Thaler Lab – Immunobiology of autoimmune encephalitis
Our Aim
Autoantibodies against neuro-glial proteins have been identified in several forms of autoimmune encephalitis (AE). They can be directed against neuronal surface antigens or against intracellular proteins. Clinical presentations range from acute to subacute encephalopathy with neurological and psychiatric symptoms to acute life threatening conditions. Although much progress has been made in the treatment of these conditions, there are still many patients suffering from progressive cognitive decline, therapy-refractive seizures, progressive cerebellar ataxia and other symptoms. We therefore aim to understand mechanisms of dysregulated immune responses in the periphery as well as in the central nervous system in these patients in order to develop more effective and specific therapies.
Our Approach
To unravel mechanisms how immune cells and autoantibodies mediate neuronal damage in AE. We use a broad spectrum of methods like single cell sorting and sequencing, EBV immortalization of B cells, cell based assays, ELISA, immunohistochemistry, production of recombinant proteins, and a diverse panel of other immunological and molecular biological techniques. Our research is hypothesis driven and oriented on questions arising in clinical practice. We translate clinical findings to research projects by analyzing blood and spinal fluid samples.
Some of our current projects
B-cell repertoire in patients with GAD-antibody-associated neurological disorders.
Antibodies against glutamic acid decarboxylase (GAD) are found in a variety of neurological disorders like stiff-person syndrom, cerebellar ataxia, limbic encephalitis, and others. GAD is an intracellular protein located in the GABA-ergic synapse. How and if GAD-antibodies can mediate pathogenicity is still a matter of debate. We previously found that patients with GAD-antibody-associated disorders exhibit a strong dysregulation of peripheral B-cell responses with a high frequency of GAD-reactive B cells in the peripheral blood as well as GAD-antibody producing plasma cells in the bone marrow. Currently, we are analysing the B-cell repertoire in these patients on a single cell level trying to understand features of autoreactive cells and uncovering differences between autoreactive cells in the periphery and in the central nervous system.
Clinical characterization of patients with autoimmune encephalitis.
Many insights into symptom constellations, as well as laboratory and MRI findings in patients with AE have been gained in recent years. We contribute to broaden our understanding of these disorders by participating in the German Network for Research on Autoimmune Encephalitis (GENERATE), where patients are combined in a common registry and where we contribute to multicentric projects.
Linking neuroinflammation and neurodegeneration in autoimmune encephalitis.
Many patients with autoimmune encephalitis develop irreversible neurological deficits especially if immune-modulatory treatment is not initiated early after disease onset. However, in some subsets of autoimmune encephalitis even with prompt and aggressive immunotherapy progressive disease is observed. This suggests neurodegenerative mechanisms. We aspire to quantify those by imaging brain atrophy in MRI as well as analyzing neurodegenerative markers. Furthermore, we aim to unravel molecular mechanisms of antibody effects on neuronal cells.
Contact
2020
Gerhards R, Pfeffer LK, Lorenz J, Starost L, Nowack L, Thaler FS, Schlüter M, Rübsamen H, Macrini C, Winklmeier S, Mader S, Bronge M, Grönlund H, Federle R, Hsia H-E, Lichtenthaler SF, Merl-Pham J, Hauck SM, Kuhlmann T, Bauer IJ, Beltrán E, Gerdes L-A, Mezydlo A, Bar-Or A, Banwell B, Khademi M, Olsson T, Hohlfeld R, Lassmann H, Kümpfel T, Kawakami N, Meinl E. OMGP as a novel target for pathogenic autoimmunity in the CNS. Acta Neuropathologica Communications. 2020 Nov 30;8(1):207.
Thaler FS, Bangol B, Biljecki M, Havla J, Schumacher AM, Kümpfel T. Possible link of genetic variants to autoimmunity in GAD-antibody-associated neurological disorders. J Neurol Sci. 2020 Jun 15;413:116860.
