Mader Lab – CNS-reactive antibodies
There is an increasing awareness of the contribution of CNS-reactive antibodies in different neurological diseases. These antibodies penetrate brain tissue upon blood brain barrier breach or early in development. Antibodies can bind to different extracellular or intracellular antigens and their contribution to tissue injury is often unclear. We aim to characterize novel CNS-reactive antibodies in different autoimmune diseases and analyze the mechanisms of autoantibody-mediated impairment of neuronal or glial cell function. Our studies provide important insights for biomarker discovery and for future therapeutic applications to prevent the pathogenic effects of CNS-reactive autoantibodies.
We aim to identify novel autoantibodies and study the mechanism by which CNS-reactive autoantibodies can lead to brain damage. Therefore, we are generating human monoclonal antibodies from CSF cells and/or from circulating autoreactive B cells that recognize brain antigen(s) (Molecular Psychiatry, 2016). We apply different methods such as single cell sorting and sequencing, immunohistochemistry of brain tissue, confocal laser scanning microscopy, cell based assays, immunoprecipitation and live neuronal cell cultures.
Some of our current projects
CNS-reactive antibodies and B cell responses in Neuromyelitis optica spectrum disorders.
Neuromyelitis optica spectrum disorders (NMOSD) are inflammatory disorders, which mainly affect the optic nerve and the spinal cord, but can also involve the brain and brainstem. The detection of antibodies (Abs) which target aquaporin-4 (AQP4) in a large group of NMOSD patients gave rise to the concept that NMOSD is distinct from multiple sclerosis. In addition, Abs to MOG have been found in a subgroup of NMOSD patients. There is still a sizeable group of patients with clinical symptoms of NMOSD without identified specific Abs, complicating diagnosis and treatment of patients. We are studying the contribution of autoantibodies and autoreactive B cells to tissue injury. Furthermore, we are investigating an association of treatment effect on circulating autoreactive B cells in NMOSD. We believe that the discovery of CNS-reactive Abs and their target antigen has immense importance for the understanding, diagnosis, and treatment of NMOSD.
Mader S, Ho S, Wong HK, Baier S, Winklmeier S, Riemer C, Rübsamen H, Fernandez IM, Gerhards R, Du C, Chuquisana O, Lünemann JD, Lux A, Nimmerjahn F, Bradl M*, Kawakami N*, Meinl E*. Dissection of complement and Fc-receptor-mediated pathomechanisms of autoantibodies to myelin oligodendrocyte glycoprotein. Proc Natl Acad Sci U S A. 2023 Mar 28;120(13):e2300648120. doi: 10.1073/pnas.2300648120.
Biljecki M, Eisenhut K, Beltrán E, Winklmeier S, Mader S, Thaller A, Eichhorn P, Steininger P, Flierl-Hecht A, Lewerenz J, Kümpfel T, Kerschensteiner M, Meinl E, Thaler FS. Antibodies Against Glutamic Acid Decarboxylase 65 Are Locally Produced in the CSF and Arise During Affinity Maturation. Neurol Neuroimmunol Neuroinflamm. 2023 Feb 23;10(3):e200090.
Ho S, Oswald E, Wong HK, Vural A, Yilmaz V, Tüzün E, Türkoğlu R, Straub T, Meinl I, Thaler F, Kümpfel T, Meinl E*, Mader S*. Ocrelizumab Treatment Modulates B-Cell Regulating Factors in Multiple Sclerosis. Neurol Neuroimmunol Neuroinflamm. 2023 Jan 26;10(2):e200083.
Tabansky I*, Tanaka A*, Wang J*, Zhang G*, Dujmovic I*, Mader S*,Jeganathan V, DeAngelis T, Funaro M, Harel A, Messina Mark, Shabbir M, Nursey V, DeGouvia W,Laurent M, Blitz K, Jindra P, Gudesblatt M, Regeneron Genetics Center, King A, Drulovic J, Yunis E, Brusic V, Shen Y, Keskin D, Najja S and Stern J N. H. Rare variants and HLA haplotypes associated in patients with neuromyelitis optica spectrum disorders. Front Immunol . 2022 Oct 4;13:900605. (* co-first authors).
