Publications by authors named "Anne K Mausberg"

34 Publications

Observational cohort study of neurological involvement among patients with SARS-CoV-2 infection.

Ther Adv Neurol Disord 2021 26;14:1756286421993701. Epub 2021 Feb 26.

Department of Neurology and Center for Translational and Behavioral Neurosciences (C-TNBS), University Medicine Essen, Hufelandstraße 55, Essen, 45147, Germany.

Background: A growing number of reports suggest that infection with SARS-CoV-2 often leads to neurological involvement; however, data on the incidence and severity are limited to mainly case reports and retrospective studies.

Methods: This prospective, cross-sectional study of 102 SARS-CoV-2 PCR positive patients investigated the frequency, type, severity and risk factors as well as underlying pathophysiological mechanisms of neurological involvement (NIV) in COVID-19 patients.

Results: Across the cohort, 59.8% of patients had NIV. Unspecific NIV was suffered by 24.5%, mainly general weakness and cognitive decline or delirium. Mild NIV was found in 9.8%; most commonly, impaired taste or smell. Severe NIV was present in 23.5%; half of these suffered cerebral ischaemia. Incidence of NIV increased with respiratory symptoms of COVID-19. Mortality was higher with increasing NIV severity. Notably, 83.3% with severe NIV had a pre-existing neurological co-morbidity. All cerebrospinal fluid (CSF) samples were negative for SARS-CoV-2 RNA, and SARS-CoV-2 antibody quotient did not suggest intrathecal antibody synthesis. Of the patients with severe NIV, 50% had blood-brain barrier (BBB) disruption and showed a trend of elevated interleukin levels in CSF. Antibodies against neuronal and glial epitopes were detected in 35% of the patients tested.

Conclusion: Cerebrovascular events were the most frequent severe NIV and severe NIV was associated with high mortality. Incidence of NIV increased with respiratory symptoms and NIV and pre-existing neurological morbidities were independent risk factors for fatality. Inflammatory involvement due to BBB disruption and cytokine release drives NIV, rather than direct viral invasion. These findings might help physicians define a further patient group requiring particular attention during the pandemic.
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http://dx.doi.org/10.1177/1756286421993701DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934032PMC
February 2021

Neurological Manifestations of COVID-19 Feature T Cell Exhaustion and Dedifferentiated Monocytes in Cerebrospinal Fluid.

Immunity 2021 01 23;54(1):164-175.e6. Epub 2020 Dec 23.

Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Münster, Germany. Electronic address:

Patients suffering from Coronavirus disease 2019 (COVID-19) can develop neurological sequelae, such as headache and neuroinflammatory or cerebrovascular disease. These conditions-termed here as Neuro-COVID-are more frequent in patients with severe COVID-19. To understand the etiology of these neurological sequelae, we utilized single-cell sequencing and examined the immune cell profiles from the cerebrospinal fluid (CSF) of Neuro-COVID patients compared with patients with non-inflammatory and autoimmune neurological diseases or with viral encephalitis. The CSF of Neuro-COVID patients exhibited an expansion of dedifferentiated monocytes and of exhausted CD4 T cells. Neuro-COVID CSF leukocytes featured an enriched interferon signature; however, this was less pronounced than in viral encephalitis. Repertoire analysis revealed broad clonal T cell expansion and curtailed interferon response in severe compared with mild Neuro-COVID patients. Collectively, our findings document the CSF immune compartment in Neuro-COVID patients and suggest compromised antiviral responses in this setting.
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http://dx.doi.org/10.1016/j.immuni.2020.12.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7831653PMC
January 2021

NK cell markers predict the efficacy of IV immunoglobulins in CIDP.

Neurol Neuroimmunol Neuroinflamm 2020 11 2;7(6). Epub 2020 Oct 2.

From the Department of Neurology (A.K.M., M.F., F.S., C.K., M.S.), Research Group for Clinical and Experimental Neuroimmunology, University Hospital Essen; Department of Neurology (M.K.H., H.-P.H., B.C.K.), Medical Faculty, Heinrich-Heine University Duesseldorf; Department of Neurology with Institute of Translational Neurology (G.M.Z.H.), University Hospital Münster; and Oncology and Tumor Immunology (S.C.), Charité University Medicine, Berlin, Germany.

Objective: To assess whether IV immunoglobulins (IVIgs) as a first-line treatment for chronic inflammatory demyelinating polyneuropathy (CIDP) have a regulative effect on natural killer (NK) cells that is related to clinical responsiveness to IVIg.

Methods: In a prospective longitudinal study, we collected blood samples of 29 patients with CIDP before and after initiation of IVIg treatment for up to 6 months. We used semiquantitative PCR and flow cytometry in the peripheral blood to analyze the effects of IVIg on the NK cells. The results were correlated with clinical aspects encompassing responsiveness.

Results: We found a reduction in the expression of several typical NK cell genes 1 day after IVIg administration. Flow cytometry furthermore revealed a reduced cytotoxic CD56 NK cell population, whereas regulatory CD56 NK cells remained mostly unaffected or were even increased after IVIg treatment. Surprisingly, the observed effects on NK cells almost exclusively occurred in IVIg-responsive patients with CIDP.

Conclusions: The correlation between the altered NK cell population and treatment efficiency suggests a crucial role for NK cells in the still speculative mode of action of IVIg treatment. Analyzing NK cell subsets after 24 hours of treatment initiation appeared as a predictive marker for IVIg responsiveness. Further studies are warranted investigating the potential of NK cell status as a routine parameter in patients with CIDP before IVIg therapy.

Classification Of Evidence: This study provides Class I evidence that NK cell markers predict clinical response to IVIg in patients with CIDP.
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http://dx.doi.org/10.1212/NXI.0000000000000884DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577535PMC
November 2020

Redefining the heterogeneity of peripheral nerve cells in health and autoimmunity.

Proc Natl Acad Sci U S A 2020 04 15;117(17):9466-9476. Epub 2020 Apr 15.

Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Münster 48149, Germany;

Peripheral nerves contain axons and their enwrapping glia cells named Schwann cells (SCs) that are either myelinating (mySCs) or nonmyelinating (nmSCs). Our understanding of other cells in the peripheral nervous system (PNS) remains limited. Here, we provide an unbiased single cell transcriptomic characterization of the nondiseased rodent PNS. We identified and independently confirmed markers of previously underappreciated nmSCs and nerve-associated fibroblasts. We also found and characterized two distinct populations of nerve-resident homeostatic myeloid cells that transcriptionally differed from central nervous system microglia. In a model of chronic autoimmune neuritis, homeostatic myeloid cells were outnumbered by infiltrating lymphocytes which modulated the local cell-cell interactome and induced a specific transcriptional response in glia cells. This response was partially shared between the peripheral and central nervous system glia, indicating common immunological features across different parts of the nervous system. Our study thus identifies subtypes and cell-type markers of PNS cells and a partially conserved autoimmunity module induced in glia cells.
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http://dx.doi.org/10.1073/pnas.1912139117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7196786PMC
April 2020

Protective effects of 4-aminopyridine in experimental optic neuritis and multiple sclerosis.

Brain 2020 04;143(4):1127-1142

NeuroCure Clinical Research Center and Experimental and Clinical Research Center, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health and Max Delbrueck Center for Molecular Medicine, Berlin, Germany.

Chronic disability in multiple sclerosis is linked to neuroaxonal degeneration. 4-aminopyridine (4-AP) is used and licensed as a symptomatic treatment to ameliorate ambulatory disability in multiple sclerosis. The presumed mode of action is via blockade of axonal voltage gated potassium channels, thereby enhancing conduction in demyelinated axons. In this study, we provide evidence that in addition to those symptomatic effects, 4-AP can prevent neuroaxonal loss in the CNS. Using in vivo optical coherence tomography imaging, visual function testing and histologic assessment, we observed a reduction in retinal neurodegeneration with 4-AP in models of experimental optic neuritis and optic nerve crush. These effects were not related to an anti-inflammatory mode of action or a direct impact on retinal ganglion cells. Rather, histology and in vitro experiments indicated 4-AP stabilization of myelin and oligodendrocyte precursor cells associated with increased nuclear translocation of the nuclear factor of activated T cells. In experimental optic neuritis, 4-AP potentiated the effects of immunomodulatory treatment with fingolimod. As extended release 4-AP is already licensed for symptomatic multiple sclerosis treatment, we performed a retrospective, multicentre optical coherence tomography study to longitudinally compare retinal neurodegeneration between 52 patients on continuous 4-AP therapy and 51 matched controls. In line with the experimental data, during concurrent 4-AP therapy, degeneration of the macular retinal nerve fibre layer was reduced over 2 years. These results indicate disease-modifying effects of 4-AP beyond symptomatic therapy and provide support for the design of a prospective clinical study using visual function and retinal structure as outcome parameters.
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http://dx.doi.org/10.1093/brain/awaa062DOI Listing
April 2020

A fatal case of daclizumab-induced liver failure in a patient with MS.

Neurol Neuroimmunol Neuroinflamm 2019 03 21;6(2):e539. Epub 2019 Jan 21.

Department of Neurology (M.S., A.K.M., R.P., C.K.), University Hospital Essen; Clinic of Neurology with Institute of Translational Neurology (C.C.G., A.S.-M., H.W., S.G.M.), University Hospital Münster, University Münster; Institute of Neuropathology (A.J.), University Hospital Essen; and Institute of Pathology (H.A.B.), University Hospital Essen, Germany.

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http://dx.doi.org/10.1212/NXI.0000000000000539DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6369971PMC
March 2019

Differential impact of pure glyphosate and glyphosate-based herbicide in a model of peripheral nervous system myelination.

Acta Neuropathol 2018 12 16;136(6):979-982. Epub 2018 Nov 16.

Department of Neurology, University Hospital Essen, University Duisburg-Essen, Hufelandstrasse 55, 45147, Essen, Germany.

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http://dx.doi.org/10.1007/s00401-018-1938-4DOI Listing
December 2018

Trapped in the epineurium: early entry into the endoneurium is restricted to neuritogenic T cells in experimental autoimmune neuritis.

J Neuroinflammation 2018 Aug 1;15(1):217. Epub 2018 Aug 1.

Department of Neurology, Medical Faculty, Heinrich Heine University Duesseldorf, 40225, Duesseldorf, Germany.

Background: Autoimmune polyneuropathies are acquired inflammatory disorders of the peripheral nervous system (PNS) characterized by inflammation, demyelination, and axonal degeneration. Although the pathogenesis has not been fully elucidated, T cells recognizing self-antigens are believed to initiate inflammation in a subgroup of patients. However, the route and time of T cell entry into the PNS have not yet been described in detail. In this study, we analyzed both kinetics as well as localization of retrovirally transfected green fluorescent protein (GFP)-expressing neuritogenic T lymphocytes in experimental autoimmune neuritis (EAN).

Methods: T lymphocytes obtained from rats following EAN induction by immunization with peripheral nerve protein peptide P2 were retrovirally engineered to express GFP. Non-specific T cells were negatively selected by in vitro restimulation, whereas GFP-expressing neuritogenic T cells (reactive to P2) were adoptively transferred into healthy rats (AT-EAN). Antigen-specific T cell tracking and localization was performed by flow cytometry and immunohistochemistry during the course of disease.

Results: After induction of autoimmune neuritis, P2-reactive T cells were detectable in the liver, spleen, lymph nodes, lung, peripheral blood, and the sciatic nerves with distinct kinetics. A significant number of GFP T cells appeared early in the lung with a peak at day four. In the peripheral nerves within the first days, GFP-negative T cells rapidly accumulated and exceeded the number of GFP-expressing cells, but did not enter the endoneurium. Very early after adoptive transfer, T cells are found in proximity to peripheral nerves and in the epineurium. However, only GFP-expressing neuritogenic T cells are able to enter the endoneurium from day five after transfer.