2019
Winklmeier S, Schlüter M, Spadaro M, Thaler FS, Vural A, Gerhards R, Macrini C, Mader S, Kurne A, Inan B, Karabudak R, Özbay FG, Esendagli G, Hohlfeld R, Kümpfel T, Meinl E. Identification of circulating MOG-specific B cells in patients with MOG antibodies. Neurol Neuroimmunol Neuroinflamm. 2019 Oct 14;6(6):625.
Thaler FS, Thaller AL, Schuh E, Biljecki M, Winklmeier S, Mahler CF, Gerhards R, Völk S, Schnorfeil F, Subklewe M, Hohlfeld R, Kümpfel T, Meinl E. Abundant GAD-reactive B cells in GAD-antibody-associated neurological disorders. Ann Neurol. 2019; 85(3):448-454.
Thaler FS, Koriath C, Vollmar C, Bardins S, Kremmyda O, Danek A. Acute frontal eye field infarction: a topodiagnostic challenge. Neurology. 2019;92(4):193-195.
2018
Schubert J, Braemer D, Huttner HB, Gerner ST, Fuhrer H, Melzer N, Dik A, Pruess H, Ly L-T, Fuchs K, Leypoldt F, Nissen G, Schirotzek I, Dohmen C, Bösel J, Lewerenz J, Thaler F, Kuempfel T, Kraft A, Juranek A, Ringelstein M, Suehs K-W, Urbanek C, Scherag A, Geis C, Witte OW, Guenther A. Management and prognostic markers in autoimmune encephalitis patients requiring ICU treatment. Neurol Neuroimmunol Neuroinflamm. 2018;6(1):e514.
Spadaro M, Winklmeier S, Beltrán E, Macrini C, Höftberger R, Schuh E, Thaler FS, Gerdes L-A, Laurent SA, Gerhards R, Brändle S, Dornmair K, Breithaupt C, Krumbholz M, Moser M, Kirshnamoorthy G, Kamp F, Jenne D, Hohlfeld R, Kümpfel T, Lassmann H, Kawakami N, Meinl E. Pathogenicity of human antibodies against myelin oligodendrocyte glycoprotein. Ann Neurol. 2018;84(2):315-328.
Mueller SH, Färber A, Prüss H, Melzer N, Golombeck KS, Kümpfel T, Thaler F, Elisak M, Lewerenz J, Kaufmann M, Sühs KW, Ringelstein M, Kellinghaus C, Bien CG, Kraft A, Zettl UK, Ehrlich S, Handreka R, Rostásy K, Then Bergh F, Faiss JH, Lieb W, Franke A, Kuhlenbäumer G, Wandinger KP, Leypoldt F; German Network for Research on Autoimmune Encephalitis (GENERATE). Genetic predisposition in anti-LGI1 and anti-NMDA receptor encephalitis. Ann Neurol. 2018;83(4):863-869.
Meinl E, Thaler FS, Lichtenthaler SF. Shedding of BAFF/APRIL receptors controls B cells. Trends Immunol. 2018;39(9):673-676.
Thaler FS, Catak C, Einhäupl M, Müller S, Seelos K, Wollenweber FA, Kümpfel T. Cerebral small vessel disease caused by a novel heterozygous mutation in HTRA1. J Neurol Sci. 2018;388:19-21.
2017
Thaler FS, Laurent SA, Huber M, Mulazzani M, Dreyling M, Ködel U, Kümpfel T, Straube A, Meinl E, von Baumgarten L. Soluble TACI and soluble BCMA as biomarkers in primary central nervous system lymphoma. Neuro Oncol. 2017; 19(12):1618-1627.
Schuh E, Musumeci A, Thaler FS, Laurent SA, Ellwart JW, Bradl M, Hohlfeld R, Krug A, Meinl E. Human plasmacytoid dendritic cells display and shed B cell maturation antigen upon TLR-engagement. J Immunol. 2017;198(8):3081-3088.
