Heinz Wiendl

Publications of Heinz Wiendl

• Immune mechanisms of stroke.

  Authors: Tim Magnus, Heinz Wiendl, Christoph Kleinschnitz

  Current opinion in neurology. 06/2012; 25(3):334-40.

  Only recently has it been realized that immune mechanisms contribute to the pathophysiology of ischemic stroke, which for many years was regarded mainly as a vascular disease. These immunologicOnly recently has it been realized that immune mechanisms contribute to the pathophysiology of ischemic stroke, which for many years was regarded mainly as a vascular disease. These immunologic processes are present during all stages of stroke and involve both the innate and adaptive immune systems. This review highlights the latest findings related to the 'immunology of stroke'. During the early phase of an ischemic insult, 'danger signals' such as ATP are released from dying tissue to subsequently attract inflammatory cells. Unexpectedly, T cells have been identified as prominent mediators of stroke-induced tissue damage. Whereas during the acute stage of infarction T cells act independently from antigen-specific stimuli but rather interact with thrombotic pathways, antigen-dependent T-cell activation might be relevant at later stages. Moreover, certain T-cell subsets like γδ T cells or regulatory T cells are able to influence stroke outcome either in a detrimental or beneficial way. Finally, proof-of-principle studies using FTY720 or VLA-4 blockers have demonstrated that the concept of 'immunomodulation in stroke' is feasible. The insight that ischemic stroke at least in part is an immune-mediated disease may open new avenues for the treatment of this devastating neurologic condition.

• Neuron-directed autoimmunity in the central nervous system: entities, mechanisms, diagnostic clues, and therapeutic options.

  Authors: Nico Melzer, Sven G Meuth, Heinz Wiendl

  Current opinion in neurology. 04/2012;

  PURPOSE OF REVIEW: The human central nervous system (CNS) can mistakenly be the target of adaptive cellular and humoral immune responses causing both functional and structural impairment. We herePURPOSE OF REVIEW: The human central nervous system (CNS) can mistakenly be the target of adaptive cellular and humoral immune responses causing both functional and structural impairment. We here provide an overview of neuron-directed autoimmunity as a novel class of inflammatory CNS disorders, their differential diagnoses, clinical hallmarks, imaging features, characteristic laboratory, electrophysiological, cerebrospinal fluid and neuropathological findings, cellular and molecular disease mechanisms, as well as therapeutic options. RECENT FINDINGS: A growing number of immune-mediated CNS disorders of both autoimmune and paraneoplastic origin have emerged, in which neurons seem to be the target of the immune response. Antibodies binding to a variety of synaptic and extrasynaptic antigens located on the neuronal surface membrane can define distinct entities. Clinically, these disorders are characterized by subacute CNS-related [and sometimes peripheral nervous system (PNS)-related] symptoms involving a variety of cortical and subcortical gray matter areas, which often reflect the expression pattern and function of the respective target antigen. Antibodies seem to be pathogenic and cause (reversible) disturbance of synaptic transmission and neuronal excitability by selective functional inhibition or crosslinking and internalization of their antigen in the absence of overt cytotoxicity, at least at early disease stages. Whether at later disease stages antibody-mediated cytotoxicity, cytotoxic CD8 T cells, or other detrimental immune mechanisms contribute to neuronal impairment is unclear at present. SUMMARY: Adaptive humoral autoimmunity directed to neuronal cell-surface antigens offers first and unique insights and provokes further investigation into the systemic, cellular, and molecular consequences of immune-mediated disruption of distinct neuronal signaling pathways within the living human CNS.

• Fulfilling the dream: tolerogenic dendritic cells to treat multiple sclerosis.

  Authors: Catharina C Gross, Helmut Jonuleit, Heinz Wiendl

  European journal of immunology. 03/2012; 42(3):569-72.

