Ausgewählte Publikationen

[ AG Kerschensteiner ]

Single-cell profiling identifies myeloid cell subsets with distinct fates during neuroinflammation

Science 363: pii.eaat7554 (2019)

In collaboration with the group of Marco Prinz we use a single cell RNAseq approach to reveal the evolution of myeloid cell diversity during different stages of neuroinflammation. Furthermore we use in vivo imaging to record the contact patterns of distinct myeloid cell subsets with T cells in neuroinflammatory lesions. [mehr...]

[ AG Kerschensteiner ]

Panoptic imaging of transparent mice reveals whole-body neuronal projections and skull-meninges connections.

Nature Neuroscience 22: 317-327 (2019)

Here we contribute to a study by Ali Ertürks lab that establishes vDISCO a pressure-driven, nanobody-based whole body immunolabeling technology that renders intact mice transparent and allows for example a comprehensive view of the inflammatory reaction to spinal cord injury. [mehr...]

[ AG Kerschensteiner ]

Calcium influx through plasma-membrane nanoruptures drives axon degeneration in a model of multiple sclerosis.

Neuron doi: 10.1016/j.neuron.2018.12.023

Here we use in vivo calcium imaging in a multiple sclerosis model to show 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. [mehr...]

[ AG Meinl ]

Pathogenicity of human antibodies against myelin oligodendrocyte glycoprotein

Ann Neurol 2018;84:315–328

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. The Abs recognized different epitopes on MOG. The anti-MOG Abs from the patients 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. [mehr...]

[ AG Dornmair ]

Unopposed IL-36 Activity Promotes Clonal CD4+ T-Cell Responses with IL-17A Production in Generalized Pustular Psoriasis

J Invest Dermatol. 2018 Jun;138(6):1338-1347. doi: 10.1016/j.jid.2017.12.024. Epub 2017 Dec 27.

Generalized pustular psoriasis is the most severe psoriasis variant. Here we reveal a pathogenic pathway where innate immune dysregulation promotes T-cell−mediated inflammation. [mehr...]

[ AG Kümpfel ]

Retinal ganglion cell loss in neuromyelitis optica: a longitudinal study

J Neurol Neurosurg Psychiatry. 2018 Jun 19. pii: jnnp-2018-318382. doi: 10.1136/jnnp-2018-318382

Neuromyelitis optica spectrum disorders (NMOSD) are inflammatory conditions of the central nervous system and an important differential diagnosis of multiple sclerosis (MS). Unlike MS, the course is usually relapsing, and it is unclear, if progressive neurodegeneration contributes to disability. This study clearly shows GCIP loss independent of ON attacks in aquaporin4-antibody-seropositive NMOSD. [mehr...]

[ AG Dornmair ]

Sex bias in MHC-I-associated shaping of the adaptive immune system

Proc Natl Acad Sci U S A. 2018 Feb 27;115(9):2168-2173. doi: 10.1073/pnas.1716146115

Most immune system dysfunctions show strong sex bias: men are more susceptible to many infectious diseases and cancers of non-reproductive organs, whereas autoimmune diseases are much more common in women. Here we analyzed large cohorts of HLA-typed subjects by high-throughput sequencing of T cell receptor chains. We found that identical HLA-molecules may shape the T cell receptor repertoires differently in men and women. [mehr...]

[ AG Kümpfel ]

[18F]-THK5351 PET Correlates with Topology and Symptom Severity in Progressive Supranuclear Palsy

Front. Aging Neurosci. | doi: 10.3389/fnagi.2017.00440

[18F]-THK5351 is a novel PET-ligand that may afford in vivo visualization and quantification of tau-related alterations. We investigated binding characteristics of [18F]-THK5351 in patients with clinically diagnosed PSP and correlate tracer uptake with clinical findings. [mehr...]

[ AG Kümpfel ]

No need for NMDA receptor antibody screening in neurologically asymptomatic patients with ovarian teratomas.

J Neurol. 2017 Dec 22. doi: 10.1007/s00415-017-8717-3. [Epub ahead of print]

No need for NMDA receptor antibody screening in neurologically asymptomatic patients with ovarian teratomas [mehr...]

[ AG Kawakami ]

Visualizing context-dependent calcium signaling in encephalitogenic T cells in vivo by two-photon microscopy

Proc Natl Acad Sci U S A. 2017 Jul 17. pii: 201701806. doi: 10.1073/pnas.1701806114. [Epub ahead of print]

Here we visualized intracellular calcium in the encephalitogenic T cells in vivo by using FRET based sensor. The T cells showed short and long lasting calcium signaling dependent on their interaction partners. The blocking of the calcium signaling can be used as target of therapeutic treatments. [mehr...]

[ AG Kawakami ]

A Novel Cervical Spinal Cord Window Preparation Allows for Two-Photon Imaging of T-Cell Interactions with the Cervical Spinal Cord Microvasculature during Experimental Autoimmune Encephalomyelitis

Front Immunol. 2017 Apr 11;8:406. doi: 10.3389/fimmu.2017.00406. eCollection 2017.

Here we described how to make spinal cord window at cervical spinal cord to observe T cell migration. The results were compared one from lumber spinal cord. [mehr...]

[ AG Kümpfel ]

Influence of female sex and fertile age on neuromyelitis optica spectrum disorders

Mult Scler. 2016 Oct 6. pii: 1352458516671203. [Epub ahead of print]

Our data suggest an influence of sex and age on susceptibility to AQP4-ab-positive NMO/SD. Genetic and hormonal factors might contribute to pathophysiology of NMO/SD [mehr...]

[ AG Kawakami ]

Lymphocyte Circadian Clocks Control Lymph Node Trafficking and Adaptive Immune Responses

Immunity. 2017 Jan 6. pii: S1074-7613(16)30517-9.