Mader S*, Kümpfel T, Meinl E. Pathomechanisms in demyelination and astrocytopathy: autoantibodies to AQP4, MOG, GFAP, GRP78 and beyond. Curr Opin Neurol . 2022 Jun 1;35(3):427-435. ( *corresponding author) Curr Opin Neurol. 2022 Jun 1;35(3):427-435.
Winklmeier S, Eisenhut K, Taskin D, Rübsamen H, Gerhards R, Schneider C, Wratil PR, Stern M, Eichhorn P, Keppler OT, Klein M, Mader S, Kümpfel T, Meinl E. Persistence of functional memory B cells recognizing SARS-CoV-2 variants despite loss of specific IgG. iScience. 2022 Jan 21;25(1):103659.
Mader S, Brimberg L, Vo A, Strohl JJ, Crawford JM, Bonnin A, Carrión J, Campbell D, Huerta TS, La Bella A, Berlin R, Dewey SL, Hellman M, Eidelberg D, Dujmovic I, Drulovic J, Bennett JL, Volpe BT, Huerta PT, Diamond B. In utero exposure to maternal anti-aquaporin-4 antibodies alters brain vasculature and neural dynamics in male mouse offspring. Sci Transl Med. 2022, 20;14(641):eabe9726.Apr 20. https://www.science.org/stoken/author-tokens/ST-442/full
Macrini C, Gerhards R, Winklmeier S, Bergmann L, Mader S, Spadaro M, Vural A , Smolle M, Hohlfeld R, Kümpfel T, Lichtenthaler S, Franquelim H, Jenne D, Meinl E. Features of MOG required for recognition by patients with MOG-antibody-associated disorders. Brain, 2021 Sep 4;144(8):2375-2389.
Beltrán E, Paunovic M, Cesur E, Gebert D, Jeitler M, Höftberger M, Malotka J, Mader S, Kawakami N, Meinl E, Bradl M, Dornmair K, Lassmann H. Archeological neuroimmunology: Resurrection of a pathogenic immune response from a historical case sheds light on human autoimmune encephalomyelitis and multiple sclerosis. Acta Neuropathologica, 2021 Jan;141(1):67-83.2020.
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.
Khatri S, Psaraftis N, Funaro A, Arinuma Y, Fujieda Y, Mader S, Jørgensen C, Astakhova K. Serological Comparison of Systemic Lupus Erythematosus with Neuropsychiatric Lupus using Synthetic Nucleic Acid Antigens. Journal of Translational Autoimmunity. 2020 Oct 28;3:100068.
Mader S*, Kümpfel T, Meinl E. Novel insights into pathophysiology and therapeutic possibilities reveal further differences between AQP4-IgG and MOG-IgG associated diseases. Current opinion in Neurology. 2020 Jun;33(3):362-371.
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.
Drulovic J, Martinovic V, Basuroski ID, Mesaros S, Mader S, Weinshenker B, Pekmezovic T. Long-term outcome and prognosis in patients with neuromyelitis optica spectrum disorder from Serbia. Mult Scler Relat Disord. 2019 Nov;36:101413.
Mader S*, Brimberg L*. Aquaporin-4 Water Channel in the Brain and Its Implication for Health and Disease. Cells. 2019 Jan 27;8(2).
(* co-senior author)
Fujieda Y, Mader S, Jeganathan V, Arinuma Y, Shimizu Y, Kato M, Oku K, Minami A, Shimizu C, Yasuda S, Atsumi T. Clinical significance of anti-DNA/N-methyl-D-aspartate receptor 2 antibodies in de novo and post-steroid cases with neuropsychiatric systemic lupus erythematosus. Int J Rheum Dis. 2019 Mar;22(3):443-448.
Mader S*, Brimberg L*, Soltys JN, Bennett JL, Diamond B. Mutations of Recombinant Aquaporin-4 Antibody in the Fc Domain Can Impair Complement-Dependent Cellular Cytotoxicity and Transplacental Transport. Front Immunol. 2018 Jul 13;9:1599.
