@article{HaarmannNehenDeissetal.2015, author = {Haarmann, Axel and Nehen, Mathias and Deiß, Annika and Buttmann, Mathias}, title = {Fumaric acid esters do not reduce inflammatory NF-\(\kappa\)B/p65 nuclear translocation, ICAM-1 expression and T-cell adhesiveness of human brain microvascular endothelial cells}, series = {International Journal of Molecular Sciences}, volume = {16}, journal = {International Journal of Molecular Sciences}, doi = {10.3390/ijms160819086}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-148295}, pages = {19086-19095}, year = {2015}, abstract = {Dimethyl fumarate (DMF) is approved for disease-modifying treatment of patients with relapsing-remitting multiple sclerosis. Animal experiments suggested that part of its therapeutic effect is due to a reduction of T-cell infiltration of the central nervous system (CNS) by uncertain mechanisms. Here we evaluated whether DMF and its primary metabolite monomethyl fumarate (MMF) modulate pro-inflammatory intracellular signaling and T-cell adhesiveness of nonimmortalized single donor human brain microvascular endothelial cells at low passages. Neither DMF nor MMF at concentrations of 10 or 50 \(\mu\)M blocked the IL-1\(\beta\)-induced nuclear translocation of NF-\(\kappa\)B/p65, whereas the higher concentration of DMF inhibited the nuclear entry of p65 in human umbilical vein endothelium cultured in parallel. DMF and MMF also did not alter the IL-1\(\beta\)-stimulated activation of p38 MAPK in brain endothelium. Furthermore, neither DMF nor MMF reduced the basal or IL-1\(\beta\)-inducible expression of ICAM-1. In accordance, both fumaric acid esters did not reduce the adhesion of activated Jurkat T cells to brain endothelium under basal or inflammatory conditions. Therefore, brain endothelial cells probably do not directly mediate a potential blocking effect of fumaric acid esters on the inflammatory infiltration of the CNS by T cells.}, language = {en} } @article{PacheZimmermannMikolajczaketal.2016, author = {Pache, Florence and Zimmermann, Hanna and Mikolajczak, Janine and Schumacher, Sophie and Lacheta, Anna and Oertel, Frederike C. and Bellmann-Strobl, Judith and Jarius, Sven and Wildemann, Brigitte and Reindl, Markus and Waldman, Amy and Soelberg, Kerstin and Asgari, Nasrin and Ringelstein, Marius and Aktas, Orhan and Gross, Nikolai and Buttmann, Mathias and Ach, Thomas and Ruprecht, Klemens and Paul, Friedemann and Brandt, Alexander U.}, title = {MOG-IgG in NMO and related disorders: a multicenter study of 50 patients. Part 4: Afferent visual system damage after optic neuritis in MOG-IgG-seropositive versus AQP4-IgG-seropositive patients}, series = {Journal of Neuroinflammation}, volume = {13}, journal = {Journal of Neuroinflammation}, number = {282}, doi = {10.1186/s12974-016-0720-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-165551}, year = {2016}, abstract = {Background Antibodies against myelin oligodendrocyte glycoprotein (MOG-IgG) have been reported in patients with aquaporin-4 antibody (AQP4-IgG)-negative neuromyelitis optica spectrum disorders (NMOSD). The objective of this study was to describe optic neuritis (ON)-induced neuro-axonal damage in the retina of MOG-IgG-positive patients in comparison with AQP4-IgG-positive NMOSD patients. Methods Afferent visual system damage following ON was bilaterally assessed in 16 MOG-IgG-positive patients with a history of ON and compared with that in 16 AQP4-IgG-positive NMOSD patients. In addition, 16 healthy controls matched for age, sex, and disease duration were analyzed. Study data included ON history, retinal optical coherence tomography, visual acuity, and visual evoked potentials. Results Eight MOG-IgG-positive patients had a previous diagnosis of AQP4-IgG-negative NMOSD with ON and myelitis, and eight of (mainly recurrent) ON. Twenty-nine of the 32 eyes of the MOG-IgG-positive patients had been affected by at least one episode of ON. Peripapillary retinal nerve fiber layer thickness (pRNFL) and ganglion cell and inner plexiform layer volume (GCIP) were significantly reduced in ON eyes of MOG-IgG-positive patients (pRNFL = 59 ± 23 μm; GCIP = 1.50 ± 0.34 mm3) compared with healthy controls (pRNFL = 99 ± 6 μm, p < 0.001; GCIP = 1.97 ± 0.11 mm3, p < 0.001). Visual acuity was impaired in eyes after ON in MOG-IgG-positive patients (0.35 ± 0.88 logMAR). There were no significant differences in any structural or functional visual parameters between MOG-IgG-positive and AQP4-IgG-positive patients (pRNFL: 59 ± 21 μm; GCIP: 1.41 ± 0.27 mm3; Visual acuity = 0.72 ± 1.09 logMAR). Importantly, MOG-IgG-positive patients had a significantly higher annual ON relapse rate than AQP4-IgG-positive patients (median 0.69 vs. 0.29 attacks/year, p = 0.004), meaning that on average a single ON episode caused less damage in MOG-IgG-positive than in AQP4-IgG-positive patients. pRNFL and GCIP loss correlated with the number of ON episodes in MOG-IgG-positive patients (p < 0.001), but not in AQP4-IgG-positive patients. Conclusions Retinal neuro-axonal damage and visual impairment after ON in MOG-IgG-positive patients are as severe as in AQP4-IgG-positive NMOSD patients. In MOG-IgG-positive patients, damage accrual may be driven by higher relapse rates, whereas AQP4-IgG-positive patients showed fewer but more severe episodes of ON. Given the marked damage in some of our MOG-IgG-positive patients, early diagnosis and timely initiation and close monitoring of immunosuppressive therapy are important.