  Autoimmune diseases including multiple sclerosis (MS) are the result of an imbalanced immune tolerance network. Dendritic cells (DCs) are key players in both initiating immunity (immunogenic DCs) andAutoimmune diseases including multiple sclerosis (MS) are the result of an imbalanced immune tolerance network. Dendritic cells (DCs) are key players in both initiating immunity (immunogenic DCs) and regulating immune responses (tolerogenic DCs = tolDCs) and are potential targets for the treatment of MS. While the immunogenic potential of DCs in fighting infection and cancer has been well established, approaches that exploit their tolerogenic features to promote transplantation tolerance and autoimmunity have emerged only more recently. TolDCs usually maintain antigen-specific T-cell tolerance either directly by inducing anergy, apoptosis, or phenotype skewing or indirectly by induction of regulatory T (Treg) cells. The use of ex vivo-generated tolDCs is an experimental approach to achieve tolerance towards myelin-antigen-specific CD4(+) T cells. In the article by Raϊch-Regué and colleagues (Eur. J. Immunol. 2011. 42:772-783) in this issue of the European Journal of Immunology, advances in human tolDC preparation and promise for autologous therapy are described. These findings raise hopes of achieving the "ideal" of a highly-specific, causally-oriented immune intervention for central nervous system (CNS) autoimmunity in MS. However, recent experience with antigen-specific immune interventions in MS and some general caveats associated with cell-based-therapies highlight the challenges for clinical translation of the "immunologist's dream" of treating autoimmunity as discussed in this Commentary.

• CD4+ CD25+ FoxP3+ regulatory T cells suppress cytotoxicity of CD8+ effector T cells: implications for their capacity to limit inflammatory central nervous system damage at the parenchymal level.

  Authors: Kerstin Göbel, Stefan Bittner, Nico Melzer, Susann Pankratz, Angela Dreykluft, Michael K Schuhmann, Sven G Meuth, Heinz Wiendl

  Journal of neuroinflammation. 02/2012; 9:41.

  ABSTRACT: CD4+ CD25+ forkhead box P3 (FoxP3)+ regulatory T cells (T reg cells) are known to suppress adaptive immune responses, key control tolerance and autoimmunity. We challenged the role of CD4+ABSTRACT: CD4+ CD25+ forkhead box P3 (FoxP3)+ regulatory T cells (T reg cells) are known to suppress adaptive immune responses, key control tolerance and autoimmunity. We challenged the role of CD4+ T reg cells in suppressing established CD8+ T effector cell responses by using the OT-I/II system in vitro and an OT-I-mediated, oligodendrocyte directed ex vivo model (ODC-OVA model). CD4+ T reg cells dampened cytotoxicity of an ongoing CD8+ T effector cell attack in vitro and within intact central nervous system tissue ex vivo. However, their suppressive effect was limited by the strength of the antigen signal delivered to the CD8+ T effector cells and the ratio of regulatory to effector T cells. CD8+ T effector cell suppression required T cell receptor-mediated activation together with costimulation of CD4+ T reg cells, but following activation, suppression did not require restimulation and was antigen non-specific. Our results suggest that CD4+ T reg cells are capable of suppressing CD8+ T effector cell responses at the parenchymal site, that is, limiting parenchymal damage in autoimmune central nervous system inflammation.

• CD4+ T Cells Predominate in Cerebrospinal Fluid and Leptomeningeal and Parenchymal Infiltrates in Cerebral Amyloid β-Related Angiitis.

  Authors: Nico Melzer, Anja Harder, Catharina C Gross, Johannes Wölfer, Walter Stummer, Thomas Niederstadt, Sven G Meuth, Martin Marziniak, Oliver Martin Grauer, Heinz Wiendl

  Archives of neurology. 02/2012;

  BACKGROUND: In amyloid β (Aβ)-related angiitis (ABRA) of the central nervous system (CNS), cerebral amyloid angiopathy occurs in association with primary vasculitis of small- and medium-sizedBACKGROUND: In amyloid β (Aβ)-related angiitis (ABRA) of the central nervous system (CNS), cerebral amyloid angiopathy occurs in association with primary vasculitis of small- and medium-sized leptomeningeal and cortical arteries. It has been suggested that ABRA is triggered by vascular deposition of Aβ followed by an Aβ-directed (auto)immune response. OBJECTIVE: To provide a detailed description of the cellular composition of the inflammatory infiltrates in the cerebrospinal fluid (CSF) and CNS and their response to immunotherapy in a typical case of ABRA. DESIGN: Report of a single case. SETTING: Neurologic referral center. Patient 67-year-old white woman. MAIN OUTCOME MEASURES: Neurologic examination, magnetic resonance imaging, lumbar puncture, flow cytometry, leptomeningeal biopsy, and histopathologic analysis. RESULTS: In a typical case of ABRA, we demonstrate for the first time the presence of a vast majority of partially activated CD4(+) T cells in CSF and leptomeningeal and parenchymal (peri)vascular infiltrates, which were frequently found in close proximity to major histocompatibility complex (MHC) class II-expressing microglia, epithelioid macrophages, and multinucleated giant cells containing intracellular deposits of Aβ. CONCLUSION: Our findings support the notion of adaptive Aß-directed autoimmunity as the underlying pathogenic mechanism in ABRA.

