Richard M Ransohoff

Lerner Research Institute, Cleveland, Ohio, United States

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Publications (374)2834.29 Total impact

  • Atsuko Katsumoto, Haiyan Lu, Aline S Miranda, Richard M Ransohoff
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    ABSTRACT: Microglia, the only nonneuroepithelial cells found in the parenchyma of the CNS, originate during embryogenesis from the yolk sac and enter the CNS quite early (embryonic day 9.5-10 in mice). Thereafter, microglia are maintained independently of any input from the blood and, in particular, do not require hematopoietic stem cells as a source of replacement for senescent cells. Monocytes are hematopoietic cells, derived from bone marrow. The ontogeny of microglia and monocytes is important for understanding CNS pathologies. Microglial functions are distinct from those of blood-derived monocytes, which invade the CNS only under pathological conditions. Recent data reveal that microglia play an important role in managing neuronal cell death, neurogenesis, and synaptic interactions. In this article, we discuss the physiology of microglia and the functions of monocytes in CNS pathology. We address the roles of microglia and monocytes in neurodegenerative diseases as an example of CNS pathology.
    Journal of immunology (Baltimore, Md. : 1950). 09/2014; 193(6):2615-2621.
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    ABSTRACT: Several Alzheimer's disease (AD) risk genes are specifically expressed by microglia within the CNS. However, the mechanisms by which microglia regulate the pathological hallmarks of AD-extracellular deposition of β-amyloid (Aβ) and intraneuronal hyperphosphorylation of microtubule-associated protein tau (MAPT)-remain to be established. Notably, deficiency for the microglial CX3CR1 receptor has opposing effects on Aβ and MAPT pathologies. CX3CL1, the neuronally derived cognate ligand for CX3CR1, signals both in membrane-anchored and soluble forms. In this study, we sought to determine the relative contribution on membrane-anchored versus soluble CX3CL1 in regulating the microglia-mediated amelioration of Aβ pathology, as well as provide insight into the potential downstream microglial-based mechanisms. As expected, CX3CL1 deficiency reduced Aβ deposition in APPPS1 animals in a similar manner to CX3CR1 deficiency. Surprisingly, however, CX3CL1-deficient APPPS1 animals exhibited enhanced neuronal MAPT phosphorylation despite reduced amyloid burden. Importantly, neither of these phenotypes was altered by transgenic expression of the soluble CX3CL1 isoform, suggesting that it is the membrane-anchored version of CX3CL1 that regulates microglial phagocytosis of Aβ and neuronal MAPT phosphorylation. Analysis of transcript levels in purified microglia isolated from APPPS1 mice with the various CX3CL1/CX3CR1 genotypes revealed increased expression of inflammatory cytokines and phagocytic markers, which was associated with activation of p38 mitogen-activated protein kinase and Aβ internalization within microglia. Together, these studies challenge the "frustrated phagocytosis" concept and suggest that neuronal-microglial communication link the two central AD pathologies.
    Journal of Neuroscience 09/2014; 34(37):12538-46. · 6.91 Impact Factor
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    Richard M Ransohoff
    08/2014; 1(2):e23.
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    ABSTRACT: Leukocyte transendothelial migration (TEM; diapedesis) is a critical event in immune surveillance and inflammation. Most TEM occurs at endothelial cell borders (paracellular). However, there is indirect evidence to suggest that, at the tight junctions of the blood-brain barrier (BBB), leukocytes migrate directly through the endothelial cell body (transcellular). Why leukocytes migrate through the endothelial cell body rather than the cell borders is unknown. To test the hypothesis that the tightness of endothelial cell junctions influences the pathway of diapedesis, we developed an in vitro model of the BBB that possessed 10-fold higher electrical resistance than standard culture conditions and strongly expressed the BBB tight junction proteins claudin-5 and claudin-3. We found that paracellular TEM was still the predominant pathway (≥98%) and TEM was dependent on PECAM-1 and CD99. We show that endothelial tight junctions expressing claudin-5 are dynamic and undergo rapid remodeling during TEM. Membrane from the endothelial lateral border recycling compartment is mobilized to the exact site of tight junction remodeling. This preserves the endothelial barrier by sealing the intercellular gaps with membrane and engaging the migrating leukocyte with unligated adhesion molecules (PECAM-1 and CD99) as it crosses the cell border. These findings provide new insights into leukocyte-endothelial interactions at the BBB and suggest that tight junctions are more dynamic than previously appreciated.
    Journal of immunology (Baltimore, Md. : 1950). 07/2014;
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    ABSTRACT: In the human disorder multiple sclerosis (MS) and in the model experimental autoimmune encephalomyelitis (EAE), macrophages predominate in demyelinated areas and their numbers correlate to tissue damage. Macrophages may be derived from infiltrating monocytes or resident microglia, yet are indistinguishable by light microscopy and surface phenotype. It is axiomatic that T cell-mediated macrophage activation is critical for inflammatory demyelination in EAE, yet the precise details by which tissue injury takes place remain poorly understood. In the present study, we addressed the cellular basis of autoimmune demyelination by discriminating microglial versus monocyte origins of effector macrophages. Using serial block-face scanning electron microscopy (SBF-SEM), we show that monocyte-derived macrophages associate with nodes of Ranvier and initiate demyelination, whereas microglia appear to clear debris. Gene expression profiles confirm that monocyte-derived macrophages are highly phagocytic and inflammatory, whereas those arising from microglia demonstrate an unexpected signature of globally suppressed cellular metabolism at disease onset. Distinguishing tissue-resident macrophages from infiltrating monocytes will point toward new strategies to treat disease and promote repair in diverse inflammatory pathologies in varied organs.
    Journal of Experimental Medicine 07/2014; · 13.21 Impact Factor
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    ABSTRACT: Axonal degeneration is a primary cause of permanent neurological disability in individuals with the CNS demyelinating disease multiple sclerosis. Dysfunction of axonal mitochondria and imbalanced energy demand and supply are implicated in degeneration of chronically demyelinated axons. The purpose of this study was to define the roles of mitochondrial volume and distribution in axonal degeneration following acute CNS demyelination. We show that the axonal mitochondrial volume increase following acute demyelination of WT CNS axons does not occur in demyelinated axons deficient in syntaphilin, an axonal molecule that immobilizes stationary mitochondria to microtubules. These findings were supported by time-lapse imaging of WT and syntaphilin-deficient axons in vitro. When demyelinated, axons deficient in syntaphilin degenerate at a significantly greater rate than WT axons, and this degeneration can be rescued by reducing axonal electrical activity with the Na(+) channel blocker flecainide. These results support the concept that syntaphilin-mediated immobilization of mitochondria to microtubules is required for the volume increase of axonal mitochondria following acute demyelination and protects against axonal degeneration in the CNS.
    Proceedings of the National Academy of Sciences 06/2014; · 9.81 Impact Factor
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    Richard M Ransohoff
    06/2014; 1(1):e15.
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    ABSTRACT: In vitro blood-brain barrier (BBB) models can be useful for understanding leukocyte-endothelial interactions at this unique vascular-tissue interface. Desirable features of such a model include shear stress, non-transformed cells and co-cultures of brain microvascular endothelial cells with astrocytes. Recovery of transmigrated leukocytes for further analysis is also appealing.
