Inflammatory diseases of the central nervous system: mechanisms and therapies

Coordinators : R. Liblau / A. Saoudi

Scientific Objectives


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.

Our Projects


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.

 

Coordinators: Prof. David Brassat and  Dr Emmanuel Treiner
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.

 

Coordinators: Dr Abdelhadi Saoudi and Dr Anne Astier
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 immune responses in the central nervous sytem

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 showed that the Foxo3-Eomes axis 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.

We also investigate the role of transcription factors in the management of neuronal death in neurodegenerative diseases. Indeed, we recently observed that Foxo3 deficient mice are resistant to the induction of neuronal death in a Parkinson’s disease model. We are now trying to elucidate the role of different cell types (neurons, microglia, CD4 T) deficient in Foxo3 in this neuroprotection, to characterize their translational and metabolic state, and interactions. We aim at proposing new therapeutics targeting both neuronal death and neuroinflammation in these multifactorial pathologies.

 

Coordinators: Dr Anne S. Dejean et Marion Szelechowski

Other information


Publications

2019

Yshii, L; Pignolet, B; Maure, E; Pierau, M; Brunner-Weinzierl, M; Hartley, O; Bauer, J; Liblau, R

IFN-gamma is a therapeutic target in paraneoplastic cerebellar degeneration Journal Article

JCI Insight, 4 (7), 2019, ISSN: 2379-3708 (Electronic) 2379-3708 (Linking).

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Walter, O; Treiner, E; Bonneville, F; Mengelle, C; Vergez, F; Lerebours, F; Delobel, P; Liblau, R; Martin-Blondel, G; Immune Checkpoint Inhibitors in, Study Group P M L

Treatment of Progressive Multifocal Leukoencephalopathy with Nivolumab Journal Article

N Engl J Med, 380 (17), pp. 1674-1676, 2019, ISSN: 1533-4406 (Electronic) 0028-4793 (Linking).

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Schwab, N; Schneider-Hohendorf, T; Pignolet, B; Bucciarelli, F; Scandella, L; Ciron, J; Biotti, D; Lebrun-Frenay, C; Mathey, G; Clavelou, P; Pelletier, J; Ostkamp, P; Meinl, I; Windhagen, S; Klotz, L; Gross, C C; Meuth, S G; Deisenhammer, F; Brassat, D; Wiendl, H; Best, Study Group M S

Prospective validation of the PML risk biomarker l-selectin and influence of natalizumab extended intervals Journal Article

Neurology, 93 (12), pp. 550-554, 2019, ISSN: 1526-632X (Electronic) 0028-3878 (Linking).

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Salvioni, A; Belloy, M; Lebourg, A; Bassot, E; Cantaloube-Ferrieu, V; Vasseur, V; Blanie, S; Liblau, R S; Suberbielle, E; Robey, E A; Blanchard, N

Robust Control of a Brain-Persisting Parasite through MHC I Presentation by Infected Neurons Journal Article

Cell Rep, 27 (11), pp. 3254-3268 e8, 2019, ISSN: 2211-1247 (Electronic).

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Rousset, S; Treiner, E; Moulis, G; Pugnet, G; Astudillo, L; Paricaud, K; Puissant-Lubrano, B; Arlet, P; Blancher, A; Sailler, L

High rate of indeterminate results of the QuantiFERON-TB Gold in-tube test, third generation, in patients with systemic vasculitis Journal Article

Rheumatology (Oxford), 2019, ISSN: 1462-0332 (Electronic) 1462-0324 (Linking).

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Klotz, L; Eschborn, M; Lindner, M; Liebmann, M; Herold, M; Janoschka, C; Torres Garrido, B; Schulte-Mecklenbeck, A; Gross, C C; Breuer, J; Hundehege, P; Posevitz, V; Pignolet, B; Nebel, G; Glander, S; Freise, N; Austermann, J; Wirth, T; Campbell, G R; Schneider-Hohendorf, T; Eveslage, M; Brassat, D; Schwab, N; Loser, K; Roth, J; Busch, K B; Stoll, M; Mahad, D J; Meuth, S G; Turner, T; Bar-Or, A; Wiendl, H

Teriflunomide treatment for multiple sclerosis modulates T cell mitochondrial respiration with affinity-dependent effects Journal Article

Sci Transl Med, 11 (490), 2019, ISSN: 1946-6242 (Electronic) 1946-6234 (Linking).

