Ralf A Linker

Publications of Ralf A Linker

• Endogenous ciliary neurotrophic factor modulates anxiety and depressive-like behavior.

  Authors: Isabella Peruga, Silvia Hartwig, Doron Merkler, Jan Thöne, Bernhard Hovemann, Georg Juckel, Ralf Gold, Ralf A Linker

  Behavioural brain research. 04/2012; 229(2):325-32.

  On a molecular level, depression is characterized by an altered monoaminergic neurotransmission as well as a modulation of cytokines and other mediators in the central nervous system. In particular,On a molecular level, depression is characterized by an altered monoaminergic neurotransmission as well as a modulation of cytokines and other mediators in the central nervous system. In particular, neurotrophic factors may influence affective behavior including depression and anxiety. Ciliary neurotrophic factor (CNTF) plays an important role in the regulation of neuronal development, neuroprotection and may also influence cognitive processes. Here we investigate the affective behavior in mice deficient for CNTF (CNTF -/- mice) at young age of 10-20 weeks. CNTF -/- mice displayed an increased anxiety-like behavior with a 30% reduction of the time spent in the bright compartment of the light/dark box as well as a significantly increased startle response. In the learned helplessness paradigm, CNTF -/- mice are more prone to depressive-like behavior. In the hippocampus of 20 weeks old, but not 10 weeks old, CNTF -/- mice, these changes correlated with a loss of parvalbumin immunoreactive GABAergic interneurons and a reduction of serotonin levels as well as 5-HT receptor 1A expression. Modulation of monoaminergic neurotransmitter levels via chronic application of the antidepressants amitriptyline and citalopram did not exert beneficial effects. These data imply that endogenous CNTF plays a pivotal role for the structural maintenance of hippocampal functions and thus has an important impact on the modulation of affective behavior in rodent models of anxiety and depression.

• The role of myelin oligodendrocyte glycoprotein in autoimmune demyelination: a target for multiple sclerosis therapy?

  Authors: De-Hyung Lee, Ralf A Linker

  Expert opinion on therapeutic targets. 04/2012;

  Introduction: Myelin oligodendrocyte glycoprotein (MOG) is a myelin antigen at the outer surface of the central nervous system (CNS) myelin sheath, which may trigger T-cell as well as B-cellIntroduction: Myelin oligodendrocyte glycoprotein (MOG) is a myelin antigen at the outer surface of the central nervous system (CNS) myelin sheath, which may trigger T-cell as well as B-cell responses. It therefore constitutes a pivotal target for autoimmune responses, which result in inflammation and also demyelination in the CNS. In particular, it is a major target for auto-antibodies in experimental autoimmune encephalomyelitis (EAE), which mimics many aspects of multiple sclerosis (MS). B-cell responses toward MOG and anti-MOG antibodies have also been demonstrated in patients with demyelinating diseases, such as MS and acute disseminating encephalomyelitis (ADEM). Co-transfer of such anti-MOG antibodies in experimental models results in a distinct lesion pattern with antibody and complement-mediated demyelination, which is also hallmark of some lesion subtypes in MS. Areas covered: A comprehensive literature search on MOG, B cells, MS, and ADEM was performed to outline the role of MOG in autoimmune demyelination in animal models and its relevance for human disease. Expert opinion: Although the definite role of MOG in the pathogenesis of MS still remains to be clarified, innovative therapeutic strategies targeting B cells may reduce pathogenic immune responses against myelin auto-antigens including anti-myelin auto-antibodies.

• Neuronal NF-κB ablation does not influence neuro-axonal degeneration in experimental autoimmune demyelination.

  Authors: De-Hyung Lee, Katharina Kubera, Bastian Rosenthal, Barbara Kaltschmidt, Christian Kaltschmidt, Ralf Gold, Ralf A Linker

  Journal of neuroimmunology. 04/2012;

  Neuro-axonal damage is a major hallmark of multiple sclerosis (MS). To date, not much is known on the underlying mechanisms of neuronal degeneration. In disease model myelin oligodendrocyteNeuro-axonal damage is a major hallmark of multiple sclerosis (MS). To date, not much is known on the underlying mechanisms of neuronal degeneration. In disease model myelin oligodendrocyte glycoprotein induced experimental autoimmune encephalomyelitis (MOG-EAE), there is a significant loss of alpha motorneurons in the cervical as well as thoracic and lumbar spinal cord. We further investigate the role of activated NF-κB for neuronal damage in a conditional ablation mouse model. A calcium calmodulin kinase II promoter-driven tetracycline transactivator is employed to regulate the expression of a human transdominant negative IκB-alpha mutant in the basal forebrain and selected neuronal subpopulations in the cerebellum and spinal cord including cerebellar Purkinje cells and spinal cord alpha motorneurons. In these mice with conditional neuronal NF-κB ablation, the clinical course of MOG-EAE, parameters of inflammation and axonal densities in the spinal cord white and grey matter as well as numbers of alpha motorneurons are not different to littermate controls. In conclusion, neuronal NF-κB ablation does not modulate neurodegeneration in autoimmune demyelination.

