Publications

February 2026 – Here the Kerschensteiner lab developed a new CRISPR-based in vivo screening platform that reveals how cytokines orchestrate macrophage behavior in multiple sclerosis. By editing progenitor cells before transplantation, they mapped how key immune signals—like IFN-γ, TNF, GM-CSF, and TGF-β—shape myeloid cell migration, phagocytosis, and activation inside the brain. The approach combines single-cell profiling and biosensors to visualize immune dynamics in real time, offering an unprecedented window into the molecular regulation of myeloid cells in neuroinflammation.

de la Rosa C, Kendirli A, Baygün S, Bauernschmitt F, Thomann AS, Kisioglu I, Beckmann D, Carpentier Solorio Y, Pfaffenstaller V, Tai YH, Mehraein N, Sanchez P, Spieth L, Gerdes LA, Beltran E, Dornmair K, Simons M, Peters A, Schmidt-Supprian M, Kerschensteiner M. (2026) In vivo CRISPR screen reveals regulation of macrophage states in neuroinflammation. Nat Neurosci. 29(2):493-509.

LINK zu SyNergy Research Spotlight: https://www.synergy-munich.de/news-events/news/in-vivo-crispr-screen-reveals-regulation-of-macrophage-states-in-neuroinflammation/d7f59c6dcb958f7d

LINK zu BMC News Feature: https://www.med.lmu.de/bmc/en/news/latest-news/news-overview/news/in-vivo-crispr-screen-reveals-regulation-of-macrophage-states-in-neuroinflammation-aaa223d5.html

October 2025 – Gray matter damage and cortical lesions drive progression in people with multiple sclerosis (PwMS). In a new study, the Kerschensteiner lab collaborated with our clinical team and the group of Matthias Brendel at the Department of Nuclear Medicine to show that positron emission tomography (PET) imaging of the synaptic vesicle protein 2A (SV2A) can reveal early synapse loss in MS. After validating SV2A as a marker of synapse density in cortical tissue and a mouse model of cortical MS, the team used SV2A-PET in 31 PwMS and detected in vivo synapse loss in cortical lesions. Interhemispheric differences in tracer uptake uncovered extensive cortical synapse pathology, exceeding MRI-visible cortical lesion volume by more than 20-fold. These PET-defined regions were larger in progressive MS and correlated with disability and cognitive performance, indicating that SV2A-PET exposes clinically relevant cortical pathology that remains invisible to conventional MRI and offers a promising tool to monitor MS progression.

Ullrich Gavilanes EM, Bartos LM, Gernert JA, Carral CA, Ruiz Navarro D, Havla J, Gerdes LA, Gnörich JS, Kunze LH, Dorneich JS, Pakula V, Tagnin L, Zimmermann H, Seelos K, Franzmeier N, Frontzkowski L, Pedrosa de Barros N, Ribbens A, Zwergal RM, Zwergal A, Vollmar C, Remi J, Picon C, Reynolds R, Merkler D, Wattjes MP, Kümpfel T, Brendel M, Kerschensteiner M. (2025) SV2A-PET imaging uncovers cortical synapse loss in multiple sclerosis. Sci Transl Med.17(818):eadt5585.

LINK zu SyNergy Research Spotlight: https://www.synergy-munich.de/aktuelles/news/using-pet-imaging-to-detect-cortical-synapse-loss-in-multiple-sclerosis/4fb10532e49e8b46

LINK zu BMC News Feature: https://www.med.lmu.de/bmc/en/news/latest-news/news-overview/news/using-pet-imaging-to-detect-cortical-synapse-loss-in-multiple-sclerosis-b938def0.html

April 2025 – Changes in the intestinal microbiota have long been associated with development of MS, but which changes are relevant for the pathogenic process remains largely unclear. Under the guidance of Emeritus Professor Hartmut Wekerle, the Gerdes lab and the Peters lab collaborated to functionally characterize the intestinal microbiota from MS-discordant monozygotic twins via transfer into a transgenic mouse model. Thereby we could show that the ileum of MS-twins harbors disease-triggering taxa and identified two candidates belonging to the family of Lachnospiraceae.

April 2025 – Meningeal lymphoid follicles (eLFs) are detected in many people with severe MS but their function is unclear. Here, the Peters lab together with the Kawakami, Beltrán and Kerschensteiner labs investigated the cellular processes inside eLFs in a model system, and could show for the first time that B and T cells form long-lasting contacts in these structures. These interactions lead not only maturation of B cells, but also to reactivation of autoreactive T cells and could thereby fuel chronic inflammatory processes in the CNS during MS.