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Giner-Delgado, C; Villatoro, S; Lerga-Jaso, J; Gaya-Vidal, M; Oliva, M; Castellano, D; Pantano, L; Bitarello, B D; Izquierdo, D; Noguera, I; Olalde, I; Delprat, A; Blancher, A; Lalueza-Fox, C; Esko, T; O'Reilly, P F; Andres, A M; Ferretti, L; Puig, M; Caceres, M

Evolutionary and functional impact of common polymorphic inversions in the human genome Journal Article

Nat Commun, 10 (1), pp. 4222, 2019, ISSN: 2041-1723 (Electronic) 2041-1723 (Linking).

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Dejean, A S; Joulia, E; Walzer, T

The role of Eomes in human CD4 T cell differentiation: A question of context Journal Article

Eur J Immunol, 49 (1), pp. 38-41, 2019, ISSN: 1521-4141 (Electronic) 0014-2980 (Linking).

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Beltran, E; Nguyen, X H; Queriault, C; Barateau, L; Dauvilliers, Y; Dornmair, K; Liblau, R S

Shared T cell receptor chains in blood memory CD4(+) T cells of narcolepsy type 1 patients Journal Article

J Autoimmun, 100 , pp. 1-6, 2019, ISSN: 1095-9157 (Electronic) 0896-8411 (Linking).

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Bassetti, C L A; Adamantidis, A; Burdakov, D; Han, F; Gay, S; Kallweit, U; Khatami, R; Koning, F; Kornum, B R; Lammers, G J; Liblau, R S; Luppi, P H; Mayer, G; Pollmacher, T; Sakurai, T; Sallusto, F; Scammell, T E; Tafti, M; Dauvilliers, Y

Narcolepsy - clinical spectrum, aetiopathophysiology, diagnosis and treatment Journal Article

Nat Rev Neurol, 15 (9), pp. 519-539, 2019, ISSN: 1759-4766 (Electronic) 1759-4758 (Linking).

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Aron Badin, R; Bugi, A; Williams, S; Vadori, M; Michael, M; Jan, C; Nassi, A; Lecourtois, S; Blancher, A; Cozzi, E; Hantraye, P; Perrier, A L

MHC matching fails to prevent long-term rejection of iPSC-derived neurons in non-human primates Journal Article

Nat Commun, 10 (1), pp. 4357, 2019, ISSN: 2041-1723 (Electronic) 2041-1723 (Linking).

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2018

Eissmann, M F; Dijkstra, C; Wouters, M A; Baloyan, D; Mouradov, D; Nguyen, P M; Davalos-Salas, M; Putoczki, T L; Sieber, O M; Mariadason, J M; Ernst, M; Masson, F

Interleukin 33 Signaling Restrains Sporadic Colon Cancer in an Interferon-gamma-Dependent Manner Journal Article

Cancer Immunol Res, 6 (4), pp. 409-421, 2018, ISSN: 2326-6074 (Electronic) 2326-6066 (Linking).

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Liblau, R S

Put to sleep by immune cells Journal Article

Nature, 562 (7725), pp. 46-48, 2018, ISSN: 1476-4687 (Electronic) 0028-0836 (Linking).

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Gaud, G; Roncagalli, R; Chaoui, K; Bernard, I; Familiades, J; Colacios, C; Kassem, S; Monsarrat, B; Burlet-Schiltz, O; de Peredo, A G; Malissen, B; Saoudi, A

The costimulatory molecule CD226 signals through VAV1 to amplify TCR signals and promote IL-17 production by CD4(+) T cells Journal Article

Sci Signal, 11 (538), 2018, ISSN: 1937-9145 (Electronic) 1945-0877 (Linking).