Lymphocytes circulate through lymph nodes (LN) in search for antigen in what is believed to be a continuous process. Here, we show that lymphocyte migration through lymph nodes and lymph occurred in a non-continuous, circadian manner. [mehr...]

[ AG Kawakami ]

In vivo imaging in autoimmune diseases in the central nervous system

Allergol Int. 2016 Jul;65(3):235-42. doi: 10.1016/j.alit.2016.02.001. Epub 2016 Feb 28.

Intravital imaging is becoming more popular and is being used to visualize cellular motility and functions. [mehr...]

[ AG Kawakami ]

Post-CNS-inflammation expression of CXCL12 promotes the endogenous myelin/neuronal repair capacity following spontaneous recovery from multiple sclerosis-like disease

J Neuroinflammation. 2016 Jan 8;13(1):7. doi: 10.1186/s12974-015-0468-4.

These data link CXCL12 expression in the DG and CC of EAE-recovering mice to the promotion of neuro/oligodendrogenesis generating CXCR4+ CXCL12+ neuronal and oligodendrocyte progenitor cells endowed with intrinsic neuro/oligondendroglial differentiation potential. These findings highlight the post-CNS-inflammation role of CXCL12 in augmenting the endogenous myelin/neuronal repair capacity in MS-like disease, likely via CXCL12/CXCR4 autocrine signaling. [mehr...]

[ AG Kümpfel ]

Myelin-oligodendrocyte-glycoprotein (MOG) autoantibodies as potential markers of severe optic neuritis and subclinical retinal axonal degeneration

J Neurol. 2017 Jan;264(1):139-151. doi: 10.1007/s00415-016-8333-7. Epub 2016 Nov 14.

Antibodies against conformation-dependent epitopes of myelin-oligodendrocyte-glycoprotein (MOG-abs) are present in subgroups of neuromyelitis optica spectrum disorder (NMOSD), recurrent optic neuritis (rON), multiple sclerosis (MS), and anti-NMDAR encephalitis. Using optical coherence tomography (OCT) we assessed whether MOG-abs might serve as potential marker of retinal axonal degeneration. [mehr...]

[ AG Kümpfel ]

Interdisciplinary Risk Management in the Treatment of Multiple Sclerosis

Dtsch Arztebl Int 2016; 113(51-52): 879-86; DOI: 10.3238/arztebl.2016.0879

The growing number of drugs used to treat MS demands great efforts to minimize the potential risks. To this end, interdisciplinary risk management plans are essential. Here we describe the type and extent of risks, the measures needed for prevention/early detection, and provide practical advice for the necessary monitoring. [mehr...]

[ AG Kerschensteiner ]

Myelinosome formation represents an early stage of oligodendrocyte damage in multiple sclerosis and its animal model.

Nat Commun. 2016 Nov 16;7:13275. doi: 10.1038/ncomms13275.

Here we investigate how oligodendrocyte damage is initiated in multiple sclerosis (MS) and EAE. We can show that oligodendrocyte damage spreads centripetally and that the formation of focal myelin outfoldings that we call “myelinosomes” is an early sign of oligodendrocyte damage both in MS and EAE. [mehr...]

[ AG Meinl ]

Features of Human CD3+CD20+ T Cells.

J Immunol. 2016 Aug 15;197(4):1111-7. doi: 10.4049/jimmunol.1600089.


[ AG Dornmair ]

CTLA4 as Immunological Checkpoint in the Development of Multiple Sclerosis.

Ann Neurol. 2016 Aug;80(2):294-300. doi: 10.1002/ana.24715.

We investigated a patient who developed multiple sclerosis (MS) during treatment with the CTLA4-blocking antibody ipilimumab for metastatic melanoma. Initially he showed subclinical magnetic resonance imaging (MRI) changes (radiologically isolated syndrome). Two courses of ipilimumab were each followed by a clinical episode of MS, 1 of which was accompanied by a massive increase of MRI activity. Brain biopsy confirmed active, T-cell type MS. Quantitative next generation sequencing of T-cell receptor genes revealed distinct oligoclonal CD4(+) and CD8(+) T-cell repertoires in the primary melanoma and cerebrospinal fluid. Our results pinpoint the coinhibitory molecule CTLA4 as an immunological checkpoint and therapeutic target in MS. Ann Neurol 2016;80:294-300. [mehr...]

[ AG Meinl ]

Autoantibodies to MOG in a distinct subgroup of adult multiple sclerosis.

Neurol Neuroimmunol Neuroinflamm. 2016 Jun 30;3(5):e257. doi: 10.1212/NXI.0000000000000257.


[ AG Kerschensteiner ]

Loss of Myelin Basic Protein Function Triggers Myelin Breakdown in Models of Demyelinating Diseases.

Cell Rep. 2016 Jul 12;16(2):314-22.

In collaboration with the group of Mikael Simons we show that the aberrant transition of MBP molecules from their cohesive state to their non-adhesive state underlies the vesicular disruption of the myelin sheath in models of demyelinating disease. [mehr...]

[ AG Dornmair ]

Distinct oligoclonal band antibodies in multiple sclerosis recognize ubiquitous self-proteins.

Proc Natl Acad Sci U S A. 2016 Jul 12;113(28):7864-9. doi: 10.1073/pnas.1522730113.

Oligoclonal band (OCB) antibodies from the cerebrospinal fluid of patients with multiple sclerosis are important diagnostic tools, but their antigens and their role in the pathogenesis were so far unknown. To identify antigens of OCB we developed a new technology that allowed us to produce recombinant antibodies resembling distinct OCB. We identified three target antigens. All of them were ubiquitous intracellular proteins not specific to brain tissue suggesting that at least these OBC were involved in secondary immune reactions, i.e. in removal of cellular debris, rather than attacking autologous tissue in a specific primary immune reaction. [mehr...]