}, language = {en} } @article{JariusRuprechtKleiteretal.2016, author = {Jarius, Sven and Ruprecht, Klemens and Kleiter, Ingo and Borisow, Nadja and Asgari, Nasrin and Pitarokoili, Kalliopi and Pache, Florence and Stich, Oliver and Beume, Lena-Alexandra and H{\"u}mmert, Martin W. and Ringelstein, Marius and Trebst, Corinna and Winkelmann, Alexander and Schwarz, Alexander and Buttmann, Mathias and Zimmermann, Hanna and Kuchling, Joseph and Franciotta, Diego and Capobianco, Marco and Siebert, Eberhard and Lukas, Carsten and Korporal-Kuhnke, Mirjam and Haas, J{\"u}rgen and Fechner, Kai and Brandt, Alexander U. and Schanda, Kathrin and Aktas, Orhan and Paul, Friedemann and Reindl, Markus and Wildemann, Brigitte}, title = {MOG-IgG in NMO and related disorders: a multicenter study of 50 patients. Part 2: Epidemiology, clinical presentation, radiological and laboratory features, treatment responses, and long-term outcome}, series = {Journal of Neuroinflammation}, volume = {13}, journal = {Journal of Neuroinflammation}, number = {280}, doi = {10.1186/s12974-016-0718-0}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-165570}, year = {2016}, abstract = {Background A subset of patients with neuromyelitis optica spectrum disorders (NMOSD) has been shown to be seropositive for myelin oligodendrocyte glycoprotein antibodies (MOG-IgG). Objective To describe the epidemiological, clinical, radiological, cerebrospinal fluid (CSF), and electrophysiological features of a large cohort of MOG-IgG-positive patients with optic neuritis (ON) and/or myelitis (n = 50) as well as attack and long-term treatment outcomes. Methods Retrospective multicenter study. Results The sex ratio was 1:2.8 (m:f). Median age at onset was 31 years (range 6-70). The disease followed a multiphasic course in 80\% (median time-to-first-relapse 5 months; annualized relapse rate 0.92) and resulted in significant disability in 40\% (mean follow-up 75 ± 46.5 months), with severe visual impairment or functional blindness (36\%) and markedly impaired ambulation due to paresis or ataxia (25\%) as the most common long-term sequelae. Functional blindness in one or both eyes was noted during at least one ON attack in around 70\%. Perioptic enhancement was present in several patients. Besides acute tetra-/paraparesis, dysesthesia and pain were common in acute myelitis (70\%). Longitudinally extensive spinal cord lesions were frequent, but short lesions occurred at least once in 44\%. Fourty-one percent had a history of simultaneous ON and myelitis. Clinical or radiological involvement of the brain, brainstem, or cerebellum was present in 50\%; extra-opticospinal symptoms included intractable nausea and vomiting and respiratory insufficiency (fatal in one). CSF pleocytosis (partly neutrophilic) was present in 70\%, oligoclonal bands in only 13\%, and blood-CSF-barrier dysfunction in 32\%. Intravenous methylprednisolone (IVMP) and long-term immunosuppression were often effective; however, treatment failure leading to rapid accumulation of disability was noted in many patients as well as flare-ups after steroid withdrawal. Full recovery was achieved by plasma exchange in some cases, including after IVMP failure. Breakthrough attacks under azathioprine were linked to the drug-specific latency period and a lack of cotreatment with oral steroids. Methotrexate was effective in 5/6 patients. Interferon-beta was associated with ongoing or increasing disease activity. Rituximab and ofatumumab were effective in some patients. However, treatment with rituximab was followed by early relapses in several cases; end-of-dose relapses occurred 9-12 months after the first infusion. Coexisting autoimmunity was rare (9\%). Wingerchuk's 2006 and 2015 criteria for NMO(SD) and Barkhof and McDonald criteria for multiple sclerosis (MS) were met by 28\%, 32\%, 15\%, 33\%, respectively; MS had been suspected in 36\%. Disease onset or relapses were preceded by infection, vaccination, or pregnancy/delivery in several cases. Conclusion Our findings from a predominantly Caucasian cohort strongly argue against the concept of MOG-IgG denoting a mild and usually monophasic variant of NMOSD. The predominantly relapsing and often severe disease course and the short median time to second attack support the use of prophylactic long-term treatments in patients with MOG-IgG-positive ON and/or myelitis.}, language = {en} } @article{JariusRuprechtKleiteretal.2016, author = {Jarius, Sven and Ruprecht, Klemens and Kleiter, Ingo and Borisow, Nadja and Asgari, Nasrin and Pitarokoili, Kalliopi and Pache, Florence and Stich, Oliver and Beume, Lena-Alexandra and H{\"u}mmert, Martin W. and Trebst, Corinna and Ringelstein, Marius and Aktas, Orhan and Winkelmann, Alexander and Buttmann, Mathias and Schwarz, Alexander and Zimmermann, Hanna and Brandt, Alexander U. and Franciotta, Diego and Capobianco, Marco and Kuchling, Joseph and Haas, J{\"u}rgen and Korporal-Kuhnke, Mirjam and Lillevang, Soeren Thue and Fechner, Kai and Schanda, Kathrin and Paul, Friedemann and Wildemann, Brigitte and Reindl, Markus}, title = {MOG-IgG in NMO and related disorders: a multicenter study of 50 patients. Part 1: Frequency, syndrome specificity, influence of disease activity, long-term course, association with AQP4-IgG, and origin}, series = {Journal of Neuroinflammation}, volume = {13}, journal = {Journal of Neuroinflammation}, number = {279}, doi = {10.1186/s12974-016-0717-1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-165659}, pages = {1-16}, year = {2016}, abstract = {Background Antibodies to myelin oligodendrocyte glycoprotein (MOG-IgG) have been suggested to play a role in a subset of patients with neuromyelitis optica and related disorders. Objective To assess (i) the frequency of MOG-IgG in a large and predominantly Caucasian cohort of patients with optic neuritis (ON) and/or myelitis; (ii) the frequency of MOG-IgG among AQP4-IgG-positive patients and vice versa; (iii) the origin and frequency of MOG-IgG in the cerebrospinal fluid (CSF); (iv) the presence of MOG-IgG at disease onset; and (v) the influence of disease activity and treatment status on MOG-IgG titers. Methods 614 serum samples from patients with ON and/or myelitis and from controls, including 92 follow-up samples from 55 subjects, and 18 