Conclusions: Our findings suggest that neuritogenic T cells invade the PNS early in the course of disease. However, neuritogenic T cells cross the blood-nerve barrier with a certain delay without preference to dorsal roots. Further understanding of the pathophysiological role of autoagressive T cells may help to improve therapeutic strategies in immune-mediated neuropathies.
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http://dx.doi.org/10.1186/s12974-018-1259-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6090976PMC
August 2018

Lysophosphatidic acid propagates post-injury Schwann cell dedifferentiation through LPA signaling.

Neurosci Lett 2018 Jan 16;662:136-141. Epub 2017 Oct 16.

Department of Neurology, Medical Faculty, University Duisburg-Essen, Essen, Germany.

Lysophosphatidic acid (LPA) is a pleiotropic signaling lipid that acts as ligand for at least six specific G-protein coupled receptors. Schwann cells (SC) are known to mainly express the LPA receptor subtype. An emerging body of evidence has linked LPA with injury-induced peripheral nerve demyelination as well as neuropathic pain. However, the molecular mechanisms underlying its demyelinating effect have not been conclusively elucidated. We aimed to decipher the demyelinating effect in vitro as well as in vivo by studying markers of SC differentiation and dedifferentiation: Myelinated dorsal root ganglia (DRG) cultures were treated either with LPA, LPA plus AM095 (LPA antagonist) or vehicle. Myelin content was subsequently investigated by Sudan Black staining and immunocytochemistry. In vivo, we performed sciatic nerve crush in C57BL/6 mice treated with AM095 at 10mg/kg. In DRG cultures, LPA caused a significant reduction of myelin as demonstrated by both Sudan Black staining and immunocytochemical analysis of myelin basic protein. Demyelination was paralleled by an upregulation of TNF-alpha as well as downregulation of Sox10, a marker for SC differentiation. LPA mediated effects were largely blocked by the addition of the LPA receptor antagonist AM095. In the in vivo model, AM095 treatment prior to crush injury increased Sox10 expression in SCs in the distal nerve stump while reducing the number of cells expressing the SC dedifferentiation marker Sox2. Additionally, TNF-alpha immunofluorescence was reduced in CD11b-positive cells. These data indicate that LPA may be a critical factor that shifts SCs towards a post-injury phenotype and contributes to the onset of Wallerian degeneration.
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http://dx.doi.org/10.1016/j.neulet.2017.10.023DOI Listing
January 2018

The Role of Peripheral Myelin Protein 2 in Remyelination.

Cell Mol Neurobiol 2018 Mar 26;38(2):487-496. Epub 2017 Apr 26.

Department of Neurology, Heinrich-Heine-University, Düsseldorf, Germany.

The protein component of the myelin layer is essential for all aspects of peripheral nerves, and its deficiency can lead to structural and functional impairment. The presence of peripheral myelin protein 2 (P2, PMP2, FABP8, M-FABP) in Schwann cells has been known for decades and shown recently to be involved in the lipid homeostasis in the peripheral neural system. However, its precise role during de- and remyelination has yet to be elucidated. To this end, we assessed remyelination after sciatic nerve crush injury in vivo, and in an experimental de/remyelination ex vivo myelinating culture model in P2-deficient (P2 ) and wild-type (WT) animals. In vivo, the nerve crush paradigm revealed temporal structural and functional changes in P2 mice as compared to WT animals. Concomitantly, P2 DRG cultures demonstrated the presence of shorter internodes and enlarged nodes after ex vivo de/remyelination. Together, these data indicate that P2 may play a role in remyelination of the injured peripheral nervous system, presumably by affecting the nodal and internodal configuration.
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http://dx.doi.org/10.1007/s10571-017-0494-0DOI Listing
March 2018

Dimethyl fumarate accelerates peripheral nerve regeneration via activation of the anti-inflammatory and cytoprotective Nrf2/HO-1 signaling pathway.

Acta Neuropathol 2017 03 20;133(3):489-491. Epub 2017 Jan 20.

Department of Neurology, Medical Faculty, Heinrich-Heine-University, Moorenstrasse 5, 40225, Düsseldorf, Germany.

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http://dx.doi.org/10.1007/s00401-017-1676-zDOI Listing
March 2017

Predicting the Response to Intravenous Immunoglobulins in an Animal Model of Chronic Neuritis.

PLoS One 2016 6;11(10):e0164099. Epub 2016 Oct 6.

Department of Neurology, Heinrich-Heine-University, Medical Faculty, Düsseldorf, Germany.

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a disabling autoimmune disorder of the peripheral nervous system (PNS). Intravenous immunoglobulins (IVIg) are effective in CIDP, but the treatment response varies greatly between individual patients. Understanding this interindividual variability and predicting the response to IVIg constitute major clinical challenges in CIDP. We previously established intercellular adhesion molecule (ICAM)-1 deficient non-obese diabetic (NOD) mice as a novel animal model of CIDP. Here, we demonstrate that similar to human CIDP patients, ICAM-1 deficient NOD mice respond to IVIg treatment by clinical and histological measures. Nerve magnetic resonance imaging and histology demonstrated that IVIg ameliorates abnormalities preferentially in distal parts of the sciatic nerve branches. The IVIg treatment response also featured great heterogeneity allowing us to identify IVIg responders and non-responders. An increased production of interleukin (IL)-17 positively predicted IVIg treatment responses. In human sural nerve biopsy sections, high numbers of IL-17 producing cells were associated with younger age and shorter disease duration. Thus, our novel animal model can be utilized to identify prognostic markers of treatment responses in chronic inflammatory neuropathies and we identify IL-17 production as one potential such prognostic marker.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0164099PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5053527PMC
June 2017

Alteration of the cytokine signature by various TLR ligands in different T cell populations in MOG37-50 and MOG35-55-induced EAE in C57BL/6 mice.

Clin Immunol 2016 09 24;170:22-30. Epub 2016 May 24.

Department of Neurology, Heinrich Heine University, Düsseldorf, Germany.