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Tugues, S; Amorim, A; Spath, S; Martin-Blondel, G; Schreiner, B; De Feo, D; Lutz, M; Guscetti, F; Apostolova, P; Haftmann, C; Hasselblatt, P; Nunez, N G; Hottiger, M O; van den Broek, M; Manz, M G; Zeiser, R; Becher, B

Graft-versus-host disease, but not graft-versus-leukemia immunity, is mediated by GM-CSF-licensed myeloid cells Journal Article

Sci Transl Med, 10 (469), 2018, ISSN: 1946-6242 (Electronic) 1946-6234 (Linking).

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Montalban, X; Gold, R; Thompson, A J; Otero-Romero, S; Amato, M P; Chandraratna, D; Clanet, M; Comi, G; Derfuss, T; Fazekas, F; Hartung, H P; Havrdova, E; Hemmer, B; Kappos, L; Liblau, R; Lubetzki, C; Marcus, E; Miller, D H; Olsson, T; Pilling, S; Selmaj, K; Siva, A; Sorensen, P S; Sormani, M P; Thalheim, C; Wiendl, H; Zipp, F

ECTRIMS/EAN Guideline on the pharmacological treatment of people with multiple sclerosis Journal Article

Mult Scler, 24 (2), pp. 96-120, 2018, ISSN: 1477-0970 (Electronic) 1352-4585 (Linking).

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Melliez, H; Mary-Krause, M; Bocket, L; Guiguet, M; Abgrall, S; De Truchis, P; Katlama, C; Martin-Blondel, G; Henn, A; Revest, M; Robineau, O; Khuong-Josses, M A; Canestri, A; De Castro, N; Joly, V; Mokhtari, S; Risso, K; Gasnault, J; Costagliola, D; French Hospital Database on, H I V

Risk of Progressive Multifocal Leukoencephalopathy in the Combination Antiretroviral Therapy Era in the French Hospital Database on Human Immunodeficiency Virus (ANRS-C4) Journal Article

Clin Infect Dis, 67 (2), pp. 275-282, 2018, ISSN: 1537-6591 (Electronic) 1058-4838 (Linking).

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Mansuy, J M; Lhomme, S; Cazabat, M; Pasquier, C; Martin-Blondel, G; Izopet, J

Detection of Zika, dengue and chikungunya viruses using single-reaction multiplex real-time RT-PCR Journal Article

Diagn Microbiol Infect Dis, 92 (4), pp. 284-287, 2018, ISSN: 1879-0070 (Electronic) 0732-8893 (Linking).

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Januel, E; Martin-Blondel, G; Lamirel, C; Picard, H; Pialoux, G; Katlama, C; Cochereau, I; Lescure, F X; Moulignier, A

Do CCR5 antagonists improve the overall survival of patients with AIDS-related progressive multifocal leucoencephalopathy? Journal Article

J Neurol Neurosurg Psychiatry, 89 (10), pp. 1125-1126, 2018, ISSN: 1468-330X (Electronic) 0022-3050 (Linking).

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2017

Yu, C; Fitzpatrick, A; Cong, D; Yao, C; Yoo, J; Turnbull, A; Schwarze, J; Norval, M; Howie, S E M; Weller, R B; Astier, A L

Nitric oxide induces human CLA+CD25+Foxp3+ regulatory T cells with skin-homing potential Journal Article

J Allergy Clin Immunol, 2017, ISSN: 1097-6825 (Electronic) 0091-6749 (Linking).

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Yshii, L M; Hohlfeld, R; Liblau, R S

Inflammatory CNS disease caused by immune checkpoint inhibitors: status and perspectives Journal Article

Nat Rev Neurol, 13 (12), pp. 755-763, 2017, ISSN: 1759-4766 (Electronic) 1759-4758 (Linking).

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Ni Choileain, S; Hay, J; Thomas, J; Williams, A; Vermeren, M M; Benezech, C; Gomez-Salazar, M; Hugues, O R; Vermeren, S; Howie, S E M; Dransfield, I; Astier, A L

TCR-stimulated changes in cell surface CD46 expression generate type 1 regulatory T cells Journal Article

Sci Signal, 10 (502), 2017, ISSN: 1937-9145 (Electronic) 1945-0877 (Linking).

