The Lunemann lab focuses on understanding the immunology of neurological disorders. We study a broad range of neurological disease conditions such as multiple sclerosis, neuromyelitis optica spectrum diseases including MOG-antibody associated disorders, autoimmune encephalitides, immune-mediated neuromuscular diseases including myasthenia gravis and inflammatory myopathies.
Antibody- and B cell-mediated mechanisms of neurological diseases.
CNS-specific autoantibodies can cause a variety of neurological symptoms ranging from epileptic seizures to psychosis and dementia. In recent years, a growing number of antibody-defined encephalitides have been identified. Antibodies contribute to the pathology of MS and they play a key role in inflammatory diseases of the peripheral nervous system as well as myasthenia. Although animal experiments have demonstrated pathogenicity for a variety of these antibody species via adoptive transfer experiments, the underlying mechanisms relevant in human IgG-mediated diseases are poorly understood. We investigate target specificities and effector functions of pathogenic antibodies in neurological disease conditions. Impaired B cell tolerance and the appearance of activated cells of the B cell lineage are core features of many autoimmune disorders of the nervous system. Here, we explore mechanisms of B cell tolerance, B cell antigen presentation and B:T cell interactions using experimental in vivo models and human material including single cell analyses. The goal of these studies is to better understand the role of B cell and antibody-mediated tissue damage and to develop novel targeted immunotherapies.
Chuquisana O, Strippel C, Tröscher AM, Baumgartner T, Rácz A, Keller CW, Elger CE, Melzer N, Kovac S, Wiendl H, Bauer J, Lünemann JD (2022) Complement activation contributes to GAD antibody-associated encephalitis. Acta Neuropathol. 144(2): 381-383. IF: 17.1
Keller CW, Chuquisana O, Derdelinckx J, Gross CC, Berger K, Robinson J, Nimmerjahn F, Wiendl H, Willcox N, Lünemann JD (2022) Impaired B Cell Expression of the Inhibitory Fcγ Receptor IIB in Myasthenia Gravis. Ann. Neurol. 92(6):1046-1051. IF: 11.3
Quast I, Keller CW, Maurer MA, Giddens JP, Tackenberg B, Wang LX, Münz C, Nimmerjahn F, Dalakas MC, Lünemann JD (2015) Sialylation of IgG Fc-domain impairs complement-dependent cytotoxicity. J Clin Invest. 125:4160-4170. IF: 19.5
Maurer MA, Rakocevic G, Leung CS, Quast I, Lukačišin M, Goebels N, Münz C, Wardemann H, Dalakas M, Lünemann JD (2012) Rituximab induces sustained reduction of pathogenic B cells in patients with peripheral nervous system autoimmunity. J Clin Invest. 122:1393-1402. IF: 19.5
Role of environmental factors, especially infections, in CNS autoimmunity
Genetic and environmental factors jointly contribute to the development of autoimmune diseases such as MS. Infection with γ-herpesvirus Epstein-Barr virus (EBV) is among the strongest risk factors. In contrast, increased immune responses to human cytomegalovirus (HCMV) are associated with a more favorable course of MS. In current studies, we are exploring cell-intrinsic effects of EBV and HCMV infection and the deregulated interaction between infected host cells with virus-specific T cells for MS. Obesity increases the risk for both the development and a more severe course of MS. We investigate mechanistic underpinnings for these associations to better understand the role of environmental and modifiable risk factors for MS development and progression.
Lutfullin I, Eveslage M, Bittner S, Antony G, Flaskamp M, Luessi F, Salmen A, Gisevius B, Klotz L, Korsukewitz C, Berthele A, Groppa S, Then Bergh F, Wildemann B, Bayas A, Tumani H, Meuth SG, Trebst C, Zettl UK, Paul F, Heesen C, Kuempfel T, Gold R, Hemmer B, Zipp F, Wiendl H, Lünemann JD, German Competence Network Multiple Sclerosis (KKNMS) (2022) Association of obesity with disease outcome in multiple sclerosis. J Neurol Neurosurg Psychiatry. doi: 10.1136/jnnp-2022-329685. (Epub 2022 Nov 1) IF: 13.7
Comabella M, Tintore M, Sao Avilés A, Carbonell-Mirabent P, Malhotra S, Rovira A, Fissolo N, Lünemann JD, Montalban X (2022) Increased cytomegalovirus immune responses at disease onset are protective in the long-term prognosis of patients with multiple sclerosis. J Neurol Neurosurg Psychiatry. doi: 10.1136/jnnp-2022-330205. (Epub 2022 Nov 7) IF: 13.7
Ascherio A, Munger KL, Lünemann JD (2012) The initiation and prevention of Multiple Sclerosis. Nat Rev Neurol. 8(11):602-12. IF: 42.9
Lünemann JD, Jelcic I, Roberts S, Lutterotti A, Tackenberg B, Martin R, Münz C (2008) EBNA1-Specific T Cells From Patients With Multiple Sclerosis Cross-React With Myelin Antigen And Co-Produce IFN-gamma and IL-2. J Exp Med. 205(8):1763-73. IF: 17.6
Regulation of glial cell activation in inflammatory CNS diseases
Microglia are CNS-resident myeloid immune cells essential for the development and homeostatic functions of the CNS while chronic activation of microglial cells is a characteristic feature of many brain disorders. Inefficient degradation of extracellular material in neurodegenerative and demyelinating disease conditions enhances the pathogenic function of microglia. In inducible-transgenic animal models, we systematically investigate the function of phagocytosis- and autophagy-associated proteins in microglia and astrocytes under physiological conditions and in models of inflammatory CNS diseases. The goal of these studies is to better understand glial cell immune functions in CNS inflammatory tissue injury and to identify target proteins and molecular networks for more effective treatment strategies.