Feil K, Forbrig R, Thaler FS, Conrad J, Heck S, Dorn F, Pfister HW, Straube A. Reversible cerebral vasoconstriction syndrome and posterior reversible encephalopathy syndrome associated with intracranial hypotension. Neurocrit Care. 2017;26(1):103-108.
2016
Spadaro M, Gerdes LA, Krumbholz M, Ertl-Wagner B, Thaler FS, Schuh E, Metz I, Blaschek A, Dick A, Brück W, Hohlfeld R, Meinl E, Kümpfel T. Autoantibodies to MOG in a distinct subgroup of adult multiple sclerosis. Neurol Neuroimmunol Neuroinflamm. 2016;3(5):e257.
2015
Hoffmann FS, Hofereiter J, Rübsamen H, Melms J, Schwarz S, Faber H, Weber P, Pütz B, Loleit V, Weber F, Hohlfeld R, Meinl E, Krumbholz M. Fingolimod induces neuroprotective factors in human astrocytes. J Neuroinflammation. 2015; 12:184.
Hoffmann FS, Kuhn P-H, Laurent SA, Hauck SM, Berer K, Krumbholz M, Khademi M, Olsson T, Dreyling M, Pfister H-W, Alexander T, Hiepe F, Kümpfel T, Wekerle H, Hohlfeld R, Lichtenthaler SF, Meinl E. The immunoregulator soluble TACI is released by ADAM10 and reflects B cell activation in autoimmunity. J Immunol. 2015; 194(2):542-52.
Laurent SA, Hoffmann FS°, Kuhn PH°, Cheng Q, Chu Y, Schmidt-Supprian M, Hauck SM, Schuh E, Krumbholz M, Rübsamen H, Wanngren J, Khademi M, Olsson T, Alexander T, Hiepe F, Pfister HW, Weber F, Jenner D, Wekerle H, Hohlfeld R, Lichtenthaler SF, Meinl E. ° FSH and P-HK contributed equally to this work. γ-Secretase directly sheds the survival receptor BCMA from plasma cells. Nat Commun. 2015;6:7333.
Hoffmann FS°, Schmidt A°, Dittmann Chevillotte M, Wisskirchen C, Hellmuth JC, Willms S, Gilmore RH, Glas J, Folwaczny M, Müller T, Berg T, Spengler U, Fitzmaurice K, Kelleher D, Reisch N, Rice CM, Endres S, Rothenfusser S. ° FSH and AS contributed equally to this work. Polymorphisms in MDA-5 link protein function to clearance of hepatitis C virus. Hepatology. 2015;61(2):460-70.
Reinholz M, Heppt MV, Hoffmann FS, Lummel N, Ruzicka T, Lehmann P, Berking C. Transient memory impairment and transient global amnesia induced by photodynamic therapy. British Journal of Dermatology. 2015;173(5): 1258-1262.
2014
Hoffmann FS, Meinl E. B cells in multiple sclerosis: good or bad guys?: An article for 28 May 2014 – World MS Day 2014. Eur J Immunol. 2014;44(5):1247-50.
2013
Hohenauer T, Berking C, Schmidt A, Haferkamp S, Senft D, Kammerbauer C, Fraschka S, Graf SA, Irmler M, Beckers J, Flaig M, Aigner A, Höbel S, Hoffmann FS, Hermeking H, Rothenfusser S, Endres S, Ruzicka T, Besch R. The neural crest transcription factor Brn3a is expressed in melanoma and required for cell cycle progression and survival. EMBO Mol Med. 2013;5(6):919-34.
2009
Schmidt A, Schwerd T, Hamm W, Hellmuth JC, Cui S, Wenzel M, Hoffmann FS, Michallet MC, Besch R, Hopfner KP, Endres S, Rothenfusser S. 5'-triphosphate RNA requires base-paired structures to activate antiviral signaling via RIG-I. Proc Natl Acad Sci U S A. 2009;106(29):12067-72.