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Fissolo, N; Pignolet, B; Matute-Blanch, C; Trivino, J C; Miro, B; Mota, M; Perez-Hoyos, S; Sanchez, A; Vermersch, P; Ruet, A; de Seze, J; Labauge, P; Vukusic, S; Papeix, C; Almoyna, L; Tourbah, A; Clavelou, P; Moreau, T; Pelletier, J; Lebrun-Frenay, C; Montalban, X; Brassat, D; Comabella, M; Biomarkers, ; in Response to Natalizumab for Multiple Sclerosis Treatment, Best EScalation Treatment Multiple Sclerosis ; the Societe Francophone de la Sclerose En Plaques, Network

Matrix metalloproteinase 9 is decreased in natalizumab-treated multiple sclerosis patients at risk for progressive multifocal leukoencephalopathy Journal Article

Ann Neurol, 82 (2), pp. 186-195, 2017, ISSN: 1531-8249 (Electronic) 0364-5134 (Linking).

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Gebauer, C; Pignolet, B; Yshii, L; Maure, E; Bauer, J; Liblau, R

CD4+ and CD8+ T cells are both needed to induce paraneoplastic neurological disease in a mouse model Journal Article

Oncoimmunology, 6 (2), pp. e1260212, 2017, ISSN: 2162-4011 (Print) 2162-4011 (Linking).

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Duguet, F; Locard-Paulet, M; Marcellin, M; Chaoui, K; Bernard, I; Andreoletti, O; Lesourne, R; Burlet-Schiltz, O; Gonzalez de Peredo, A; Saoudi, A

Proteomic Analysis of Regulatory T Cells Reveals the Importance of Themis1 in the Control of Their Suppressive Function Journal Article

Mol Cell Proteomics, 16 (8), pp. 1416-1432, 2017, ISSN: 1535-9484 (Electronic) 1535-9476 (Linking).

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Yu, C; Fitzpatrick, A; Cong, D; Yao, C; Yoo, J; Turnbull, A; Schwarze, J; Norval, M; Howie, S E M; Weller, R B; Astier, A L

Nitric oxide induces human CLA+CD25+Foxp3+ regulatory T cells with skin-homing potential Journal Article

J Allergy Clin Immunol, 2017, ISSN: 1097-6825 (Electronic) 0091-6749 (Linking).

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Yshii, L M; Hohlfeld, R; Liblau, R S

Inflammatory CNS disease caused by immune checkpoint inhibitors: status and perspectives Journal Article

Nat Rev Neurol, 13 (12), pp. 755-763, 2017, ISSN: 1759-4766 (Electronic) 1759-4758 (Linking).

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2016

Bernard-Valnet, R; Yshii, L; Queriault, C; Nguyen, X H; Arthaud, S; Rodrigues, M; Canivet, A; Morel, A L; Matthys, A; Bauer, J; Pignolet, B; Dauvilliers, Y; Peyron, C; Liblau, R S

CD8 T cell-mediated killing of orexinergic neurons induces a narcolepsy-like phenotype in mice Journal Article

Proc Natl Acad Sci U S A, 113 (39), pp. 10956-61, 2016, ISSN: 1091-6490 (Electronic) 0027-8424 (Linking).

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Kassem, S; Gaud, G; Bernard, I; Benamar, M; Dejean, A S; Liblau, R; Fournie, G J; Colacios, C; Malissen, B; Saoudi, A

A Natural Variant of the T Cell Receptor-Signaling Molecule Vav1 Reduces Both Effector T Cell Functions and Susceptibility to Neuroinflammation Journal Article

PLoS Genet, 12 (7), pp. e1006185, 2016, ISSN: 1553-7404 (Electronic) 1553-7390 (Linking).

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Martin-Blondel, G; Brassat, D; Bauer, J; Lassmann, H; Liblau, R S

CCR5 blockade for neuroinflammatory diseases--beyond control of HIV Journal Article

Nat Rev Neurol, 12 (2), pp. 95-105, 2016, ISSN: 1759-4766 (Electronic) 1759-4758 (Linking).

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Pignolet, B; Schwab, N; Schneider-Hohendorf, T; Bucciarelli, F; Biotti, D; Averseng-Peaureaux, D; Outteryck, O; Ongagna, J C; de Seze, J; Brochet, B; Ouallet, J C; Debouverie, M; Pittion, S; Defer, G; Derache, N; Hautecoeur, P; Tourbah, A; Labauge, P; Castelnovo, G; Clavelou, P; Berger, E; Pelletier, J; Rico, A; Zephir, H; Laplaud, D; Wiertlewski, S; Camu, W; Thouvenot, E; Casez, O; Moreau, T; Fromont, A; Vukusic, S; Papeix, C; Vermersch, P; Comabella, M; Lebrun-Frenay, C; Wiendl, H; Brassat, D; Bionat, Sfsep ; networks , Best-Ms

CD62L test at 2 years of natalizumab predicts progressive multifocal leukoencephalopathy Journal Article

Neurology, 87 (23), pp. 2491-2494, 2016, ISSN: 1526-632X (Electronic) 0028-3878 (Linking).

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Schwab, N; Schneider-Hohendorf, T; Pignolet, B; Spadaro, M; Gorlich, D; Meinl, I; Windhagen, S; Tackenberg, B; Breuer, J; Canto, E; Kumpfel, T; Hohlfeld, R; Siffrin, V; Luessi, F; Posevitz-Fejfar, A; Montalban, X; Meuth, S G; Zipp, F; Gold, R; Du Pasquier, R A; Kleinschnitz, C; Jacobi, A; Comabella, M; Bertolotto, A; Brassat, D; Wiendl, H

PML risk stratification using anti-JCV antibody index and L-selectin Journal Article

Mult Scler, 22 (8), pp. 1048-60, 2016, ISSN: 1477-0970 (Electronic) 1352-4585 (Linking).

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Yshii, L M; Gebauer, C M; Pignolet, B; Maure, E; Queriault, C; Pierau, M; Saito, H; Suzuki, N; Brunner-Weinzierl, M; Bauer, J; Liblau, R

CTLA4 blockade elicits paraneoplastic neurological disease in a mouse model Journal Article

Brain, 2016, ISSN: 1460-2156 (Electronic) 0006-8950 (Linking).

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Stienne, C; Michieletto, M F; Benamar, M; Carrie, N; Bernard, I; Nguyen, X H; Lippi, Y; Duguet, F; Liblau, R S; Hedrick, S M; Saoudi, A; Dejean, A S

Foxo3 Transcription Factor Drives Pathogenic T Helper 1 Differentiation by Inducing the Expression of Eomes Journal Article

Immunity, 45 (4), pp. 774-787, 2016, ISSN: 1097-4180 (Electronic) 1074-7613 (Linking).

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Mansuy, J M; Suberbielle, E; Chapuy-Regaud, S; Mengelle, C; Bujan, L; Marchou, B; Delobel, P; Gonzalez-Dunia, D; Malnou, C E; Izopet, J; Martin-Blondel, G

Zika virus in semen and spermatozoa Journal Article

Lancet Infect Dis, 16 (10), pp. 1106-1107, 2016, ISSN: 1474-4457 (Electronic) 1473-3099 (Linking).

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Mansuy, J M; Dutertre, M; Mengelle, C; Fourcade, C; Marchou, B; Delobel, P; Izopet, J; Martin-Blondel, G

Zika virus: high infectious viral load in semen, a new sexually transmitted pathogen? Journal Article

Lancet Infect Dis, 16 (4), pp. 405, 2016, ISSN: 1474-4457 (Electronic) 1473-3099 (Linking).

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Hartmann, F J; Bernard-Valnet, R; Queriault, C; Mrdjen, D; Weber, L M; Galli, E; Krieg, C; Robinson, M D; Nguyen, X H; Dauvilliers, Y; Liblau, R S; Becher, B

High-dimensional single-cell analysis reveals the immune signature of narcolepsy Journal Article

J Exp Med, 213 (12), pp. 2621-2633, 2016, ISSN: 1540-9538 (Electronic) 0022-1007 (Linking).