Interleukin 17 (IL-17), produced by T cells, plays an important role in Multiple Sclerosis (MS) and its animal model, Experimental Autoimmune Encephalomyelitis (EAE). In contrast to IL-17-producing CD4+ T cells, the contribution of IL-17-producing CD8+ T cells (Tc17) in CNS autoimmunity has been investigated less intensively. Here we investigate the role of TC17 in EAE. We compare different T cell populations and their cytokine pattern in the MOG35-55- and MOG37-50-induced EAE. We detected a similar cytokine phenotype for both EAE models in the autoimmune process assessed at different stages. Regarding the migratory activity, an involvement of IL-17 and IFN-γ in disease onset was suggested. Furthermore, we show that PAMPs have the ability to drive autoimmune process. To modify the cytokine pattern of different T cell populations, a combination of distinct factors is required (the activation of MyD88 or Syk, the genetic background, the presence of APCs and CD4+ T cells).
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http://dx.doi.org/10.1016/j.clim.2016.05.008DOI Listing
September 2016

Oral Tolerance Induction in Experimental Autoimmune Encephalomyelitis with Candida utilis Expressing the Immunogenic MOG35-55 Peptide.

PLoS One 2016 9;11(5):e0155082. Epub 2016 May 9.

Institute of Molecular Mycology, Department Biology, Heinrich-Heine-University, Düsseldorf, Germany.

Multiple sclerosis (MS) is an autoimmune disease that attacks myelinated axons in the central nervous system. Induction of oral tolerance is a potent mechanism to prevent autoimmunity. The food yeast Candida utilis was used to test the therapeutic potential of oral tolerance induction in an animal model of human multiple sclerosis (MS). We constructed a C. utilis strain, which displays a fusion peptide composed of the encephalitogenic MOG35-55 peptide and the C. utilis Gas1 cell wall protein on its surface.By immunizing mice with MOG35-55 peptide experimental autoimmune encephalomyelitis (EAE) was induced in a mouse model. Feeding of mice with C. utilis that expresses MOG35-55 peptide on its surface was started seven days prior to immunization and was continued for ten days. Control animals were treated with wild-type fungus or left untreated. Untreated mice developed first clinical symptoms ten days post immunization (p. i.) with an ascending paralysis reaching maximal clinical disability at day 18 to 20 p. i.. Treatment with the wild-type strain demonstrated comparable clinical symptoms. In contrast, oral gavage of MOG35-55-presenting fungus ameliorated the development of EAE. In addition, incidence as well as maximal clinical disease severity were significantly reduced. Interestingly, reduction of disease severity also occurred in animals treated with heat-inactivated C. utilis cells indicating that tolerance induction was independent of fungal viability. Better disease outcome correlated with reduced demyelination and cellular inflammation in the spinal cord, lower T cell proliferation against rechallenge with MOG35-55 and more regulatory T cells in the lymph nodes. Our data demonstrate successful that using the food approved fungus C. utilis presenting the immunogenic MOG35-55 peptide on its surface induced an oral tolerance against this epitope in EAE. Further studies will reveal the nature and extent of an anti-inflammatory environment established by the treatment that prevents the development of an autoimmune disorder affecting the CNS.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0155082PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4861260PMC
July 2017

Pseudomonas aeruginosa and Its Bacterial Components Influence the Cytokine Response in Thymocytes and Splenocytes.

Infect Immun 2016 05 22;84(5):1413-1423. Epub 2016 Apr 22.

Department of Neurology, Medical Faculty, Heinrich Heine University, Dusseldorf, Germany.

Infections with Pseudomonas aeruginosa may cause many different diseases. The spectrum of such infections in general includes inflammation and bacterial sepsis. Hospital-acquired pneumonia, naturally resistant to a wide range of antibiotics, is associated with a particularly high mortality rate in mechanically ventilated patients. The pathogenesis of P. aeruginosa is complex and mediated by several virulence factors, as well as cell-associated factors. We have previously demonstrated that stimulation with different bacteria triggers the cytokine response of thymocytes. In this study, we investigated the effect of P. aeruginosa and its different components on the cytokine production of immature and mature immune cells. We found that the induced cytokine pattern in the thymus and the spleen after infections with P. aeruginosa is primarily mediated by lipopolysaccharide (LPS) of the outer cell membrane, but other components of the bacterium can influence the cytokine secretion as well. Stimulation with heat-killed P. aeruginosa and LPS does not influence the amount of cytokine-producing CD4(+) T cells but instead suppresses the emergence of Th17 cells. However, stimulation with P. aeruginosa or its components triggers the interleukin-17 (IL-17) response both in thymocytes and in splenocytes. We conclude that infections with P. aeruginosa affect the cytokine secretion of immature and mature cells and that IL-17 and Th17 cells play only a minor role in the development of pathological systemic inflammatory disease conditions during P. aeruginosa infections. Therefore, other inflammatory immune responses must be responsible for septic reactions of the host.
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http://dx.doi.org/10.1128/IAI.00905-15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4862705PMC
May 2016

Natalizumab exerts a suppressive effect on surrogates of B cell function in blood and CSF.

Mult Scler 2015 Jul 12;21(8):1036-44. Epub 2014 Nov 12.

Department of Neurology, Medical Faculty, Heinrich-Heine-University, Duesseldorf, Germany.

Background: Natalizumab for multiple sclerosis (MS) increases the risk of progressive multifocal leukoencephalopathy (PML).

Objective: We aimed to assess the effect of natalizumab on cellular composition and functional B cell parameters including patients with natalizumab-associated PML (n=37).

Methods: Cellular composition by flow cytometry, levels of immunoglobulin (Ig)G/IgM by immunonephelometry, and oligoclonal bands by isoelectric focusing were studied in blood and cerebrospinal fluid.