Franziska Thaler, principal investigator
Read more about the PI on the next tab
Michelle Biljecki, PhD Student
While pursuing my Bachelor´s degree in nutritional science at the University of Hohenheim (Stuttgart, Germany) I got fascinated by immunology. That’s why I started studying the M.Sc. in molecular cell biology and immunology at the University of Tübingen. After my time in Tübingen I wanted to learn more about Neuroimmunology and applied for the PhD position at the Institute of Clinical Neuroimmunology in 2018 as well as for the PhD program of the Graduate School of Systemic Neuroscience (GSN). Since then, I´m investigating on B cell-mediated immune responses in auto-antibody-associated neurological disorders (SPS, LE). Besides working, I am passionate about climbing, table soccer, dancing, and food. Of course also about many other outdoor activities like hiking.
Katharina Eisenhut, MD and PhD Student
Since I started my residency at the Institute of Clinical Neuroimmunology in 01/2020 I have been involved in research revolving around the GENERATE registry (GErman NEtwork for Research on AuToimmune Encephalitis) with a particular focus on GAD-antibody-associated diseases. Further, I am interested in the immune response to SARS-CoV-2 through a neuroimmunological perspective. In 05/2021 I will join the Thaler lab as a PhD student.
Dr. med. Franziska Thaler
As a clinician scientist I am both involved in the care of neuroimmunological patients as well as in performing translational research projects. My scientific work focuses on the B-cell-response in neuroimmunological disorders especially in autoimmune encephalitis (AE). Here, I am particularly interested in neurological disorders associated with antibodies against glutamic acid decarboxylase (GAD). Our aim is to understand the immunopathogenesis of these disorders in order to develop more effective and more specific treatment strategies. Furthermore, I am part of the German Network for the Research on Autoimmune Encephalitis (GENERATE) which aims in combining patients with AE in a common registry and coordinating multicentric projects. Additionally, I am member of the Hertie Network of Excellence in Clinical Neuroscience connecting researchers involved in neuroscience throughout Germany. In 2021 I received an independent group leader award of the Clinician Scientist Program by the Munich Cluster for Systems Neurology.
Medical Education
05/2011 Medical license (Approbation), approval as a physician by the Bavarian State Medical Association
2004 – 2011 Medical School, Ludwig-Maximilians-University, Munich; clinical fellowships at UCL London (Institute of Neurology), Jimma University, Ethiopia, and Universidad de Buenos Aires, Argentina
2007 - 2012 MD thesis, summa cum laude, Institute of Clinical Pharmacology, Ludwig-Maximilians-University, Munich
Professional Activity
08/2014 – today Assistant neurologist and research fellow at the Institute of Clinical Neuroimmunology and Department of Neurology, LMU Klinikum, Munich; 03/2020 – 02/2021: psychiatry rotation at Klinikum Fünfseenland Gauting
12/2012-07/2014 Post doctoral fellow at the Institute of Clinical Neuroimmunology in the research group of Prof. Edgar Meinl
12/2011-11/2012 Assistant neurologist at the Department of Neurology, LMU Klinikum, Munich
09/2011-11/2011 Post doctoral fellow at the Max-Planck-Institute for Neurobiology, Munich
Awards and Honors
2021 Independent group leader award - Clinician Scientist Program by the Munich Cluster for Systems Neurology (SyNergy)
Since 2019 Member of the Hertie Network of Excellence in Clinical Neuroscience
2015 Helmut Bauer Prize for research on Multiple Sclerosis
2008-2011 Scholarship of the Max Weber Programme, Elitenetzwerk Bavaria
2007-2008 Research scholarship of the German Research Foundation within the Graduate School „oligonucleotides in cell biology and therapy“
Memberships:
German Society of Neurology (DGN), German Network for Research on Autoimmune Encephalitis (GENERATE)
We gratefully acknowledge support for our work by the following agencies:
Munich Cluster for Systems Neurology (SyNergy)
Friedrich Bauer Stiftung
Gemeinnützige Hertie Stiftung
Else Kröner-Fresenius-Stiftung
Novartis Pharma GmbH