September 2024 – Here the Gerdes lab together with the Beltran lab analyzed CD8 T cells from the blood and cerebrospinal fluid of monozygotic twins, where one twin had MS and the other showed no signs or subclinical signs of neuroinflammation (SCNI). The Study demonstrates that CD8 T cells from twin with MS and cotwin with SCNI displayed proinflammatory immunological and metabolic features consistent with enhanced activation and migration. This provides insights about CD8 T cells in MS progression. Read more.

April 2024 – Membrane damage is key step in the pathological cascade that leads to neuronal death or axon degeneration. Here, the Kerschensteiner lab worked together with a research team headed by Oliver Thorn-Seshold at the LMU Department of Pharmacy to develop new modular fluorogenic probes that reveal the whole cytosolic volume of damaged cells, with near-zero background fluorescence. We identify a specific disulfonated fluorogenic probe type that only enters cells with damaged membranes, then is enzymatically activated and marks them. By showing that these fluorescent probes can label membrane damaged neurons in vitro and in vivo we provide a powerful new tool for wash-free in vivo imaging of membrane damage and outline chemical designs that may be adapted for the selective delivery of drug cargos to damaged neurons.

November 2023 – B cells critically contribute to pathogenesis in Multiple sclerosis, however B cell effector functions are not featured well in classical EAE models. Here, the Peters lab developed a new model, where myelin-specific B cells activate myelin-specific T cells and thereby provide the critical stimulus for disease development. Furthermore, our system allows for genetic manipulation of B cells prior to transfer and thus represents a new tool to investigate the role of specific factors such as pro-inflammatory cytokines for B cell pathogenicity.

October 2023 –The infiltration of autoreactive T cells to the central nervous system (CNS) triggers lesion formation in the common neuroinflammatory condition multiple sclerosis (MS). Here, the Kawakami and Kerschensteiner labs worked together to provide a comprehensive characterization of the essential molecules that regulate this transmigration process. By performing a genome-wide CRISPR screen in a rat MS model they could identify 18 essential facilitators of T cell migration to the CNS. These can be grouped into three functional modules that regulate T cell adhesion, chemotaxis and egress. Notably, many of these molecules show regulated expression in T cell from MS patients and include prominent targets of approved MS therapies.

Kendirli A, de la Rosa C, Lämmle KF, Eglseer K, Bauer IJ, Kavaka V, Winklmeier S, Zhuo L, Wichmann C, Gerdes LA, Kümpfel T, Dornmair K, Beltrán E, Kerschensteiner M, Kawakami N. (2023) A genome-wide in vivo CRISPR screen identifies essential regulators of T cell migration to the CNS in a multiple sclerosis model. Nat Neurosci. 26(10):1713-1725.

Press release : https://www.lmu.de/en/newsroom/news-overview/news/identified-key-regulators-involved-in-genesis-of-multiple-sclerosis-lesions.html

August 2023 – Inflammation in the central nervous system can impair the function of neuronal mitochondria, the energy-producing components within nerve cells, which contributes to axonal degeneration in multiple sclerosis (MS). Here the Kerschensteiner lab at LMU Munich and the Misgeld lab at TU Munich have teamed up to unravel how inflammation changes the molecular composition and functional capacity of neuronal mitochondria. This work identifies the TCA cycle as new potential target for therapeutic interventions to protect nerve cells in MS.

Tai YH, Engels D, Locatelli G, Emmanouilidis I, Fecher C, Theodorou D, Müller SA, Licht-Mayer S, Kreutzfeldt M, Wagner I, de Mello NP, Gkotzamani SN, Trovò L, Kendirli A, Aljović A, Breckwoldt MO, Naumann R, Bareyre FM, Perocchi F, Mahad D, Merkler D, Lichtenthaler SF, Kerschensteiner M, Misgeld T. (2023). Targeting the TCA cycle can ameliorate widespread axonal energy deficiency in neuroinflammatory lesions. Nature metabolism, 5(8), 1364–1381.