Results: In MS patients treated with natalizumab without PML (n=59) the proportion of CD19+ B cells was higher in blood, but lower in cerebrospinal fluid compared with MS patients not treated with natalizumab (n=17). The CD4/CD8-ratio in cerebrospinal fluid was lower, and IgG and IgM levels as well as the IgG index dropped in longitudinal samples during natalizumab therapy. Oligoclonal bands persisted, but the total amount of the intrathecally produced IgG fraction, and the polyclonal intrathecal IgG reactivity to measles, rubella, and zoster declined. At the time of diagnosis of PML patients with natalizumab-associated PML had low total IgG levels in blood and cerebrospinal fluid.

Conclusions: Natalizumab impacts B and T cell distribution and exerts an inhibitory effect on surrogates of B cell function in periphery and in cerebrospinal fluid, potentially contributing to the increased risk of developing PML.
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http://dx.doi.org/10.1177/1352458514556296DOI Listing
July 2015

FoxP3+ regulatory T cells determine disease severity in rodent models of inflammatory neuropathies.

PLoS One 2014 6;9(10):e108756. Epub 2014 Oct 6.

Department of Neurology, Heinrich-Heine-University, Medical Faculty, Düsseldorf, Germany.

Inflammatory neuropathies represent disabling human autoimmune disorders with considerable disease variability. Animal models provide insights into defined aspects of their disease pathogenesis. Forkhead box P3 (FoxP3)+ regulatory T lymphocytes (Treg) are anti-inflammatory cells that maintain immune tolerance and counteract tissue damage in a variety of immune-mediated disorders. Dysfunction or a reduced frequency of Tregs have been associated with different human autoimmune disorders. We here analyzed the functional relevance of Tregs in determining disease manifestation and severity in murine models of autoimmune neuropathies. We took advantage of the DEREG mouse system allowing depletion of Treg with high specificity as well as anti-CD25 directed antibodies to deplete Tregs in mice in actively induced experimental autoimmune neuritis (EAN). Furthermore antibody-depletion was performed in an adoptive transfer model of chronic neuritis. Early Treg depletion increased clinical EAN severity both in active and adoptive transfer chronic neuritis. This was accompanied by increased proliferation of myelin specific T cells and histological signs of peripheral nerve inflammation. Late stage Treg depletion after initial disease manifestation however did not exacerbate inflammatory neuropathy symptoms further. We conclude that Tregs determine disease severity in experimental autoimmune neuropathies during the initial priming phase, but have no major disease modifying function after disease manifestation. Potential future therapeutic approaches targeting Tregs should thus be performed early in inflammatory neuropathies.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0108756PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4186754PMC
June 2015

Thymic epithelium determines a spontaneous chronic neuritis in Icam1(tm1Jcgr)NOD mice.

J Immunol 2014 Sep 8;193(6):2678-90. Epub 2014 Aug 8.

Department of Neurology, Medical Faculty, Heinrich-Heine-University, 40225 Düsseldorf, Germany;

The NOD mouse strain spontaneously develops autoimmune diabetes. A deficiency in costimulatory molecules, such as B7-2, on the NOD genetic background prevents diabetes but instead triggers an inflammatory peripheral neuropathy. This constitutes a shift in the target of autoimmunity, but the underlying mechanism remains unknown. In this study, we demonstrate that NOD mice deficient for isoforms of ICAM-1, which comediate costimulatory functions, spontaneously develop a chronic autoimmune peripheral neuritis instead of diabetes. The disease is transferred by CD4(+) T cells, which infiltrate peripheral nerves together with macrophages and B cells and are autoreactive against peripheral myelin protein zero. These Icam1(tm1Jcgr)NOD mice exhibit unaltered numbers of regulatory T cells, but increased IL-17-producing T cells, which determine the severity, but not the target specificity, of autoimmunity. Ab-mediated ICAM-1 blockade triggers neuritis only in young NOD mice. Thymic epithelium from Icam1(tm1Jcgr)NOD mice features an altered expression of costimulatory molecules and induces neuritis and myelin autoreactivity after transplantation into nude mice in vivo. Icam1(tm1Jcgr)NOD mice exhibit a specifically altered TCR repertoire. Our findings introduce a novel animal model of chronic inflammatory neuropathies and indicate that altered expression of ICAM-1 on thymic epithelium shifts autoimmunity specifically toward peripheral nerves. This improves our understanding of autoimmunity in the peripheral nervous system with potential relevance for human diseases.
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http://dx.doi.org/10.4049/jimmunol.1400367DOI Listing
September 2014

Interleukin-17 impedes Schwann cell-mediated myelination.

J Neuroinflammation 2014 Mar 29;11:63. Epub 2014 Mar 29.

Department of Neurology, Medical Faculty, Research Group for Clinical and Experimental Neuroimmunology, Heinrich-Heine-University, Moorenstraße 5, 40225 Düsseldorf, Germany.

Background: Pro-inflammatory cytokines are known to have deleterious effects on Schwann cells (SCs). Interleukin 17 (IL-17) is a potent pro-inflammatory cytokine that exhibits relevant effects during inflammation in the peripheral nervous system (PNS), and IL-17-secreting cells have been reported within the endoneurium in proximity to the SCs.

Methods: Here, we analyzed the effects of IL-17 on myelination and the immunological properties of SCs. Dorsal root ganglia (DRG) co-cultures containing neurons and SCs from BL6 mice were used to define the impact of IL-17 on myelination and on SC differentiation; primary SCs were analyzed for RNA and protein expression to define the putative immunological alignment of the SCs.

Results: SCs were found to functionally express the IL-17 receptors A and B. In DRG cultures, stimulation with IL-17 resulted in reduced myelin synthesis, while pro-myelin gene expression was suppressed at the mRNA level. Neuronal outgrowth and SC viability, as well as structural myelin formation, remained unaffected. Co-cultures exhibited SC-relevant pro-inflammatory markers, such as matrix metalloproteinase 9 and SCs significantly increased the expression of the major histocompatibility complex (MHC) I and exhibited a slight, nonsignificant increase in expression of MHCII, and a transporter associated with antigen presentation (TAP) II molecules relevant for antigen processing and presentation.