• Central nervous system rather than immune cell-derived BDNF mediates axonal protective effects early in autoimmune demyelination.

  Authors: De-Hyung Lee, Eva Geyer, Anne-Christine Flach, Klaus Jung, Ralf Gold, Alexander Flügel, Ralf A Linker, Fred Lühder

  Acta neuropathologica. 02/2012; 123(2):247-58.

  Brain-derived neurotrophic factor (BDNF) is involved in neuronal and glial development and survival. While neurons and astrocytes are its main cellular source in the central nervous system (CNS),Brain-derived neurotrophic factor (BDNF) is involved in neuronal and glial development and survival. While neurons and astrocytes are its main cellular source in the central nervous system (CNS), bioactive BDNF is also expressed in immune cells and in lesions of multiple sclerosis and its animal model experimental autoimmune encephalomyelitis (EAE). Previous data revealed that BDNF exerts neuroprotective effects in myelin oligodendrocyte glycoprotein-induced EAE. Using a conditional knock-out model with inducible deletion of BDNF, we here show that clinical symptoms and structural damage are increased when BDNF is absent during the initiation phase of clinical EAE. In contrast, deletion of BDNF later in the disease course of EAE did not result in significant changes, either in the disease course or in axonal integrity. Bone marrow chimeras revealed that the deletion of BDNF in the CNS alone, with no deletion of BDNF in the infiltrating immune cells, was sufficient for the observed effects. Finally, the therapeutic effect of glatiramer acetate, a well-characterized disease-modifying drug with the potential to modulate BDNF expression, was partially reversed in mice in which BDNF was deleted shortly before the onset of disease. In summary, our data argue for an early window of therapeutic opportunity where modulation of BDNF may exert neuroprotective effects in experimental autoimmune demyelination.

• Constitutive activity of NF-kappa B in myeloid cells drives pathogenicity of monocytes and macrophages during autoimmune neuroinflammation.

  Authors: Gisa Ellrichmann, Jan Thöne, De-Hyung Lee, Rudolph A Rupec, Ralf Gold, Ralf A Linker

  Journal of neuroinflammation. 01/2012; 9:15.

  ABSTRACT: The NF-κB/REL-family of transcription factors plays a central role in coordinating the expression of a wide variety of genes controlling immune responses including autoimmunity of theABSTRACT: The NF-κB/REL-family of transcription factors plays a central role in coordinating the expression of a wide variety of genes controlling immune responses including autoimmunity of the central nervous system (CNS). The inactive form of NF-κB consists of a heterodimer which is complexed with its inhibitor, IκB. Conditional knockout-mice for IκBα in myeloid cells (lysMCreIκBαfl/fl) have been generated and are characterized by a constitutive activation of NF-κB proteins allowing the study of this transcription factor in myelin-oligodendrocyte-glycoprotein induced experimental autoimmune encephalomyelitis (MOG-EAE), a well established experimental model for autoimmune demyelination of the CNS.In comparison to controls, lysMCreIκBαfl/fl mice developed a more severe clinical course of EAE. Upon histological analysis on day 15 p.i., there was an over two fold increased infiltration of T-cells and macrophages/microglia. In addition, lysMCreIκBαfl/fl mice displayed an increased expression of the NF-κB dependent factor inducible nitric oxide synthase in inflamed lesions. These changes in the CNS are associated with increased numbers of CD11b positive splenocytes and a higher expression of Ly6c on monocytes in the periphery. Well in accordance with these changes in the myeloid cell compartment, there was an increased production of the monocyte cytokines interleukin(IL)-12 p70, IL-6 and IL-1beta in splenocytes. In contrast, production of the T-cell associated cytokines interferon gamma (IFN-gamma) and IL-17 was not influenced.In summary, myeloid cell derived NF-κB plays a crucial role in autoimmune inflammation of the CNS and drives a pathogenic role of monocytes and macrophages independently from T-cells.

• Modulation of autoimmune demyelination by laquinimod via induction of brain-derived neurotrophic factor.