CSF samples were tested for MOG-IgG using a live cell-based assay (CBA) employing full-length human MOG-transfected HEK293A cells. Results MOG-IgG was detected in 95 sera from 50 patients with ON and/or myelitis, including 22/54 (40.7\%) patients with a history of both ON and myelitis, 22/103 (21.4\%) with a history of ON but no myelitis and 6/45 (13.3\%) with a history of longitudinally extensive transverse myelitis but no ON, and in 1 control patient with encephalitis and a connective tissue disorder, all of whom were negative for AQP4-IgG. MOG-IgG was absent in 221 further controls, including 83 patients with AQP4-IgG-seropositive neuromyelitis optica spectrum disorders and 85 with multiple sclerosis (MS). MOG-IgG was found in 12/18 (67\%) CSF samples from MOG-IgG-seropositive patients; the MOG-IgG-specific antibody index was negative in all cases, indicating a predominantly peripheral origin of CSF MOG-IgG. Serum and CSF MOG-IgG belonged to the complement-activating IgG1 subclass. MOG-IgG was present already at disease onset. The antibodies remained detectable in 40/45 (89\%) follow-up samples obtained over a median period of 16.5 months (range 0-123). Serum titers were higher during attacks than during remission (p < 0.0001), highest during attacks of simultaneous myelitis and ON, lowest during acute isolated ON, and declined following treatment. Conclusions To date, this is the largest cohort studied for IgG to human full-length MOG by means of an up-to-date CBA. MOG-IgG is present in a substantial subset of patients with ON and/or myelitis, but not in classical MS. Co-existence of MOG-IgG and AQP4-IgG is highly uncommon. CSF MOG-IgG is of extrathecal origin. Serum MOG-IgG is present already at disease onset and remains detectable in the long-term course. Serum titers depend on disease activity and treatment status.}, language = {en} } @article{HaarmannDeissProchaskaetal.2010, author = {Haarmann, Axel and Deiss, Annika and Prochaska, Juergen and Foerch, Christian and Weksler, Babette and Romero, Ignacio and Couraud, Pierre-Olivier and Stoll, Guido and Rieckmann, Peter and Buttmann, Mathias}, title = {Evaluation of Soluble Junctional Adhesion Molecule-A as a Biomarker of Human Brain Endothelial Barrier Breakdown}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-68468}, year = {2010}, abstract = {Background: An inducible release of soluble junctional adhesion molecule-A (sJAM-A) under pro-inflammatory conditions was described in cultured non-CNS endothelial cells (EC) and increased sJAM-A serum levels were found to indicate inflammation in non-CNS vascular beds. Here we studied the regulation of JAM-A expression in cultured brain EC and evaluated sJAM-A as a serum biomarker of blood-brain barrier (BBB) function. Methodology/Principal Findings: As previously reported in non-CNS EC types, pro-inflammatory stimulation of primary or immortalized (hCMEC/D3) human brain microvascular EC (HBMEC) induced a redistribution of cell-bound JAM-A on the cell surface away from tight junctions, along with a dissociation from the cytoskeleton. This was paralleled by reduced immunocytochemical staining of occludin and zonula occludens-1 as well as by increased paracellular permeability for dextran 3000. Both a self-developed ELISA test and Western blot analysis detected a constitutive sJAM-A release by HBMEC into culture supernatants, which importantly was unaffected by pro-inflammatory or hypoxia/reoxygenation challenge. Accordingly, serum levels of sJAM-A were unaltered in 14 patients with clinically active multiple sclerosis compared to 45 stable patients and remained unchanged in 13 patients with acute ischemic non-small vessel stroke over time. Conclusion: Soluble JAM-A was not suited as a biomarker of BBB breakdown in our hands. The unexpected non-inducibility of sJAM-A release at the human BBB might contribute to a particular resistance of brain EC to inflammatory stimuli, protecting the CNS compartment.}, subject = {Biomarker}, language = {en} } @article{BrechtWeissbrichBraunetal.2012, author = {Brecht, Isabel and Weissbrich, Benedikt and Braun, Julia and Toyka, Klaus Viktor and Weishaupt, Andreas and Buttmann, Mathias}, title = {Intrathecal, Polyspecific Antiviral Immune Response in Oligoclonal Band Negative Multiple Sclerosis}, series = {PLoS One}, volume = {7}, journal = {PLoS One}, number = {7}, doi = {10.1371/journal.pone.0040431}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-134426}, pages = {e40431}, year = {2012}, abstract = {Background: Oligoclonal bands (OCB) are detected in the cerebrospinal fluid (CSF) in more than 95\% of patients with multiple sclerosis (MS) in the Western hemisphere. Here we evaluated the intrathecal, polyspecific antiviral immune response as a potential diagnostic CSF marker for OCB-negative MS patients. Methodology/Principal Findings: We tested 46 OCB-negative German patients with paraclinically well defined, definite MS. Sixteen OCB-negative patients with a clear diagnosis of other autoimmune CNS disorders and 37 neurological patients without evidence for autoimmune CNS inflammation served as control groups. Antibodies against measles, rubella, varicella zoster and herpes simplex virus in paired serum and CSF samples were determined by ELISA, and virus-specific immunoglobulin G antibody indices were calculated. An intrathecal antibody synthesis against at least one neurotropic virus was detected in 8 of 26 (31\%) patients with relapsing-remitting MS, 8 of 12 (67\%) with secondary progressive MS and 5 of 8 (63\%) with primary progressive MS, in 3 of 16 (19\%) CNS autoimmune and 3 of 37 (8\%) non-autoimmune control patients. Antibody synthesis against two or more viruses was found in 11 of 46 (24\%) MS patients but in neither of the two control groups. On average, MS patients with a positive antiviral immune response were older and had a longer disease duration than those without. Conclusion: Determination of the intrathecal, polyspecific antiviral immune response may allow to establish a CSF-supported diagnosis of MS in OCB-negative patients when two or more of the four virus antibody indices are elevated.