Press release Synergy: https://www.synergy-munich.de/news/news/kerschensteiner-misgeld/index.html

April 2023 – In multiple sclerosis immune-mediated myelin loss can be partially reversed by remyelination. Here the Kerschensteiner lab and the Misgeld lab at TUM investigate if and how mature oligodendrocytes that survive in the lesion area in both MS patients and models can contribute to the myelin repair process. In a mouse model of cortical MS pathology they show that while surviving oligodendrocytes can extend new proximal processes they rarely form new myelin internodes. Furthermore drugs that boost myelin recovery by targeting oligodendrocyte precursor cells did not enhance myelin repair by surviving oligodendrocytes indicating that distinct therapeutic approaches are required to recruit surviving oligodendrocytes to the remyelination process.

March 2023 - Autoantibodies against myelin oligodendrocyte glycoprotein (MOG) define a new disease entity, MOG-antibody-associated disease (MOGAD) for which no therapy has yet been approved. MOG-Abs from patients are pathogenic, but precise effector mechanisms are unclear. Here the AGs Mader & Meinl together with AGs Kawakami and Bradl (Vienna) revealed new insights into pathomechanisms of MOG antibodies, as published in the journal Proceedings of the National Academy of Sciences of the US (PNAS). Starting from a pathogenic MOG-specific monoclonal antibody, several Fc mutants with differential FcR and complement binding were generated and studied for their pathogenic activity in two animal models. First, MOG-Abs induced demyelination, about equally by FcR activation and complement activation. Second, MOG-Abs enhanced infiltration and activation of cognate MOG-specific T cells via FcRs. These findings have implications for developing therapeutic strategies in MOGAD.

Mader S, Ho S§, Wong H K§, Baier S§, Winklmeier S, Riemer C, Rübsamen H, Fernandez I, Gerhards R , Du C, Chuquisana Omar, Lünemann J, 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.

Press release - LMU: https://www.lmu.de/de/newsroom/newsuebersicht/news/autoimmunerkrankung-mogad-neue-einblicke-in-die-pathomechanismen.html

January 2023- Therapies with anti-CD20 mAbs are beneficial in multiple sclerosis patients, commonly attributed to depletion of B cells. We (the Mader and Meinl labs together with the clinical Kümpfel team and collaborators) found a further effect of anti-CD20 on the immune system, namely reduction of the free soluble receptor and decoy sTACI due to complex formation with its ligand BAFF. Since a previous clinical trial revealed that a pharmacological variant of sTACI (TACI-Fc; atacicept) unexpectedly worsened MS, the reduction of the endogenous sTACI might contribute to the beneficial effect anti-CD20 in MS by enhancing the activity of APRIL (proposed mechanism illustrated in our cartoon).

Figure Legend: The upper part shows our findings: ocrelizumab (anti-CD20) treatment results in an increase of BAFF, formation of sTACI-BAFF complexes and reduction of free sTACI. The lower part links our findings to published work: sTACI is a decoy for APRIL (left). In the absence of the decoy sTACI (right), APRIL might induce IL10 production from astrocytes and promote the development of regulatory IgA plasma cells, which can home to the brain and secrete IL-10.

January 2023- The Bareyre Lab establishes FGF22 gene therapy as a new synaptogenic treatment that improves neuronal rewiring and functional recovery following spinal cord injury and determines the temporal constraints for its application in a paper published in EMBO Molecular Medicine.

• Following incomplete spinal cord injury, transected motor circuits rewire to contribute to functional recovery.

• FGF22 gene therapy induces synaptogenesis and allows targeted support of neuronal rewiring following spinal cord injury.

• Delivery of FGF22 gene therapy acutely and up to 1 day following spinal cord injury improves functional recovery while delayed application fails to do so.

December 2022- Functional recovery after incomplete spinal cord injury depends on the effective rewiring of neuronal circuits. Here the Bareyre Lab shows in a paper published by the Journal of Experimental Medicine that selective chemogenetic activation of either corticospinal projection neurons or intraspinal relay neurons alone led to anatomically restricted plasticity and little functional recovery. In contrast, coordinated stimulation of both supraspinal centers and spinal relay stations resulted in marked and circuit specific enhancement of neuronal rewiring, shortened EMG latencies and improved locomotor recovery. Taken together, our study demonstrates that a refined anatomical understanding of the neuronal circuits that reform in the injured CNS, empowers the design of targeted multi-level neurostimulation strategies that selectively foster adaptive circuit rewiring and thereby unlock the CNS´s potential for recovery.

