Group name: Neuroimmunology, Dept. Neurology, OUH
Group leader: Zsolt Illes MD, PhD, DSc
Group members: Nellie A. Martin MSc, PhD student, Maria L. Elkjaer MSc, PhD student, Tobias Sejbaek MD, PhD student, Tobias Frisch MSc, PhD student (co-supervisor), Viktoria Papp MD, PhD student (co-supervisor), Malte Roar, mediacl student, Kirsten Hyrlov BSc student, Helle H. Nielsen MD, PhD, Morten Blaabjerg MD, PhD
Department & University/Hospital/Other:
Department of Neurology, OUH
Institute of Molecular Medicine, SDU,
Institute of Clinical Research, SDU,
BRIDGE, Brain Research – Interdisciplinary Guided Excellence, SDU
Funding sources: Lundbeckfonden, Scleroseforeningen, Region Syddanmark, Odense University Hospital, Biogen-Idec, Merck-Serono, Sanofi-Genzyme, Direktør Ejnar Jonasson kaldet Johnsen, og Hustru’s Mindelaget, University of Southern Denmark, Jascha Fonden, Hungarian National Research Fund OTKA, Fonden for Lægevidenskabensfremme, The Foundation for the Advancement of Medical Science and Brogaards Memorial Grant, Dir. Leo Nielsens Foundation
Description of research:
1. We use the cuprizone (CPZ) model of experimental de- and remyelination to examine (i) microRNA, (ii) transcriptome, (iii) and proteome/post-translational proteome of de- and remyelination in the brain. By using these databases, we found that absence of miR-146a protects against demyelination and increases microglia function. We identified homologous genes in multiple sclerosis (MS) lesions related to de- and remyelination by overlapping transcriptome of MS lesions with the CPZ transcriptomes. We quantified 130 peptides of these genes in the 97 CSF by targeted proteomics, and identified 4 proteins differentially regulated between progressive and relapsing MS: all expressed during acute remyelination and correlate negatively pro-inflammatory responses. (manuscripts in prep)
2. We performed next-generation RNA sequencing of 73 brain lesions of progressive MS that covers the different phases of lesion evolution, and 25 contols brain areas. We establish the transcriptome signature of MS lesion evolution, and look for endogeneous and exogeneous viral sequences. We link these data to genome-wide DNA methylation and proteome/metabolome of the same MS lesions in order to examine epigenetic effect of viral sequences and their association with lesion evolution. We also plan to examine if these transcriptome signatures are differentially regulated in the CSF proteome of relapsing versus progressive MS as potential composite biomarkers predicting disease progression.
3. In our prospective ProActive study, we examined social cognition and emotion recognition in 85 MS patients and correlate data with eye motion, cognition, optical coherence tomography (OCT) and clinical outcomes. We also examine biomarkers related to axonal damage and neuroinflammation in the CSF of MS patients after a novel oral treatment in our prospective , ongoing TREMEND trial. We also used frequent MRI combined with protein array, proteomics and endothelial-microvesicle array to examine pathogenesis and biomarkers related to inflammatory blood-brain barrier disruption (manuscripts partly in prep)
4. We compared the urine proteome and metabolome of patients with neuromyelitis optica spectrum disorders (NMOSD) and MS. We examine, if pathological antibody responses are reflected by urine immunoglobulins, and can be used as diagnostic tools in suspected antibody-mediated diseases, when antibodies are not known. We compare the nationwide epidemiology of NMOSD in Denmark versus Hungary, and collect blood samples for antibody studies.
5. We examine the pathogenesis of rare neuroimmunological diseases. By using 7T MRI and brain samples, we showed that CLIPPERS is characterized by diffuse brain inflammation. Our recent proteome data of CLIPPERS CSF have been validated by brain histology and protein arrays, and identified complement activation as a major pathway and 4 biomarkers differentiating CLIPPERS from MS (manuscripts partly in prep).