}, language = {en} } @article{GrohStadlerButtmannetal.2014, author = {Groh, Janos and Stadler, David and Buttmann, Mathias and Martini, Rudolf}, title = {Non-invasive assessment of retinal alterations in mouse models of infantile and juvenile neuronal ceroid lipofuscinosis by spectral domain optical coherence tomography}, doi = {10.1186/2051-5960-2-54}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-110566}, year = {2014}, abstract = {Introduction The neuronal ceroid lipofuscinoses constitute a group of fatal inherited lysosomal storage diseases that manifest in profound neurodegeneration in the CNS. Visual impairment usually is an early symptom and selective degeneration of retinal neurons has been described in patients suffering from distinct disease subtypes. We have previously demonstrated that palmitoyl protein thioesterase 1 deficient (Ppt1-/-) mice, a model of the infantile disease subtype, exhibit progressive axonal degeneration in the optic nerve and loss of retinal ganglion cells, faithfully reflecting disease severity in the CNS. Here we performed spectral domain optical coherence tomography (OCT) in Ppt1-/- and ceroid lipofuscinosis neuronal 3 deficient (Cln3-/-) mice, which are models of infantile and juvenile neuronal ceroid lipofuscinosis, respectively, in order to establish a non-invasive method to assess retinal alterations and monitor disease severity in vivo. Results Blue laser autofluorescence imaging revealed increased accumulation of autofluorescent storage material in the inner retinae of 7-month-old Ppt1-/- and of 16-month-old Cln3-/- mice in comparison with age-matched control littermates. Additionally, optical coherence tomography demonstrated reduced thickness of retinae in knockout mice in comparison with age-matched control littermates. High resolution scans and manual measurements allowed for separation of different retinal composite layers and revealed a thinning of layers in the inner retinae of both mouse models at distinct ages. OCT measurements correlated well with subsequent histological analysis of the same retinae. Conclusions These results demonstrate the feasibility of OCT to assess neurodegenerative disease severity in mouse models of neuronal ceroid lipofuscinosis and might have important implications for diagnostic evaluation of disease progression and therapeutic efficacy in patients. Moreover, the non-invasive method allows for longitudinal studies in experimental models, reducing the number of animals used for research.}, language = {en} } @article{BenkertDietzHartmannetal.2012, author = {Benkert, Thomas F. and Dietz, Lena and Hartmann, Elena M. and Leich, Ellen and Rosenwald, Andreas and Serfling, Edgar and Buttmann, Mathias and Berberich-Siebelt, Friederike}, title = {Natalizumab Exerts Direct Signaling Capacity and Supports a Pro-Inflammatory Phenotype in Some Patients with Multiple Sclerosis}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-77905}, year = {2012}, abstract = {Natalizumab is a recombinant monoclonal antibody raised against integrin alpha-4 (CD49d). It is approved for the treatment of patients with multiple sclerosis (MS), a chronic inflammatory autoimmune disease of the CNS. While having shown high therapeutic efficacy, treatment by natalizumab has been linked to progressive multifocal leukoencephalopathy (PML) as a serious adverse effect. Furthermore, drug cessation sometimes induces rebound disease activity of unknown etiology. Here we investigated whether binding of this adhesion-blocking antibody to T lymphocytes could modulate their phenotype by direct induction of intracellular signaling events. Primary CD4+ T lymphocytes either from healthy donors and treated with natalizumab in vitro or from MS patients receiving their very first dose of natalizumab were analyzed. Natalizumab induced a mild upregulation of IL-2, IFN-c and IL-17 expression in activated primary human CD4+ T cells propagated ex vivo from healthy donors, consistent with a pro-inflammatory costimulatory effect on lymphokine expression. Along with this, natalizumab binding triggered rapid MAPK/ERK phosphorylation. Furthermore, it decreased CD49d surface expression on effector cells within a few hours. Sustained CD49d downregulation could be attributed to integrin internalization and degradation. Importantly, also CD4+ T cells from some MS patients receiving their very first dose of natalizumab produced more IL-2, IFN-c and IL-17 already 24 h after infusion. Together these data indicate that in addition to its adhesion-blocking mode of action natalizumab possesses mild direct signaling capacities, which can support a pro-inflammatory phenotype of peripheral blood T lymphocytes. This might explain why a rebound of disease activity or IRIS is observed in some MS patients after natalizumab cessation.}, subject = {Medizin}, language = {en} } @phdthesis{Buttmann2002, author = {Buttmann, Mathias}, title = {Molekularbiologische Untersuchung intrazellul{\"a}rer Signalwege, die in T-Lymphozyten zur Aktivierung des Transkriptionsfaktors NF-ATc f{\"u}hren}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-1181516}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2002}, abstract = {Der Transkriptionsfaktor NF-ATc (Nuclear Factor of Activated T cells) kontrolliert die Genexpression in T-Lymphozyten. In dieser Arbeit, in der Jurkat-T-Zellen und embryonale 293-Zellen als Modellsysteme verwendet wurden, konnte gezeigt werden, daß die N-terminale transaktivierende Dom{\"a}ne TAD-A von NF-ATc in vivo induzierbar durch den Phorbolester TPA, in vitro durch die MAP-Kinase Erk2 phosphoryliert wird. In Transfektionsexperimenten mit einer TAD-A-Mutante, in der alle f{\"u}nf Serinreste, die theoretisch durch MAP-Kinasen phosphoryliert werden k{\"o}nnen, durch Alaninreste ersetzt worden waren, konnte gezeigt werden, daß diese Phosphorylierung nicht notwendig f{\"u}r die Aktivierung von TAD-A ist. Vielmehr gelang der Nachweis, daß verschiedene MAP-Kinasen-Signalwege ihre Wirkung auf NF-ATc {\"u}ber die transkriptionellen Koaktivatoren CBP und p300 entfalten, die an die N-terminale transaktivierende Dom{\"a}ne TAD-A von NF-ATc binden und dessen Aktivit{\"a}t kontrollieren. Der Nachweis, daß konstitutiv aktive Mutanten von c-Raf und Rac synergistisch die CBP/p300-vermittelte TAD-A-Aktivierung verst{\"a}rken, unterstreicht die wichtige Rolle, die CBP/p300 bei der Integration von T-Zell-Aktivierungssignalen spielt.