• Cytosolic RIG-I-like helicases act as negative regulators of sterile inflammation in the CNS.

  Authors: Angela Dann, Hendrik Poeck, Andrew L Croxford, Stefanie Gaupp, Katrin Kierdorf, Markus Knust, Dietmar Pfeifer, Cornelius Maihoefer, Stefan Endres, Ulrich Kalinke, Sven G Meuth, Heinz Wiendl, Klaus-Peter Knobeloch, Shizuo Akira, Ari Waisman, Gunther Hartmann, Marco Prinz

  Nature neuroscience. 12/2011; 15(1):98-106.

  The action of cytosolic RIG-I-like helicases (RLHs) in the CNS during autoimmunity is largely unknown. Using a mouse model of multiple sclerosis, we found that mice lacking the RLH adaptor IPS-1The action of cytosolic RIG-I-like helicases (RLHs) in the CNS during autoimmunity is largely unknown. Using a mouse model of multiple sclerosis, we found that mice lacking the RLH adaptor IPS-1 developed exacerbated disease that was accompanied by markedly higher inflammation, increased axonal damage and elevated demyelination with increased encephalitogenic immune responses. Furthermore, activation of RLH ligands such as 5'-triphosphate RNA oligonucleotides decreased CNS inflammation and improved clinical signs of disease. RLH stimulation repressed the maintenance and expansion of committed T(H)1 and T(H)17 cells, whereas T-cell differentiation was not altered. Notably, T(H)1 and T(H)17 suppression required type I interferon receptor engagement on dendritic cells, but not on macrophages or microglia. These results identify RLHs as negative regulators of T(H)1 and T(H)17 responses in the CNS, demonstrate a protective role of the RLH pathway for brain inflammation, and establish oligonucleotide ligands of RLHs as potential therapeutics for the treatment of multiple sclerosis.

• Pathology of immune reconstitution inflammatory syndrome in multiple sclerosis with natalizumab-associated progressive multifocal leukoencephalopathy.

  Authors: Imke Metz, Ernst-Wilhelm Radue, Agustin Oterino, Tania Kümpfel, Heinz Wiendl, Sven Schippling, Jens Kuhle, Mohammad Ali Sahraian, Francoise Gray, Veronika Jakl, Darius Häusler, Wolfgang Brück

  Acta neuropathologica. 11/2011; 123(2):235-45.

  Natalizumab is an approved medication for highly active multiple sclerosis (MS). Progressive multifocal leukoencephalopathy (PML) may occur as a severe side effect of this drug. Here, we describeNatalizumab is an approved medication for highly active multiple sclerosis (MS). Progressive multifocal leukoencephalopathy (PML) may occur as a severe side effect of this drug. Here, we describe pathological and radiological characteristics of immune reconstitution inflammatory syndrome (IRIS), which occurs in natalizumab-associated PML after the cessation of therapy, and we differentiate it from ongoing PML. Brain biopsy tissue and MRI scans from five MS patients with natalizumab-associated PML were analyzed and their histology compared with non-MS PML. Histology showed an extensive CD8-dominated T cell infiltrate and numerous macrophages within lesions, and in nondemyelinated white and grey matter, in four out of five cases. Few or no virally infected cells were found. This was indicative of IRIS as known from HIV patients with PML. Outstandingly high numbers of plasma cells were present as compared to non-MS PML and typical MS lesions. MRI was compatible with IRIS, revealing enlarging lesions with a band-like or speckled contrast enhancement either at the lesion edge or within lesions. Only the fifth patient showed typical PML pathology, with low inflammation and high numbers of virally infected cells. This patient showed a similar interval between drug withdrawal and biopsy (3.5 months) to the rest of the cohort (range 2.5-4 months). MRI could not differentiate between PML-associated IRIS and ongoing PML. We describe in detail the histopathology of IRIS in natalizumab-associated PML. PML-IRIS, ongoing PML infection, and MS exacerbation may be impossible to discern clinically alone. MRI may provide some clues for distinguishing different pathologies that can be differentiated histologically. In our individual cases, biopsy helped to clarify diagnoses in natalizumab-associated PML.