September 2022- Epstein–Barr virus (EBV) infection precedes multiple sclerosis (MS) pathology and cross-reactive antibodies might link EBV infection to CNS autoimmunity. As an altered anti-EBV T cell reaction was suggested in MS, in collaboration with the Institute of Translational Neurology in Münster, we queried peripheral blood T cell receptor β chain (TCRβ) repertoires in 35 monozygotic, MS-discordant twin pairs and larger control groups for multimer-confirmed, viral antigen–specific TCRβ sequences. We detected more MHC-I–restricted EBV-specific TCRβ sequences in MS patients. In MS patients, cerebrospinal fluid also contained EBV-specific central memory CD8+ T cells, suggesting recent priming. Therefore, MS is not only preceded by EBV infection, but also associated with broader EBV-specific TCR repertoires, consistent with an ongoing anti-EBV immune reaction in MS.

July 2022 – In contrast to multiple sclerosis, it was not sufficiently investigated whether patients with myelin-oligodendrocyte-glycoprotein-antibody (MOG-IgG)-associated disease (MOGAD) also show a relapse-independent, subclinical retinal neuro-axonal loss. Therefore, initiated by @NeuroVisionLab (Havla Lab), eighty MOGAD patients and 139 healthy controls (HC) were included in a worldwide multicenter study with longitudinal optical coherence tomography (OCT) data. Longitudinally (follow-up up to 3 years), our analysis showed no attack-independent retinal damage in MOGAD. Nevertheless, ongoing neuroaxonal damage or edema resolution appears to occur up to 12 months after optic neuritis (ON), which is longer than has been reported for other forms of ON. These findings suggest that the pathomechanisms underlying optic nerve involvement and the development of OCT retinal changes after ON are different in MOGAD.

Oertel FC*, Sotirchos ES*, Zimmermann HG, Motamedi S, Specovius S, Asseyer ES, Chien C, Cook L, Vasileiou E, Filippatou A, Calabresi PA, Saidha S, Pandit L, D'Cunha A, Outteryck O, Zéphir H, Pittock S, Flanagan EP, Bhatti MT, Rommer PS, Bsteh G, Zrzavy T, Kuempfel T, Aktas O, Ringelstein M, Albrecht P, Ayzenberg I, Pakeerathan T, Knier B, Aly L, Asgari N, Soelberg K, Marignier R, Tilikete CF, Calvo AC, Villoslada P, Sanchez-Dalmau B, Martinez-Lapiscina EH, Llufriu S, Green AJ, Yeaman MR, Smith TJ, Brandt AU, Chen J*, Paul F*, Havla J*; with the GJCF International Clinical Consortium for NMOSD and the CROCTINO study group. Longitudinal retinal changes in MOGAD. Ann Neurol. 2022 Jun 15. doi: 10.1002/ana.26440. Epub ahead of print.

May 2022 – The Bareyre lab studied which contralesional circuits adapt following traumatic brain injury (TBI). Laura Empl and Alexandra Chovsepian used in vivo imaging, retrograde labeling, rabies tracing, tissue clearing and functional imaging to demonstrate in Nature Communications that callosal neurons selectively adapt after TBI in mice..

Traumatic brain injury (TBI) results in deficits that are often followed by recovery. The contralesional cortex can contribute to this process but how distinct contralesional neurons and circuits respond to injury remains to be determined. To unravel adaptations in the contralesional cortex, we used chronic in vivo two-photon imaging. We observed a general decrease in spine density with concomitant changes in spine dynamics over time. With retrograde co-labeling techniques, we showed that callosal neurons are uniquely affected by and responsive to TBI. To elucidate circuit connectivity, we used monosynaptic rabies tracing, clearing techniques and histology. We demonstrate that contralesional callosal neurons adapt their input circuitry by strengthening ipsilateral connections from pre-connected areas. Finally, functional in vivo two-photon imaging demonstrates that the restoration of pre-synaptic circuitry parallels the restoration of callosal activity patterns. Taken together our study thus delineates how callosal neurons structurally and functionally adapt following a contralateral murine TBI.

February 2022 – The Beltrán and Gerdes labs studied the immune profiles in the MS TWIN STUDY to differentiate the influence of the environment and genetics in multiple sclerosis. In collaboration with the Becher lab from the University of Zurich they may have discovered precursor cells of the disease-causing T cells.

