Inflammatory diseases of the central nervous system: mechanisms and therapies
Coordinators : R. Liblau / A. Saoudi
Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) that usually begins in young adulthood and progressively leads to disability in most patients. Due to its increasing prevalence, its chronic course, and the partial effect of current disease-modifying drugs, MS has major socio-economical consequences. The overarching objective of our team is to decipher the pathophysiology of inflammatory diseases that target the CNS, with a particular focus on MS as well as other CNS autoimmune or infectious diseases.
AXE 1: T cells in autoimmune diseases of the CNS: migration, functions and regulation
Our aim is to better understand the cellular and molecular determinants leading to ageing and inflammation of the central nervous system (CNS).
To this end we have gathered unique experimental models as well as biological samples from patients. We wish to study the transmigration and effector functions of T cells, notably CD8 T cells, using several animal models of CNS inflammation that we have recently developed in the laboratory. More specifically:
1/ We study the immune mechanisms underlying type 1 narcolepsy, a chronic sleep disorder secondary to the loss of hypothalamic neurons secreting orexin/hypocretin. To this end, we study PBMCs and CSF from patients with type 1 narcolepsy, patients with other sleep disorders and healthy individuals. In addition, we have developed a unique mouse model of immune-mediated narcolepsy allowing us to study the mechanisms of hypothalamus tissue damage as well as the link between type 1 narcolepsy and the pandemic H1N1 influenza vaccine of 2009.
2/ Prof. Guillaume Martin-Blondel et Roland Liblau evaluate, using both in vivo mouse models and in vitro co-culture experiments, the bilateral interactions between T cells and BBB endothelial cells and their potential contribution to the development of inflammatory diseases of the CNS (ageing, multiple sclerosis, SUSAC syndrome, cerebral malaria,… ).
3/ In the frame of paraneoplastic neurological diseases we evaluate the mechanistic link between anti-tumor immune responses, cancer immunotherapy, and autoimmunity within the CNS.
4/ Using animal models of multiple sclerosis, we evaluate the possibility to reprogram regulatory T cells for therapeutic goals.
Coordinators: Prof Roland Liblau and Prof Guillaume Martin-Blondel
AXE 2: Functional genomics and biomarkers of MS treatment
Our team focus on biomarkers associated with response and serious adverse event (SAE) risk in the context of Multiple sclerosis biologic treatment revolution, based on a unique cohort of 1500 patients followed prospectively up to 10 years.
Our main objective is to find biomarkers associated with response and serious adverse events (SAE) prediction during a biological MS treatment. Using Natalizumab (NTZ) as a paradigm, we built up a unique prospective multicentric cohort of 1500 MS patients (The BioNat and Best-MS cohorts) that we followed for up to 10 years using clinical and radiological information as well as biological samples.
We proposed that L-selectin (CD62L) expression in peripheral blood mononuclear cells (PBMC) could be considered as a new risk minimization factor for progressive multifocal leukoencephalopathy (PML) since a 9-fold lower percentage of CD62L was correlated with the risk of PML. It was later confirmed that low CD62L increased the relative risk of PML by 55. Low CD62L values were also associated with AIDS-related PML. The determination of CD62L levels at 2 years of treatment with NTZ was a reliable marker of risk of PML, diagnosed up to 35 infusions later (sensitivity 80%, specificity 87%, hazard ratio=7). We are now performing a prospective study (BEST-MS) in high-risk patients (JCV index >= 0.9 and more than 18 months NTZ) in order to replicate the results found in the retrospectively analyzed BIONAT cohort and to determine optimal thresholds.
We investigate the therapeutic use of CCR5 antagonists in PML-associated immune reconstitution inflammatory syndrome and found that it is supported by strong expression of CCR5 on CD8+ T cells. Our second objective is to investigate the immunogenetics of MS. We found a positive association for TYK2. We showed that TYK2 protective polymorphisms is linked to a Th2 pathway upregulation. We are currently using a genomic approach with a GWAS, exome sequencing, RNA sequencing, miRNA, methylome, and microbiote biomarkers in order to propose the best benefit to risk ratio.
