• Jérôme HONNORAT
  PU-PH UCBL
• Lucie Aliouane
  CR UCBL
• Jean-Christophe ANTOINE
  PU-PH UJM
  
• Sarah BENKEDER
  DOCTORANTE INSERM
• Roger BESANCON
  MCU UCBL
• Nadia BOUTAHAR
  MCU-PH UJM
  
• Pauline BOUVET
  DOCTORANTE UCBL
• Jean-Philippe CAMDESSANCHE
  PU-PH UJM
  
• Naura CHOUNLAMOUNTRI
  AI INSERM
• Sterenn CLOSS
  AI INSERM
• Kassandre COMBET
  DOCTORANTE INSERM
• Priscille DE GEA
  DOCTORANTE UCBL
• Virginie DESESTRET
  MCU-PH UCBL
• Le Duy DO
  CR HCL
• Fabrice FAURE
  IE UCBL
• Elodie FELS
  DOCTORANTE UCBL
• Bastien JOUBERT
  PH HCL
• Céline MALLEVAL
  IE INSERM
• Claire MEISSIREL  CV
  CR INSERM
• Christian MORITZ
  Post-Doc UJM
  
• Sergio MUNIZ CASTRILLO
  Post-Doc HCL
• Yara NASSER
  DOCTORANTE UJM
• Nelly NORAZ-BUET
  CR INSERM
• Olivier PASCUAL CV
  CR INSERM
• Célia PAUME
  AI INSERM
• Véronique PELLIER-MONNIN
  MCU UCBL
• Anne-Laurie PINTO
  IE INSERM
  
• Mélisse ROBERT
  DOCTORANTE UCBL
• Véronique ROGEMOND
  IR  HCL
• Yannick THOLANCE
  MCUPH UJM
• Clémentine VINCENT
  POST-DOC INSERM
• Alberto VOGRIG
  IR INSERM
• Valentin WUCHER
  POST-DOC UCBL

PROJECTS

The goal of our research is to better understand the cellular and molecular mechanisms involved in neuronal and synaptic dysfunctions in neuropsychiatric diseases. We are particularly interested in the pathophysiology of autoimmune encephalitis (AE) and paraneoplastic neurological syndromes (PNS). These neuropsychiatric diseases are associated with autoantibodies present in patients’ serum and CSF, which target neuronal proteins involved in synaptic transmission (ie, NMDAR, AMPAR, GABABR), synapse organization (LGI1, CASPR2), or signaling (DPPX, CRMP). Each of these autoantibodies is associated with a clinical syndrome similar to what is observed when these same proteins are disrupted by pharmacological or genetic means. These autoantibodies have an impact on the structure and function of the antigens they target. Our strategy is to integrate basic and clinical research to study the mechanism of action of autoantibodies and their effects on synaptic and neuronal functions and associated neuro-inflammatory processes. We study synaptic functions in a physiological and pathological context, using patient autoantibodies as research tools. We focus in particular on NMDA receptors and some of their partners, such as VEGFR2, and on proteins involved in neuronal excitability, such as LGI1 or CASPR2. We have developed animal models with autoantibody infusion in the hippocampus via osmotic pumps, and in vitro models of neuronal primary cultures and organotypic brain slices. The use of these different models allows us to study the effect of the inflammatory response on neurons and glial cells, the transport of glutamate, and the modulation of neurotransmission.

Our biological collection of serum and CSF from SNP and EA patients allows us to detect autoantibodies targeting unknown proteins or neuronal receptors. A translational approach is then used to identify the targeted proteins and understand their roles. These new targets can also serve as biomarkers of the disease and contribute to the development of new therapeutic strategies.

This work should lead to a better understanding of neuropsychiatric diseases associated with autoantibodies, but also of neurodegenerative pathologies such as Alzheimer’s disease.

The BETPSY project, coordinated by Prof. Honnorat, has received a 7.3 million euro “Future Investment Program (PIA)” funding. It is based on the collaboration of 5 academic research teams (UCBL, HCL, ICM, CLB and INSERM), and an industrial partner (Euroimmun), specialized in the development and marketing of autoantibody detection kits.

The aim of the BETPSY project is to better characterize EA and SNPs in order to improve the care and treatment of patients suffering from these diseases, through the identification of new biomarkers, the understanding of the mechanisms involved in these autoimmune diseases and the development of animal models: https://www.rhu-betpsy.fr/.