The impact of genetic risk has been studied for years, however the genetic background is far from deterministic and interaction with environmental factors is needed for MS to evolve. However, which part of the aberrant immune response is guided by either genes or environment is difficult to decipher. With the help of the unique setting of the MS TWIN STUDY we could show that about half of the composition of our immune system is determined by the genetic background. In this project, peripheral blood mononuclear cells of 61 pairs of identical twins with discordance for MS were examined with the use of cutting-edge single-cell technologies and artificial intelligence to describe the immune profiles of the twin pairs in rich detail and with full control of genetic influences. Thereby we could not only identify characteristic proteins in the immune cells of the MS affected twin, but also decode which transcriptional programs are switched on in these cells. Specifically, in the blood of MS twins we detected T cells with characteristics of recently activated cells, which are more likely to migrate into the central nervous system and cause damage there.

November 2021 – Progressive multifocal leukoencephalopathy (PML) is a severe CNS infection that can occur in MS patients treated with Natalizumab. Clinical management of patients with Natalizumab-associated PML is challenging not least to detect, monitor and differentiate PML lesions are limited. Here the Kerschensteiner lab and Kümpfel group teamed up to investigate whether TSPO PET imaging can be applied to monitor the inflammatory activity of PML lesions over time. The results of this monocentre pilot study now indicate that TSPO PET imaging may faciliate longitudinal monitoring of disease activity and help distinguish recurrent multiple sclerosis activity from PML progression.

June 2021 – Nerve cells in the brain possess small protrusions, so called dendritic spines, to communicate with other nerve cells by forming a synapse. These contact sites can be both, short- or long-lived thereby existing for even up to an entire lifetime. Short-lived contact sites reflect an ever- adapting brain, which is necessary to process novel experiences. Long-lived, stable contact sites, on the other hand, form the basis of our memory. But even stable memory content can vary to some extent over time. The basis of this process still remains incompletely understood. The work, published in the journal Science Advances, shows that although a subset of synaptic structures remain present at the same location over a period of at least one month, their subunits underwent a remarkable and unexpected strong change in size and shape. Synaptic structures are thus both stable and dynamic – 'volatile' – at the same time, offering a glimpse into the complexity of synaptic remodelling and computational power mammalian brains are endowed with. Press release

June 2021 – Antibodies (Abs) to myelin oligodendrocyte glycoprotein (MOG) define a distinct disease entity, MOGAD. We report that the intracellular part of MOG, specifically its second hydrophobic domain enhances the recognition of the extracellular part of MOG by autoantibodies from patients. This explains the need for a cell-based assay to identify patients with MOG-Abs. We further found that MOG-Abs from patients require bivalent binding to recognize MOG. Since bivalently bound MOG-Abs poorly bind C1q, this indicates that complement-mediated demyelination is not the major pathomechanism of MOG-Abs.

June 2021 – The Liebscher lab together with the Dupuis group in Strasbourg, France and a highly collaborative international team of several other groups have found the missing pieces between genetic mutations linked to the development of Amyotrophic lateral sclerosis and Frontotemporal Dementia and the consecutive behavioral deficits. Using a wide array of methodological approaches they found that cytoplasmic mislocalization of the protein Fused-in-Sarcoma (FUS) causes its synaptic accumulation and local transcriptional dysregulation, leading to synaptic deficits of primarily inhibitory synapses in frontal cortex, which is causing neuronal hyperexcitability and consequently behavioral alterations. These data thus indicate that cytoplasmic FUS can excert deleterious effects beyond motor neuron degeneration, which are mainly caused by synaptic alterations.

Jelena Scekic-Zahirovic*, Inmaculada Sanjuan-Ruiz*, Vanessa Kan, Salim Megat, Pierre De Rossi, Stéphane Dieterlé, Raphaelle Cassel, Marguerite Jamet, Pascal Kessler, Diana Wiesner, Laura Tzeplaeff, Valérie Demais, Sonu Sahadevan, Katharina M. Hembach, Hans-Peter Muller, Gina Picchiarelli, Nibha Mishra, Stefano Antonucci, Sylvie Dirrig-Grosch, Jan Kassubek, Volker Rasche, Albert Ludolph, Anne-Laurence Boutillier, Francesco Roselli, Magdalini Polymenidou, Clotilde Lagier-Tourenne, Sabine Liebscher# and Luc Dupuis#, Cytoplasmic FUS triggers early behavioral alterations linked to cortical neuronal hyperactivity and inhibitory synaptic defects, Nature Communications, 2021,12:3028