}, language = {de} } @article{JariusKleiterRuprechtetal.2016, author = {Jarius, Sven and Kleiter, Ingo and Ruprecht, Klemens and Asgari, Nasrin and Pitarokoili, Kalliopi and Borisow, Nadja and H{\"u}mmert, Martin W. and Trebst, Corinna and Pache, Florence and Winkelmann, Alexander and Beume, Lena-Alexandra and Ringelstein, Marius and Stich, Oliver and Aktas, Orhan and Korporal-Kuhnke, Mirjam and Schwarz, Alexander and Lukas, Carsten and Haas, J{\"u}rgen and Fechner, Kai and Buttmann, Mathias and Bellmann-Strobl, Judith and Zimmermann, Hanna and Brandt, Alexander U. and Franciotta, Diego and Schanda, Kathrin and Paul, Friedemann and Reindl, Markus and Wildemann, Brigitte}, title = {MOG-IgG in NMO and related disorders: a multicenter study of 50 patients. Part 3: Brainstem involvement - frequency, presentation and outcome}, series = {Journal of Neuroinflammation}, volume = {13}, journal = {Journal of Neuroinflammation}, number = {281}, doi = {10.1186/s12974-016-0719-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-165543}, pages = {1-23}, year = {2016}, abstract = {Background Myelin oligodendrocyte glycoprotein antibodies (MOG-IgG) are present in a subset of aquaporin-4 (AQP4)-IgG-negative patients with optic neuritis (ON) and/or myelitis. Little is known so far about brainstem involvement in MOG-IgG-positive patients. Objective To investigate the frequency, clinical and paraclinical features, course, outcome, and prognostic implications of brainstem involvement in MOG-IgG-positive ON and/or myelitis. Methods Retrospective case study. Results Among 50 patients with MOG-IgG-positive ON and/or myelitis, 15 (30 \%) with a history of brainstem encephalitis were identified. All were negative for AQP4-IgG. Symptoms included respiratory insufficiency, intractable nausea and vomiting (INV), dysarthria, dysphagia, impaired cough reflex, oculomotor nerve palsy and diplopia, nystagmus, internuclear ophthalmoplegia (INO), facial nerve paresis, trigeminal hypesthesia/dysesthesia, vertigo, hearing loss, balance difficulties, and gait and limb ataxia; brainstem involvement was asymptomatic in three cases. Brainstem inflammation was already present at or very shortly after disease onset in 7/15 (47 \%) patients. 16/21 (76.2 \%) brainstem attacks were accompanied by acute myelitis and/or ON. Lesions were located in the pons (11/13), medulla oblongata (8/14), mesencephalon (cerebral peduncles; 2/14), and cerebellar peduncles (5/14), were adjacent to the fourth ventricle in 2/12, and periaqueductal in 1/12; some had concomitant diencephalic (2/13) or cerebellar lesions (1/14). MRI or laboratory signs of blood-brain barrier damage were present in 5/12. Cerebrospinal fluid pleocytosis was found in 11/14 cases, with neutrophils in 7/11 (3-34 \% of all CSF white blood cells), and oligoclonal bands in 4/14. Attacks were preceded by acute infection or vaccination in 5/15 (33.3 \%). A history of teratoma was noted in one case. The disease followed a relapsing course in 13/15 (87 \%); the brainstem was involved more than once in 6. Immunosuppression was not always effective in preventing relapses. Interferon-beta was followed by new attacks in two patients. While one patient died from central hypoventilation, partial or complete recovery was achieved in the remainder following treatment with high-dose steroids and/or plasma exchange. Brainstem involvement was associated with a more aggressive general disease course (higher relapse rate, more myelitis attacks, more frequently supratentorial brain lesions, worse EDSS at last follow-up). Conclusions Brainstem involvement is present in around one third of MOG-IgG-positive patients with ON and/or myelitis. Clinical manifestations are diverse and may include symptoms typically seen in AQP4-IgG-positive neuromyelitis optica, such as INV and respiratory insufficiency, or in multiple sclerosis, such as INO. As MOG-IgG-positive brainstem encephalitis may take a serious or even fatal course, particular attention should be paid to signs or symptoms of additional brainstem involvement in patients presenting with MOG-IgG-positive ON and/or myelitis.}, language = {en} } @article{SadovnickTraboulseeBernalesetal.2016, author = {Sadovnick, A. Dessa and Traboulsee, Anthony L. and Bernales, Cecily Q. and Ross, Jay P. and Forwell, Amanda L. and Yee, Irene M. and Guillot-Noel, Lena and Fontaine, Bertrand and Cournu-Rebeix, Isabelle and Alcina, Antonio and Fedetz, Maria and Izquierdo, Guillermo and Matesanz, Fuencisla and Hilven, Kelly and Dubois, B{\´e}n{\´e}dicte and Goris, An and Astobiza, Ianire and Alloza, Iraide and Antig{\"u}edad, Alfredo and Vandenbroeck, Koen and Akkad, Denis A. and Aktas, Orhan and Blaschke, Paul and Buttmann, Mathias and Chan, Andrew and Epplen, Joerg T. and Gerdes, Lisa-Ann and Kroner, Antje and Kubisch, Christian and K{\"u}mpfel, Tania and Lohse, Peter and Rieckmann, Peter and Zettl, Uwe K. and Zipp, Frauke and Bertram, Lars and Lill, Christina M. and Fernandez, Oscar and Urbaneja, Patricia and Leyva, Laura and Alvarez-Cerme{\~n}o, Jose Carlos and Arroyo, Rafael and Garagorri, Aroa M. and Garc{\´i}a-Mart{\´i}nez, Angel and Villar, Luisa M. and Urcelay, Elena and Malhotra, Sunny and Montalban, Xavier and Comabella, Manuel and Berger, Thomas and Fazekas, Franz and Reindl, Markus and Schmied, Mascha C. and Zimprich, Alexander and Vilari{\~n}o-G{\"u}ell, Carles}, title = {Analysis of Plasminogen Genetic Variants in Multiple Sclerosis Patients}, series = {G3: Genes Genomes Genetics}, volume = {6}, journal = {G3: Genes Genomes Genetics}, number = {7}, doi = {10.1534/g3.116.030841}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-165405}, pages = {2073-2079}, year = {2016}, abstract = {Multiple sclerosis (MS) is a prevalent neurological disease of complex etiology. Here, we describe the characterization of a multi-incident MS family that nominated a rare missense variant (p.G420D) in plasminogen (PLG) as a putative genetic risk factor for MS. Genotyping of PLG p.G420D (rs139071351) in 2160 MS patients, and 886 controls from Canada, identified 10 additional probands, two sporadic patients and one control with the variant. Segregation in families harboring the rs139071351 variant, identified p.G420D in 26 out of 30 family members diagnosed with MS, 14 unaffected parents, and 12 out of 30 family members not diagnosed with disease. Despite considerably reduced penetrance, linkage analysis supports cosegregation of PLG p.G420D and disease. Genotyping of PLG p.G420D in 14446 patients, and 8797 controls from Canada, France, Spain, Germany, Belgium, and Austria failed to identify significant association with disease (P = 0.117), despite an overall higher prevalence in patients (OR = 1.32; 95\% CI = 0.93-1.87). To assess whether additional rare variants have an effect on MS risk, we sequenced PLG in 293 probands, and genotyped all rare variants in cases and controls. This analysis identified nine rare missense variants, and although three of them were exclusively observed in MS patients, segregation does not support pathogenicity. PLG is a plausible biological candidate for MS owing to its involvement in immune system response, blood-brain barrier permeability, and myelin degradation. Moreover, components of its activation cascade have been shown to present increased activity or expression in MS patients compared to controls; further studies are needed to clarify whether PLG is involved in MS susceptibility.}, language = {en} } @article{WieseDennstaedtHollmannetal.2021, author = {Wiese, Teresa and Dennst{\"a}dt, Fabio and Hollmann, Claudia and Stonawski, Saskia and Wurst, Catherina and Fink, Julian and Gorte, Erika and Mandasari, Putri and Domschke, Katharina and Hommers, Leif and Vanhove, Bernard and Schumacher, Fabian and Kleuser, Burkard and Seibel, J{\"u}rgen and Rohr, Jan and Buttmann, Mathias and Menke, Andreas and Schneider-Schaulies, J{\"u}rgen and Beyersdorf, Niklas}, title = {Inhibition of acid sphingomyelinase increases regulatory T cells in humans}, series = {Brain Communications}, volume = {3}, journal = {Brain Communications}, number = {2}, doi = {10.1093/braincomms/fcab020}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-259868}, year = {2021}, abstract = {Genetic deficiency for acid sphingomyelinase or its pharmacological inhibition has been shown to increase Foxp3\(^+\) regulatory T-cell frequencies among CD4\(^+\) T cells in mice. We now investigated whether pharmacological targeting of the acid sphingomyelinase, which catalyzes the cleavage of sphingomyelin to ceramide and phosphorylcholine, also allows to manipulate relative CD4\(^+\) Foxp3\(^+\) regulatory T-cell frequencies in humans. Pharmacological acid sphingomyelinase inhibition with antidepressants like sertraline, but not those without an inhibitory effect on acid sphingomyelinase activity like citalopram, increased the frequency of Foxp3\(^+\) regulatory T cell among human CD4\(^+\) T cells in vitro. In an observational prospective clinical study with patients suffering from major depression, we observed that acid sphingomyelinase-inhibiting antidepressants induced a stronger relative increase in the frequency of CD4\(^+\) Foxp3\(^+\) regulatory T cells in peripheral blood than acid sphingomyelinase-non- or weakly inhibiting antidepressants. This was particularly true for CD45RA\(^-\) CD25\(^{high}\) effector CD4\(^+\) Foxp3\(^+\) regulatory T cells. Mechanistically, our data indicate that the positive effect of acid sphingomyelinase inhibition on CD4\(^+\) Foxp3\(^+\) regulatory T cells required CD28 co-stimulation, suggesting that enhanced CD28 co-stimulation was the driver of the observed increase in the frequency of Foxp3+ regulatory T cells among human CD4\(^+\) T cells. In summary, the widely induced pharmacological inhibition of acid sphingomyelinase activity in patients leads to an increase in Foxp3+ regulatory T-cell frequencies among CD4\(^+\) T cells in humans both in vivo and in vitro.}, language = {en} } @article{HussHalbgebauerOeckletal.2016, author = {Huss, Andr{\´e} M. and Halbgebauer, Steffen and {\"O}ckl, Patrick and Trebst, Corinna and Spreer, Annette and Borisow, Nadja and Harrer, Andrea and Brecht, Isabel and Balint, Bettina and Stich, Oliver and Schlegel, Sabine and Retzlaff, Nele and Winkelmann, Alexander and Roesler, Romy and Lauda, Florian and Yildiz, {\"O}zlem and Voß, Elke and Muche, Rainer and Rauer, Sebastian and Bergh, Florian Then and Otto, Markus and Paul, Friedemann and Wildemann, Brigitte and Kraus, J{\"o}rg and Ruprecht, Klemens and Stangel, Martin and Buttmann, Mathias and Zettl, Uwe K. and Tumani, Hayrettin}, title = {Importance of cerebrospinal fluid analysis in the era of McDonald 2010 criteria: a German-Austrian retrospective multicenter study in patients with a clinically isolated syndrome}, series = {Journal of Neurology}, volume = {263}, journal = {Journal of Neurology}, number = {12}, doi = {10.1007/s00415-016-8302-1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-186619}, pages = {2499-2504}, year = {2016}, abstract = {The majority of patients presenting with a first clinical symptom suggestive of multiple sclerosis (MS) do not fulfill the MRI criteria for dissemination in space and time according to the 2010 revision of the McDonald diagnostic criteria for MS and are thus classified as clinically isolated syndrome (CIS). To re-evaluate the utility of cerebrospinal fluid (CSF) analysis in the context of the revised McDonald criteria from 2010, we conducted a retrospective multicenter study aimed at determining the prevalence and predictive value of oligoclonal IgG bands (OCBs) in patients with CIS. Patients were recruited from ten specialized MS centers in Germany and Austria. We collected data from 406 patients; at disease onset, 44/406 (11 \%) fulfilled the McDonald 2010 criteria for MS. Intrathecal IgG OCBs were detected in 310/362 (86 \%) of CIS patients. Those patients were twice as likely to convert to MS according to McDonald 2010 criteria as OCB-negative individuals (hazard ratio = 2.1, p = 0.0014) and in a shorter time period of 25 months (95 \% CI 21-34) compared to 47 months in OCB-negative individuals (95 \% CI 36-85). In patients without brain lesions at first attack and presence of intrathecal OCBs (30/44), conversion rate to MS was 60 \% (18/30), whereas it was only 21 \% (3/14) in those without OCBs. Our data confirm that in patients with CIS the risk of conversion to MS substantially increases if OCBs are present at onset. CSF analysis definitely helps to evaluate the prognosis in patients who do not have MS according to the revised McDonald criteria.}, language = {en} } @article{GomezFernandezLopezdeLapuentePortillaAstobizaetal.2020, author = {G{\´o}mez-Fern{\´a}ndez, Paloma and Lopez de Lapuente Portilla, Aitzkoa and Astobiza, Ianire and Mena, Jorge and Urtasun, Andoni and Altmann, Vivian and Matesanz, Fuencisla and Otaegui, David and Urcelay, Elena and Antig{\"u}edad, Alfredo and Malhotra, Sunny and Montalban, Xavier and Castillo-Trivi{\~n}o, Tamara and Espino-Pais{\´a}n, Laura and Aktas, Orhan and Buttmann, Mathias and Chan, Andrew and Fontaine, Bertrand and Gourraud, Pierre-Antoine and Hecker, Michael and Hoffjan, Sabine and Kubisch, Christian and K{\"u}mpfel, Tania and Luessi, Felix and Zettl, Uwe K. and Zipp, Frauke and Alloza, Iraide and Comabella, Manuel and Lill, Christina M. and Vandenbroeck, Koen}, title = {The rare IL22RA2 signal peptide coding variant rs28385692 decreases secretion of IL-22BP isoform-1, -2 and -3 and is associated with risk for multiple sclerosis}, series = {Cells}, volume = {9}, journal = {Cells}, number = {1}, issn = {2073-4409}, doi = {10.3390/cells9010175}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-200769}, year = {2020}, abstract = {The IL22RA2 locus is associated with risk for multiple sclerosis (MS) but causative variants are yet to be determined. In a single nucleotide polymorphism (SNP) screen of this locus in a Basque population, rs28385692, a rare coding variant substituting Leu for Pro at position 16 emerged significantly (p = 0.02). This variant is located in the signal peptide (SP) shared by the three secreted protein isoforms produced by IL22RA2 (IL-22 binding protein-1(IL-22BPi1), IL-22BPi2 and IL-22BPi3). Genotyping was extended to a Europe-wide case-control dataset and yielded high significance in the full dataset (p = 3.17 × 10\(^{-4}\)). Importantly, logistic regression analyses conditioning on the main known MS-associated SNP at this locus, rs17066096, revealed that this association was independent from the primary association signal in the full case-control dataset. In silico analysis predicted both disruption of the alpha helix of the H-region of the SP and decreased hydrophobicity of this region, ultimately affecting the SP cleavage site. We tested the effect of the p.Leu16Pro variant on the secretion of IL-22BPi1, IL-22BPi2 and IL-22BPi3 and observed that the Pro16 risk allele significantly lowers secretion levels of each of the isoforms to around 50\%-60\% in comparison to the Leu16 reference allele. Thus, our study suggests that genetically coded decreased levels of IL-22BP isoforms are associated with augmented risk for MS.}, language = {en} } @article{SilwedelSpeerHaarmannetal.2018, author = {Silwedel, Christine and Speer, Christian P. and Haarmann, Axel and Fehrholz, Markus and Claus, Heike and Buttmann, Mathias and Glaser, Kirsten}, title = {Novel insights into neuroinflammation: bacterial lipopolysaccharide, tumor necrosis factor α, and Ureaplasma species differentially modulate atypical chemokine receptor 3 responses in human brain microvascular endothelial cells}, series = {Journal of Neuroinflammation}, volume = {15}, journal = {Journal of Neuroinflammation}, number = {156}, doi = {10.1186/s12974-018-1170-0}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-175952}, year = {2018}, abstract = {Background: Atypical chemokine receptor 3 (ACKR3, synonym CXCR7) is increasingly considered relevant in neuroinflammatory conditions, in which its upregulation contributes to compromised endothelial barrier function and may ultimately allow inflammatory brain injury. While an impact of ACKR3 has been recognized in several neurological autoimmune diseases, neuroinflammation may also result from infectious agents, including Ureaplasma species (spp.). Although commonly regarded as commensals of the adult urogenital tract, Ureaplasma spp. may cause invasive infections in immunocompromised adults as well as in neonates and appear to be relevant pathogens in neonatal meningitis. Nonetheless, clinical and in vitro data on Ureaplasma-induced inflammation are scarce. Methods: We established a cell culture model of Ureaplasma meningitis, aiming to analyze ACKR3 variances as a possible pathomechanism in Ureaplasma-associated neuroinflammation. Non-immortalized human brain