(* co-first author)
Mader S*, Jeganathan V*, Arinuma Y, Fujieda Y, Dujmovic I, Drulovic J, Shimizu Y, Sakuma Y, Stern JNH, Aranow C, Mackay M, Yasuda S, Atsumi T, Hirohata S, Diamond B. Understanding the Antibody Repertoire in Neuropsychiatric Systemic Lupus Erythematosus and Neuromyelitis Optica Spectrum Disorder: Do They Share Common Targets? Arthritis Rheumatol. 2018 Feb;70(2):277-286.
(* co-first author) - # article featured as a research highlight in Arthritis and Rheumatology, February 2018
Mader S, Brimberg L, Diamond B. The Role of Brain-Reactive Autoantibodies in Brain Pathology and Cognitive Impairment. Front Immunol. 2017 Sep 11;8:1101.
Hennes EM, Baumann M, Schanda K, Anlar B, Bajer-Kornek B, Blaschek A, Brantner-Inthaler S, Diepold K, Eisenkölbl A, Gotwald T, Kuchukhidze G, Gruber-Sedlmayr U, Häusler M, Höftberger R, Karenfort M, Klein A, Koch J, Kraus V, Lechner C, Leiz S, Leypoldt F, Mader S, Marquard K, Poggenburg I, Pohl D, Pritsch M, Raucherzauner M, Schimmel M, Thiels C, Tibussek D, Vieker S, Zeches C, Berger T, Reindl M, Rostásy K; BIOMARKER Study Group. Prognostic relevance of MOG antibodies in children with an acquired demyelinating syndrome. Neurology. 2017 Aug 29;89(9):900-908.
Brimberg L*, Mader S*, Jeganathan V, Berlin R, Gregersen P, Huerta P, Volpe B, Diamond B. Caspr2-reactive antibody cloned from a mother of an ASD child mediates ASD-like phenotype in mice. Molecular Psychiatry. 2016 Dec;21(12):1663-1671.
(* co-first authors) - # featured as research highlight in Nature Reviews Neurology: Neurodevelopmental disorders: Maternal antibodies induce autism-like phenotype in mice (Hemi Malkki)
# selected for the International Society of Autism Research (INSAR's) Young Investigator Award for the best Autism-related empirical research studies conducted by up-and-coming scientists (award received by Brimberg L)
# selected for press release, Society for Neuroscience, Chicago, IL.2015
Honig G, Mader S, Chen H, Porat A, Ochani M, Wang P, Volpe BT, Diamond B. Blood-Brain Barrier Deterioration and Hippocampal Gene Expression in Polymicrobial Sepsis: An Evaluation of Endothelial MyD88 and the Vagus Nerve. PLoS One. 2016 Jan 20;11(1):e0144215.
Zeka B, Hastermann M, Hochmeister S, Kögl N, Kaufmann N, Schanda K, Mader S, Misu T, Rommer P, Fujihara K, Illes Z, Leutmezer F, Sato DK, Nakashima I, Reindl M, Lassmann H, Bradl M. Highly encephalitogenic aquaporin 4-specific T cells and NMO-IgG jointly orchestrate lesion location and tissue damage in the CNS. Acta Neuropathol. 2015 Dec;130(6):783-98
Brimberg L, Mader S, Fujieda Y, Kowal C, et al, Antibodies as mediators of brain pathology.
Trends in Immunol. 2015; 36(11):709-24.
Sankovski R*, Mader S*, Valdes S*. Systemic inflammation and the brain: novel roles of genetic, molecular, and environmental cues as drivers of neurodegeneration. Front Cell Neurosci. 2015;9:28.
(* co-senior author)
Chang E, Volpe B, Mackay M, Aranow C, Watson P, Kowal C, Storbeck J, Mattis P, Berlin R, Chen H, Mader S, Tomas S. Huerta T. Huerta P, Diamond B. Selective impairment of spatial cognition caused by autoantibodies to the N-methyl-D-aspartate receptor. EbioMedicine. 2015 May 30;2(7):755-64.