March 2021 – The Dornmair group together with the Meuth/Melzer group from Münster, Germany and several other colleagues investigated antibodies recognizing the neuronal gamma-aminobutyric-acid-A receptor (GABAA-R), which cause severe encephalitis. From the cerebrospinal fluid of a patient with GABAA–R encephalitis, they cloned a highly expressed antibody and showed that it binds the GABAA-R and influences signal transduction in neurons explaining clinical symptoms. They confirmed that the antibody cross-reacts to an onco-protein, which is known to be involved in several malignancies and showed that cross-reactivity to this onco-protein may also be detected in two other GABAA-R patients. This suggests that such cross-reactivity is presumably a key event in the pathogenesis of GABAA-R encephalitis.

January 2021 – Gray matter pathology is a critical contributor to disability in advanced stages of multiple sclerosis. Here the Kerschensteiner lab teamed up with the Misgeld and Merkler lab to investigate how neuronal structure and function is impacted in the neuronal gray matter. In a mouse model they show that gray matter inflammation leads to a synapse loss that is accompagnied by neuronal silencing and can be reversible. Synapse loss is primed by local calcium increases, executed by activated microglial cells and infiltrating monocyte-derived macrophages and can be mitigated by therapeutic strategies that interfer with pathological activation of phagocytes. The authors hope that their work can help the development of therapeutic approaches that curb progression in MS patients.

January 2021 – The Dornmair group together with the Lassmann/Bradl group from the Medical University of Vienna and colleagues of the Meinl and Kawakami groups analyzed a historic case of a patient who died 60 years ago from a disease closely resembling multiple sclerosis, following a misguided immunization with lyophilized calf brain tissue. Transcriptome analyses by mRNAseq and antibody reconstruction by bioinformatics revealed an autoantibody (rAb-hAE) against myelin oligodendrocytes glycoprotein (MOG), similar to the encephalitogenic anti-MOG antibody 8-18C5. Both antibodies induced demyelination after injection into animals, whereas the negative control antibody rMS3-s1 did not. This “archeological neuroimmunology” approach shows that autoimmunization with brain tissue in humans may induce a disease that is similar to multiple sclerosis.

September 2020 – To interrogate the rules that govern myelin replacement in the cortex the Kerschensteiner group together with the Misgeld lab at TUM studied the response to the ablation of single cortical oligodendrocytes. Using timelapse imaging and correlated ultrastructural reconstructions they were able to show that a loss of a single oligodendrocyte is sufficient to cause robust cell and myelin replacement. In this process internodes along partially myelinated axons were typically not reestablished, while myelin sheaths forming continuous patterns showed remarkable homeostatic resiliences and remyelinated with single axon precision. Understanding these principles is particularly important in the context of multiple sclerosis which extensive cortical demyelination is a major pathological feature and target of remyelination therapies.

September 2020 – In this study we used our unique setting of the MS TWIN STUDY to explore the peripheral immune signature in collaboration with the UK Münster. In each twin pair, the immune signatures were remarkably similar, pointing to a strong influence of shared genetic and environmental factors. However, when we focused on a subgroup of seemingly healthy cotwins who showed subtle signs of “subclinical neuro-inflammation,” we identified a distinct signature of memory T cells.

Press Release

Commentary

November 2019 – Here we report on the principles that drive functional circuit remodeling following spinal cord injury. We demonstrate in this paper that functional circuit remodeling critically depends on the selection of appropriate synaptic connections between cortical projection and spinal relay neurons. In particular, we use in this paper a combination of genetic and chemogenetic tools to modulate NMDA receptor (NMDAR) integrity and function, CREB-mediated transcription, and neuronal firing of relay neurons during injury-induced corticospinal remodeling. We show that NMDAR signaling and CREB-mediated transcription maintain nascent corticospinal tract (CST)–relay neuron contacts. These activity-dependent signals act during a defined period of circuit remodeling and do not affect mature or uninjured circuits. Furthermore, chemogenetic modulation of relay neuron activity reveals that the regrowing CST axons select their postsynaptic partners in a competitive manner and that preventing such activity-dependent shaping of corticospinal circuits limits motor recovery after spinal cord injury.