• Immunological and clinical consequences of treating a patient with natalizumab.

  Authors: Nicholas Schwab, Karin G Höhn, Tilman Schneider-Hohendorf, Imke Metz, Max-Philipp Stenner, Samantha Jilek, Renaud A Du Pasquier, Ralf Gold, Sven G Meuth, Richard M Ransohoff, Wolfgang Brück, Heinz Wiendl

  Multiple sclerosis (Houndmills, Basingstoke, England). 09/2011; 18(3):335-44.

  Background: Long-term therapy with natalizumab increases the risk of progressive multifocal leukoencephalopathy (PML). Objectives: We present a patient study through therapy, the diagnosis of PMLBackground: Long-term therapy with natalizumab increases the risk of progressive multifocal leukoencephalopathy (PML). Objectives: We present a patient study through therapy, the diagnosis of PML (after 29 infusions), plasma exchange (PE) and development of immune reconstitution inflammatory syndrome (IRIS). Methods: Routine diagnostics, magnetic resonance imaging (MRI), immunological status (flow cytometry, T-cell migration assays and T-cell repertoire analysis), and brain biopsy with immunohistological analysis. Results: CD49d decreased after 12 months of treatment. At PML diagnosis, CD49d expression and migratory capacity of T cells was low and peripheral T-cell receptor (TCR) complexity showed severe perturbations. The distribution of peripheral monocytes changed from CCR5+ to CCR7+. After PE some changes reverted: CD49d increased and overshot earliest levels, migratory capacities of T cells recovered and peripheral TCR complexity increased. With no clinical, routine laboratory or cerebrospinal fluid (CSF) changes, MRI 2 months after PE demonstrated progressive lesion development. Brain histopathology confirmed the presence of infiltrates indicative of IRIS without clinical signs, immunologically accompanied by CCR7/CCR5 recovery of peripheral monocytes. Conclusion: Natalizumab-associated immunological changes accompanying PML were reversible after PE; IRIS can occur very late, remain asymptomatic and be elusive to CSF analysis. Our study may provide insights into the changes under treatment with natalizumab associated with JC virus control.

• Volume regulation of murine T lymphocytes relies on voltage-dependent and two-pore domain potassium channels.

  Authors: Nicole Bobak, Stefan Bittner, Joseph Andronic, Susanne Hartmann, Friederike Mühlpfordt, Tilman Schneider-Hohendorf, Karen Wolf, Carsten Schmelter, Kerstin Göbel, Patrick Meuth, Heiko Zimmermann, Frank Döring, Erhard Wischmeyer, Thomas Budde, Heinz Wiendl, Sven G Meuth, Vladimir L Sukhorukov

  Biochimica et biophysica acta. 08/2011; 1808(8):2036-44.

  A variety of ion channels are supposed to orchestrate the homoeostatic volume regulation in T lymphocytes. However, the relative contribution of different potassium channels to the osmotic volumeA variety of ion channels are supposed to orchestrate the homoeostatic volume regulation in T lymphocytes. However, the relative contribution of different potassium channels to the osmotic volume regulation and in particular to the regulatory volume decrease (RVD) in T cells is far from clear. This study explores a putative role of the newly identified K(2P) channels (TASK1, TASK2, TASK3 and TRESK) along with the voltage-gated potassium channel K(V)1.3 and the calcium-activated potassium channel K(Ca)3.1 in the RVD of murine T lymphocytes, using genetic and pharmacological approaches. K(2P) channel knockouts exerted profound effects on the osmotic properties of murine T lymphocytes, as revealed by reduced water and RVD-related solute permeabilities. Moreover, both genetic and pharmacological data proved a key role of K(V)1.3 and TASK2 channels in the RVD of murine T cells exposed to hypotonic saline. Our experiments demonstrate a leading role of potassium channels in the osmoregulation of T lymphocytes under different conditions. In summary, the present study sheds new light on the complex and partially redundant network of potassium channels involved in the basic physiological process of the cellular volume homeostasis and extends the repertoire of potassium channels by the family of K(2P) channels.

• Transforming multiple sclerosis trials into practical reality.

  Authors: Bernd C Kieseier, Heinz Wiendl

  Lancet neurology. 06/2011; 10(6):493-4.

• Risks and benefits of multiple sclerosis therapies: need for continual assessment?