Baumann M, Sahin K, Lechner C, Hennes EM, Schanda K, Mader S et al., Clinical and neuroradiological differences of pediatric acute disseminating encephalomyelitis with and without antibodies to the myelin oligodendrocyte glycoprotein. J Neurol Neurosurg Psychiatry. 2015 Mar;86(3):265-72.
Diamond B, Honig, Mader S, Brimberg L, Volpe B. Brain-Reactive Antibodies and Disease. Annu Rev Immunol 2013 31:345-85.
Pohl M, Kawakami N, Kitic M, Bauer J, Martins R, Fischer MT, Machado-Santos J, Mader S et al., T cell-activation in neuromyelitis optica lesions plays a role in their formation. Acta Neuropathol Commun. 2013;1(1):85.
Gredler V*, Mader S*, Schanda K, Hegen H, Di Pauli F, Kuenz B, Deisenhammer F, Berger T, Reindl M, Lutterotti A. Clinical and immunological follow-up of B-cell depleting therapy in CNS demyelinating diseases. J Neurol Science. 2013 May;328(1-2):77-82.
(* co-first author)
Rostásy K, Mader S, Hennes E, Schanda K et al., Persisting myelin oligodendrocyte glycoprotein antibodies in aquaporin-4 antibody negative pediatric neuromyelitis optica. Mult Scler. 2013; 19(8):1052-9.
Kitic M, Hochmeister S, Wimmer I, Bauer J, Misu T, Mader S, et al., Intrastriatal injection of interleukin-1 beta triggers the formation of neuromyelitis optica-like lesions in NMO-IgG seropositive rats. Acta Neuropathol Commun. 2013;1(1):5.
Aboul-Enein F, Seifert-Held T, Mader S, et.al., Neuromyelitis Optica in Austria in 2011: To Bridge the Gap between Neuroepidemiological Research and Practice in a Study Population of 8.4 Million People. PLoS One. 2013 Nov 5;8(11):e79649.
Rostasy K, Mader S, Di Pauli F, Huppke P, Gärtner J, Marquart F, Karenfurt M, Tibussek D, Blaschek A, Kornek B, Leitz S, Berger T, Reindl M. Anti-myelin oligodendrocyte glycoprotein antibodies in pediatric patients with optic neuritis. Archives of Neurology, 2012;69(6):752-756.
Mader S, Gredler V, Schanda K, Rostasy K, Dujmovic I, Pfaller K, Lutterotti A, Jarius S, Di Pauli F, Kuenz B, Ehling R, Hegen H, Deisenhammer F, Aboul-Enein F, Storch M K, Koson P, Drulovic J, Kristoferitsch W, Berger T, Reindl M; Complement activating antibodies to myelin oligodendrocyte glycoprotein in neuromyelitis optica and related disorders. J Neuroinflammation. 2011;8:184.
Jarius S, Jacobi C, de Seze J, Zephir H, Paul F, Franciotta D, Rommer P, Mader S, et al., Frequency and syndrome specificity of antibodies to aquaporin-4 in neurological patients with rheumatic diseases. Multiple Sclerosis Journal. 2011 Sep | 17(9):1067-73.
Pohl M, Fischer M, Mader S, Schanda K, Kitic M, Sharma R, MisuT, Fujihara K, Reindl M, Lassmann H & Bradl M. Pathogenic T cell responses against aquaporin 4. Acta Neuropathologica, 2011 Jul | 122(1):21-34.
Dujmovic I*, Mader S *, Schanda K, Deisenhammer F, Stojsavljevic N, Kostic V, Berger T, Drulovic J, Reindl M. Temporal dynamics of cerebrospinal fluid anti-aquaporin-4 antibodies in patients with neuromyelitis optica spectrum disorders. J Neuroimmunology. 2011; 234(1-2):124-30.
(* co-first author)
Di Pauli F*, Mader S*, Rostasy K, Schanda K, Bajer-Kornek B, Ehling R, Deisenhammer F, Reindl M, Berger T. Temporal dynamics of anti-MOG antibodies in CNS demyelinating diseases. Clin Immunol. 2011;138(3):247-54.