[ AG Kerschensteiner ]

Origin, fate and dynamics of macrophages at central nervous system interfaces.

Nat Immunol. 2016 May 2. doi: 10.1038/ni.3423

Here we contribute to the characterization of perivascular, subdural and choroid plexus macrophages and reveal their dynamic behaviour in the intact central nervous system. [mehr...]

[ AG Dornmair ]

Multiple sclerosis: Molecular mimicry of an antimyelin HLA class I restricted T-cell receptor.

Neurol Neuroimmunol Neuroinflamm. 2016 May 17;3(4):e241. doi: 10.1212/NXI.0000000000000241.

We employed a new antigen search technology to identify target antigens presented by HLA-A*02:01 to the myelin-reactive human T-cell receptor 2D1, which originates from a T-cell clone recognizing proteolipid protein in the context of HLA-A*03:01. [mehr...]

[ AG Dornmair ]

Impaired NK-mediated regulation of T-cell activity in multiple sclerosis is reconstituted by IL-2 receptor modulation.

Proc Natl Acad Sci U S A. 2016 May 24;113(21):E2973-82. doi: 10.1073/pnas.1524924113.

We analyzed the role of natural killer (NK) cells in multiple sclerosis. [mehr...]

[ AG Dornmair ]

CD8(+) T-cell pathogenicity in Rasmussen encephalitis elucidated by large-scale T-cell receptor sequencing.

Nat Commun. 2016 Apr 4;7:11153. doi: 10.1038/ncomms11153.

We analyzed the immunopathology of Rasmussen encephalitis, a rare pediatric epilepsy, by deep sequencing of T cell receptor chains. We identified public T cell clones, i.e. clones that are shared between different patients. This suggests that antigen-driven T cell expansions are a major cause of the lymphocyte attack against brain tissue. [mehr...]

[ Prof. Hohlfeld ]

Cytotoxic T cells go awry in inclusion body myositis

Brain 2016: 139; 1312–1324 DOI: . [Epub ahead of print]


[ Prof. Hohlfeld ]

Alemtuzumab and Multiple Sclerosis: Another Note of Caution.

JAMA Neurol. 2016 Apr 4. doi: 10.1001/jamaneurol.2016.0259. [Epub ahead of print]


[ AG Kümpfel ]

Cryopyrin-associated periodic fever syndrome manifesting as Tolosa-Hunt syndrome

Cephalalgia. 2016 Feb 3. pii: 0333102416629239. [Epub ahead of print]

Tolosa-Hunt syndrome (THS) is characterized by unilateral orbital pain, ipsilateral oculomotor paresis and a prompt response to treatment with corticosteroids. We report the case of a patient diagnosed with THS after an episode of unilateral orbital pain and diplopia with demonstration of granulomatous inflammation of both cavernous sinus on cerebral magnetic resonance imaging and an immediate response to treatment with corticosteroids. Progression of the disease over the following years, accompanied by increasing signs of inflammation on cerebral magnetic resonance imaging and cerebrospinal fluid pleocytosis, led to further diagnostic tests. Genetic analyses revealed a heterozygote low-penetrance mutation (Q703K) of the cryopyrin/NLRP3 gene compatible with a cryopyrin-associated periodic fever syndrome. This case report demonstrates that THS can be a central nervous system manifestation of cryopyrin-associated periodic fever syndrome, which therefore represents a differential diagnosis of THS, even in elderly patients. [mehr...]

[ Prof. Hohlfeld ]

The search for the target antigens of multiple sclerosis, part 2: CD8+ T cells, B cells, and antibodies in the focus of reverse-translational research

Lancet Neurol. 2015 Dec 23. pii: S1474-4422(15)00313-0. doi: 10.1016/S1474-4422(15)00313-0.

Part 2 In part 2 of this Review, we consider CD8+ T-cell- and B-cell responses, interest in which was prompted by observations in human multiple sclerosis – an example of reverse-translational research. [mehr...]

[ Prof. Hohlfeld ]

The search for the target antigens of multiple sclerosis, part 1: autoreactive CD4+ T lymphocytes as pathogenic effectors and therapeutic targets

Lancet Neurol. 2015 Dec 23. pii: S1474-4422(15)00334-8. doi: 10.1016/S1474-4422(15)00334-8.

Part 1 Identification of the target antigens of adaptive immunity (B cells and T cells) is of fundamental importance for understanding the pathogenesis of multiple sclerosis and for the development of personalized therapies. In part 1 of this two-part Review, we focus on CD4+ T lymphocytes as major pathogenic effector cells and prime therapeutic targets. The review is accompanied by an in context Profile about Prof. R. Hohlfeld. [mehr...]

[ AG Dornmair ]

Melanocyte antigen triggers autoimmunity in human psoriasis

J Exp Med. 2015 Dec 14;212(13):2203-12. doi: 10.1084/jem.20151093. Epub 2015 Nov 30.

Using plasmid-encoded combinatorial peptide libraries (Siewert et al 2012), we identified ADAMTSL5 as a melanocyte autoantigen in human psoriasis. ADAMTSL5 is presented in HLA-C*06:02 molecules on melanocytes, which triggers IL-17 production from CD8+ T cells. [mehr...]

[ AG Kerschensteiner ]

Reconstruction of single cortical projection neurons reveals primary spine loss in multiple sclerosis

Brain. 2016 Jan;139(Pt 1):39-46. doi: 10.1093/brain/awv353. Epub 2015 Dec 14.

Here we we use confocal microscopy of Golgi-Cox impregnated tissue sections to reconstruct single cortical projection neurons in brain sections from multiple sclerosis and control patients. Our study reveals a widespread loss 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. [mehr...]