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Ramadan, A; Lucca, L E; Carrie, N; Desbois, S; Axisa, P P; Hayder, M; Bauer, J; Liblau, R S; Mars, L T

In situ expansion of T cells that recognize distinct self-antigens sustains autoimmunity in the CNS Journal Article

Brain, 139 (Pt 5), pp. 1433-46, 2016, ISSN: 1460-2156 (Electronic) 0006-8950 (Linking).

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Kieback, E; Hilgenberg, E; Stervbo, U; Lampropoulou, V; Shen, P; Bunse, M; Jaimes, Y; Boudinot, P; Radbruch, A; Klemm, U; Kuhl, A A; Liblau, R; Hoevelmeyer, N; Anderton, S M; Uckert, W; Fillatreau, S

Thymus-Derived Regulatory T Cells Are Positively Selected on Natural Self-Antigen through Cognate Interactions of High Functional Avidity Journal Article

Immunity, 44 (5), pp. 1114-26, 2016, ISSN: 1097-4180 (Electronic) 1074-7613 (Linking).

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Hartmann, F J; Bernard-Valnet, R; Queriault, C; Mrdjen, D; Weber, L M; Galli, E; Krieg, C; Robinson, M D; Nguyen, X H; Dauvilliers, Y; Liblau, R S; Becher, B

High-dimensional single-cell analysis reveals the immune signature of narcolepsy Journal Article

J Exp Med, 213 (12), pp. 2621-2633, 2016, ISSN: 1540-9538 (Electronic) 0022-1007 (Linking).

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Aloulou, M; Carr, E J; Gador, M; Bignon, A; Liblau, R S; Fazilleau, N; Linterman, M A

Follicular regulatory T cells can be specific for the immunizing antigen and derive from naive T cells Journal Article

Nat Commun, 7 , pp. 10579, 2016, ISSN: 2041-1723 (Electronic) 2041-1723 (Linking).

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Yshii, L M; Gebauer, C M; Pignolet, B; Maure, E; Queriault, C; Pierau, M; Saito, H; Suzuki, N; Brunner-Weinzierl, M; Bauer, J; Liblau, R

CTLA4 blockade elicits paraneoplastic neurological disease in a mouse model Journal Article

Brain, 2016, ISSN: 1460-2156 (Electronic) 0006-8950 (Linking).

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2015

Hafler, D A; Astier, A L

Editorial: T cell regulation by the environment Journal Article

Front Immunol, 6 , pp. 229, 2015, ISSN: 1664-3224 (Print) 1664-3224 (Linking).

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Martin-Blondel, G; Bauer, J; Uro-Coste, E; Biotti, D; Averseng-Peaureaux, D; Fabre, N; Dumas, H; Bonneville, F; Lassmann, H; Marchou, B; Liblau, R S; Brassat, D

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).

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Pedros, C; Gaud, G; Bernard, I; Kassem, S; Chabod, M; Lagrange, D; Andreoletti, O; Dejean, A S; Lesourne, R; Fournie, G J; Saoudi, A

An Epistatic Interaction between Themis1 and Vav1 Modulates Regulatory T Cell Function and Inflammatory Bowel Disease Development Journal Article

J Immunol, 195 (4), pp. 1608-16, 2015, ISSN: 1550-6606 (Electronic) 0022-1767 (Linking).

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Martin-Blondel, G; Bauer, J; Uro-Coste, E; Biotti, D; Averseng-Peaureaux, D; Fabre, N; Dumas, H; Bonneville, F; Lassmann, H; Marchou, B; Liblau, R S; Brassat, D

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).

Links | BibTeX

2014

Outteryck, O; Ongagna, J C; Brochet, B; Rumbach, L; Lebrun-Frenay, C; Debouverie, M; Zephir, H; Ouallet, J C; Berger, E; Cohen, M; Pittion, S; Laplaud, D; Wiertlewski, S; Cabre, P; Pelletier, J; Rico, A; Defer, G; Derache, N; Camu, W; Thouvenot, E; Moreau, T; Fromont, A; Tourbah, A; Labauge, P; Castelnovo, G; Clavelou, P; Casez, O; Hautecoeur, P; Papeix, C; Lubetzki, C; Fontaine, B; Couturier, N; Bohossian, N; Clanet, M; Vermersch, P; de Seze, J; Brassat, D; Network, Bionat ; Cfsep,

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).

