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, pluripotent stem cell technologies, 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. Furthermore, we detected GAD-specific B cells in the cerebrospinal fluid (CSF) of patients and were able to recombinantly produce monoclonal antibodies derived from these CSF cells. Detailed molecular analysis revealed that affinity maturation e.g. somatic hypermutations are required to confer GAD-reactivity. Currently, we are interested in characterizing the molecular properties of GAD-specific cells on a single cell level and to understand which mechanisms account for the development of autoreactivity against GAD.
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. Here, we are currently especially interested in understanding common dysregulated pathways in neuroimmunological and hematological disorders and initiated the project LIGHTNING (Linking HemaTology and NeuroImmuNoloGy).
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.
Human pluripotent stem cell-derived models of autoimmune encephalitis and related diseases
While animal models have yielded important insights into the pathophysiology of various neuroimmune disorders, clinical translation has often been complicated by considerable species-specific differences. To bridge this gap, we are leveraging recent progress in pluripotent stem cell technology and develop human in vitro models of autoimmune encephalitis and related disorders.
2023
Strippel C, Herrera-Rivero M, Wendorff M, Tietz AK, Degenhardt F, Witten A, Schroeter C, Nelke C, Golombeck KS, Madlener M, Rüber T, Ernst L, Racz A, Baumgartner T, Widman G, Doppler K, Thaler FS, Siebenbrodt K, Dik A, Kerin C, Räuber S, Gallus M, Kovac S, Grauer OM, Grimm A, Prüss H, Wickel J, Geis C, Lewerenz J, Goebels N, Ringelstein M, Menge T, Tackenberg B, Kellinghaus C, Bien CG, Kraft A, Zettl U, Ismail FS, Ayzenberg I, Urbanek C, Sühs KW, Tauber SC, Mues S, Körtvélyessy P, Markewitz R, Paliantonis A, Elger CE, Surges R, Sommer C, Kümpfel T, Gross CC, Lerche H, Wellmer J, Quesada CM, Then Bergh F, Wandinger KP, Becker AJ, Kunz WS, Meyer Zu Hörste G, Malter MP, Rosenow F, Wiendl H, Kuhlenbäumer G, Leypoldt F, Lieb W, Franke A, Meuth SG, Stoll M, Melzer N; German Network for Research on Autoimmune Encephalitis (GENERATE). (2023) A genome-wide association study in autoimmune neurological syndromes with anti-GAD65 autoantibodies. Brain. 146(3):977-990.
Grüter T, Möllers FE, Tietz A, Dargvainiene J, Melzer N, Heidbreder A, Strippel C, Kraft A, Höftberger R, Schöberl F, Thaler FS, Wickel J, Chung HY, Seifert F, Tschernatsch M, Nagel M, Lewerenz J, Jarius S, Wildemann BC, de Azevedo L, Heidenreich F, Heusgen R, Hofstadt-van Oy U, Linsa A, Maaß JJ, Menge T, Ringelstein M, Pedrosa DJ, Schill J, Seifert-Held T, Seitz C, Tonner S, Urbanek C, Zittel S, Markewitz R, Korporal-Kuhnke M, Schmitter T, Finke C, Brüggemann N, Bien CI, Kleiter I, Gold R, Wandinger KP, Kuhlenbäumer G, Leypoldt F, Ayzenberg I; German Network for Research on Autoimmune Encephalitis (GENERATE). (2023) Clinical, serological and genetic predictors of response to immunotherapy in anti IgLON5 disease. Brain. 146(2):600-611.
Madlener M, Strippel C, Thaler FS, Doppler K, Wandinger KP, Lewerenz J, Ringelstein M, Roessling R, Menge T, Wickel J, Kellingshaus C, Mues S, Kraft A, Linsa A, Tauber SC, Berg FT, Gerner ST, Paliantonis A, Finke A, Priller J, Schirotzek I, Süße M, Sühs KW, Urbanek C, Senel M, Sommer C, Kuempfel T, Pruess H, Fink GR, Leypoldt F, Melzer N, Malter MP; German Network for Research on Autoimmune Encephalitis (GENERATE). (2023) Glutamic acid decarboxylase antibody-associated neurological syndromes: Clinical and antibody characteristics and therapy response. J Neurol Sci. 445:120540.
Eisenhut K, Faber J, Engels D, Gerhards R, Lewerenz J, Doppler K, Sommer C, Markewitz R, Falk KK, Rössling R, Prüss H, Finke C, Wickel J, Geis C, Ratuszny D, Pfeffer LK, Bittner S, Piepgras J, Kraft A, Klausewitz J, Nuscher B, Kümpfel T, Thaler FS; German Network for Research on Autoimmune Encephalitis (GENERATE). (2023) Early neuroaxonal damage in neurological disorders associated with GAD65-antibodies. Neurol Neuroimmunol Neuroinflamm. 11(1):e200176.