[ AG Meinl ]

Fingolimod induces neuroprotective factors in human astrocytes

J Neuroinflammation. 2015 Sep 30;12:184. doi: 10.1186/s12974-015-0393-6.

Fingolimod is the first sphingosine-1-phosphate receptor modulator approved for the treatment of multiple sclerosis. It reduces brain atrophy and neuroprotective effects are hypothesized. We identified effects of fingolimod on astrocytes, namely induction of neurotrophic mediators (LIF, HBEGF, and IL11) and inhibition of TNF-induced inflammatory genes (CXCL10, BAFF, MX1, and OAS2). This supports the view that a part of the effects of fingolimod may be mediated via astrocytes. [mehr...]

[ AG Kümpfel ]

Neuromyelitis optica: Evaluation of 871 attacks and 1,153 treatment courses

Ann Neurol. 2015 Nov 4. doi: 10.1002/ana.24554

Neuromyelitis optica (NMO) attacks often are severe, are difficult to treat, and leave residual deficits. Here, we analyzed the frequency, sequence, and efficacy of therapies used for NMO attacks. We were able to show, that particularly myelitis and bilateral optic neuritis have poor remission rates. However, escalation of attack therapy improves outcome. [mehr...]

[ AG Kerschensteiner ]

Astrocyte Depletion Impairs Redox Homeostasis and Triggers Neuronal Loss in the Adult CNS

Cell Rep. 2015 Sep 1;12(9):1377-84. doi: 10.1016/j.celrep.2015.07.051.

Although the importance of reactive astrocytes during CNS pathology is well established, the function of astroglia in adult CNS homeostasis is less well understood. With the use of conditional, astrocyte-restricted protein synthesis termination, we found that selective paralysis of GFAP(+) astrocytes in vivo led to rapid neuronal cell loss and severe motor deficits. [mehr...]

[ AG Meinl ]

γ-secretase directly sheds the survival receptor BCMA from plasma cells

Nat. Commun. 6:7333 doi: 10.1038/ncomms8333

Plasma cells produce antibodies that inactivate pathogens, but may also cause autoimmune diseases. Therefore a balanced regulation of plasma cells is essential. We found that the lifespan of plasma cells is regulated through shedding of their survival receptor BCMA by γ-secretase. The released part of BCMA reflects the antibody production by plasma cells in the brain of MS patients. Please find the press release here: [mehr...]

[ AG Kümpfel ]

Expanding spectrum of neurologic manifestations in patients with NLRP3 low-penetrance mutations.

Neurol Neuroimmunol Neuroinflamm. 2015 May 14;2(4):e109. doi: 10.1212/NXI.0000000000000109. eCollection 2015.

We evaluated the frequency of the cryoporin/NLRP3 low-penetrance mutations V198M and Q703K in patients who reported at least 2 symptoms compatible with cryopyrin-associated periodic syndromes (CAPS) and characterized the phenotype in mutation-positive patients. Seventeen patients (16%) tested positive for either of the 2 mutations (V198M: n = 2; Q703K: n = 15). Eleven patients (65%) had severe headache syndromes. Six of these 11 patients were diagnosed with migraine. Nine patients (53%) had a concomitant diagnosis of multiple sclerosis (MS). In 3 patients, we identified additional family members with the respective mutation as well as the diagnosis of MS. Severe recurrent cranial nerve (CN) affection was the hallmark feature in 7 of the 8 (88%) non-MS mutation carriers. Brain MRI showed abnormalities in all but 2 patients (88%) and detected CN inflammation in 4 patients. Interleukin-6 was elevated in the CSF of 2 patients in the non-MS cohort during acute CAPS episodes with severe CNS inflammation. 5 of 9 treated patients (56%) responded to anti-interleukin-1 therapy. CAPS constitute rare but treatable and commonly misdiagnosed autoinflammatory syndromes. Our data expand the spectrum of CAPS-associated neurologic manifestations. They also broaden our concept of autoimmunity and autoinflammation by linking CAPS and MS. [mehr...]

[ AG Kerschensteiner ]

Role of the innate and adaptive immune responses in the course of multiple sclerosis

Lancet Neurology 14: 406-419 (2015)

In this review the role of the innate and adaptive immune responses in the course of multiple sclerosis is discussed. [mehr...]

[ AG Bareyre ]

FGF22 signaling regulates synapse formation during post-injury remodeling of the spinal cord

EMBO J. 2015 Mar 12. pii: e201490578. [Epub ahead of print]

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. Here, we show that: • FGF22 and FGF22 receptors are expressed in the adult nervous system. • FGF22 deficiency or deletion of FGF22 receptors restricts the formation and maturation of new synapses in the injured spinal cord. • Genetic disruption of FGF22 signaling impedes spontaneous functional recovery following spinal cord injury. [mehr...]

[ AG Kümpfel ]

Immunotherapies for multiple sclerosis : Review and update

Internist (Berl). 2015 Feb 28

In this review particular attention is given to the risks of new therapies, monitoring, and on special aspects needing attention when changing treatments. [mehr...]

[ AG Kawakami ]

Treg cells mediate recovery from EAE by controlling effector T cell proliferation and motility in the CNS

Acta Neuropathol Commun. 2014 Dec 5;2(1):163.

Here, we showed the role of regulatory T cells in the CNS during inflammation. Two-photon imaging revealed the interaction with other T cells and antigen presenting cells. [mehr...]

[ AG Kawakami ]

From classic to spontaneous and humanized models of multiple sclerosis: impact on understanding pathogenesis and drug development

J Autoimmun. 2014 Nov;54:33-50. doi: 10.1016/j.jaut.2014.06.004. Epub 2014 Aug 28.