  Authors: Jan Thöne, Gisa Ellrichmann, Silvia Seubert, Isabella Peruga, De-Hyung Lee, Rebecca Conrad, Liat Hayardeny, Giancarlo Comi, Stefan Wiese, Ralf A Linker, Ralf Gold

  The American journal of pathology. 11/2011; 180(1):267-74.

  Laquinimod is a promising, orally available compound that has been successfully evaluated in placebo-controlled phase II/III studies of relapsing-remitting multiple sclerosis (MS). Studies areLaquinimod is a promising, orally available compound that has been successfully evaluated in placebo-controlled phase II/III studies of relapsing-remitting multiple sclerosis (MS). Studies are ongoing to further define laquinimod's modulatory mechanisms. Analyses in the animal model of experimental autoimmune encephalomyelitis (EAE) demonstrate that laquinimod reduces infiltration of leukocytes into the central nervous system, induces a Th1 to Th2/3 shift, and suppresses Th17 responses. To evaluate the potential neuroprotective capacity of laquinimod via modulation of brain-derived neurotrophic factor (BDNF), we analyzed the expression of BDNF in blood samples from 203 MS patients treated with laquinimod. Furthermore, we investigated the effect of laquinimod in EAE using a conditional BDNF knockout strain lacking BDNF expression in myeloid cells and T cells (LLF mice). Treatment with laquinimod resulted in a significant and persistent increase in BDNF serum levels of MS patients when compared to baseline and placebo-treated patients. LLF mice treated with laquinimod display a more severe EAE disease course in comparison to wild-type mice. Furthermore, laquinimod-treated wild-type monocytes secreted an anti-inflammatory cytokine pattern in comparison to untreated wild-type monocytes and treated LLF monocytes. Adoptive transfer of laquinimod stimulated monocytes into mice with EAE ameliorated the disease course. Consistent with immunomodulatory properties, laquinimod skewed monocytes toward a regulatory phenotype and also acted via modulation of BDNF, which may contribute to neuroprotection in MS patients.

• Polymorphisms in genes encoding leptin, ghrelin and their receptors in German multiple sclerosis patients.

  Authors: Linda K Rey, Stefan Wieczorek, Denis A Akkad, Ralf A Linker, Andrew Chan, Sabine Hoffjan

  Molecular and cellular probes. 06/2011; 25(5-6):255-9.

  Multiple sclerosis (MS) is a neuro-inflammatory, autoimmune disease influenced by environmental and polygenic components. There is growing evidence that the peptide hormone leptin, known to regulateMultiple sclerosis (MS) is a neuro-inflammatory, autoimmune disease influenced by environmental and polygenic components. There is growing evidence that the peptide hormone leptin, known to regulate energy homeostasis, as well as its antagonist ghrelin play an important role in inflammatory processes in autoimmune diseases, including MS. Recently, single nucleotide polymorphisms (SNPs) in the genes encoding leptin, ghrelin and their receptors were evaluated, amongst others, in Wegener's granulomatosis and Churg-Strauss syndrome. The Lys656Asn SNP in the LEPR gene showed a significant but contrasting association with these vasculitides. We therefore aimed at investigating these polymorphisms in a German MS case-control cohort. Twelve SNPs in the LEP, LEPR, GHRL and GHSR genes were genotyped in 776 MS patients and 878 control subjects. We found an association of a haplotype in the GHSR gene with MS that could not be replicated in a second cohort. Otherwise, no significant differences in allele or genotype frequencies were observed between patients and controls in this particular cohort. Thus, the present results do not support the hypothesis that genetic variation in the leptin/ghrelin system contributes substantially to the pathogenesis of MS. However, a modest effect of GHSR variation cannot be ruled out and needs to be further evaluated in future studies.

• Fumaric acid esters exert neuroprotective effects in neuroinflammation via activation of the Nrf2 antioxidant pathway.

  Authors: Ralf A Linker, De-Hyung Lee, Sarah Ryan, Anne M van Dam, Rebecca Conrad, Pradeep Bista, Weike Zeng, Xiaoping Hronowsky, Alex Buko, Sowmya Chollate, Gisa Ellrichmann, Wolfgang Brück, Kate Dawson, Susan Goelz, Stefan Wiese, Robert H Scannevin, Matvey Lukashev, Ralf Gold

  Brain : a journal of neurology. 03/2011; 134(Pt 3):678-92.