  Authors: Bernd C Kieseier, Heinz Wiendl, Hans-Peter Hartung, Verena-Isabell Leussink, Olaf Stüve

  Current opinion in neurology. 06/2011; 24(3):238-43.

  The aim is to describe and discuss the ongoing debate on how to balance an increase in clinical efficacy against a heightened risk of developing serious side-effects, as has surfaced recently withThe aim is to describe and discuss the ongoing debate on how to balance an increase in clinical efficacy against a heightened risk of developing serious side-effects, as has surfaced recently with some novel therapies for relapsing forms of multiple sclerosis. New therapies are emerging that differ with regard to their mechanism of action, their mode of administration, their side-effect profile and the clinical benefits that they offer to patients in comparison with established therapeutic modalities in multiple sclerosis. Treating physicians will need to make choices on the best treatments for their patients on the basis of limited experience. This process requires optimal assessment of risks and benefits. Careful assessment of the risk-benefit profile of the various options may allow treatment choices and perhaps ensure that patients obtain the most benefit from treatment without being exposed to unnecessary risk.

• Safety and clinical outcomes of rituximab therapy in patients with different autoimmune diseases: experience from a national registry (GRAID).

  Authors: Hans-Peter Tony, Gerd Burmester, Hendrik Schulze-Koops, Mathias Grunke, Joerg Henes, Ina Kötter, Judith Haas, Leonore Unger, Svjetlana Lovric, Marion Haubitz [......] Claudia Metzler, Uwe Zettl, Jens Westphal, Stefan Heitmann, Anna L Herzog, Heinz Wiendl, Waltraud Jakob, Elvira Schmidt, Klaus Freivogel, Thomas Dörner

  Arthritis research & therapy. 05/2011; 13(3):R75.

  Evidence from a number of open-label, uncontrolled studies has suggested that rituximab may benefit patients with autoimmune diseases who are refractory to standard-of-care. The objective of thisEvidence from a number of open-label, uncontrolled studies has suggested that rituximab may benefit patients with autoimmune diseases who are refractory to standard-of-care. The objective of this study was to evaluate the safety and clinical outcomes of rituximab in several standard-of-care-refractory autoimmune diseases (within rheumatology, nephrology, dermatology and neurology) other than rheumatoid arthritis or non-Hodgkin's lymphoma in a real-life clinical setting. Patients who received rituximab having shown an inadequate response to standard-of-care had their safety and clinical outcomes data retrospectively analysed as part of the German Registry of Autoimmune Diseases. The main outcome measures were safety and clinical response, as judged at the discretion of the investigators. A total of 370 patients (299 patient-years) with various autoimmune diseases (23.0% with systemic lupus erythematosus, 15.7% antineutrophil cytoplasmic antibody-associated granulomatous vasculitides, 15.1% multiple sclerosis and 10.0% pemphigus) from 42 centres received a mean dose of 2,440 mg of rituximab over a median (range) of 194 (180 to 1,407) days. The overall rate of serious infections was 5.3 per 100 patient-years during rituximab therapy. Opportunistic infections were infrequent across the whole study population, and mostly occurred in patients with systemic lupus erythematosus. There were 11 deaths (3.0% of patients) after rituximab treatment (mean 11.6 months after first infusion, range 0.8 to 31.3 months), with most of the deaths caused by infections. Overall (n = 293), 13.3% of patients showed no response, 45.1% showed a partial response and 41.6% showed a complete response. Responses were also reflected by reduced use of glucocorticoids and various immunosuppressives during rituximab therapy and follow-up compared with before rituximab. Rituximab generally had a positive effect on patient well-being (physician's visual analogue scale; mean improvement from baseline of 12.1 mm). Data from this registry indicate that rituximab is a commonly employed, well-tolerated therapy with potential beneficial effects in standard of care-refractory autoimmune diseases, and support the results from other open-label, uncontrolled studies.

• Symptomatic therapy in multiple sclerosis: a review for a multimodal approach in clinical practice.

  Authors: João Carlos Correia de Sa, Laura Airas, Emmanuel Bartholome, Nikolaos Grigoriadis, Heinrich Mattle, Celia Oreja-Guevara, Jonathan O'Riordan, Finn Sellebjerg, Bruno Stankoff, Karl Vass, Agata Walczak, Heinz Wiendl, Bernd C Kieseier

  Therapeutic advances in neurological disorders. 05/2011; 4(3):139-68.