Reviewing the Experimental Autoimmune Encephalomyelitis as animal model for Multiple Sclerosis [mehr...]

[ AG Kawakami ]

T cell-activation in neuromyelitis optica lesions plays a role in their formation

Acta Neuropathol Commun. 2013 Dec 24;1(1):85. doi: 10.1186/2051-5960-1-85.

Here, we showed that T cell activation in the neuromyelitis optica lesions is critical step for disease onset. [mehr...]

[ AG Kümpfel ]

Histopathology and clinical course of MOG-antibody-associated encephalomyelitis.

Ann Clin Transl Neurol. 2015 Mar;2(3):295-301. doi: 10.1002/acn3.164. Epub 2015 Jan 14.

We present histological, MRI, and clinical features of an adult patient with relapsing encephalomyelitis and antibodies against myelin oligodendrocyte glycoprotein (MOG). Furthermore, we report molecular details of the recognized epitope that is specific for human MOG. A brain biopsy revealed multiple sclerosis (MS)-type II pathology. Some features overlapped with both MS and neuromyelitis optica spectrum disorders (NMOSD), whereas others were distinct from both MS and NMOSD. Immunoadsorption and rituximab induced clinical stabilization. This case contributes a new, so far missing link in the emerging spectrum of MOG-antibody-associated encephalomyelitis. [mehr...]

[ AG Meinl ]

Histopathology and clinical course of MOG-antibody-associated encephalomyelitis.

Ann Clin Transl Neurol. 2015 Mar;2(3):295-301. doi: 10.1002/acn3.164.


[ AG Meinl ]

The Immunoregulator Soluble TACI Is Released by ADAM10 and Reflects B Cell Activation in Autoimmunity

J Immunol. 2015 Jan 15;194(2):542-52. doi: 10.4049/jimmunol.1402070.

The cytokines BAFF and APRIL regulate B cell survival and activation. In this study we identify a soluble form of the BAFF/APRIL receptor TACI that is present in blood and CSF. Soluble TACI acts as a decoy receptor for its ligands and may serve as a useful biomarker for the optimization of therapeutic approaches targeting the BAFF/APRIL system. [mehr...]

[ AG Kerschensteiner ]

Pervasive axonal transport deficits in multiple sclerosis models

Neuron 84: 1183-1190 (2014)

Here we visualize the dynamics of organelles in individual spinal axons and reveal widespread impairment of organelle transport in MS models. Transport deficits precede structural alterations of axons, myelin or microtubules. They persist in chronic MS models and lead to a reduced distal organelle density. [mehr...]

[ AG Kümpfel ]

Multiple sclerosis-like lesions and type I interferon signature in a patient with RVCL.

Neurol Neuroimmunol Neuroinflamm. 2014 Dec 23;2(1):e55. doi: 10.1212/NXI.0000000000000055. eCollection 2015.

Retinal vasculopathy with cerebral leukodystrophy (RVCL) is a rare late-onset autosomal dominant systemic microvascular disease due to C-terminal truncation mutations in the three prime repair exonuclease 1 gene, TREX1.1 Patients present with varying degrees of progressive bilateral vision loss, renal impairment, and neurologic symptoms. Cerebral MRI shows either confluent tumorlike signal alterations or multiple small white matter lesions.2,3 Herein we demonstrate a case of RVCL caused by a novel TREX1 mutation with distinct lesions on cerebral MRI and type I interferon (IFN) activation. [mehr...]

[ AG Kerschensteiner ]

A recoverable state of axon injury persists for hours after spinal contusion in vivo

Nature Communications 5:5683 doi:10.1038/ncomms6683 (2014)

Here we use spinal in vivo imaging to show that axons persist in a metastable state for hours after spinal contusion injury. During this time the intra-axonal calcium dynamics determine the axonal fate. Those axons that manage to re-establish calcium homoestasis will survive longterm while those that fail to do so will degenerate. This study identifies an inherent self-preseravtion process in contused axons and a window of opportunity for rescuing axonal connectivity after contusion injury. [mehr...]

[ AG Kerschensteiner ]

An assay to image neuronal microtubule dynamics in mice

Nature Communications 5:4827 doi:10.1038/ncomms5827 (2014)

Here we contribute to the development of a novel in vivo assay that allows visualizing neuronal microtubule dynamics in the peripheral and central nervous system. [mehr...]

[ AG Dornmair ]

Intrathecal somatic hypermutation of IgM in multiple sclerosis and neuroinflammation

First published online: July 23, 2014, Brain (2014) doi: 10.1093/brain/awu205

Oligoclonal bands in the cerebrospinal fluid are the most important immunological marker of multiple sclerosis. Whereas oligoclonal IgG bands were intensely investigated in the past, little is known about intrathecal IgM antibodies. Using state-of-the-art technologies, including deep sequencing and single-cell PCR, we identified novel features of the intrathecal IgM repertoire. [mehr...]

[ AG Bareyre ]

Abundant Expression of Guidance and Synaptogenic Molecules in the Injured Spinal Cord

PLoS ONE 9(2): e88449.

Here we investigate which molecules could regulate the formation of neuronal circuits in the injured spinal cord. Using an situ hybridization screen we show that many of the guidance and synaptogenic cues that regulate neuronal circuit formation in development are also present in the adult CNS and therefore likely contribute to the remodelling of axonal connections in the injured spinal cord. [mehr...]

[ AG Kerschensteiner ]

A unified cell biological perspective on axon-myelin injury

Journal of Cell Biology 206, 335-345 (2014)

Here we review recent advances in our understanding of the mechanisms that mediate axon and myelin injury in neuroinflammatory conditions and propose that the close cell biological interconnection of the axon-myelin unit could help explain the spread of pathology in advanced stages of MS. [mehr...]