microvascular endothelial cells (HBMEC) were exposed to bacterial lipopolysaccharide (LPS) or tumor necrosis factor-α (TNF-α), and native as well as LPS-primed HBMEC were cultured with Ureaplasma urealyticum serovar 8 (Uu8) and U. parvum serovar 3 (Up3). ACKR3 responses were assessed via qRT-PCR, RNA sequencing, flow cytometry, and immunocytochemistry. Results: LPS, TNF-α, and Ureaplasma spp. influenced ACKR3 expression in HBMEC. LPS and TNF-α significantly induced ACKR3 mRNA expression (p < 0.001, vs. control), whereas Ureaplasma spp. enhanced ACKR3 protein expression in HBMEC (p < 0.01, vs. broth control). Co-stimulation with LPS and either Ureaplasma isolate intensified ACKR3 responses (p < 0.05, vs. LPS). Furthermore, stimulation wielded a differential influence on the receptor's ligands. Conclusions: We introduce an in vitro model of Ureaplasma meningitis. We are able to demonstrate a pro-inflammatory capacity of Ureaplasma spp. in native and, even more so, in LPS-primed HBMEC, underlining their clinical relevance particularly in a setting of co-infection. Furthermore, our data may indicate a novel role for ACKR3, with an impact not limited to auto-inflammatory diseases, but extending to infection-related neuroinflammation as well. AKCR3-induced blood-brain barrier breakdown might constitute a potential common pathomechanism.}, language = {en} } @article{ButtmannSeuffertMaederetal.2016, author = {Buttmann, Mathias and Seuffert, Linda and M{\"a}der, Uwe and Toyka, Klaus V.}, title = {Malignancies after mitoxantrone for multiple sclerosis: a retrospective cohort study}, series = {Neurology}, volume = {86}, journal = {Neurology}, doi = {10.1212/WNL.0000000000002745}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-188300}, pages = {2203-2207}, year = {2016}, abstract = {Objective: To assess the therapy-related risk of malignancies in mitoxantrone-treated patients with multiple sclerosis. Methods: This retrospective observational cohort study included all mitoxantrone-treated patients with multiple sclerosis seen at our department between 1994 and 2007. We collected follow-up information on medically confirmed malignancies, life status, and cause of death, as of 2010. Malignancy rates were compared to the German national cancer registry matched for sex, age, and year of occurrence. Results: Follow-up was completed in 676 of 677 identified patients. Median follow-up time was 8.7 years (interquartile range 6.8-11.2), corresponding to 6,220 person-years. Median cumulative mitoxantrone dose was 79.0 mg/m(2) (interquartile range 50.8-102.4). Thirty-seven patients (5.5\%) were diagnosed with a malignancy after mitoxantrone initiation, revealing a standardized incidence ratio of 1.50 (95\% confidence interval CI] 1.05-2.08). Entities included breast cancer (n = 9), colorectal cancer (n = 7), acute myeloid leukemia (n = 4, 0.6\%), and others (each entity n = 1 or 2). The standardized incidence ratio of colorectal cancer was 2.98 (95\% CI 1.20-6.14) and of acute myeloid leukemia 10.44 (95\% CI 3.39-24.36). It was not increased for other entities including breast cancer. Multivariate Cox regression identified higher age at treatment initiation but neither cumulative mitoxantrone dose (>75 vs 75 mg/m(2)) nor treatment with other immunosuppressive drugs or sex as a risk factor. Fifty-five patients had died, among them 12 of a malignancy and 43 reportedly of other causes. Conclusions: While the overall incidence of malignancies was only mildly increased, the risk of leukemia and colorectal cancer was heightened. If confirmed, posttherapy colonoscopy could become advisable.}, language = {en} } @article{HaarmannSchuhmannSilwedeletal.2019, author = {Haarmann, Axel and Schuhmann, Michael K. and Silwedel, Christine and Monoranu, Camelia-Maria and Stoll, Guido and Buttmann, Mathias}, title = {Human brain endothelial CXCR2 is inflammation-inducible and mediates CXCL5- and CXCL8-triggered paraendothelial barrier breakdown}, series = {International Journal of Molecular Science}, volume = {20}, journal = {International Journal of Molecular Science}, number = {3}, issn = {1422-0067}, doi = {10.3390/ijms20030602}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201297}, year = {2019}, abstract = {Chemokines (C-X-C) motif ligand (CXCL) 5 and 8 are overexpressed in patients with multiple sclerosis, where CXCL5 serum levels were shown to correlate with blood-brain barrier dysfunction as evidenced by gadolinium-enhanced magnetic resonance imaging. Here, we studied the potential role of CXCL5/CXCL8 receptor 2 (CXCR2) as a regulator of paraendothelial brain barrier function, using the well-characterized human cerebral microvascular endothelial cell line hCMEC/D3. Low basal CXCR2 mRNA and protein expression levels in hCMEC/D3 were found to strongly increase under inflammatory conditions. Correspondingly, immunohistochemistry of brain biopsies from two patients with active multiple sclerosis revealed upregulation of endothelial CXCR2 compared to healthy control tissue. Recombinant CXCL5 or CXCL8 rapidly and transiently activated Akt/protein kinase B in hCMEC/D3. This was followed by a redistribution of tight junction-associated protein zonula occludens-1 (ZO-1) and by the formation of actin stress fibers. Functionally, these morphological changes corresponded to a decrease of paracellular barrier function, as measured by a real-time electrical impedance-sensing system. Importantly, preincubation with the selective CXCR2 antagonist SB332235 partially prevented chemokine-induced disturbance of both tight junction morphology and function. We conclude that human brain endothelial CXCR2 may contribute to blood-brain barrier disturbance under inflammatory conditions with increased CXCL5 and CXCL8 expression, where CXCR2 may also represent a novel pharmacological target for blood-brain barrier stabilization.}, language = {en} }