SELECTED PUBLICATIONS

• Goudot M., Frismand S., Hopes L., Verger A., Joubert B., Honnorat J., Tyvaert L. (2021). Recurrent seizures of autoimmune origin: emerging phenotypes. J Neurol, 268(8):3000-3010.
• Hubert V., Hristovska I., Karpati S., Benkeder S., Dey A., Dumot C., Amaz C., Chounlamountri N., Watrin C., Comte J.C., Chauveau F., Brun E., Marche P., Lerouge F., Parola S., Berthezène Y., Vorup-Jensen T., Pascual O., Wiart M. (2021). Multimodal Imaging with NanoGd Reveals Spatiotemporal Features of Neuroinflammation after Experimental Stroke. Adv Sci (Weinh), e2101433.
• Martin L., Bouvet P., Chounlamountri N., Watrin C., Besançon R., Pinatel D., Meyronet D., Honnorat J., Buisson A., Salin P.A., Meissirel C. (2021). Multimodal Imaging with NanoGd Reveals Spatiotemporal Features of Neuroinflammation after Experimental Stroke. Cell Rep, 35(6):109121.
• Muñiz-Castrillo S., Hedou J.J., Ambati A., Jones D., Vogrig A., Pinto A.L., Benaiteau M., de Broucker T., Fechtenbaum L., Labauge P., Murnane M., Nocon C., Taifas I., Vialatte de Pémille C., Psimaras D., Joubert B., Dubois V., Wucher V., Desestret V., Mignot E., Honnorat J. (2021). Multimodal Imaging with NanoGd Reveals Spatiotemporal Features of Neuroinflammation after Experimental Stroke. Brain, Apr 12:awab153.
• Takata-Tsuji F., Chounlamountri N., Do LD., Philippot C., Novion Ducassou J., Couté Y., Ben Achour S., Honnorat J., Place C., Pascual O. (2021). Microglia modulate gliotransmission through the regulation of VAMP2 proteins in astrocytes. Glia, 69(1):61-72.
• Saint-Martin M., Pieters A., Déchelotte B., Malleval C., Pinatel D., Pascual O., Karagogeos D., Honnorat J., Pellier-Monnin V., Noraz N. (2019). Impact of anti-CASPR2 autoantibodies from patients with autoimmune encephalitis on CASPR2/TAG-1 interaction and Kv1 expression. Journal of Autoimmunity.103:102284.
• Chefdeville A., Treilleux I., Mayeur M.E., Couillault C., Picard G., Bost C., Mokhtari K., Vasiljevic A., Meyronet D., Rogemond V., Psimaras D., Dubois B., Honnorat J., Desestret V. (2019). Immunopathological characterization of ovarian teratomas associated with anti-N-methyl-D-aspartate receptor encephalitis. Acta Neuropathol Commun, 7(1):38.
• Moritz C. P., Tholance Y., Rosier C., Reynaud-Federspiel E., Svahn J., Camdessanché J.-P. and Antoine J.-C. (2019a). Completing the Immunological Fingerprint by Refractory Proteins: Autoantibody Screening via an Improved Immunoblotting Technique. Clinical Applications: e1800157.
• Saint-Martin M., Liang W., Zhang J., Xu F., Noraz N., Liu J., Honnorat J. and Liu H. (2019). Structural mapping of hot spots within human CASPR2 discoidin domain for autoantibody recognition. Journal of Autoimmunity, 96: 168-177.
• Naudet N., Moutal A., Vu H. N., Chounlamountri N., Watrin C., Cavagna S., Malleval C., Benetollo C., Bardel C., Dronne M.-A., Honnorat J., Meissirel C. and Besançon R. (2018). Transcriptional regulation of CRMP5 controls neurite outgrowth through Sox5. Cellular and molecular life sciences: CMLS, 75(1): 67-79.
• Small M., Treilleux I., Couillault C., Pissaloux D., Picard G., Paindavoine S., Attignon V., Wang Q., Rogemond V., Lay S., Ray-Coquard I., Pfisterer J., Joly F., Du Bois A., Psimaras D., Bendriss-Vermare N., Caux C., Dubois B., Honnorat J. and Desestret V. (2018). Genetic alterations and tumor immune attack in Yo paraneoplastic cerebellar degeneration. Acta Neuropathologica, 135(4): 569-579.
• Vialatte de Pémille C., Berzero G., Small M., Psimaras D., Giry M., Daniau M., Sanson M., Delattre J.-Y., Honnorat J., Desestret V. and Alentorn A. (2018). Transcriptomic immune profiling of ovarian cancers in paraneoplastic cerebellar degeneration associated with anti-Yo antibodies. British Journal of Cancer, 119(1): 105-113.