Key publications (last 10 years):
- Palotai M…Illes Z, Guttmann RCG (eqaully contributed). 2017. Changes to the septo-fornical area might play a role in the pathogenesis of anxiety in multiple sclerosis. Multiple Sclerosis, in press
- Blaabjerg M, … Illes Z. 2016. Wide-spread inflammation in CLIPPERS syndrome indicated by autopsy and ultra high field 7T MRI. Neurology: Neuroimmunol Neuroinflam, 3:e226.
- Herwerth M, … Illes Z, … Hemmer B. 2016. In vivo imaging of axon damage in a model of neuromyelitis optica-related pathology. Ann Neurol, Mar 6. doi: 10.1002/ana.24630.
- Zeka B, …Illes Z, … Bradl M. 2015. Highly encephalitogenic aquaporin 4-specific T cells and NMO-IgG jointly orchestrate lesion location and tissue damage in the CNS. Acta Neuropathol. 130:783.
- Nielsen HH, …Illes Z. 2015. The urine proteome profile is different in neuromyelitis optica compared to MS. PLoS One. PLoS One. 2015;10:e0139659.
- Massilamany C, … Illes Z, Reddy J. 2014. SJL mice infected with Acanthamoeba castellanii develop central nervous system autoimmunity through the generation of cross-reactive T cells for myelin antigens. PLoS One. 9:e98506.
- Mike A, … Illes Z. 2013. Disconnection mechanism and regional cortical atrophy contribute to impaired processing of facial expressions in multiple sclerosis: a structural MRI study. PLoS One. 8:e8242
- Kalluri SR, Illes Z, … Hemmer B. 2010. A novel bioassay to quantify and functionally characterise antibod-ies to native aquaporin-4 in neuromyelitis optica. Arch Neurol. 67:1201.
- Veto S, … Illes Z. 2010. Inhibiting poly(ADP-ribose) polymerase: a potential therapy against oligodendro-cyte death. Brain. 133:822
- Banati M, … Illes Z. 2010. Social cognition and Theory of Mind in patients with relapsing-remitting multiple sclerosis. Eur J Neurol. 17:426.
- Blaabjerg M…Illes Z. 2017. Omics-based approach reveals complement-mediated inflammation in CLIPPERS (submitted to Ann Neurol)
- Martin NA…Illes Z. 2017. MicroRNA-146a deficiency protects against cuprizone-induced demyelination (submitted to J Neurosci)
- Nielsen HH…Illes Z. 2017. Integrin and IL-16/Th17 biomarker cluster differentiate AQP4-IgG+ NMO spectrum disorders, relapsing-remitting MS and healthy controls (submitted to Mult Scler)
- Martin NA…Illes Z. 2017. Translational mult-omics identifies biomarkers related to acute remyelination in the CSF of multiple sclerosis patients (submitted to Brain)
- Gallyas F…Illes Z. 2009. Combination of a PARP inhibitor and an AKT kinase activating compound. NSZO: A61K 45/06,
- PCT/HU2009/000055 esp@cenet link; Submitted: 2008, Hungary (NoP0800414); Pub-lic:2009
- Powers R…Illes Z. Biomarkers used to detect and monitor neurological autoimmune diseases. 2014. Pub. No.: US 2014/0045197 Al. Pub. Date: Feb. 13,2014.
- Lambertsen K...Illes. Z. 2015. Fumaric acid derivatives for medical use.
Finn Sellebjerg (CU), Thor Petersen (AU), Peter Garred (CU), Allan Stensballe (AAU), Torben Kruse (SDU), Mads Thomassen (SDU), Jan Baumbach (SDU), Martin R. Larsen (SDU), Trevor Owens (SDU), Asa Fex-Svenningsen (SDU)
Charles Guttmann (Harvard Medical School), Richard Reynolds (Imperial College, UK), Bernhard Hemmer (Technische Universitat, Munich), Hans Lassmann (Medical University of Vienna), Friedemann Paul (Charite, Berlin), Jacqueline Palace (Oxford University), Francois Cotton and Romain Marignier (University Lyon)
cuprizone and EAE model of MS, Mesoscale array (neurofilament, inflammation), microglia-related in vitro assays, cellular immunology, working with KO and transgenic mice, RNA sequencing, real-time PCR, apoptosis, cognition, clinical trials