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2011

Colacios, C; Casemayou, A; Dejean, A S; Gaits-Iacovoni, F; Pedros, C; Bernard, I; Lagrange, D; Deckert, M; Lamouroux, L; Jagodic, M; Olsson, T; Liblau, R S; Fournie, G J; Saoudi, A

The p.Arg63Trp polymorphism controls Vav1 functions and Foxp3 regulatory T cell development Journal Article

J Exp Med, 208 (11), pp. 2183-91, 2011, ISSN: 1540-9538 (Electronic) 0022-1007 (Linking).

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Couturier, N; Bucciarelli, F; Nurtdinov, R N; Debouverie, M; Lebrun-Frenay, C; Defer, G; Moreau, T; Confavreux, C; Vukusic, S; Cournu-Rebeix, I; Goertsches, R H; Zettl, U K; Comabella, M; Montalban, X; Rieckmann, P; Weber, F; Muller-Myhsok, B; Edan, G; Fontaine, B; Mars, L T; Saoudi, A; Oksenberg, J R; Clanet, M; Liblau, R S; Brassat, D

Tyrosine kinase 2 variant influences T lymphocyte polarization and multiple sclerosis susceptibility Journal Article

Brain, 134 (Pt 3), pp. 693-703, 2011, ISSN: 1460-2156 (Electronic) 0006-8950 (Linking).

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Dejean, A S; Hedrick, S M; Kerdiles, Y M

Highly specialized role of Forkhead box O transcription factors in the immune system Journal Article

Antioxid Redox Signal, 14 (4), pp. 663-74, 2011, ISSN: 1557-7716 (Electronic) 1523-0864 (Linking).

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International Multiple Sclerosis Genetics, Consortium ; Wellcome Trust Case Control, Consortium ; Sawcer, S; Hellenthal, G; Pirinen, M; Spencer, C C; Patsopoulos, N A; Moutsianas, L; Dilthey, A; Su, Z; Freeman, C; Hunt, S E; Edkins, S; Gray, E; Booth, D R; Potter, S C; Goris, A; Band, G; Oturai, A B; Strange, A; Saarela, J; Bellenguez, C; Fontaine, B; Gillman, M; Hemmer, B; Gwilliam, R; Zipp, F; Jayakumar, A; Martin, R; Leslie, S; Hawkins, S; Giannoulatou, E; D'Alfonso, S; Blackburn, H; Martinelli Boneschi, F; Liddle, J; Harbo, H F; Perez, M L; Spurkland, A; Waller, M J; Mycko, M P; Ricketts, M; Comabella, M; Hammond, N; Kockum, I; McCann, O T; Ban, M; Whittaker, P; Kemppinen, A; Weston, P; Hawkins, C; Widaa, S; Zajicek, J; Dronov, S; Robertson, N; Bumpstead, S J; Barcellos, L F; Ravindrarajah, R; Abraham, R; Alfredsson, L; Ardlie, K; Aubin, C; Baker, A; Baker, K; Baranzini, S E; Bergamaschi, L; Bergamaschi, R; Bernstein, A; Berthele, A; Boggild, M; Bradfield, J P; Brassat, D; Broadley, S A; Buck, D; Butzkueven, H; Capra, R; Carroll, W M; Cavalla, P; Celius, E G; Cepok, S; Chiavacci, R; Clerget-Darpoux, F; Clysters, K; Comi, G; Cossburn, M; Cournu-Rebeix, I; Cox, M B; Cozen, W; Cree, B A; Cross, A H; Cusi, D; Daly, M J; Davis, E; de Bakker, P I; Debouverie, M; D'Hooghe M, B; Dixon, K; Dobosi, R; Dubois, B; Ellinghaus, D; others,

Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis Journal Article

Nature, 476 (7359), pp. 214-9, 2011, ISSN: 1476-4687 (Electronic) 0028-0836 (Linking).