[ AG Kerschensteiner ]

Multparametric optical analysis of mitochondrial redox signals during neuronal physiology and pathology in vivo

Nature Medicine 20, 555-560 (2014)

Here we establish a novel multiparametric imaging approach that allows us to visualize and mechanistically dissect mitochondrial redox signals with high temporal and spatial resolution in the living nervous system. [mehr...]

[ AG Kümpfel ]

Predictors for multiple sclerosis relapses after switching from natalizumab to fingolimod.

Mult Scler. 2014 May 19. pii: 1352458514533398.

The objective of this paper was to identify risk factors for recurrence of relapses after switching from NAT to fingolimod (FTY) in relapsing-remitting multiple sclerosis (RRMS). [mehr...]

[ AG Meinl ]

B cells in Multiple Sclerosis: Good or bad guys?

Eur. J. Immunol. 2014. 44: 1247–1250, an article for 28 May 2014 - World MS Day 2014

Review related to the World MS Day 2014. A pathogenic role of B cells in MS is indicated by the success of B-cell depleting therapy with anti-CD20 mAbs. Unexpectedly, however, targeting of survival factors for B cells by atacicept worsened MS. In this review, we discuss pro- and anti-inflammatory features of B cells. [mehr...]

[ AG Meinl ]

IL-35-producing B cells are critical regulators of immunity during autoimmune and infectious diseases

The Meinl group contributed to a very recent paper published in Nature. This paper shows that B cells down-regulate inflammation via production of the cytokine IL-35. [mehr...]

[ AG Kümpfel ]

Late-onset neutropenia during long-term rituximab therapy in neuromyelitis optica

Mult Scler Relat Disord. 2014 Mar;3(2):269-72. doi: 10.1016/j.msard.2013.08.001.

Late-onset neutropenia (LON) has been described as a side effect of rituximab (RX) therapy in patients with rheumatological and/or haematooncological diseases but not neuromyelitis optica (NMO). We describe a 71-year old female patient, who had NMO for 22 years, had been treated with RX monotherapy five times before she developed severe neutropenia (IV) 3 months after the last RX infusion. [mehr...]

[ AG Meinl ]

Multiple sclerosis: An old drug plays a new trick

Nature. 2013 Oct 9. doi: 10.1038/nature12694

In this News & Views article we present an advance towards repair of multiple sclerosis lesions. [mehr...]

[ AG Bareyre ]

STAT3 promotes corticospinal remodelling and functional recovery after spinal cord injury

EMBO Rep. 2013 Sep 30;14(10):931-7. doi: 10.1038/embor.2013.117

Here we show that viral gene transfer of the transcription factor STAT3 can induce remodeling if unlesioned fibers and thereby improve functional recovery after spinal cord injury. [mehr...]

[ AG Meinl ]

Distinction and temporal stability of conformational epitopes on myelin oligodendrocyte glycoprotein recognized by patients with different inflammatory central nervous system diseases

J Immunol. 2013 Oct 1;191(7):3594-604. doi: 10.4049/jimmunol.1301296

Autoantibodies targeting myelin oligodendrocyte glycoprotein (MOG) are found in different inflammatory diseases of the CNS. Here we distinguish different conformational epitopes of MOG. [mehr...]

[ AG Kerschensteiner ]

Neuroprotective intervention by interferon-γ blockade prevents CD8+ T cell-mediated dendrite and synapse loss

J Exp Med. 2013 Sep 23;210(10):2087-103. doi: 10.1084/jem.20122143

Here we show that CD8+ T cells induce neuronal deafferentiation in a viral encephalitis model via the secretion of interferon gamma. [mehr...]

[ AG Meinl ]

The utility of cerebrospinal fluid analysis in patients with multiple sclerosis

Nat Rev Neurol. 2013 May;9(5):267-76. doi: 10.1038/nrneurol.2013.41

Alterations of the cerebrospinal fluid are commonly found in multiple sclerosis. This review presents the utility of cerebrospinal fluid analysis for diagnosis, its impact on our understanding of the pathophysiology and therapy mechanisms, as well as for monitoring inflammatory and neurodegenerative processes. [mehr...]

[ AG Liebscher ]

Clustering of plaques contributes to plaque growth in a mouse model of Alzheimer's disease.

Acta Neuropathol. 2013 Aug;126(2):179-88. doi: 10.1007/s00401-013-1137-2.


[ AG Kümpfel ]

MANBA, CXCR5, SOX8, RPS6KB1 and ZBTB46 are genetic risk loci for multiple sclerosis.

Brain. 2013 Jun;136(Pt 6):1778-82. doi: 10.1093/brain/awt101

We tested five single nucleotide polymorphisms rs228614 (MANBA), rs630923 (CXCR5), rs2744148 (SOX8), rs180515 (RPS6KB1), and rs6062314 (ZBTB46) for association with multiple sclerosis risk in a total of 8499 cases with multiple sclerosis, 8765 unrelated control subjects and 958 trios of European descent. [mehr...]

[ AG Kawakami ]

Real-time in vivo analysis of T cell activation in the central nervous system using a genetically encoded calcium indicator

Nature Medicine 2013 May 12; doi:10.1038/nm.3180 [Epub ahead of print]

Here, we introduce fluorescence resonance energy transfer (FRET) based activation sensor, which can be expressed stably in T cells. Intravital imaging detects the change of intracellular calcium level. [mehr...]

[ AG Kawakami ]

2-photon imaging of phagocyte-mediated T cell activation in the CNS

J Clin Invest. 2013;123(3):1192–1201. doi:10.1172/JCI67233

Here, we show T cell activation within the CNS by using NFAT-GFP fusion protein and two-photon intravital microscopy. A part of APCs in the spinal cord leptomeninges present endogenous antigens to infiltrated autoreactive T cells and activate them. [mehr...]