Srimat Kandadai K, Kotur MB, Dokalis N, Amrein I, Keller CW, Münz C, Wolfer D, Prinz M, Lünemann JD (2021) ATG5 in microglia does not contribute vitally to autoimmune neuroinflammation in mice. Autophagy. 17(11): 3566-3576. IF: 16.0
Keller CW, Münz C, Lünemann JD (2020) Autophagy Pathways in CNS Myeloid Cell Immune Functions. Trends Neurosci. 43(12): 1024-1033. IF: 17.4
Keller CW, Kotur MB, Mundt S, Dokalis N, Ligeon LA, Shah AM, Prinz M, Becher B, Münz C, Lünemann JD (2021) CYBB/NOX2 in conventional DCs controls T cell encephalitogenicity during neuroinflammation. Autophagy. 17(5): 1244-1258. IF: 16.0
Keller CW, Sina C, Kotur MB, Ramelli G, Mundt S, Quast I, Ligeon LA, Weber P, Becher B, Münz C, Lünemann JD (2017) ATG-dependent phagocytosis in dendritic cells drives myelin-specific CD4+ T cell pathogenicity during CNS inflammation. Proc Natl Acad Sci U S A. 114(52): E11228-E11237. IF: 12.5
Precision medicine and therapy development
Inflammatory diseases of the nervous system are characterized by a strong heterogeneity in terms of clinical manifestation, course and therapeutic response. The arsenal of immunotherapeutic options, differing in mechanism of action, continues to grow and the earlier effective immunoprophylactic therapies are applied, the more sustainable they can favorably modify disease course. The development of personalized, data-driven precision medicine to better understand the heterogeneity of neuroimmunological diseases and to achieve effective immunotherapeutic disease control as early as possible is a core goal of my research program. To identify disease and progression-specific signatures, we integrate digitized demographic, clinical, and immunological high-resolution, -omics-based parameters using complex mutivariate and machine learning-based algorithms. We have successfully implemented this approach in MOG antibody-mediated CNS diseases and will now apply it to additional nervous system diseases. Early innovative investigator-initiated phase I/II studies are developed and carried out in collaboration with other Departments of the UKM (link early clinical trial unit).
Ruck T, Nimmerjahn F, Wiendl H, Lünemann JD (2022) Next-generation antibody-based therapies in neurology. Brain. 145 (4): 1229-1241. IF: 15.3
Boligan KF, Oechtering J, Keller CW, Peschke B, Rieben R, Bovin N, Kappos L, Cummings RD, Kuhle J, von Gunten S, Lünemann JD (2020) Xenogeneic Neu5Gc and self-glycan Neu5Ac epitopes are potential immune targets in MS. Neurol Neuroimmunol Neuroinflamm. 7(2): e676. IF: 11.4
Lünemann JD, Ruck T, Muraro PA, Bar-Or A, Wiendl H (2020) Immune reconstitution therapies: concepts for durable remission in multiple sclerosis. Nat Rev Neurol. 16(1): 56-62. IF: 42.9
Lünemann JD*, Wandinger KP*, Wengert O, Bellmann-Strobl J, Aktas O, Weber A, Grundstrom E, Ehrlich S, Wernecke KD, Volk HD, Zipp F (2003) TRAIL as a potential response marker for IFN-beta therapy in multiple sclerosis. Lancet 361:2036-2043. (*equally contributing). IF: 79.3
Deutsche Forschungsgesellschaft (LU 900/3-1; LU 900/4-1; INST 211/962-2)
Interdisziplinäres Zentrum für Klinische Forschung (IZKF), Medizinische Fakultät der WWU