  Inflammation and oxidative stress are thought to promote tissue damage in multiple sclerosis. Thus, novel therapeutics enhancing cellular resistance to free radicals could prove useful for multipleInflammation and oxidative stress are thought to promote tissue damage in multiple sclerosis. Thus, novel therapeutics enhancing cellular resistance to free radicals could prove useful for multiple sclerosis treatment. BG00012 is an oral formulation of dimethylfumarate. In a phase II multiple sclerosis trial, BG00012 demonstrated beneficial effects on relapse rate and magnetic resonance imaging markers indicative of inflammation as well as axonal destruction. First we have studied effects of dimethylfumarate on the disease course, central nervous system, tissue integrity and the molecular mechanism of action in an animal model of chronic multiple sclerosis: myelin oligodendrocyte glycoprotein induced experimental autoimmune encephalomyelitis in C57BL/6 mice. In the chronic phase of experimental autoimmune encephalomyelitis, preventive or therapeutic application of dimethylfumarate ameliorated the disease course and improved preservation of myelin, axons and neurons. In vitro, the application of fumarates increased murine neuronal survival and protected human or rodent astrocytes against oxidative stress. Application of dimethylfumarate led to stabilization of the transcription factor nuclear factor (erythroid-derived 2)-related factor 2, activation of nuclear factor (erythroid-derived 2)-related factor 2-dependent transcriptional activity and accumulation of NADP(H) quinoline oxidoreductase-1 as a prototypical target gene. Furthermore, the immediate metabolite of dimethylfumarate, monomethylfumarate, leads to direct modification of the inhibitor of nuclear factor (erythroid-derived 2)-related factor 2, Kelch-like ECH-associated protein 1, at cysteine residue 151. In turn, increased levels of nuclear factor (erythroid-derived 2)-related factor 2 and reduced protein nitrosylation were detected in the central nervous sytem of dimethylfumarate-treated mice. Nuclear factor (erythroid-derived 2)-related factor 2 was also upregulated in the spinal cord of autopsy specimens from untreated patients with multiple sclerosis. In dimethylfumarate-treated mice suffering from experimental autoimmune encephalomyelitis, increased immunoreactivity for nuclear factor (erythroid-derived 2)-related factor 2 was detected by confocal microscopy in neurons of the motor cortex and the brainstem as well as in oligodendrocytes and astrocytes. In mice deficient for nuclear factor (erythroid-derived 2)-related factor 2 on the same genetic background, the dimethylfumarate mediated beneficial effects on clinical course, axon preservation and astrocyte activation were almost completely abolished thus proving the functional relevance of this transcription factor for the neuroprotective mechanism of action. We conclude that the ability of dimethylfumarate to activate nuclear factor (erythroid-derived 2)-related factor 2 may offer a novel cytoprotective modality that further augments the natural antioxidant responses in multiple sclerosis tissue and is not yet targeted by other multiple sclerosis therapies.

• Stability of cognitive functions under mitoxantrone therapy in patients with progressive multiple sclerosis: a pilot analysis.

  Authors: Alexandra Schröder, Peter Klotz, De-Hyung Lee, Ralf Gold, Ralf A Linker

  Clinical neurology and neurosurgery. 03/2011; 113(7):527-30.

  Mitoxantrone (MX) is a potent immunosuppressant that is licensed as escalation therapy for the treatment of active multiple sclerosis (MS). In an open-label, retrospective analysis, we investigatedMitoxantrone (MX) is a potent immunosuppressant that is licensed as escalation therapy for the treatment of active multiple sclerosis (MS). In an open-label, retrospective analysis, we investigated effects of MX therapy on parameters of cognitive functions in patients with progressive MS and significant disability. Twenty patients received a total of 42 mg/m(2) MX in 4 cycles. Six patients who fulfilled the criteria for MX therapy, yet did not receive this treatment, served as controls. Before initiation of therapy and after a mean observation period of 24 months, neurological examination and a neuropsychological test battery were performed. Neuropsychological analyses comprised tests for cognitive flexibility as a part of executive functioning, and verbal as well as non-verbal tests for memory and attention. Additionally, intelligence and symptoms of depression were investigated. While there was stability of EDSS over time, there were no differences in cognitive functions before and after MX treatment. In contrast, patients not receiving MX showed a worsening of verbal short term memory and cognitive flexibility over the same time period. In conclusion, this preliminary observational study points at stability of cognitive functions under MX therapy in patients with progressive multiple sclerosis.

• Glatiramer acetate treatment normalizes deregulated microRNA expression in relapsing remitting multiple sclerosis.

  Authors: Anne Waschbisch, Monika Atiya, Ralf A Linker, Sergej Potapov, Stefan Schwab, Tobias Derfuss

  PloS one. 01/2011; 6(9):e24604.

  The expression of selected microRNAs (miRNAs) known to be involved in the regulation of immune responses was analyzed in 74 patients with relapsing remitting multiple sclerosis (RRMS) and 32 healthyThe expression of selected microRNAs (miRNAs) known to be involved in the regulation of immune responses was analyzed in 74 patients with relapsing remitting multiple sclerosis (RRMS) and 32 healthy controls. Four miRNAs (miR-326, miR-155, miR-146a, miR-142-3p) were aberrantly expressed in peripheral blood mononuclear cells from RRMS patients compared to controls. Although expression of these selected miRNAs did not differ between treatment-naïve (n = 36) and interferon-beta treated RRMS patients (n = 18), expression of miR-146a and miR-142-3p was significantly lower in glatiramer acetate (GA) treated RRMS patients (n = 20) suggesting that GA, at least in part, restores the expression of deregulated miRNAs in MS.

• Vascular pathology in multiple sclerosis: mind boosting or myth busting?

  Authors: Anne Waschbisch, Arndt Manzel, Ralf A Linker, De-Hyung Lee

  Experimental & translational stroke medicine. 01/2011; 3(1):7.

  ABSTRACT: The investigation of central nervous system vascular changes in the pathophysiology of multiple sclerosis (MS) is a time-honored concept. Yet, recent reports on changes in venousABSTRACT: The investigation of central nervous system vascular changes in the pathophysiology of multiple sclerosis (MS) is a time-honored concept. Yet, recent reports on changes in venous cerebrospinal outflow, the advent of new magnetic resonance imaging techniques and the investigation of immunomodulatory properties of several vascular mediators on the molecular level have added new excitement to hypotheses centering around vascular pathology as determining factor in the pathophysiology of MS. Here we critically review the concept of chronic cerebrospinal venous insufficiency in MS patients and describe new imaging techniques including perfusion weighted imaging, susceptibility weighted imaging and diffusion weighted imaging which reveal central nervous system hypoperfusion, perivascular iron deposition and diffuse structural changes in the MS brain. On a molecular basis, vascular mediators represent interesting targets connecting vascular pathology with immunomodulation. In summary, the relation of venous changes to the pathophysiology of MS may not be as simple as initially described and it certainly seems awkward to think of the complex disease MS solely as result of a simple venous outflow obstruction. Yet, the investigation of new vascular concepts as one variable in the pathophysiology of the autoimmune attack seems very worthwhile and may add to a better understanding of this devastating disorder.

• Inflammation modulates anxiety in an animal model of multiple sclerosis.

  Authors: Isabella Peruga, Silvia Hartwig, Jan Thöne, Bernhard Hovemann, Ralf Gold, Georg Juckel, Ralf A Linker

  Behavioural brain research. 01/2011; 220(1):20-9.

  Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) characterized by inflammation, but also degenerative changes. Besides neurological deficits, the rate ofMultiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) characterized by inflammation, but also degenerative changes. Besides neurological deficits, the rate of affective disorders such as depression and anxiety is at least six fold increased. Many aspects of MS can be mimicked in the animal model of myelin oligodendrocyte glycoprotein experimental autoimmune encephalomyelitis (MOG-EAE). Here we investigate behavioral changes in C57BL/6 mice suffering from mild MOG-EAE. In the later phase of the disease, mice were subjected to behavioral tests including the light-dark-box (LD Box), the acoustic startle response (SR) with a pre-pulse inhibition protocol as well as the learned helplessness (LH) paradigm. Behavioral data were correlated with the motor performance in an open field and rotarod test (RR). In the RR and open field, there was no significant difference in the motor performance between controls and mice suffering from mild MOG-EAE. Yet EAE mice displayed an increased anxiety-like behavior with a 23% reduction of the time spent in the bright compartment of the LD Box as well as an increased SR. In the LH paradigm, mice suffering from MOG-EAE were twice as much prone to depressive-like behavior. These changes correlate with an increase of hippocampal tissue tumor necrosis factor alpha levels and neuronal loss in the hippocampus. Modulation of monoaminergic transmission by chronic application of the antidepressant amitriptyline resulted in a decreased startle reaction and increased hippocampal norepinephrine levels. These data imply that chronic inflammation in the CNS may impact on emotional responses in rodent models of anxiety.

• Efficacy of fumaric acid esters in the R6/2 and YAC128 models of Huntington's disease.

  Authors: Gisa Ellrichmann, Elisabeth Petrasch-Parwez, De-Hyung Lee, Christiane Reick, Larissa Arning, Carsten Saft, Ralf Gold, Ralf A Linker

  PloS one. 01/2011; 6(1):e16172.

  Huntington's disease (HD) is an autosomal dominantly inherited progressive neurodegenerative disease. The exact sequel of events finally resulting in neurodegeneration is only partially understoodHuntington's disease (HD) is an autosomal dominantly inherited progressive neurodegenerative disease. The exact sequel of events finally resulting in neurodegeneration is only partially understood and there is no established protective treatment so far. Some lines of evidence speak for the contribution of oxidative stress to neuronal tissue damage. The fumaric acid ester dimethylfumarate (DMF) is a new disease modifying therapy currently in phase III studies for relapsing-remitting multiple sclerosis. DMF potentially exerts neuroprotective effects via induction of the transcription factor "nuclear factor E2-related factor 2" (Nrf2) and detoxification pathways. Thus, we investigated here the therapeutic efficacy of DMF in R6/2 and YAC128 HD transgenic mice which mimic many aspects of HD and are characterized by an enhanced generation of free radicals in neurons. Treatment with DMF significantly prevented weight loss in R6/2 mice between postnatal days 80-90. At the same time, DMF treatment led to an attenuated motor impairment as measured by the clasping score. Average survival in the DMF group was 100.5 days vs. 94.0 days in the placebo group. In the histological analysis on day 80, DMF treatment resulted in a significant preservation of morphologically intact neurons in the striatum as well as in the motor cortex. DMF treatment resulted in an increased Nrf2 immunoreactivity in neuronal subpopulations, but not in astrocytes. These beneficial effects were corroborated in YAC128 mice which, after one year of DMF treatment, also displayed reduced dyskinesia as well as a preservation of neurons. In conclusion, DMF may exert beneficial effects in mouse models of HD. Given its excellent side effect profile, further studies with DMF as new therapeutic approach in HD and other neurodegenerative diseases are warranted.

• Successful management of natalizumab-associated progressive multifocal leukoencephalopathy and immune reconstitution syndrome in a patient with multiple sclerosis.

  Authors: Alexandra Schröder, De-Hyung Lee, Kerstin Hellwig, Carsten Lukas, Ralf A Linker, Ralf Gold

  Archives of neurology. 11/2010; 67(11):1391-4.

  To describe a case of successful clinical management of natalizumab-associated progressive multifocal leukoencephalopathy (PML) and immune reconstitution syndrome (IRIS) in a patient with multipleTo describe a case of successful clinical management of natalizumab-associated progressive multifocal leukoencephalopathy (PML) and immune reconstitution syndrome (IRIS) in a patient with multiple sclerosis. Case report. University hospital. A 41-year-old woman with relapsing-remitting multiple sclerosis developed PML after 29 natalizumab infusions. Immediate plasma exchange was combined for removal of natalizumab with application of mefloquine and mirtazapine to limit viral replication and oligodendrocyte infection. A subsequent IRIS was treated with glucocorticosteroids. After 3 months of treatment, cerebrospinal fluid tested negative for JC virus. There was a favorable outcome, and the Expanded Disability Status Scale score remained stable at 3.5 compared with before PML. In the setting of early diagnosis and consequent treatment, natalizumab-associated PML can be well managed in some cases. This situation differs from the course of PML in other conditions, eg, after the application of depleting monoclonal antibodies, in which irreversible cellular effects are associated with very high mortality.

• Functional role of brain-derived neurotrophic factor in neuroprotective autoimmunity: therapeutic implications in a model of multiple sclerosis.

  Authors: Ralf A Linker, De-Hyung Lee, Seray Demir, Stefan Wiese, Niels Kruse, Ines Siglienti, Ellen Gerhardt, Harald Neumann, Michael Sendtner, Fred Lühder, Ralf Gold

  Brain : a journal of neurology. 08/2010; 133(Pt 8):2248-63.

  Brain-derived neurotrophic factor plays a key role in neuronal and axonal survival. Brain-derived neurotrophic factor is expressed in the immune cells in lesions of experimental autoimmuneBrain-derived neurotrophic factor plays a key role in neuronal and axonal survival. Brain-derived neurotrophic factor is expressed in the immune cells in lesions of experimental autoimmune encephalomyelitis and multiple sclerosis, thus potentially mediating neuroprotective effects. We investigated the functional role of brain-derived neurotrophic factor in myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. Mice deficient for brain-derived neurotrophic factor in immune cells displayed an attenuated immune response in the acute phase of experimental autoimmune encephalomyelitis, but progressive disability with enhanced axonal loss in the chronic phase of the disease. In mice deficient for central nervous system-derived brain-derived neurotrophic factor via glial fibrillary acidic protein-crescentin-mediated deletion, a more severe course of experimental autoimmune encephalomyelitis and an overall increased axonal loss was observed. In a lentiviral approach, injection of brain-derived neurotrophic factor-overexpressing T cells led to a less severe course of experimental autoimmune encephalomyelitis and direct axonal protection. Our data imply a functional role of brain-derived neurotrophic factor in autoimmune demyelination by mediating axon protection.

• Role of the renin-angiotensin system in autoimmune inflammation of the central nervous system.

  Authors: Johannes Stegbauer, De-Hyung Lee, Silvia Seubert, Gisa Ellrichmann, Arndt Manzel, Heda Kvakan, Dominik N Muller, Stefanie Gaupp, Lars Christian Rump, Ralf Gold, Ralf A Linker

  Proceedings of the National Academy of Sciences of the United States of America. 09/2009;

  Angiotensin II is the principle effector molecule of the renin angiotensin system (RAS). It exerts its various actions on the cardiovascular and renal system, mainly via interaction with theAngiotensin II is the principle effector molecule of the renin angiotensin system (RAS). It exerts its various actions on the cardiovascular and renal system, mainly via interaction with the angiotensin II type-1 receptor (AT1R), which contributes to blood pressure regulation and development of hypertension but may also mediate effects on the immune system. Here we study the role of the RAS in myelin-oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis (MOG-EAE), a model mimicking many aspects of multiple sclerosis. Quantitative RT-PCR analyses showed an up-regulation of renin, angiotensin-converting enzyme, as well as AT1R in the inflamed spinal cord and the immune system, including antigen presenting cells (APC). Treatment with the renin inhibitor aliskiren, the angiotensin II converting-enzyme inhibitor enalapril, as well as preventive or therapeutic application of the AT1R antagonist losartan, resulted in a significantly ameliorated course of MOG-EAE. Blockade of AT1R did not directly impact on T-cell responses, but significantly reduced numbers of CD11b(+) or CD11c(+) APC in immune organs and in the inflamed spinal cord. Additionally, AT1R blockade impaired the expression of CCL2, CCL3, and CXCL10, and reduced CCL2-induced APC migration. Our findings suggest a pivotal role of the RAS in autoimmune inflammation of the central nervous system and identify RAS blockade as a potential new target for multiple sclerosis therapy.

• Plasmapheresis for neurological disorders.

  Authors: Alexandra Schröder, Ralf A Linker, Ralf Gold

  Expert review of neurotherapeutics. 09/2009; 9(9):1331-9.

  Apheresis is a general term that describes removal of abnormal blood constituents by extracorporeal blood purification methods. To date, therapeutic plasma exchange (PE) is the most common apheresisApheresis is a general term that describes removal of abnormal blood constituents by extracorporeal blood purification methods. To date, therapeutic plasma exchange (PE) is the most common apheresis procedure. Here, plasma is separated from corpuscular blood constituents and replaced with a substitution fluid. In contrast to immunoadsorption, PE is a nonspecific treatment modality with elimination of the entire plasma. The therapeutic effect is based on the removal of circulating, pathogenic immune factors including autoantibodies. Currently, PE is used for treatment of several immune-mediated neurological disorders. While first experiences relate to acute life-threatening conditions, such as treatment of Guillain-Barré syndrome or myasthenic crisis, therapeutic success was also shown in chronic diseases where immunosuppressive therapy is often required for long-term management. PE has been applied successfully in chronic inflammatory demyelinating polyneuropathy, paraproteinemic polyneuropathy, stiff person syndrome, and may also be tried in several diseases of paraneoplastic origin. In recent years, PE was also established as an escalation therapy for steroid-unresponsive relapses of multiple sclerosis, and thus has gained more widespread attention. Adding to its increasing application in clinical practice, the procedure is usually well tolerated. Possible adverse reactions mainly relate to vascular access, the use of replacement fluids and the need for anticoagulation.

• Proteome profiling in murine models of multiple sclerosis: identification of stage specific markers and culprits for tissue damage.

  Authors: Ralf A Linker, Peter Brechlin, Sarah Jesse, Petra Steinacker, D H Lee, Abdul R Asif, Olaf Jahn, Hayrettin Tumani, Ralf Gold, Markus Otto

  PloS one. 01/2009; 4(10):e7624.