Coordinator: Prof. David Brassat
AXE 3: Role of T cell signaling molecules in central nervous system inflammation
Controlled T cell immunity is a prerequisite for health. An unbalanced response may lead to autoimmune diseases if the immune system reacts too strongly, or allow tumor expansion due to inadequate immune response. Hence, the control mechanisms for accurate T cell activation and differentiation are essential to maintain a good immune homeostasis. Signaling after the engagement of receptors expressed by T cells play an important role in controlling T cell functions and polymorphism or deficiency for these signaling genes could predispose to immune-mediated diseases.
In this regards, our recent studies revealed the implication of Vav1, Themis, CD46 and CD226 in T cell functions and susceptibility to immune mediated disorders. However, the cellular and molecular mechanisms by which these signaling molecules cooperate to regulate T cell function remain unknown.
The objectives of our project are therefore to:
AIM1: To investigate, using novel genetically engineered murine models, how Themis1 and Vav1 signaling molecules regulate T cell functions by dissecting the molecular mechanisms involved.
AIM2: To study how CD226 and CD46 contribute to aberrant response in patients with chronic inflammatory diseases such as multiple sclerosis.
AIM3: To analyze how environmental factors, or their deficiency such as ultraviolet radiation, affect T cell activation and may contribute to pathogenesis.
Coordinator: Dr Abdelhadi Saoudi
AXE4: Transcription factors in normal and pathological immune responses
Our group main interest is to dissect the cellular and molecular mechanisms whereby transcription factors drive pathogenic CD4 T cell differentiation.
We recently demonstrated that the transcription factor Foxo3 plays a key role in the physiopathology of CNS autoimmunity since Foxo3-deficiency is associated with a significant decrease in the severity of EAE. We also provided evidence that this decreased severity of EAE is the consequence of the inability of Foxo3-deficient CD4 T cells to differentiate into pathogenic T helper-1 (Th1) cells producing interferon- (IFN- and granulocyte monocyte colony stimulating factor (GM-CSF).
At the molecular level, we identified Eomes as a direct target gene for Foxo3 in CD4+ T cells and we have shown that lentiviral-based overexpression of Eomes in Foxo3-deficient CD4+ T cells restored both IFN-g and GM-CSF production. Thus, the Foxo3-Eomes pathway is central to achieve the complete specialized gene program required for pathogenic Th1 cell differentiation and development of neuroinflammation.
In direct line with these data, our current project is to analyze the functions of the transcription factor Eomes in normal and pathological conditions and to evaluate the relevance of our results in humans by assessing the impact of a functional defect of FOXO3 and/or EOMES on T cell function from healthy donors or MS patients.
Coordinator: Dr Anne S. Dejean
Cancer Immunol Res, 6 (4), pp. 409-421, 2018, ISSN: 2326-6074 (Electronic) 2326-6066 (Linking).
Put to sleep by immune cells Journal Article
Nature, 562 (7725), pp. 46-48, 2018, ISSN: 1476-4687 (Electronic) 0028-0836 (Linking).
Ann Neurol, 82 (2), pp. 186-195, 2017, ISSN: 1531-8249 (Electronic) 0364-5134 (Linking).
J Allergy Clin Immunol, 2017, ISSN: 1097-6825 (Electronic) 0091-6749 (Linking).
Nat Rev Neurol, 13 (12), pp. 755-763, 2017, ISSN: 1759-4766 (Electronic) 1759-4758 (Linking).
Sci Signal, 10 (502), 2017, ISSN: 1937-9145 (Electronic) 1945-0877 (Linking).
Proc Natl Acad Sci U S A, 113 (39), pp. 10956-61, 2016, ISSN: 1091-6490 (Electronic) 0027-8424 (Linking).
J Exp Med, 213 (12), pp. 2621-2633, 2016, ISSN: 1540-9538 (Electronic) 0022-1007 (Linking).
PLoS Genet, 12 (7), pp. e1006185, 2016, ISSN: 1553-7404 (Electronic) 1553-7390 (Linking).
Nat Rev Neurol, 12 (2), pp. 95-105, 2016, ISSN: 1759-4766 (Electronic) 1759-4758 (Linking).
