Synaptopathies and autoantibodies (SYNATAC)
Principal investigator: Jérôme HONNORAT
Autoimmune encephalitis | NMDA receptor | VEGF | Paraneoplastic neurological syndromes | Glial cells | Synaptic proteins
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.
RHU BETPSY
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/
Team Members
- Jerome HONNORAT — PUPH, UCBL, HCL – jerome.honnorat@chu-lyon.fr – 04 26 67 28 01
- Lucie ALIOUANE — Chercheur, UCBL – lucie.aliouane@univ-lyon1.fr – 04 72 35 78 13
- Jean-Christophe ANTOINE — PUPH, CNRS – j.christophe.antoine@chu-st-etienne.fr – 04 77 12 78 05
- Sarah BENKEDER — Doctorante, INSERM – sarah.benkeder@univ-lyon1.fr – 04 26 67 28 01
- Roger BESANCON — MCU, UCBL – roger.besancon@univ-lyon1.fr – 04 26 67 28 01
- Nadia BOUTAHAR — MCU-PH, CNRS – nadia.boutahar@chu-st-etienne.fr – 04 77 82 83 10
- Pauline BOUVET — Doctorante, INSERM – pauline.bouvet@univ-lyon1.fr – 04 26 67 28 01
- Jean-Philippe CAMDESSANCHE — PH, CNRS – j.philippe.camdessanche@chu-st-etienne.fr – 04 77 12 05 59
- Naura CHOUNLAMOUNTRI — Technicien, CNRS – naura.chounlamountri@univ-lyon1.fr – 04 26 67 28 01
- Sterenn CLOSS — Technicien, CNRS – sterenn.closss@chu-lyon.fr –
- Kassandre COMBET — Doctorante, CNRS – Kassandre.combet@univ-lyon1.fr – 04 26 67 28 01
- Priscille DE GEA — Doctorante, CNRS – priscille.de-gea@univ-lyon1.fr – 04 26 67 28 01
- Virginie DESESTRET — PUPH, CNRS – virginie.desestret@univ-lyon1.fr –
- Le Duy DO — Chercheur, CNRS – le-duy.do@univ-lyon1.fr – 04 26 67 28 01
- Fabrice FAURE — IE, CNRS – fabrice.faure@univ-lyon1.fr – 04 26 67 28 01
- Bastien JOUBERT — Chercheur, CNRS – bastien.joubert@chu-lyon.fr –
- Mathilde MILLOT — Chercheur, CNRS – –
- Claire MEISSEREL — CV — Chercheur, INSERM, HDR – Claire.meissirel@inserm.fr – 04 26 67 28 01
- Christian MORITZ — Chercheur, CNRS – christian.moritz@univ-st-etienne.fr –
- Olivier PASCUAL CV — Chercheur, INSERM, HDR – olivier.pascual@inserm.fr – 04 26 68 82 74
- Veronique PELLIER-MONIN — MCU, UCBL – veronique.pellier-monnin@univ-lyon1.fr – 04 26 67 28 01
- Géraldine PICARD — Chercheur, HCL – geraldine.picard@chu-lyon.fr –
- Elise PETER — Chercheur, UCBL – –
- Antonio FARINA — Chercheur, HCL – antoniofarina100791@gmail.com –
- Macarena GARCIA — Chercheur, INSERM – ext-macarena.villagran@chu-lyon.fr –
- Anne-Laurie PINTO — Chercheur, HCL – anne-laure.pinto@chu-lyon.fr –
- Mélisse ROBERT — Doctorante, HCL – melisse.robert@univ-lyon1.fr – 04 26 67 28 01
- Veronique ROGEMOND — Chercheur, HCL – veronique.rogemond@chu-lyon.fr – 04 72 35 58 40
- Yannick THOLANCE — MCU-PH, UCBL – Yannick.Tholance@chu-st-etienne.fr –
- MArine VILLARD — Chercheur, HCL – marine.villard@chu-lyon.fr –
- Clementine VINCENT — Post-doctorante, INSERM – clementine.vincent@univ-lyon1.fr – 04 26 67 28 01
- Valentin WUCHER — Post-doctorant, UCBL – valentin.wucher@univ-lyon1.fr – 04 26 73 94 04
Selected publications
Different Genetic Signatures of Small‐Cell Lung Cancer Characterize
Vogrig A., Pegat A., Villagrán‐García M., et al.. 🔗 https://doi.org/10.1002/ana.26784
Résumé :