[ AG Kerschensteiner ]

Cellular, subcellular and functional in vivo labeling of the spinal cord using vital dyes

Nature Protocols 8, 481–490 (2013) doi:10.1038/nprot.2013.022

Here we show how vital dyes can be used to label and image cells, subcellular organelles and effector molecules in the spinal cord of living mice. [mehr...]

[ AG Meinl ]

B cells and antibodies in multiple sclerosis pathogenesis and therapy

Nat Rev Neurol. 2012 Oct 9. doi: 10.1038/nrneurol.2012.203

In diesem Übersichtsartikel beschreiben wir wie das Milieu im ZNS von MS Patienten das Überleben von B-Lymphozyten fördert und diskutieren mögliche Zielstrukturen für Autoantikörper von MS Patienten. Therapeutische Strategien, die B-Lymphozyten direkt entfernen oder einen Effekt auf diese Immunzelltypen haben, werden vorgestellt. [mehr...]

[ Prof. Hohlfeld ]

β-Amyloid: enemy or remedy?

Sci Transl Med. 2012 Aug 1;4(145):145fs24.


[ AG Kawakami ]

An autoimmunity odyssey: how autoreactive T cells infiltrate into the CNS

Immunol Rev. 2012 Jul;248(1):140-55

This manuscript summarizes fate of autoreactive T cells after adoptive transfer into the recipients. [mehr...]

[ AG Dornmair ]

Target Specificity of an Autoreactive Pathogenic Human γδ-T Cell Receptor in Myositis

J. Biol. Chem. 2012 287: 20986-20995

We identify antigens and the recognition motif of a pathogenic gamma/delta T cell receptor that was isolated from tissue lesions of a patient with polymyositis. [mehr...]

[ AG Dornmair ]

Unbiased identification of target antigens of CD8+ T-cells with combinatorial libraries coding for short peptides

Nat Med. 2012 May;18(5):824-9

We describe an unbiased and generally applicable technology to identify the antigens of MHC class-I restricted T cell receptors. [mehr...]

[ AG Kerschensteiner ]

Axonal transport deficits and degeneration can evolve independently in mouse models of amyotrophic lateral sclerosis

Proc Natl Acad Sci U S A. 2012 Mar 13;109(11):4296-301. Epub 2012 Feb 27

Here, we investigate the relation between axonal transport and degeneration in an animal model of ALS. [mehr...]

[ AG Bareyre ]

Single Collateral Reconstructions Reveal Distinct Phases of Corticospinal Remodeling after Spinal Cord Injury

PLoS One. 2012;7(1):e30461. Epub 2012 Jan 24

Here, we describe distinct phases of axonal remodelling after spinal cord injury. [mehr...]

[ Prof. Hohlfeld ]

Update on sporadic inclusion body myositis

Brain. 2011 Nov;134(Pt 11):3141-5. Epub 2011 Sep 29


[ AG Kerschensteiner ]

Near-infrared branding efficiently correlates light and electron microscopy

Nat Methods. 2011 Jun 5;8(7):568-70

Here, we describe a new technique that uses fiduciary marks set by a 2-photon laser to correlate light and electron microscopic images. [mehr...]

[ AG Bareyre ]

In vivo imaging reveals a phase-specific role of STAT3 during central and peripheral nervous system axon regeneration

Proc Natl Acad Sci U S A. 2011 Apr 12;108(15):6282-7

Here, we show that the transcription factor STAT3 regulates the initiation but not the elongation phase of axonal regeneration in the PNS and CNS. [mehr...]

[ AG Kerschensteiner ]

A reversible form of axon damage in experimental autoimmune encephalomyelitis and multiple sclerosis

Nature Medicine 2011 Vol. 17 No. 4

Here, we use in vivo multiphoton imaging to identify a novel form of axonal degeneration that contributes to axon loss in multiple sclerosis and its animal model. [mehr...]

[ AG Kawakami ]

Knocking at the brain's door: intravital two-photon imaging of autoreactive T cell interactions with CNS structures

Semin Immunopathol. 2010 Sep;32(3):275-87. Epub 2010 Jul 11

Reviewing intravital imaging of autoreactive T cell infiltration into the CNS. [mehr...]

[ AG Kawakami ]

Nicotinic acid adenine dinucleotide phosphate-mediated calcium signalling in effector T cells regulates autoimmunity of the central nervous system

Brain. 2010 Jul;133(Pt 7):1930-43. Epub 2010 Jun 2

Effects of calcium channel inhibitor on animal model of autoimmunity. [mehr...]

[ AG Kawakami ]

Effector T cell interactions with meningeal vascular structures in nascent autoimmune CNS lesions

Nature. 2009 Nov 5;462(7269):94-8. Epub 2009 Oct 14

Intravital two-photon imaging first time shows how auto-antigen specific T cells infiltrate into the CNS. [mehr...]

[ AG Dornmair ]

Inclusion Body Myositis: Laser Microdissection Reveals Differential Up-Regulation of IFN-γ Signaling Cascade in Attacked versus Nonattacked Myofibers

Am J Pathol. 2011 Sep;179(3):1347-59

Using isolated muscle fibers from patients with inclusion body myositis, we identify differentially regulated signaling pathways in fibers that were attacked by T cells. [mehr...]

[ AG Liebscher ]

CK2 negatively regulates Galphas signaling.

Proc Natl Acad Sci U S A. 2009 Aug 18;106(33):14096-101. doi: 10.1073/pnas.0906857106. Epub 2009 Aug 3.