• Do L. D., Gupton S. L., Tanji K., Joubert B., Brugière S., Couté Y., Quadrio I., Rogemond V., Fabien N., Desestret V. and Honnorat J. (2018). TRIM9 and TRIM67 Are New Targets in Paraneoplastic Cerebellar Degeneration. Cerebellum, 18(2):245-254.
• Do L.-D., Chanson E., Desestret V., Joubert B., Ducray F., Brugière S., Couté Y., Formaglio M., Rogemond V., Thomas-Antérion C., Borrega L., Laurens B., Tison F., Curot J., De Brouker T., Lebrun-Frenay C., Delattre J.-Y., Antoine J.-C. and Honnorat J. (2017). Characteristics in limbic encephalitis with anti-adenylate kinase 5 autoantibodies. Neurology, 88(6): 514-524.
• Jézéquel J., Johansson E. M., Dupuis J. P., Rogemond V., Gréa H., Kellermayer B., Hamdani N., Le Guen E., Rabu C., Lepleux M., Spatola M., Mathias E., Bouchet D., Ramsey A. J., Yolken R. H., Tamouza R., Dalmau J., Honnorat J., Leboyer M. and Groc L. (2017a). Dynamic disorganization of synaptic NMDA receptors triggered by autoantibodies from psychotic patients. Nature Communications, 8(1): 1791.
• Joubert B., Gobert F., Thomas L., Saint-Martin M., Desestret V., Convers P., Rogemond V., Picard G., Ducray F., Psimaras D., Antoine J.-C., Delattre J.-Y. and Honnorat J. (2017b). Autoimmune episodic ataxia in patients with anti-CASPR2 antibody-associated encephalitis. Neurology(R) Neuroimmunology & Neuroinflammation, 4(4): e371.
• Jézéquel J., Rogemond V., Pollak T., Lepleux M., Jacobson L., Gréa H., Iyegbe C., Kahn R., McGuire P., Vincent A., Honnorat J., Leboyer M. and Groc L. (2017b). Cell- and Single Molecule-Based Methods to Detect Anti-N-Methyl-D-Aspartate Receptor Autoantibodies in Patients With First-Episode Psychosis From the OPTiMiSE Project. Biological Psychiatry, 82(10): 766-772.
• Noraz N., Jaaoini I., Charoy C., Watrin C., Chounlamountri N., Benon A., Malleval C., Boudin H., Honnorat J., Castellani V. and Pellier-Monnin V. (2016). Syk kinases are required for spinal commissural axon repulsion at the midline via the ephrin/Eph pathway. Development (Cambridge, England), 143(12): 2183-2193.
• Joubert B., Saint-Martin M., Noraz N., Picard G., Rogemond V., Ducray F., Desestret V., Psimaras D., Delattre J.-Y., Antoine J.-C. and Honnorat J. (2016a). Characterization of a Subtype of Autoimmune Encephalitis With Anti-Contactin-Associated Protein-like 2 Antibodies in the Cerebrospinal Fluid, Prominent Limbic Symptoms, and Seizures. JAMA neurology, 73(9): 1115-1124.
• De Rossi P., Harde E., Dupuis J. P., Martin L., Chounlamountri N., Bardin M., Watrin C., Benetollo C., Pernet-Gallay K., Luhmann H. J., Honnorat J., Malleret G., Groc L., Acker-Palmer A., Salin P. A. and Meissirel C. (2016b). A critical role for VEGF and VEGFR2 in NMDA receptor synaptic function and fear-related behavior. Molecular Psychiatry, 21(12): 1768-1780.
• Navarro V., Kas A., Apartis E., Chami L., Rogemond V., Levy P., Psimaras D., Habert M.-O., Baulac M., Delattre J.-Y., Honnorat J. and collaborators. (2016). Motor cortex and hippocampus are the two main cortical targets in LGI1-antibody encephalitis. Brain: A Journal of Neurology, 139(Pt 4): 1079-1093.

FUNDING

• Ministry of Health: Reference center on rare diseases. Autoimmune encephalitis and paraneoplastic neurological syndromes.
• Inca: Protéines de guidage axonal et tumeurs neuroendocrines gastro-entero-pancréatiques: rôle dans la progression tumorale
• ANR: Identification de biomarqueurs diagnostiques, physiopathologiques, pronostiques et de progression des troubles
• ANR-PRTS: MECANO : Mechanisms of autoimmune encephalitis
• FRC: Mechanisms of autoimmune abnormal behaviour