ObjectiveSmall‐cell lung cancer (SCLC) is the malignancy most frequently associated with paraneoplastic neurological syndromes (PNS) and can trigger different antibody responses against intracellular (Hu) or neuronal surface (GABABR) antigens. Our aim was to clarify whether the genomic and transcriptomic features of SCLC are different in patients with anti‐GABABR or anti‐Hu PNS compared with SCLC without PNS.MethodsA total of 76 SCLC tumor samples were collected: 34 anti‐Hu, 14 anti‐GABABR, and 28 SCLC without PNS. The study consisted of 4 steps: (1) pathological confirmation; (2) next generation sequencing using a panel of 98 genes, including those encoding the autoantibodies targets ELAVL1‐4, GABBR1‐2, and KCTD16; (3) genome‐wide copy number variation (CNV); and (4) whole‐transcriptome RNA sequencing.ResultsCNV analysis revealed that patients with anti‐GABABR PNS commonly have a gain in chromosome 5q, which contains KCTD16, whereas anti‐Hu and control patients often harbor a loss. No significantly different number of mutations regarding any onconeural genes was observed. Conversely, the transcriptomic profile of SCLC was different, and the differentially expressed genes allowed effective clustering of the samples into 3 groups, reflecting the antibody‐based classification, with an overexpression of KCTD16 specific to anti‐GABABR PNS. Pathway analysis revealed that tumors of patients with anti‐GABABR encephalitis were enriched in B‐cell signatures, as opposed to those of patients with anti‐Hu, in which T‐cell‐ and interferon‐γ‐related signatures were overexpressed.InterpretationSCLC genetic and transcriptomic features differentiate anti‐GABABR, anti‐Hu, and non‐PNS tumors. The role of KCTD16 appears to be pivotal in the tumor immune tolerance breakdown of anti‐GABABR PNS. ANN NEUROL 2023;94:1102–1115
Annals of Neurology 94, 1102-1115 (2023)
Detection of
Bartley C., Ngo T., Do L., et al.. 🔗 https://doi.org/10.1002/ana.26776
Résumé :
ObjectiveCo‐occurring anti‐tripartite motif‐containing protein 9 and 67 autoantibodies (TRIM9/67‐IgG) have been reported in only a very few cases of paraneoplastic cerebellar syndrome. The value of these biomarkers and the most sensitive methods of TRIM9/67‐IgG detection are not known.MethodsWe performed a retrospective, multicenter study to evaluate the cerebrospinal fluid and serum of candidate TRIM9/67‐IgG cases by tissue‐based immunofluorescence, peptide phage display immunoprecipitation sequencing, overexpression cell‐based assay (CBA), and immunoblot. Cases in which TRIM9/67‐IgG was detected by at least 2 assays were considered TRIM9/67‐IgG positive.ResultsAmong these cases (n = 13), CBA was the most sensitive (100%) and revealed that all cases had TRIM9 and TRIM67 autoantibodies. Of TRIM9/67‐IgG cases with available clinical history, a subacute cerebellar syndrome was the most common presentation (n = 7/10), followed by encephalitis (n = 3/10). Of these 10 patients, 70% had comorbid cancer (7/10), 85% of whom (n = 6/7) had confirmed metastatic disease. All evaluable cancer biopsies expressed TRIM9 protein (n = 5/5), whose expression was elevated in the cancerous regions of the tissue in 4 of 5 cases.InterpretationTRIM9/67‐IgG is a rare but likely high‐risk paraneoplastic biomarker for which CBA appears to be the most sensitive diagnostic assay. ANN NEUROL 2023;94:1086–1101
Annals of Neurology 94, 1086-1101 (2023)
Immune and Genetic Signatures of Breast Carcinomas Triggering Anti-Yo–Associated Paraneoplastic Cerebellar Degeneration
Peter E., Treilleux I., Wucher V., et al.. 🔗 https://doi.org/10.1212/nxi.0000000000200015
Résumé :
Résumé non disponible.
Neurology Neuroimmunology & Neuroinflammation 9, (2022)
Funding & Support
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