Conclusions: IL-17 may act as a myelin-suppressive mediator in the peripheral nerve, directly propagating SC-mediated demyelination, paralleled by an inflammatory alignment of the SCs. Further analyses are warranted to elucidate the role of IL-17 during inflammation in the PNS in vivo, which could be useful in the development of target therapies.
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http://dx.doi.org/10.1186/1742-2094-11-63DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3977670PMC
March 2014

In astrocytes the accumulation of the immunity-related GTPases Irga6 and Irgb6 at the vacuole of Toxoplasma gondii is dependent on the parasite virulence.

ScientificWorldJournal 2013 12;2013:480231. Epub 2013 Nov 12.

Institute of Medical Microbiology and Hospital Hygiene, Heinrich-Heine-University, Universitaetsstrasse 1, 40225 Duesseldorf, Germany.

Toxoplasma gondii is an obligate intracellular protozoan parasite responsible for a common infection of the central nervous system. Interferon (IFN) γ is the key cytokine of host defence against T. gondii. However, T. gondii strains differ in virulence and T. gondii factors determining virulence are still poorly understood. In astrocytes IFN γ primarily induces immunity-related GTPases (IRGs), providing a cell-autonomous resistance system. Here, we demonstrate that astrocytes prestimulated with IFN γ inhibit the proliferation of various avirulent, but not virulent, T. gondii strains. The two analyzed immunity-related GTPases Irga6 and Irgb6 accumulate at the PV only of avirulent T. gondii strains, whereas in virulent strains this accumulation is only detectable at very low levels. Both IRG proteins could temporarily be found at the same PV, but did only partially colocalize. Coinfection of avirulent and virulent parasites confirmed that the accumulation of the two analyzed IRGs was a characteristic of the individual PV and not determined by the presence of other strains of T. gondii in the same host cell. Thus, in astrocytes the accumulation of Irga6 and Irgb6 significantly differs between avirulent and virulent T. gondii strains correlating with the toxoplasmacidal properties suggesting a role for this process in parasite virulence.
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http://dx.doi.org/10.1155/2013/480231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3845628PMC
July 2014

Natalizumab affects the T-cell receptor repertoire in patients with multiple sclerosis.

Neurology 2013 Oct 18;81(16):1400-8. Epub 2013 Sep 18.

From the Department of Neurology (C.W., A.K.M., M.S., T.D., L.N., G.M.z.H., H.-P.H., B.C.K.) and Institute for Virology (O.A.), Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany; and the Department of Clinical Neuroscience (C.W., A.F.-H.), Karolinska Institutet, Stockholm, Sweden.

Objective: To assess changes in the T-cell receptor (TCR) repertoire in peripheral venous blood and CSF of patients with multiple sclerosis (MS) treated with natalizumab and the potential implication for developing progressive multifocal leukoencephalopathy (PML) and PML-immune reconstitution inflammatory syndrome (IRIS).

Methods: The TCR repertoire in blood and CSF was assessed by complementarity determining region 3 spectratyping in 59 patients with MS treated with natalizumab for at least 18 months, 5 cases of natalizumab-associated PML, 17 age- and sex-matched patients with MS not treated with natalizumab, and 12 healthy controls.

Results: Patients with MS presented with peripheral TCR repertoire expansions in blood, which appeared less prominent during therapy with natalizumab. TCR repertoire restrictions observed in CSF were most pronounced in patients with MS treated with natalizumab. In patients who developed PML with longitudinal samples available, new identical TCR receptor length expansions in blood and CSF were observed following plasma exchange, and preceded the development of IRIS.

Conclusions: Profound TCR repertoire restrictions in CSF of patients treated with natalizumab reflect an altered immune surveillance of the CNS, which may contribute to an increased risk of developing PML. Natalizumab seems to prompt an impaired or delayed peripheral expansion of antigen-specific T cells, whereas increased reconstitution of peripheral T-cell expansion following plasma exchange may trigger PML-IRIS. Our data suggest that treatment with natalizumab results in broader changes in the T-cell immune repertoire beyond lymphocyte migration.
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http://dx.doi.org/10.1212/WNL.0b013e3182a84101DOI Listing
October 2013

Induction of pro-inflammatory cytokine production in thymocytes by the immune response modifiers Imiquimod and Gardiquimod™.

Int Immunopharmacol 2013 Oct 15;17(2):427-31. Epub 2013 Jul 15.

Department of Neurology, Heinrich Heine University, Düsseldorf, Germany.

An emerging role is postulated for IL-17-producing thymocytes, which in their majority consist of IL-17-producing CD4(+) cells. For these, a specific role in the immediate defense against infectious pathogens is suggested, independent from the development of an adaptive immune response in the immune periphery. Immune response modifiers, like the TLR7 ligands Imiquimod and Gardiquimod™ are effective pharmacological therapeutics applied topically against dermal tumors and virus infections and have been demonstrated to activate immune cells. In this study, we investigated the effect of Imiquimod and Gardiquimod™ on murine thymocyte cytokine production with a particular focus on IL-17. We find that both substances dose-dependently are able to trigger IFN-γ and IL-6 production, but no IL-17 production. Moreover, a strong co-stimulating effect is detected on α-CD3-induced IFN-γ, IL-6 and IL-17 production. We conclude that Imiquimod and Gardiquimod™ are not only modifiers of the adaptive immune response, but might also have additional therapeutic potential by modifying the immune activity in the thymus.
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http://dx.doi.org/10.1016/j.intimp.2013.06.023DOI Listing
October 2013

Promoting myelination in an in vitro mouse model of the peripheral nervous system: the effect of wine ingredients [corrected].

PLoS One 2013 7;8(6):e66079. Epub 2013 Jun 7.

Department of Neurology, Medical Faculty, Research Group for Clinical and Experimental Neuroimmunology, Heinrich-Heine-University, Düsseldorf, Germany.