2022
Kaaden T, Madlener M, Angstwurm K, Bien CG, Bogarin Y, Doppler K, Finke A, Gerner ST, Reimann G, Häusler M, Handreka R, Hellwig K, Kaufmann M, Kellinghaus C, Koertvelyessy P, Kraft A, Lewerenz J, Menge T, Paliantonis A, von Podewils F, Prüss H, Rauer S, Ringelstein M, Rostásy K, Schirotzek I, Schwabe J, Sokolowski P, Suesse M, Sühs KW, Surges R, Tauber SC, Thaler F, Bergh FT, Urbanek C, Wandinger KP, Wildemann B, Mues S, Zettl U, Leypoldt F, Melzer N, Geis C, Malter M, Kunze A; and the Generate study group. Seizure Semiology in Antibody-Associated Autoimmune Encephalitis. Neurol Neuroimmunol Neuroinflamm. 2022 Oct 20;9(6):e200034.
2021
Dürr M, Nissen G, Sühs KW, Schwenkenbecher P, Geis C, Ringelstein M, Hartung HP, Friese MA, Kaufmann M, Malter MP, Madlener M, Thaler FS, Kümpfel T, Senel M, Häusler MG, Schneider H, Bergh FT, Kellinghaus C, Zettl UK, Wandinger KP, Melzer N, Gross CC, Lange P, Dreyhaupt J, Tumani H, Leypoldt F, Lewerenz J; German Network for Research on Autoimmune Encephalitis. CSF Findings in Acute NMDAR and LGI1 Antibody-Associated Autoimmune Encephalitis. Neurol Neuroimmunol Neuroinflamm. 2021 Oct 25;8(6):e1086.
Thaler FS, Zimmermann L, Kammermeier S, Strippel C, Ringelstein M, Kraft A, Sühs K-W,Wickel J, Geis C, Markewitz R, Urbanek C, Sommer C, Doppler K, Penner L, Lewerenz J, Rößling R, Finke C, Prüss H, Melzer N, Wandinger K-P, Leypoldt F, Kümpfel T. Rituximab treatment and long-term outcome of patients with autoimmune encephalitis: real-world evidence from the GENERATE registry. Neurol Neuroimmunol Neuroinflamm. 2021 Oct 1;8(6):e1088.
Schwenkenbecher P, Skripuletz T, Lange P, Dürr M, Konen F, Möhn N, Ringelstein M, Menge T, Friese MA, Melzer N, Malter MP, Häusler M, Thaler FS, Stangel M, Lewerenz J, Sühs K-W. Intrathecal antibody production against Epstein-Barr, herpes simplex, and other neurotropic viruses in autoimmune encephalitis. Neurol Neuroimmunol Neuroinflamm. 2021 Aug 24;8(6):e1062
Gaig C, Compta Y, Heidbreder A, Marti MJ, Titulaer MJ, Crijnen Y, Högl B, Lewerenz J, Erro ME, Garcia-Monco JC, Nigro P, Tambasco N, Patalong-Ogiewa M, Erdler M, Macher S, Berger-Sieczkowski E, Höftberger R, Geis C, Hutterer M, Milán-Tomás A, Martin-Bastida A, Lopez Manzanares L, Quintas S, Höglinger GU, Möhn N, Schoeberl F, Thaler FS, Asioli GM, Provini F, Plazzi G, Berganzo K, Blaabjerg M, Brüggemann N, Farias T, Ng CF, Giordana C, Herrero-San Martín A, Huebra L, Kotschet K, Liendl H, Montojo T, Morata C, Perez Perez J, Puertas I, Seifert-Held T, Seitz C, Mistieri Simabukuro M, Tellez N, Villacieros-Álvarez J, Willekens B, Sabater L, Iranzo A, Santamaria Cano J, Dalmau J, Graus F. Frequency and Characterization of Movement Disorders in Anti-IgLON5 Disease. Neurology. 2021 Aug 11;10.1212.
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
Katharina Eisenhut, MD and PhD Student
Ever since medical school I have been intrigued by the molecular mechanisms underlying diseases of the nervous system. After my MD thesis at the Walter Brendel Center of Experimental Medicine at LMU, I joined the Institute of Clinical Neuroimmunology in 01/2020 as neurology resident and started my PhD in 05/2021. Here, I am developing advanced pluripotent stem cell-derived models to study neurodevelopment and disease. Additionally, I am investigating the B cell receptor repertoire of patients with GAD65 antibody associated neurological syndromes on a single-cell level.
Jan Bartosch, PhD student
After conducting my Bachelor’s and Master’s studies in Biochemistry at the TUM, I joined the Thaler Lab in 2023 for my PhD. My project is focused on profiling the immune response in patients with GAD65 antibody associated neurological syndromes on a single-cell level. Beside the fascinating, translational work in close collaboration with the clinic, I really enjoy the mutual supportive atmosphere within this nice & friendly international team. Since I am also really eager to promote sustainability, I am happy to help the Green Initiative of the Institute (grINIM) to implement relevant local changes within our labs. When I am not in the lab, you can find me doing almost any kind of sports like soccer, table tennis or yoga or outside in the nature on a hike or on a biking trip.
Ebru Haholu, HiWi Student
Alumni
Michelle Biljecki, PhD Student
PD 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
01/2022 Venia legendi (Habilitation)
06/2021 Medical specialist neurology
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
Since 06/2021 Medical specialist neurology and junior group leader at the Institute of Clinical Neuroimmunology, LMU Klinikum, Munich
08/2014 – 06/2021 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
2019-2022 Member of the Hertie Network of Excellence in Clinical Neuroscience
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
Novartis Pharma GmbH
LMU Excellent
Fritz Thyssen Stiftung
Studienstiftung des detuschen Volkes
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