(* co-first author)
Mader S, Lutterotti A, DiPauli F, Kuenz B, Schanda K, AboulEnein F, Khalil M, Storch MK, Jarius S, Kristoferitsch W, Berger T, Reindl M. Patterns of antibody binding to aquaporin-4 isoforms in neuromyelitis optica. PLoS One. 2010;5(5):e10455.
Bradl M, Misu T, Takahashi T, Watanabe M, Mader S, Reindl M, Adzemovic M, Bauer J, Berger T, Fujihara K, Itoyama Y, Lassmann H. Neuromyelitis optica: pathogenicity of patient immunoglobulin in vivo. Annals of Neurology. 2009 Nov | 66(5):630-43.
2020 Diamond B., Mader S., Brimberg L., Gregerson P.: Inhibition of autism spectrum disorder using decoy antigens to maternal brain-reactive antibodies, Patent number: 10654919
Samantha Ho, PhD Student
My fascination for neuroscience commenced during my Bachelor’s study of Neuroscience at the University of Alberta in Canada. Captivated by the complexity and adaptability of the nervous system alongside an urge to experience cultures abroad, I relocated to Munich, Germany in 2018 and pursued my Masters study in Neuroscience with the Graduate School of Systemic Neuroscience (GSN). During this time, I discovered the field of Neuroimmunology and joined the lab for my Masters thesis, where I investigated novel brain-reactive antibodies in sporadic cerebellar ataxia patients. Currently, I am continuing to indulge in the topic of brain reactive antibodies in inflammatory and degenerative diseases of the central nervous system as my PhD project. My life a bike-ride away from the lab includes more bike-rides and hikes in the nature. On stormy days, I am found under layers of blankets knitting socks.
Katie Hoi Kiu Wong, PhD Student
I studied Applied Biology for my Bachelor’s degree in Hong Kong, and have always been intrigued in immunology especially after I started my Bachelor thesis on investigating the cytotoxicity of NK cells. During my Bachelor in 2016, I also had the opportunity to participate in a half-year exchange programme at the LMU Munich, where I was very much fascinated by the profession and diversity of biological fields. After my graduation in 2017, I came back to the LMU as a Master student in Biology, focusing mainly on human biology and cell biology, where I then had the great chance to work as a student at the Meinl lab on neuroimmunology. After completing my master thesis in the same lab, I was highly motivated to continue my PhD studies with my research project, aiming to identify novel autoantibodies as diagnostic markers and to understand the disease pathomechanisms behind a CNS demyelinating disease, known as Neuromyelitis Optica. The best free-time activity for me is to play with my dog, relax and being lazy in a cozy sofa at home. Otherwise you will find me in the kitchen as I love baking a lot, as I was always dreaming of having my own bakery!
Leonie Erpenbeck, FöFoLe doctoral student
I am a student of medicine currently in my seventh semester at the LMU Munich. During my preclinical studies, I uncovered a profound interest in the intricate details of histological samples and began to appreciate the fact that histological morphologies are closely intertwined with their astounding biochemical capacities. Especially longing to deepen my understanding of the sophisticated physiological and pathological workings of the immune system, I started searching for an experimental dissertation thesis via the LMU`s FöFoLe program. I am more than happy and curious to find this fascination embedded within the field of Neuroimmunology in a thesis that will focus on examining long-term treatment effects on autoreactive memory B cells in samples obtained from patients with neuromyelitis optica spectrum disorders.
Being able to join the Mader Lab as a FöFoLe doctoral student, collaborating on this project with the AG Meinl and the clinical groups of the Institute of Clinical Neuroimmunology, learning from and working with such a skilled and kind team fills me with great joy and excitement.
Studies aside, I am very keen on art and literature and love being outdoors, taking long walks as well as bike rides and going hiking in the mountains.