  As more investigations into factors affecting the quality of life of patients with multiple sclerosis (MS) are undertaken, it is becoming increasingly apparent that certain comorbidities andAs more investigations into factors affecting the quality of life of patients with multiple sclerosis (MS) are undertaken, it is becoming increasingly apparent that certain comorbidities and associated symptoms commonly found in these patients differ in incidence, pathophysiology and other factors compared with the general population. Many of these MS-related symptoms are frequently ignored in assessments of disease status and are often not considered to be associated with the disease. Research into how such comorbidities and symptoms can be diagnosed and treated within the MS population is lacking. This information gap adds further complexity to disease management and represents an unmet need in MS, particularly as early recognition and treatment of these conditions can improve patient outcomes. In this manuscript, we sought to review the literature on the comorbidities and symptoms of MS and to summarize the evidence for treatments that have been or may be used to alleviate them.

• Ion channels in autoimmune neurodegeneration.

  Authors: Petra Ehling, Stefan Bittner, Thomas Budde, Heinz Wiendl, Sven G Meuth

  FEBS letters. 04/2011; 585(23):3836-42.

  Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system characterized by widespread inflammation, focal demyelination and a variable degree of axonal and neuronalMultiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system characterized by widespread inflammation, focal demyelination and a variable degree of axonal and neuronal loss. Ionic conductances regulate T cell activation as well as neuronal function and thus have been found to play a crucial role in MS pathogenesis. Since present therapeutical approaches are only partially effective so far, ion channel modulation as a future strategy was brought into focus. Here, we review the status quo concerning recent findings from ion channel research in MS and its animal model, experimental autoimmune encephalomyelitis.

• Natalizumab restores evoked potential abnormalities in patients with relapsing-remitting multiple sclerosis.

  Authors: Sven G Meuth, Stefan Bittner, Carola Seiler, Kerstin Göbel, Heinz Wiendl

  Multiple sclerosis (Houndmills, Basingstoke, England). 02/2011; 17(2):198-203.

  The objective of this study was to examine the effects of natalizumab on functional parameters assessed by evoked potentials (visual [VEP], somatosensory [SEP] and motor evoked potentials [MEP]) in aThe objective of this study was to examine the effects of natalizumab on functional parameters assessed by evoked potentials (visual [VEP], somatosensory [SEP] and motor evoked potentials [MEP]) in a cohort study in relapsing-remitting multiple sclerosis patients. EP data of 44 patients examined 12 months prior to natalizumab treatment, at the timepoint of treatment initiation and 1 year later were compared. Sum scores (VEP, MEP, SEP) were evaluated and correlated with the Expanded Disability Status Scale. Improvement of the VEP sum score was found in 33% of natalizumab-treated patients but only in 9% of the same patients prior to treatment (p = 0.041). A comparable situation was found for SEP (improvement: 32% versus 5%; worsening: 11% versus 37%; p = 0.027). For MEP no significant differences were seen (improvement: 10% versus 18%; worsening: 5% versus 29%; p = 0.60). EP recordings (VEP = SEP > MEP) have the capacity to demonstrate treatment effects of natalizumab on a functional level. Natalizumab therapy increases the percentage of patients showing stable or even ameliorated electrophysiological parameters in the investigated functional systems.

• Expression of K2P5.1 potassium channels on CD4+ T lymphocytes correlates with disease activity in rheumatoid arthritis patients.

  Authors: Stefan Bittner, Nicole Bobak, Martin Feuchtenberger, Alexander M Herrmann, Kerstin Göbel, Raimund W Kinne, Anker J Hansen, Thomas Budde, Christoph Kleinschnitz, Oliver Frey, Hans-Peter Tony, Heinz Wiendl, Sven G Meuth

  Arthritis research & therapy. 02/2011; 13(1):R21.