November 2019 – The early immunological events that drive MS are still enigmatic. To add a piece to the jigsaw we analyzed CSF samples of a unique selection of our MS TWIN STUDY. Using single-cell RNA sequencing we identified clonally expanded CD8+ T cells, plasmablasts, and, to a lesser extent, CD4+ T cells not only from MS co-twins but also from clinical healthy co-twins with signs of subclinical neuroinflammation as detected on MRI and/or CSF. Strikingly, clonally expanded T cells showed characteristics of activated tissue-resident memory T (TRM) cells and were already detectable in prodromal stages but more pronounced in patients with definite MS. Our data provide evidence for very early concomitant activation of 3 components of the adaptive immune system in MS, with a notable contribution of clonally expanded TRM-like CD8+ cells.

Press Release

Februar 2019 – To reveal the mechanisms that drive inflammatory axon degeneration the Kerschensteiner lab has used in vivo calcium imaging in a multiple sclerosis model. Dynamic tracking of individual axons in the inflamed spinal cord shows that cytoplasmic calcium levels determine the choice between axon loss and survival. Calcium can enter the axon through nanoscale ruptures of the axonal plasma membrane that are induced in inflammatory lesions. These results thus identify a unusual axon injury pathway that can contribute to neurodegeneration in multiple sclerosis and may represent a novel target for protective therapy.

Press Release

May 2019 – The modest concordance rate for MS in monozygotic twins strongly argues for involvement of epigenetic factors. To check the contribution of epigenetic modifications we looked at the methylomes of 45 pairs from the MS TWIN STUDY together with our collaborators Nicole Souren and Jörn Walter, Saarland Universtiy. We identified seven MS-associated differentially methylated positions (DMPs) of which we validated two, including a region in the TMEM232 promoter and ZBTB16 enhancer. Not expected but not of less relevance we presented epigenetic biomarkers for current interferon-beta treatment, and that the ZBTB16 DMP is a signature for prior glucocorticoid treatment. Taken together, this study represents an important reference for epigenomic MS studies, identifies new candidate epigenetic markers, and highlights treatment effects and genetic background as major confounders.

Press Release

August 2018 –Autoantibodies against myelin oligodendrocyte glycoprotein (MOG) can be detected in the blood of a proportion of patients with inflammatory demyelinating diseases of the CNS. We affinity-purified MOG-Abs from the blood of two patients. These anti-MOG Abs were pathogenic upon transfer into rats and we could dissect two different mechanisms by which these MOG-Abs enhanced pathology. First, together with cognate MOG-specific T cells, these Abs enhanced T cell infiltration; Second, together with MBP-specific T cells that strongly breach the blood-brain barrier, these MOG-Abs induced demyelination associated with deposition of C9neo, resembling a multiple sclerosis type II pathology. This suggests that MOG-Abs are similarly pathogenic in patients.

Februar 2018 – Mononuclear phagocytes can both promote and inhibit inflammation. Here the Kerschensteiner lab uses an in vivo imaging approach to follow the evolution of phagocyte phenotypes in neuroinflammatory lesions. By tracking phagocytes over time they can show that individual phagocytes switch their phenotype as lesions move from expansion to resolution. This phenotype shift appears to be initiated by signals derived from the nervous system tissue. Understanding the molecular nature of these signals might thus provide the basis for therapeutic manipulation of phagocyte function in the inflamed CNS.

Press Release

August 2017 – Studies using experimental models have indicated that MS like disease can be triggered in the gut following interactions of brain autoimmune T lymphocytes with local microbiota. In this key paper, we studied the composition of the gut microbiota in our MS TWIN STUDY and in addition transferred human-derived microbiota into transgenic mice expressing a myelin autoantigen-specific T cell receptor. Strikingly, we detected that gut microbiota from MS-affected twins induced CNS-specific autoimmunity at a higher incidence than microbiota from healthy co-twins. Our results offered functional evidence that human microbiome components contribute to CNS-specific autoimmunity and opened up the field for further studies of the gut microbiome in MS.