Protective properties of moderate wine consumption against cancers, cardiovascular, metabolic and degenerative diseases have been reported in various clinical studies. Here, we analysed the effect of red wine (RW) and white wine (WW) on myelination using an in vitro embryonic co-culture mouse model. The total amount of myelin was found to be significantly increased after RW and WW treatment, while only RW significantly increased the number of internodes. Both types of wine increased rat Schwann cell- (rSC) expression of the NAD+-dependent deacetylase sirtuin-two-homolog 2 (Sirt2), a protein known to be involved in myelination. Detailed chemical analysis of RW revealed a broad spectrum of anthocyanins, piceids, and phenolics, including resveratrol (RSV). In our assay system RSV in low concentrations induced myelination. Furthermore RSV raised intracellular glutathione concentrations in rSCs and in co-cultures and therefore augmented antioxidant capacity. We conclude that wine promotes myelination in a rodent in vitro model by controlling intracellular metabolism and SC plasticity. During this process, RSV exhibits protective properties; however, the fostering effect on myelinaton during exposure to wine appears to be a complex interaction of various compounds.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0066079PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3676361PMC
January 2014

Disease amelioration with tocilizumab in a treatment-resistant patient with neuromyelitis optica: implication for cellular immune responses.

JAMA Neurol 2013 Mar;70(3):390-3

Department of Neurology, Heinrich-Heine-University, Moorenstrasse 5, Düsseldorf, Germany.

Background: Neuromyelitis optica (NMO) is an autoimmune disease of the central nervous system in which aberrant antibody responses to the astrocytic water channel aquaporin 4 have been described. Experimental evidence is emerging that NMO is partly driven by the proinflammatory cytokine interleukin 6 (IL-6), which propagates the survival of disease-specific B cell subclasses, and deviates CD4+ T helper cell differentiation toward IL-17-producing T helper 17 cells. Tocilizumab is a recombinant humanized monoclonal antibody against the IL-6 receptor approved for treatment of rheumatoid arthritis.

Objectives: To study clinical and paraclinical effects of tocilizumab in a patient with NMO.

Design: Case report.

Setting: Academic neurology department.

Patient: A patient with highly active aquaporin 4–seropositive NMO who failed numerous immunosuppressive interventions, including high-dose corticosteroids, mitoxantrone, plasma exchange (PE), rituximab (anti-CD20), and alemtuzumab (anti-CD52), before receiving tocilizumab.

Main Outcome Measures: Clinical disability, magnetic resonance imaging, cytokines and transcription factors levels in the cerebrospinal fluid, and peripheral blood mononuclear cells.

Results: A patient who continued to accumulate neurological disability and magnetic resonance imaging activity while receiving numerous immunoactive therapies stabilized, and eventually improved clinically and on magnetic resonance metrics after treatment initiation with tocilizumab. Treatment and clinical response correlated with a significant reduction of IL-6 levels in the CSF as well as a diminished expression of signal transducer and activator of transcription 3.

Conclusions: Tocilizumab might be effective in NMO, here in a patient not responding to leukocyte depletion. Our findings further support data that implicate IL-6 as a critical molecule in the immunopathogenesis of NMO, and a critical role for T cells in the pathogenesis of this disorder.
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http://dx.doi.org/10.1001/jamaneurol.2013.668DOI Listing
March 2013

A reliable in vitro model for studying peripheral nerve myelination in mouse.

J Neurosci Methods 2013 Mar 21;214(1):69-79. Epub 2013 Jan 21.

Department of Neurology, Medical Faculty, Research Group for Clinical and Experimental Neuroimmunology, Heinrich-Heine-University, Düsseldorf, Germany.

The rat dorsal root ganglia (DRG) model is a long-standing in vitro model for analysis of myelination in the peripheral nervous system. For performing systematic, high throughput analysis with transgenic animals, a simplified BL6 mouse protocol is indispensable. Here we present a stable and reliable protocol for myelinating co-cultures producing a high myelin ratio using cells from C57BL/6 mice. As an easy accessible and operable method, Sudan staining proved to be efficient in myelin detection for fixed cultures. Green fatty acid stain turned out to be highly reliable for analysis of the dynamic biological processes of myelination in vital cultures. Once myelinated we were able to induce demyelination by the addition of forskolin into the model system. In addition, we provide an optimised rat DRG protocol with significantly improved myelin ratio and a comparison of the protocols presented. Our results strengthen the value of ex vivo myelination models in neurobiology.
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http://dx.doi.org/10.1016/j.jneumeth.2013.01.009DOI Listing
March 2013

Recovery of the T-cell repertoire in CIDP by IV immunoglobulins.

Neurology 2013 Jan 26;80(3):296-303. Epub 2012 Dec 26.

Department of Neurology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.

Objective: To investigate changes in the T-cell repertoire in patients with chronic inflammatory demyelinating polyneuropathy (CIDP) without and with treatment of IV immunoglobulins (IVIg).

Methods: The T-cell receptor (TCR) repertoire of CD4+ and CD8+ T cells in the peripheral blood was analyzed using CDR3 spectratyping. Patients with CIDP were included without (n = 14) and with IVIg treatment (n = 11) cross-sectionally and longitudinally (n = 2).

Results: While the TCR length distribution of patients with CIDP was only moderately altered for most of the Vβ elements of CD4+ T cells, the CD8+ population displayed extensive oligoclonal expansions in all analyzed 24 Vβ elements. A public expansion of a distinct TCR length in one Vβ element within a majority of affected patients was not detectable. Treatment with IVIg reduced the oligoclonal expansions within both the CD4+ and CD8+ population.

Conclusions: Our data demonstrate that cytotoxic CD8+ T cells exhibit a much broader activation than CD4+ T cells, indicating a potentially crucial role of CD8+ T cells in the immunopathogenesis of CIDP. The profound oligoclonal response in T-cell activation suggests that multiple peptides may induce and propagate this autoimmune-driven disease. The observed reduction of highly activated T cells may contribute to the therapeutic effects of IVIg.
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http://dx.doi.org/10.1212/WNL.0b013e31827debadDOI Listing
January 2013

Murine guanylate binding protein 2 (mGBP2) controls Toxoplasma gondii replication.

Proc Natl Acad Sci U S A 2013 Jan 17;110(1):294-9. Epub 2012 Dec 17.