  CD4+ T cells express K(2P)5.1 (TWIK-related acid-sensitive potassium channel 2 (TASK2); KCNK5), a member of the two-pore domain potassium channel family, which has been shown to influence T cellCD4+ T cells express K(2P)5.1 (TWIK-related acid-sensitive potassium channel 2 (TASK2); KCNK5), a member of the two-pore domain potassium channel family, which has been shown to influence T cell effector functions. Recently, it was shown that K(2P)5.1 is upregulated upon (autoimmune) T cell stimulation. The aim of this study was to correlate expression levels of K(2P)5.1 on T cells from patients with rheumatoid arthritis (RA) to disease activity in these patients. Expression levels of K(2P)5.1 were measured by RT-PCR in the peripheral blood of 58 patients with RA and correlated with disease activity parameters (C-reactive protein levels, erythrocyte sedimentation rates, disease activity score (DAS28) scores). Twenty patients undergoing therapy change were followed-up for six months. Additionally, synovial fluid and synovial biopsies were investigated for T lymphocytes expressing K(2P)5.1. K(2P)5.1 expression levels in CD4+ T cells show a strong correlation to DAS28 scores in RA patients. Similar correlations were found for serological inflammatory parameters (erythrocyte sedimentation rate, C-reactive protein). In addition, K(2P)5.1 expression levels of synovial fluid-derived T cells are higher compared to peripheral blood T cells. Prospective data in individual patients show a parallel behaviour of K(2P)5.1 expression to disease activity parameters during a longitudinal follow-up for six months. Disease activity in RA patients correlates strongly with K(2P)5.1 expression levels in CD4+ T lymphocytes in the peripheral blood in cross-sectional as well as in longitudinal observations. Further studies are needed to investigate the exact pathophysiological mechanisms and to evaluate the possible use of K(2P)5.1 as a potential biomarker for disease activity and differential diagnosis.

• Blockade of the kinin receptor B1 protects from autoimmune CNS disease by reducing leukocyte trafficking.

  Authors: Kerstin Göbel, Susann Pankratz, Tilman Schneider-Hohendorf, Stefan Bittner, Michael K Schuhmann, Harald F Langer, Guido Stoll, Heinz Wiendl, Christoph Kleinschnitz, Sven G Meuth

  Journal of autoimmunity. 01/2011; 36(2):106-14.

  Disruption of the blood brain barrier (BBB) and transendothelial trafficking of immune cells into the central nervous system (CNS) are pathophysiological hallmarks of Multiple Sclerosis (MS) and itsDisruption of the blood brain barrier (BBB) and transendothelial trafficking of immune cells into the central nervous system (CNS) are pathophysiological hallmarks of Multiple Sclerosis (MS) and its animal model, Experimental Autoimmune Encephalomyelitis (EAE). Kinins are proinflammatory peptides which are released during tissue injury including EAE. They increase vascular permeability and enhance inflammation by acting on distinct bradykinin receptors, B1R and B2R. We studied the expression of B1R and B2R and the effect of their inhibition on the disease course, BBB integrity and T cell migration following myelin oligodendrocyte glycoprotein (MOG(35-55))-induced EAE. B1R, but not B2R expression was markedly enhanced in inflammatory CNS lesions in mice and humans. Brain endothelial cells could be identified as major source of B1R protein. The severity of EAE was significantly alleviated in B1R(-/-) mice compared with wild-type (WT) controls (P<0.05). Treatment of WT mice with the B1R antagonist R715 before and after disease onset was equally effective (P<0.05) while B1R activation by R838 promoted EAE (P<0.05). B1R inhibition was accompanied by a remarkable reduction of BBB disruption and tissue inflammation. In vitro analyses revealed that B1R suppression reverses the upregulation of ICAM-I and VCAM-I at the inflamed BBB thereby limiting T cell transmigration. In contrast, blocking B2R had no significant impact on EAE. We conclude that B1R inhibition can reduce BBB damage and cell invasion during autoimmune CNS disease and may offer a novel anti-inflammatory strategy for the treatment of MS.

• Regulatory T cells exhibit enhanced migratory characteristics, a feature impaired in patients with multiple sclerosis.

  Authors: Tilman Schneider-Hohendorf, Max-Philipp Stenner, Christian Weidenfeller, Alla L Zozulya, Ole J Simon, Nicholas Schwab, Heinz Wiendl

  European journal of immunology. 12/2010; 40(12):3581-90.