[ AG Dornmair ]

Myelin-specific T cells also recognize neuronal autoantigen in a transgenic mouse model of multiple sclerosis

Nat Med. 2009 Jun;15(6):626-32

We explain the paradox that transgenic mice which express a T cell receptor against the brain-specific antigen „MOG“, but do not express MOG protein, develop spontaneous disease. [mehr...]

[ AG Dornmair ]

CD8+ T-cell clones dominate brain infiltrates in Rasmussen encephalitis and persist in the periphery

Brain. 2009 132(Pt 5):1236-46

T cell receptor repertoire analysis reveals persistent autoaggressive CD8+ T cell clones in brain tissue of patients with Rasmussen encephalitis. [mehr...]

[ AG Kerschensteiner ]

Ex vivo imaging of motor axon dynamics in murine triangularis sterni explants

Nat Protoc. 2008;3(10):1645-53

Here, we describe a neuromuscular explant system that is particularly suited for ex vivo imaging. [mehr...]

[ AG Dornmair ]

Matching of oligoclonal immunoglobulin transcriptomes and proteomes of cerebrospinal fluid in multiple sclerosis

Nat Med. 2008 14(6):688-93

We link proteomes and transcriptomes of B cells from the cerebrospinal fluid of MS patients providing evidence that CSF-resident B cells may produce oligoclonal band antibodies. [mehr...]

[ AG Bareyre ]

Neuronal repair and replacement in spinal cord injury

J Neurol Sci. 2008 Feb 15;265(1-2):63-72. Epub 2007 Jun 12

Here, I discuss how injured axonal connections can be repaired after spinal cord injury. [mehr...]

[ AG Kawakami ]

Blood-borne soluble protein antigen intensifies T cell activation in autoimmune CNS lesions and exacerbates clinical disease

Proc Natl Acad Sci U S A. 2007 Nov 20;104(47):18625-30. Epub 2007 Nov 13

Soluble antigen treatment after onset of EAE induces disaster in the host. [mehr...]

[ AG Dornmair ]

Multiple sclerosis: T-cell receptor expression in distinct brain regions

Brain. 2007 130:2789-99

Here, we compare the T cell receptor repertoires in different lesions and normal appearing white matter of MS patients and identify pervasive CD8+ T cell clones. [mehr...]

[ AG Bareyre ]

Imaging axonal transport of mitochondria in vivo

Nat Methods. 2007 Jul;4(7):559-61. Epub 2007 Jun 10

Here, we establish a novel approach that allows to image the transport of fluorescently labelled mitochondria in the intact nervous system. [mehr...]

[ AG Kerschensteiner ]

In vivo imaging of single axons in the mouse spinal cord

Nat Protoc. 2007;2(2):263-8

Here, we describe how to image fluorescently labelled axons in the spinal cord of living mice. [mehr...]

[ AG Kawakami ]

Instant effect of soluble antigen on effector T cells in peripheral immune organs during immunotherapy of autoimmune encephalomyelitis

Proc Natl Acad Sci U S A. 2007 Jan 16;104(3):920-5. Epub 2007 Jan 9

Soluble antigen treatment before onset of EAE ameliorates EAE dramatically. Intravital imaging shows T cell arrest in the spleen in short time after treatment. [mehr...]

[ AG Dornmair ]

Reconstitution of paired T cell receptor α- and β-chains from microdissected single cells of human inflammatory tissues

Proc Natl Acad Sci U S A. 2006 103(32):12057-62

We describe a technology to functionally “resurrect” disease-related T cells that belong to expanded clones from frozen patient´s tissue. [mehr...]

[ AG Kerschensteiner ]

In vivo imaging of the diseased nervous system

Nat Rev Neurosci. 2006 Jun;7(6):449-63

Here, we discuss how in vivo imaging techniques can help us to better understand neurological conditions. [mehr...]

[ AG Bareyre ]

Transgenic labeling of the corticospinal tract for monitoring axonal responses to spinal cord injury

Nat Med. 2005 Dec;11(12):1355-60. Epub 2005 Nov 13

Here, we describe how mice with a fluorescently labelled corticospinal tract can improve the analysis of axonal plasticity after spinal cord injury. [mehr...]

[ AG Kawakami ]

Live imaging of effector cell trafficking and autoantigen recognition within the unfolding autoimmune encephalomyelitis lesion

J Exp Med. 2005 Jun 6;201(11):1805-14

Spinal cord acute slice imaging illustrates autoantigen specific T cells recognize endogenous antigen in the CNS parenchyma. [mehr...]

[ AG Kerschensteiner ]

In vivo imaging of axonal degeneration and regeneration in the injured spinal cord

Nat Med. 2005 May;11(5):572-7. Epub 2005 Apr 10

Here, we visualize for the first time fluorescently labelled axons and their response to transection in the spinal cord of living mice. [mehr...]

[ AG Bareyre ]

Remodeling of Axonal Connections Contributes to Recovery in an Animal Model of Multiple Sclerosis

J Exp Med. 2004 Oct 18;200(8):1027-38

Here, we show that axonal connections are remodelled on multiple anatomical levels in response to a targeted inflammatory lesion of the spinal cord. [mehr...]

[ AG Bareyre ]

The injured spinal cord spontaneously forms a new intraspinal circuit in adult rats

Nat Neurosci. 2004 Mar;7(3):269-77. Epub 2004 Feb 15

Here, we demonstrate that the spontaneous formation of intraspinal detour circuits contributes to functional recovery after spinal cord injury. [mehr...]

[ AG Bareyre ]

Inflammation, degeneration and regeneration in the injured spinal cord: insights from DNA microarrays

Trends in Neurosciences, Volume 26, Issue 10, 555-563

Here, we discuss how microarray analyses can improve our understanding of spinal cord injuries. [mehr...]


Prof. Dr.

Reinhard Hohlfeld


Prof. Dr.

Martin Kerschensteiner


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