The goal of our research is to better understand the cellular and molecular mechanisms involved in neuronal and synaptic dysfunctions characterizing neuropsychiatric diseases. Our purpose is to focus on the pathophysiology of autoimmune encephalitis (AE) and paraneoplastic neurological syndromes (PNS). These neuropsychiatric diseases are associated with autoantibodies present in patients’ sera and CSF and directed to neuronal proteins involved in synaptic transmission and excitability (i.e., NMDAr, AMPAr, GABAr), synaptic organization (LGI1, CASPR2), or in somatodendritic signaling modulation (DPPX, CRMP). Interestingly, each of these autoantibodies defines a syndrome that resembles models of pharmacological or genetic disruption of the corresponding antigen. Indeed, patients’ autoantibodies have structural and functional effects on the target antigens by a mechanism of antibody-mediated internalization of the antigen. By integrating basic and clinical researches, we propose to study at the cellular and molecular levels how autoantibodies and associated euro-inflammatory processes impact on synaptic and neuronal functions. Synaptic functions will be investigated in physiological and pathological context, using patient’s autoantibodies as research tools, by focusing on NMDA receptor and key partners, VEGFR2, EphB2, CRMP2 and CRMP5. To determine the role of inflammatory response in the pathophysiology of these diseases, glial cell morphology and essential functions, such as glutamate transport, ion recapture and modulation of neurotransmission will be evaluated following infusion of autoantibodies in the hippocampus. To address these different topics we are developing relevant animal models that will be used in combination with primary neuronal cultures, rodent brain slices, and brain tissues. Furthermore, using our biological collection of serum and CSF of patients with PNS and AE, we already identified samples with autoantibodies targeting unknown neuronal protein or receptors. Translational approaches will be used to identify the targeted proteins. Importantly, newly identified proteins will serve as disease biomarkers and will contribute to the development of novel therapeutic strategies. This work should lead to a better understanding of not only neuropsychiatric diseases associated with autoantibodies but also of more common neurological or psychiatric diseases in which similar protein dysfunction are reported.
- Clinical Spectrum of Encephalitis Associated With Antibodies Against the alpha-Amino-3-Hydroxy-5-Methyl-4-Isoxazolepropionic Acid Receptor: Case Series and Review of the Literature.
Joubert B, Kerschen P, Zekeridou A, Desestret V, Rogemond V, Chaffois MO, Ducray F, Larrue V, Daubail B, Idbaih A, Psimaras D, Antoine JC, Delattre JY, Honnorat J. JAMA Neurol (2015) Oct 1;72(10):1163-9.
- Inhibitory axons are targeted in hippocampal cell culture by anti-Caspr2 autoantibodies associated with limbic encephalitis.
Pinatel D, Hivert B, Boucraut J, Saint-Martin M, Rogemond V, Zoupi L, Karagogeos D, Honnorat J, Faivre Sarrailh C. Front Cell Neurosci. (2015) Jul 9;9:265.
- Antifibroblast growth factor receptor 3 antibodies identify a subgroup of patients with sensory neuropathy.
Antoine JC, Boutahar N, Lassablière F, Reynaud E, Ferraud K, Rogemond V, Paul S, Honnorat J, Camdessanché JP. J Neurol Neurosurg Psychiatry (2015) pii: jnnp-2014-309730.
- Surface dynamics of GluN2B-NMDA receptors controls plasticity of maturing glutamate synapses.
Dupuis JP, LadépÍche L, Seth H, Bard L, Varela J, Mikasova L, Bouchet D, Rogemond V, Honnorat J, Hanse E, Groc L. EMBO J (2014) Apr 16;33(8):842-61.
- Clinical specificities of adult male patients with NMDA receptor antibodies encephalitis.
Viaccoz A, Desestret V, Ducray F, Picard G, Cavillon G, Rogemond V, Antoine JC, Delattre JY, Honnorat J. Neurology (2014) Feb 18;82(7):556-63.
- Autoimmune limbic encephalopathy and anti-Hu antibodies in children without cancer.
Honnorat J, Didelot A, Karantoni E, Ville D, Ducray F, Lambert L, Deiva K, Garcia M, Pichit P, Cavillon G, Rogemond V, DeLattre JY, Tardieu M. Neurology (2013) Jun 11;80(24): 2226-32.
- Dramatic improvement after rituximab in a patient with paraneoplastic treatment-refractory Morvan syndrome associated with anti-CASPR2 antibodies.
Ong E, Viaccoz A, Ducray F, Pérol M, Cavillon G, Rogemond V, Honnorat J, Petiot P. Eur J Neurol. (2013) Jul;20(7):e96-7.
- Disrupted surface cross-talk between NMDA andEphrin-B2 receptors in anti-NMDA encephalitis.
Mikasova L, De Rossi P, Bouchet D, Georges F, Rogemond V, Didelot A, Meissirel C, Honnorat J, Groc L. Brain (2012) May;135(Pt 5):1606-21.
- Microglia activation triggers astrocyte-mediated modulation of excitatory neurotransmission.
Pascual O, Ben Achour S, Rostaing P, Triller A, Bessis A. Proc Natl Acad Sci U S A (2012) 109(4):E197-205.
- VEGF modulates NMDA receptors activity in cerebellar granule cells through Src-family kinases before synapse formation.
Meissirel C, Ruiz de Almodovar C, Knevels E, Coulon C, Chounlamountri N, Segura I, de Rossi P, Vinckier S, Anthonis K, Deléglise B, de Mol M, Ali C, Dassonville K, Loyens E, Honnorat J, Michotte Y, Rogemond V, Smolders I, Voets T, Vivien D, Vanden Berghe P, Van den Bosch L, Robberecht W, Chédotal A, Oliviero S, Dewerchin M, Schmucker D, Thomasset N, Salin P, Carmeliet P. Proc Natl Acad Sci U S A (2011) Aug 16;108(33):13782-7.
- 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