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2009

Dejean, A S; Beisner, D R; Ch'en, I L; Kerdiles, Y M; Babour, A; Arden, K C; Castrillon, D H; DePinho, R A; Hedrick, S M

Transcription factor Foxo3 controls the magnitude of T cell immune responses by modulating the function of dendritic cells Journal Article

Nat Immunol, 10 (5), pp. 504-13, 2009, ISSN: 1529-2916 (Electronic) 1529-2908 (Linking).

Links | BibTeX

Societal impact

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 ranging from mechanistic studies to pre-clinical therapeutic testing. We have also developed unique biological resources from patients with MS or narcolepsy that allow us to translate directly to the clinic the relevance of our key findings (identification or validation of pathways contributing to disease susceptibility, identification of new biomarkers). Finally, we are involved in investigator-initiated therapeutic trials that open new possibilities for patients with CNS inflammatory or infectious diseases.

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.

Alumni

Post-docs :

  • Mars Lennart T
  • Piaggio Eliane
  • Zapula Jacques
  • Scheikl Tanja
  • Lazarczyk Macjek
  • Céline Colacios
  • Lamouroux Lucile
  • Ramadan Raouf
  • Xuan-Hung Nguyen
  • Manish Malviya
  • Lidia Yshii
  • Guillaume Gaud
  • Myriam Hayder
  • Familiades Julien

 

PhD

  • Céline Meyer
  • Pierre-Paul Axisa
  • Guillaume Martin-Blondel
  • Michael Michieletto
  • Mehdi Benamar
  • Raphaël Bernard-Valnet
  • 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
Collaborations
Becher Burkhard , Institute of Experimental Immunology, University of Zurich, Switzerland
Casanova Jean-Laurent , the Rockfeller University , NY, USA
Dauvilliers Yves, Department of Sleep Disorders, Montpellier, France
Engelhardt Britta, Theodor Kocher Institute, University of Bern, Switzerland
Hedrick Stephen M , UCSD, La jolla, CA, USA)
Lassmann Hans & Jan Bauer, Brain Research Institute, Vienne, Austria
Malissen Bernard, CIML, Marseille, France
Olsson Tomas, Karolinska Hospital, Stockholm, Sweden
Peyron Christelle, INSERM U1028, CNRS UMR 5292, Center for Research in Neuroscience, Lyon, France
Sarry Jean-Emmanuel , centre de recherche en cancérologie de Toulouse, FranceManuel Comabella VHIR, Barcelone, Spain
Schiltz Odile & Anne Gonzalez-de-Peredo, IPBS, Toulouse, France
Sieger Dirk, University of Edinburgh, UK
Simon Michel, UDEAR, Toulouse, France
Tafti Mehdi, Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
Thouvenot Eric, Institute of functional genomic, Montpellier, France
Walzer Thierry, Centre International de Recherche en Infectiologie, Lyon, France
Wiendl Heinz, Department of Neurology, University of Münster, Germany
Zytnicki Matthias, Unité de Mathématiques et Informatique Appliquées de Toulouse, France

Collaborations within the Center:

Daniel Dunia
Jacques Izopet
Jean-Charles Guery
Manuel Diaz-Munoz
Michel Simon
Nabila Jabrane
Nicolas Blanchard
Nicolas Fazilleau
Rémi Poupot
Renaut Lesourne
Sylvie Gerder
Loic Dupré
Joost van Meerwijk

ARSEP

ARSEP

Agence nationale de la recherche

Agence nationale de la recherche

INSERM

INSERM

Région Occitanie

Région Occitanie

Université Toulouse Paul Sabatier

Université Toulouse Paul Sabatier

AFM

AFM

GSK

GSK

Fondation Bettencourt Schueller

Fondation Bettencourt Schueller

Fondation maladies rares

Fondation maladies rares

CNRS

CNRS

Seventh Framework Programme

Seventh Framework Programme

Fondation ARC

Fondation ARC