Neurology, 87 (23), pp. 2491-2494, 2016, ISSN: 1526-632X (Electronic) 0028-3878 (Linking).
Mult Scler, 22 (8), pp. 1048-60, 2016, ISSN: 1477-0970 (Electronic) 1352-4585 (Linking).
Immunity, 45 (4), pp. 774-787, 2016, ISSN: 1097-4180 (Electronic) 1074-7613 (Linking).
Brain, 2016, ISSN: 1460-2156 (Electronic) 0006-8950 (Linking).
Editorial: T cell regulation by the environment Journal Article
Front Immunol, 6 , pp. 229, 2015, ISSN: 1664-3224 (Print) 1664-3224 (Linking).
Therapeutic use of CCR5 antagonists is supported by strong expression of CCR5 on CD8(+) T cells in progressive multifocal leukoencephalopathy-associated immune reconstitution inflammatory syndrome Journal Article
Acta Neuropathol, 129 (3), pp. 463-5, 2015, ISSN: 1432-0533 (Electronic) 0001-6322 (Linking).
J Immunol, 195 (4), pp. 1608-16, 2015, ISSN: 1550-6606 (Electronic) 0022-1767 (Linking).
A prospective observational post-marketing study of natalizumab-treated multiple sclerosis patients: clinical, radiological and biological features and adverse events. The BIONAT cohort Journal Article
Eur J Neurol, 21 (1), pp. 40-8, 2014, ISSN: 1468-1331 (Electronic) 1351-5101 (Linking).
J Exp Med, 208 (11), pp. 2183-91, 2011, ISSN: 1540-9538 (Electronic) 0022-1007 (Linking).
Brain, 134 (Pt 3), pp. 693-703, 2011, ISSN: 1460-2156 (Electronic) 0006-8950 (Linking).
Antioxid Redox Signal, 14 (4), pp. 663-74, 2011, ISSN: 1557-7716 (Electronic) 1523-0864 (Linking).
Nature, 476 (7359), pp. 214-9, 2011, ISSN: 1476-4687 (Electronic) 0028-0836 (Linking).
Nat Immunol, 10 (5), pp. 504-13, 2009, ISSN: 1529-2916 (Electronic) 1529-2908 (Linking).
Our team aims at understanding the cellular and molecular determinants leading to inflammation and autoimmunity in the central nervous system. To this end, we have generated unique genetically modified mouse models on which innovative research can be conducted. We have also contributed to local and national biological resources from patients with MS or narcolepsy that allow us to translate directly to the clinic the relevance of our key findings (validation of pathways contributing to disease susceptibility, identification of new biomarkers, and even investigator-initiated therapeutic trials).s).
Our scientific program relies in part on the in-depth analysis of key pathways that we have pinpointed over the recent years (self molecular mimicry, Vav1, Themis, TYK2, CD226). In addition, we now propose emerging projects related to topics for which we have made novel observations (Foxo3, Eomes, Blimp) or generated unique tools (narcolepsy, paraneoplastic neurological disease).
Our team is composed of a mix of senior and more junior investigators from seven countries and diverse backgrounds (physician, scientist, veterinary, pharmacist…). This favors a vivid and dynamic scientific environment and provides unique opportunities to develop both basic and translational research and even investigator-sponsored clinical trials. We benefit from a solid international visibility in the field of neuroimmunology. National and international collaborations of the highest scientific level have been built over the years. These networks give access to both scientific inputs and technological expertise for our projects. Some of our current lines of research have raised interest from Biotech or Pharma such as GSK, Biogen and Genzyme providing possible alternative sources of funding, while keeping our research independent.
Our team has been successful in obtaining a number of grants for the proposed projects from local, national or international origins.