  The identification of new biomarkers is of high interest for the prediction of the disease course and also for the identification of pathomechanisms in multiple sclerosis (MS). To specify markers ofThe identification of new biomarkers is of high interest for the prediction of the disease course and also for the identification of pathomechanisms in multiple sclerosis (MS). To specify markers of the chronic disease phase, we performed proteome profiling during the later phase of myelin oligodendrocyte glycoprotein induced experimental autoimmune encephalomyelitis (MOG-EAE, day 35 after immunization) as a model disease mimicking many aspects of secondary progressive MS. In comparison to healthy controls, high resolution 2 dimensional gel electrophoresis revealed a number of regulated proteins, among them glial fibrilary acidic protein (GFAP). Phase specific up-regulation of GFAP in chronic EAE was confirmed by western blotting and immunohistochemistry. Protein levels of GFAP were also increased in the cerebrospinal fluid of MS patients with specificity for the secondary progressive disease phase. In a next step, proteome profiling of an EAE model with enhanced degenerative mechanisms revealed regulation of alpha-internexin, syntaxin binding protein 1, annexin V and glutamate decarboxylase in the ciliary neurotrophic factor (CNTF) knockout mouse. The identification of these proteins implicate an increased apoptosis and enhanced axonal disintegration and correlate well the described pattern of tissue injury in CNTF -/- mice which involve oligodendrocyte (OL) apoptosis and axonal injury.In summary, our findings underscore the value of proteome analyses as screening method for stage specific biomarkers and for the identification of new culprits for tissue damage in chronic autoimmune demyelination.

• Models of autoimmune demyelination in the central nervous system: on the way to translational medicine.

  Authors: Ralf A Linker, De-Hyung Lee

  Experimental & translational stroke medicine. 01/2009; 1:5.

  Multiple sclerosis (MS) is the most common neurologic disease of young adults. In the recent years, our understanding on disease pathomechanisms has considerably improved and new therapies haveMultiple sclerosis (MS) is the most common neurologic disease of young adults. In the recent years, our understanding on disease pathomechanisms has considerably improved and new therapies have emerged. Yet a cure for this devastating disorder is still a far cry away and human resources on ex vivo specimens are limited. More than 70 years after its first description, experimental autoimmune encephalomyelitis (EAE) remains an important tool to understand concepts of T cell mediated autoimmunity as well as the roles of the innate and the humoral immune systems. Some EAE models also well reflect mechanisms of tissue damage including demyelination, axonal injury and also cortical changes. A limitation of the classical EAE model is a neglect of CD8 T cell mediated immune mechanisms. Moreover, well characterized models for primary progressive MS or demyelination patterns involving primary oligodendrocyte dystrophy are still not available. Yet many current therapeutic concepts including glatiramer acetate or natalizumab stem from their successful first application in EAE models. New strategies include the widespread use of conditional knockout mice to understand the cell-type specific function of single genes, innovative approaches to establish models on the roles of B cells and CD8 T cells as well as on the relation of inflammation to primary degeneration. In summary, EAE models continue to play an important role in neuroimmunology thereby also stimulating research in other fields of the neurosciences and immunobiology.

• Fumarates for the treatment of multiple sclerosis: potential mechanisms of action and clinical studies.

  Authors: Ralf A Linker, De-Hyung Lee, Martin Stangel, Ralf Gold

  Expert review of neurotherapeutics. 12/2008; 8(11):1683-90.

  All licensed disease-modifying drugs for the treatment of relapsing-remitting multiple sclerosis (MS) only display partial efficacy and hitherto require parenteral administration. Thus, there is aAll licensed disease-modifying drugs for the treatment of relapsing-remitting multiple sclerosis (MS) only display partial efficacy and hitherto require parenteral administration. Thus, there is a high demand for innovative and at the same time orally available MS therapeutics. Fumaric acids and their esters (FAE) may represent such a new class of compounds. FAE display immunomodulatory properties and may also exert neuroprotective effects, as shown in vitro as well as in experimental models of MS. A first Phase II study with the new, modified FAE BG00012/FAG-201 (BG-12) in relapsing-remitting MS revealed significant effects on MRI parameters such as gadolinium-enhancing lesions, T1 hypointense lesions and T2 lesion load after 24 weeks of treatment. The trial also underlined the safety and good tolerability of FAE that are already in clinical use for the systemic treatment of severe psoriasis. Presently, two Phase III studies are ongoing to investigate the clinical long-term efficacy of BG-12. In summary, FAE are potential candidates that may open a new therapeutic option for relapsing-remitting MS in the near future.