Press Release

Awarded for highlights of MPG Research 2017

November 2016 – Damage to oligodendrocytes and their myelin sheaths is a central feature of multiple sclerosis pathology. Here the Kerschensteiner lab investigates how oligodendrocyte damage is initiated in multiple sclerosis (MS) and EAE using in vivo imaging, confocal microscopy as well as electron microscopy. They can show that oligodendrocyte damage spreads centripetally and that the formation of focal myelin outfoldings that they call “myelinosomes” is an early sign of oligodendrocyte damage both in MS and EAE…

January 2016 – How neurodegeneration starts in the brains of progressive multiple sclerosis patients is only incompletely understood. Here the Kerschensteiner lab joined forces with the Merkler lab at the University of Genevan and used confocal microscopy of Golgi-Cox impregnated tissue sections to reconstruct single cortical projection neurons in brain sections from multiple sclerosis and control patients. Their study reveals a widespread and pronounced loss of dendritic spines that occurs independently of cortical demyelination and axon loss and indicates the presence of a primary synaptic pathology in multiple sclerosis…

May 2015 – Following spinal cord injury, transected projections form detour circuits that circumvent the lesion and contribute to functional recovery. The formation of new synaptic contacts is a crucial step of the process, but its molecular regulation is currently not understood. Members of the FGF family can promote synapse formation during nervous system development, suggesting that they might have a similar function in the injured adult CNS. Here, we show that: (i) FGF22 and FGF22 receptors are expressed in the adult nervous system. (ii) FGF22 deficiency or deletion of FGF22 receptors restricts the formation and maturation of new synapses in the injured spinal cord. (iii) Genetic disruption of FGF22 signaling impedes spontaneous functional recovery following spinal cord injury

Publications

In vivo CRISPR screen reveals regulation of macrophage states in neuroinflammation

SV2A-PET imaging uncovers cortical synapse loss in multiple sclerosis

Multiple sclerosis and gut microbiota: Lachnospiraceae from the ileum of MS twins trigger MS-like disease in germfree transgenic mice

T–B cell cooperation in ectopic lymphoid follicles propagates CNS autoimmunity

LMU researchers demonstrate that certain immune cells already play an important role in the early stages of multiple sclerosis

Fluorogenic chemical probes for wash-free imaging of cell membrane damage in ferroptosis, necrosis and axon injury

A B cell–driven EAE mouse model reveals the impact of B cell–derived cytokines on CNS autoimmunity

A genome-wide in vivo CRISPR screen identifies essential regulators of T cell migration to the CNS in a multiple sclerosis model.

Targeting the TCA cycle can ameliorate widespread axonal energy deficiency in neuroinflammatory lesions.

Remyelination by surviving oligodendrocytes is inefficient in the inflamed mammalian cortex

New insights into effector functions of autoantibodies to myelin oligodendrocyte glycoprotein

Anti-CD20 therapy in multiple sclerosis: effects beyond B cell depletion

Synaptogenic gene therapy with FGF22 improves circuit plasticity and functional recovery following spinal cord injury

Coordinated neurostimulation promotes circuit rewiring and unlocks recovery after spinal cord injury

Broader Epstein–Barr virus–specific T cell receptor repertoire in the MS TWIN STUDY

Longitudinal retinal changes in MOGAD

Selective plasticity of callosal neurons in the adult contralesional cortex following murine traumatic brain injury

MS discordant monozygotic twins help to untangle environmental and genetic influences in immune profiles

PET imaging can improve montoring of Natalizumab-associated PML

Secret, highly active life of nerve cell contacts in the brain revealed

Details of target-recognition by autoantibodies to myelin oligodendrocyte glycoprotein uncovered

Synaptic FUS(S) at the heart of neuronal dysfunction in ALS/FTD

An encephalitogenic autoantibody cross-reacts to a tumor antigen

Immune cells remove synapses in the inflamed gray matter

Resurrection of a pathogenic immune response from a historical case

Single cell ablation reveals the rules of myelin replacement

Twin effect overrides disease specific immune signatures

Neuronal activity controls circuit formation following spinal cord injury

Detection of early adaptive immune activation in prodromal MS

Circulating autoreactive B cells specific for GAD65

Leaky membranes promote axon degeneration in MS model

DNA methylation signatures are associated with MS phenotype

Pathogenic mechanisms of patient antibodies recognizing MOG

Shifty phagocytes track the fate of neuroinflammatory lesions

What´s it got to do with our guts? A possible link between the gut microbiome and MS!

Novel biomarkers for a subset of brain tumors

Early stages of myelin injury revealed by ultrastructural and dynamic analysis

Widespread synapse loss in multiple sclerosis gray matter

New immunoregulation and biomarker

FGF22 regulates circuit formation following spinal cord injury

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