PD Dr. Simone Mader
I am a neuroimmunologist with over ten years of research experience in multiple sclerosis (MS) and associated disorders such as Neuromyelitis optica spectrum disorders (NMOSD) and Acute disseminated encephalitis (ADEM). I discovered my passion for research on CNS-reactive antibodies during my PhD thesis at Innsbruck Medical University, Austria, where I worked on the role of aquaporin-4 (AQP4) antibodies in NMOSD and discovered antibodies to myelin oligodendrocyte glycoprotein (MOG) in a subgroup of NMOSD patients (Journal of Neuroinflammation, 2011). I continued to study CNS-reactive antibodies in NMOSD and Neuropsychiatric Lupus as a Postdoc in the lab of Betty Diamond at the Feinstein Institute for Medical Research, New York (EbioMedicine, 2015; Arthritis and Rheumatology, 2018). We discovered that maternal antibodies can reach fetal brain tissue during pregnancy and may contribute to neurodevelopmental diseases, such as autism spectrum disorders (Molecular Psychiatry, 2016; Frontiers in Immunology, 2018). Back in Germany I am now interested in novel autoantibody discovery and antibody-mediated damage in different neurological diseases, such as NMOSD and cerebellar ataxia, which has important therapeutic implications.
2001 – 2005 Bachelor studies in Biology at the Leopold-Franzens University, Innsbruck, Austria (graduation to Bakk. rer. nat.)
2005-2007 Master program in Molecular Biology, Leopold-Franzens University Innsbruck, Austria (passed with distinction)
2008-2011 Ph.D. program at the Medical University of Innsbruck, Department of Neurology, research group of Multiple Sclerosis (Prof.Dr. Markus Reindl), (passed with distinction)
01/2022 Venia legendi (Habilitation)
2011-2012 Post Doc, Clinical Department of Neurology, Innsbruck Medical University
2012 – 2017 Post Doc, Feinstein Institute for Medical Research, NY, USA, Center for Autoimmune and Musculoskeletal Disease (Prof. Dr. Betty Diamond)
2017 – 2018 Junior Faculty Position, Instructor, Feinstein Institute for Medical Research NY, USA
since 2018 Instructor at the Institute of Clinical Neuroimmunology, LMU Munich (Prof. Dr. Edgar Meinl)
since 2021 Junior Group leader at the Institute of Clinical Neuroimmunology, LMU Munich
Awards and Honors
2022 Eureka Grant, The Guthy-Jackson Charitable Foundation
2020 Novartis funding for Oppenheim Award Application- Novartis Pharma GmbH LMU Junior Researcher Funding- LMUexcellent
2019 Young Investigator Fund for Innovative Research Ideas - Schering Stiftung & Fritz Thyssen Foundation
Synergy Award- Munich Cluster for Systems Neurology (SyNergy)
Research Grant - Else Kröner Fresenius Stiftung
2017 Speaker Recognition Award - Feinstein Institute for Medical Research, USA
Autism Society Award for best manuscript (Brimberg & Mader et al.,), USA
AWSM Postdoc Fellows Award- Advancing Women in Science and Medicine (AWSM), Feinstein Institute, NY, USA
2013-2016 Basic Science Fellowship Recipient - S.L.E. Foundation, Inc., USA
2016 Excellence in Research award- Feinstein Institute for Medical Research, NY, USA
Deirdre Costa Major Post Doctoral Educational Award - Advancing Women in Science and Medicine (AWSM), Feinstein Institute, NY, USA
C/STEP Research Mentor Award - Science and Technology Entry Program (STEP)/ The Collegiate Science and Technology Entry Program, Farmingdale, USA
2015 Travel award - 4th European Congress of Immunology, Vienna, Austria
FOCIS poster and Travel award- Federation of Clinical Immunology Societies, San Diego, USA
L’ORÉAL Fellowships/ Young Female Scientists in Basic Research (award declined)
2013 Travel award- Federation of Clinical Immunology Societies (FOCIS), Boston, USA
2012 Ursula & Fritz Melchers Award: PhD Award, Austrian Society of Allergology and Immunology (ÖGAI)/ Austria
2011 Poster Award, XI Neuroscience Wintermeeting, Kitzbühel, Austria
2010 Poster Award, 8th Annual Meeting of the Austrian Neurological Society (ÖGN)
2009 ECTRIMS 2009 Travel Award- 25th Congress of the European Committee for the Treatment and Research in Multiple Sclerosis
Poster Award, Landsteiner Meeting, Salzburg, Austria
We gratefully acknowledge support for our work by the following agencies: