neural Injury Group Research Group
Medical Research Council (2017-present)
Academy of Medical Sciences (2014-2016 )
University of Oxford Medical Research Fund (2014-2017 )
National Institute of Health Research (2012-2016 )
Wellcome Trust (2007-2010)
MRC Clinician Scientist and Senior Clinical Researcher
- Assistant Director, Clinical Neurosciences Undergraduate Education
- Honorary Consultant Neurologist
Latest paper now published in Brain - Co-cultures with stem cell-derived human sensory neurons reveal regulators of peripheral myelination
Sensory neurons derived from human stem cells
Sensory neurons differentiated from human induced pluripotent stem cells form ganglia like clusters (Brn3a, purple) and extend axons (neurofilament, green) in culture.
I lead the University of Oxford's programme of research into the inflammatory neuropathies.
Guillain-Barré syndrome (GBS) is a devastating, acute inflammatory neuropathy with substantial mortality as well as morbidity. There is an urgent need to improve upon the current situation where 4-5% of GBS patients die, 20-25% require mechanical ventilation, 14-20% have severe disability at 1 year, and many more are left with residual weakness, persistent pain and/or are unable to resume their former occupation.
Chronic inflammatory demyelinating polyradiculo-neuropathy (CIDP) and multifocal motor neuropathy (MMN) are chronic inflammatory neuropathies which produce significant long-term and often progressive disability with a sizeable economic cost.
Despite this, disease modifying therapies for these conditions have not advanced in over 20 years, the pathological mechanisms driving them are incompletely characterised, and there is no reliable way to identify early those patients who respond poorly to standard treatments and are thus most likely to benefit from additional therapy.
We have now successfully achieved myelination with human induced pluripotent stem cell derived neurons and Schwann cells in co-culture, a goal of numerous peripheral nerve laboratories around the world. Given the differences between rodent and human myelin, this offers clear advantages for the study of peripheral nerve injury and repair processes relevant to human health and disease.
Furthermore, the complex landscape of the live neural membrane, with interactions between neighbouring molecules, including those at specialised regions such as the node of Ranvier, is known to influence antibody-antigen interactions, yet cannot be accurately recapitulated in solid phase assays or in frozen sections. As well as better assessing these interactions, this technique allows the simultaneous evaluation of pathogenic effects and injury mechanisms.
Our research also includes a clinical / observational study of chronic inflammatory neuropathy (Bio-SPiN) and the group contributes to and benefits from close links with the comprehensive and high-quality clinical-serological database of over 1400 patients encapsulated in the International GBS Outcome Study (IGOS). We have previously been involved in therapeutic trials of fingolimod for CIDP and eculizumab for GBS.
Antibodies to heteromeric glycolipid complexes in Guillain-Barré syndrome.
Rinaldi S. et al, (2013), PLoS One, 8
The GD1a glycan is a cellular receptor for adenoviruses causing epidemic keratoconjunctivitis.
Nilsson EC. et al, (2011), Nat Med, 17, 105 - 109
Analysis of lectin binding to glycolipid complexes using combinatorial glycoarrays.
Rinaldi S. et al, (2009), Glycobiology, 19, 789 - 796
The neuropathic potential of anti-GM1 autoantibodies is regulated by the local glycolipid environment in mice.
Greenshields KN. et al, (2009), J Clin Invest, 119, 595 - 610
Co-cultures with stem cell-derived human sensory neurons reveal regulators of peripheral myelination.
Clark AJ. et al, (2017), Brain, 140, 898 - 913
CIDP presenting as recurrent severe back pain without weakness or sensory loss.
Bäumer D. et al, (2016), Pract Neurol, 16, 488 - 492
Complex antibodies provide a simple explanation for the plurality of clinical presentations in the Guillain Barré syndromes.
Rinaldi S., (2016), Eur J Neurol, 23, 235 - 236
Transfected Cell Based Immunoassays
Human embryonic kidney cells transfected with neurofascin-155 (green) are bound by IgG (red) in the serum of a patient with CIDP.
In parallel to to work using human induced pluripotent stem cells, we have also established a transfected cell based assay to detect antibodies against the paranodal proteins neurofascin-155 and contactin-1, known to be associated with certain subtypes of CIDP and combined central and peripheral demyelination (CCPD). These will soon be available for clinical testing.
Neuronal calcium flux in response to antibody and complement mediated injury
Sensory neurons demonstrate a somal calcium spike in the early stages of immune mediated injury.