Institute of Medical Microbiology and Hospital Hygiene, Heinrich-Heine-University Duesseldorf, Duesseldorf 40225, Germany.

IFN-γ orchestrates the host response against intracellular pathogens. Members of the guanylate binding proteins (GBP) comprise the most abundant IFN-γ-induced transcriptional response. mGBPs are GTPases that are specifically up-regulated by IFN-γ, other proinflammatory cytokines, toll-like receptor agonists, as well as in response to Listeria monocytogenes and Toxoplasma gondii infection. mGBP2 localizes at the parasitophorous vacuole (PV) of T. gondii; however, the molecular function of mGBP2 and its domains in T. gondii infection is not known. Here, we show that mGBP2 is highly expressed in several cell types, including T and B cells after stimulation. We provide evidence that the C-terminal domain is sufficient and essential for recruitment to the T. gondii PV. Functionally, mGBP2 reduces T. gondii proliferation because mGBP2-deficient cells display defects in the replication control of T. gondii. Ultimately, mGBP2-deficient mice reveal a marked immune susceptibility to T. gondii. Taken together, mGBP2 is an essential immune effector molecule mediating antiparasitic resistance.
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http://dx.doi.org/10.1073/pnas.1205635110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3538222PMC
January 2013

Erythropoietin ameliorates rat experimental autoimmune neuritis by inducing transforming growth factor-β in macrophages.

PLoS One 2011 17;6(10):e26280. Epub 2011 Oct 17.

Department of Neurology, Heinrich-Heine-University, Duesseldorf, Germany.

Erythropoietin (EPO) is a pleiotropic cytokine originally identified for its role in erythropoiesis. In addition, in various preclinical models EPO exhibited protective activity against tissue injury. There is an urgent need for potent treatments of autoimmune driven disorders of the peripheral nervous system (PNS), such as the Guillain-Barré syndrome (GBS), a disabling autoimmune disease associated with relevant morbidity and mortality. To test the therapeutic potential of EPO in experimental autoimmune neuritis (EAN) - an animal model of human GBS--immunological and clinical effects were investigated in a preventive and a therapeutic paradigm. Treatment with EPO reduced clinical disease severity and if given therapeutically also shortened the recovery phase of EAN. Clinical findings were mirrored by decreased inflammation within the peripheral nerve, and myelin was well maintained in treated animals. In contrast, EPO increased the number of macrophages especially in later stages of the experimental disease phase. Furthermore, the anti-inflammatory cytokine transforming growth factor (TGF)-beta was upregulated in the treated cohorts. In vitro experiments revealed less proliferation of T cells in the presence of EPO and TGF-beta was moderately induced, while the secretion of other cytokines was almost not altered by EPO. Our data suggest that EPO revealed its beneficial properties by the induction of beneficial macrophages and the modulation of the immune system towards anti-inflammatory responses in the PNS. Further studies are warranted to elaborate the clinical usefulness of EPO for treating immune-mediated neuropathies in affected patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0026280PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3197078PMC
April 2012

Levetiracetam exhibits protective properties on rat Schwann cells in vitro.

J Peripher Nerv Syst 2011 Sep;16(3):250-60

Department of Neurology, Research Group for Clinical and Experimental Neuroimmunology, Heinrich-Heine-University, Düsseldorf, Germany.

Oxidative stress and inflammation represent pathways causing substantial damage to the peripheral nervous system. Levetiracetam (LEV) is a commonly used antiepileptic drug targeting high-voltage activated N-type calcium channels. Recent evidence suggests that LEV may also act as a histone deacetylase inhibitor, suggesting that this drug exhibits both anti-inflammatory and anti-oxidative effects, and as such may represent an interesting candidate for treating inflammatory diseases affecting the peripheral nerve. Therefore, we analysed the influence of LEV ex vivo on purified Schwann cells from neonatal P3 rats as well as on dorsal root ganglia prepared from E15 rat embryos. LEV diminished a lipopolysaccharide (LPS)-induced increase of the pro-inflammatory signature molecules tumour necrosis factor alpha, matrix metalloproteinase 9 (MMP-9), and caspase 6. Furthermore, LEV decreased LPS-induced cell death and protected cells against oxidative stress in a glutamate-based oxidative stress model. MMP-2 activity, usually elevated during myelination and repair, was also found to be up-regulated following LEV, while LEV exhibited no negative effects on myelination. Intracellular sodium or calcium concentrations were unaltered by LEV. Thus, LEV may be a promising, well-tolerated drug that - besides its antiepileptic potential - mediates anti-inflammatory, anti-oxidative, and anti-apoptotic properties that may potentially be useful in treating diseases of the peripheral nerve.
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http://dx.doi.org/10.1111/j.1529-8027.2011.00355.xDOI Listing
September 2011

Quinpramine ameliorates rat experimental autoimmune neuritis and redistributes MHC class II molecules.

PLoS One 2011 16;6(6):e21223. Epub 2011 Jun 16.

Department of Neurology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.

Activation of inflammatory cells is central to the pathogenesis of autoimmune demyelinating diseases of the peripheral nervous system. The novel chimeric compound quinpramine--generated from imipramine and quinacrine--redistributes cholesterol rich membrane domains to intracellular compartments. We studied the immunological and clinical effects of quinpramine in myelin homogenate induced Lewis rat experimental autoimmune neuritis (EAN), a model system for acute human inflammatory neuropathies, such as the Guillain-Barré syndrome. EAN animals develop paresis of all limbs due to autoimmune inflammation of peripheral nerves. Quinpramine treatment ameliorated clinical disease severity of EAN and infiltration of macrophages into peripheral nerves. It reduced expression of MHC class II molecules on antigen presenting cells and antigen specific T cell proliferation both in vitro and in vivo. Quinpramine exerted its anti-proliferatory effect on antigen presenting cells, but not on responder T cells. Our data suggest that quinpramine represents a candidate pharmaceutical for inflammatory neuropathies.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0021223PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3116892PMC
November 2011