  Migration of immune cells characterizes inflammation and plays a key role in autoimmune diseases such as MS. CD4(+)Foxp3(+) regulatory T cells (Treg) have the potential to dampen immune responses butMigration of immune cells characterizes inflammation and plays a key role in autoimmune diseases such as MS. CD4(+)Foxp3(+) regulatory T cells (Treg) have the potential to dampen immune responses but show functional impairment in patients with MS. We here show that murine Treg exhibit higher constitutive cell motility in horizontal migration on laminin, surpass non-Treg in transwell assays through microporous membranes as well as across primary brain endothelium and are present in the naïve CNS to a significantly higher extent compared to spleen, lymph nodes and blood. Likewise, human Treg from healthy donors significantly exceed non-Treg in migratory rates across primary human brain endothelium. Finally, we investigated whether the propensity to migrate is impaired as a feature of autoimmunity and therefore tested patients with MS. Treg from patients with stable relapsing-remitting MS show significantly impaired migratory capacity under non-inflammatory conditions compared to healthy donors. We hypothesize that the enhanced propensity to migrate is a feature of Treg that allows for an equilibrium in parenchymal immune surveillance, e.g. of the CNS. Impaired Treg migration across the intact blood-brain barrier, as observed for Treg from patients with MS, indicates a broader functional deficiency hypothetically contributing to early CNS lesion development or phases of MS remissions.

• Active immunization with proteolipid protein (190-209) induces ascending paralysing experimental autoimmune encephalomyelitis in C3H/HeJ mice.

  Authors: Kerstin Göbel, Stefan Bittner, Tobias Ruck, Thomas Budde, Erhard Wischmeyer, Frank Döring, Heinz Wiendl, Sven G Meuth

  Journal of immunological methods. 12/2010; 367(1-2):27-32.

  Experimental autoimmune encephalomyelitis (EAE) is a demyelinating disease of the central nervous system (CNS) that shares clinical and pathophysiological feature with multiple sclerosis (MS) and isExperimental autoimmune encephalomyelitis (EAE) is a demyelinating disease of the central nervous system (CNS) that shares clinical and pathophysiological feature with multiple sclerosis (MS) and is commonly used as an animal model for the human disease. Upon active immunization, different myelin proteins and other neuronal antigens are known to induce EAE in susceptible mouse strains. However, there are rodent strains reputed to be resistant to actively-induced EAE and the correct combination of animal strains and their respective autoantigen is absolutely critical as some antigens are encephalitogenic in one animal strain, but not in another. Here we describe actively-induced EAE in C3H/HeJ mice with different myelin peptides. Whereas no clinical signs could be found by immunization with myelin oligodendrocyte glycoprotein 35-55, significant weight loss as well as rapidly occurring severe ascending paralysis was found in animals immunized with proteolipid protein 190-209 (PLP(190-209)). Histologically, this form of EAE was characterized by predominant involvement of the spinal cord. As PLP is one of the major lipid antigens putatively involved in the pathogenesis of MS, this model may be useful for further studies of the disease.

• CD34+ progenitor cells mobilized by natalizumab are not a relevant reservoir for JC virus.

  Authors: Clemens Warnke, Vsevolod Smolianov, Thomas Dehmel, Marcel Andrée, Hartmut Hengel, Fabian Zohren, Gabriele Arendt, Heinz Wiendl, Rainer Haas, Hans-Peter Hartung, Ortwin Adams, Bernd C Kieseier

  Multiple sclerosis (Houndmills, Basingstoke, England). 11/2010; 17(2):151-6.

  Progressive multifocal leukoencephalopathy (PML) is associated with natalizumab treatment in patients with multiple sclerosis (MS). It has been hypothesized that natalizumab mobilizes JC virusProgressive multifocal leukoencephalopathy (PML) is associated with natalizumab treatment in patients with multiple sclerosis (MS). It has been hypothesized that natalizumab mobilizes JC virus (JCV)-infected haematopoietic progenitor cells mediating viraemia and subsequently this disease. The objective of this study was to investigate peripheral haematopoietic progenitor cells for evidence of JCV DNA in MS patients treated with natalizumab. We assessed JCV and cytomegalovirus (CMV) DNA in magnetically separated CD34+ haematopoietic progenitor cells, peripheral blood mononuclear cells and plasma of 67 natalizumab-treated patients with MS and six PML patients. Viral DNA was not detectable in CD34+ haematopoietic progenitor or peripheral blood mononuclear cells from any sample. Two plasma samples from patients with MS while undergoing natalizumab treatment were JCV-positive. In one case clinically manifest PML developed 8 months thereafter. Our findings do not support the hypothesis that natalizumab mobilizes JC virus-infected CD34+ cells from the bone marrow mediating JC viraemia. Notably, JC viraemia was detected in one patient with MS prior to developing clinical PML. This warrants further study.