- Mars Lennart T
- Piaggio Eliane
- Zapula Jacques
- Hayder Myriam
- Gaud Guillaume
- Scheikl Tanja
- Lazarczyk Macjek
- Céline Colacios
- Lamouroux Lucile
- Ramadan Raouf
- Lucca Liliana
- Stienne Caroline
- Gebauer Christina
- Kassem Sahar
- Pedros Christophe
- Saxena Amit
- Couturier Nicolas
- Bergereau Emilie
- Bohossian Nora
- Ordonez Laurence
- Casemaiyou Audrey
- Duguet Fanny
- Chabod Mariane
- Cabarocas Julie
- Cassan Cécile
Hans Lassmann et Jan Bauer Brain Research Institute, Vienne, Austria
Britta Engelhardt, Theodor Kocher Institute, University of Bern, Switzerland
Burkhard Becher, Institute of Experimental Immunology, University of Zurich, Switzerland
Mehdi Tafti, Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
Heinz Wiendl, Department of Neurology, University of Münster, Germany
Yves Dauvilliers, Department of Sleep Disorders, Montpellier, France
Christelle Peyron, INSERM U1028, CNRS UMR 5292, Center for Research in Neuroscience, Lyon, France
Nicolas Fazilleau, CPTP Inserm UMR1043 – CNRS 5282, Toulouse, France
Pr Tomas Olsson (Neuroimmunology Unit, Karolinska Hospital, Stockholm, Suède).
Dr Bernard Malissen (CIML, Marseille)
Drs Bernard Monsarrat et Anne Gonzalez-de-Peredo (Génopole Midi-Pyrénées, IPBS, Toulouse)
Pr Eric Oswald (IRSD, Toulouse) et le Dr Bernhard Ryffel (CNRS, Orléans)
Pr Ariel Miller (Technion-Israel Institute of Technology, Haïfa, Israël)
Pr Chantal Tallaksen (University of Oslo, Norvège)
Drs Renato Mantegazza et Fulvio Baggi (Fondazione Istituto Neurologico Carlo Besta, Milan, Italie)
Dr Konstantinos Poulas (University of Patras, Grèce)
Pr Arthur Melms (Tübingen University Medical Center, Tubingen, Allemagne)
Dr Socrates Tzartos (Pasteur Institute, Athens, Grèce),
DR Zsolt Illes (University of Pecs, Pecs, Hongrie)
Dr Carlos Casasnovas Pons (Hospital Universitari de Bellvitge, Barcelona, Espagne)
Dr Nicholas Willcox (University of Oxford, Oxford, UK)
Dr Anna Kostera-Pruszczyk (Medical University of Warsaw, Pologne)
Dr Sonia Berrih-Aknin (Institut de Myologie, Paris, France).
Dr. Heinz Wiendl! http://www.uni-muenster.de/Cells-in-Motion/people/all/wiendl-h.php
Dr. Richard Weller https://www.ed.ac.uk/pathway-medicine/our-staff/staff-profiles/drrichardweller
Dr. Bruno Peault http://www.crm.ed.ac.uk/people/bruno-p%C3%A9ault
Dr. Dirk Sieger https://www.ed.ac.uk/centre-neuroregeneration/cnr-research-groups/dirk-sieger
Dr. Anna Williams http://www.crm.ed.ac.uk/people/anna-williams
Dr. Britta Engelhardt http://www.tki.unibe.ch/research/research_groups/britta_engelhardt/index_eng.html
Dr. Andre Lieber http://depts.washington.edu/iscrm/research/faculty/andre-lieber
Anne Dejean :
Dr. Thierry Walzer (Centre International de Recherche en Infectiologie, Lyon, France)
Pr. Stephen M Hedrick (UCSD, La jolla, CA, USA)
Dr Georges Bismuth (Institut Cochin, Paris, France)
Matthias ZYTNICKI (Unité de Mathématiques et Informatique Appliquées de Toulouse (MIAT)
Dr Jean Emmanuel Sarry (centre de recherche en cancérologie de Toulouse, France)
Gabrielle Belz (Walter and Eliza Hall Institute, Parkville, Australia)
Marco Herold (Walter and Eliza Hall Institute, Parkville, Australia)
Hans Hacker (Saint-Jude Children’s Hospital, Memphis, US)
– Manuel Comabella VHIR, Barcelone, Espagne
– Heinz Wiendl, Muenster University, Allemagne
– Jean-Laurent Casanova, the Rockfeller University , NY, USA