    Journal of Neuroscience Methods 05/2014; · 2.11 Impact Factor
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    ABSTRACT: Aminoglycoside antibiotics are highly effective agents against gram-negative bacterial infections, but they cause adverse effects on hearing and balance dysfunction as a result of toxicity to hair cells of the cochlea and vestibular organs. While ototoxicity has been comprehensively studied, the contributions of the immune system, which controls the host response to infection, have not been studied in antibiotic ototoxicity. Recently, it has been shown that an inflammatory response is induced by hair cell injury. In this study, we found that lipopolysaccharide (LPS), an important component of bacterial endotoxin, when given in combination with kanamycin and furosemide, augmented the inflammatory response to hair cell injury and exacerbated hearing loss and hair cell injury. LPS injected into the peritoneum of experimental mice induced a brisk cochlear inflammatory response with recruitment of mononuclear phagocytes into the spiral ligament, even in the absence of ototoxic agents. While LPS alone did not affect hearing, animals that received LPS prior to ototoxic agents had worse hearing loss compared to those that did not receive LPS pretreatment. The poorer hearing outcome in LPS-treated mice did not correlate to changes in endocochlear potential. However, LPS-treated mice demonstrated an increased number of CCR2(+) inflammatory monocytes in the inner ear when compared with mice treated with ototoxic agents alone. We conclude that LPS and its associated inflammatory response are harmful to the inner ear when coupled with ototoxic medications and that the immune system may contribute to the final hearing outcome in subjects treated with ototoxic agents.
    Journal of the Association for Research in Otolaryngology 05/2014; · 2.95 Impact Factor
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    Journal of Experimental Medicine 05/2014; 211(5):1003. · 13.21 Impact Factor
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    ABSTRACT: After traumatic spinal cord injury, functional deficits increase as axons die back from the center of the lesion and the glial scar forms. Axonal die back occurs in two phases: an initial axon intrinsic stage that occurs over the first several hours and a secondary phase which takes place over the first few weeks after injury. Here, we examine the secondary phase, which is marked by infiltration of macrophages. Using powerful time lapse multi-photon imaging, we captured images of interactions between Cx3cr1(+/GFP) macrophages and microglia and Thy-1(YFP) axons in a mouse dorsal column crush spinal cord injury model. Over the first few weeks after injury, axonal retraction bulbs within the lesion are static except when axonal fragments are lost by a blebbing mechanism in response to physical contact followed by phagocytosis by mobile Cx3Cr1(+/GFP) cells. Utilizing a radiation chimera model to distinguish marrow-derived cells from radio-resistant CNS resident microglia, we determined that the vast majority of accumulated cells in the lesion are derived from the blood and only these are associated with axonal damage. Interestingly, CNS-resident Cx3Cr1(+/GFP)microglia did not increasingly accumulate nor participate in neuronal destruction in the lesion during this time period. Additionally, we found that the blood-derived cells consisted mainly of singly labeled Ccr2(+/RFP)macrophages, singly labeled Cx3Cr1(+/GFP)macrophages and a small population of double-labeled cells. Since all axon destructive events were seen in contact with a Cx3Cr1(+/GFP)cell, we infer that the CCR2 single positive subset is likely not robustly involved in axonal dieback. Finally, in our model, deletion of CCR2, a chemokine receptor, did not alter the position of axons after dieback. Understanding the in vivo cellular interactions involved in secondary axonal injury may lead to clinical treatment candidates involving modulation of destructive infiltrating blood monocytes.
    Experimental Neurology 01/2014; · 4.65 Impact Factor
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    ABSTRACT: Background:In experimental models of glioblastoma multiforme (GBM), irradiation (IR) induces local expression of the chemokine CXCL12/SDF-1, which promotes tumour recurrence. The role of CXCR7, the high-affinity receptor for CXCL12, in the tumour's response to IR has not been addressed.Methods:We tested CXCR7 inhibitors for their effects on tumour growth and/or animal survival post IR in three rodent GBM models. We used immunohistochemistry to determine where CXCR7 protein is expressed in the tumours and in human GBM samples. We used neurosphere formation assays with human GBM xenografts to determine whether CXCR7 is required for cancer stem cell (CSC) activity in vitro.Results:CXCR7 was detected on tumour cells and/or tumour-associated vasculature in the rodent models and in human GBM. In human GBM, CXCR7 expression increased with glioma grade and was spatially associated with CXCL12 and CXCL11/I-TAC. In the rodent GBM models, pharmacological inhibition of CXCR7 post IR caused tumour regression, blocked tumour recurrence, and/or substantially prolonged survival. CXCR7 expression levels on human GBM xenograft cells correlated with neurosphere-forming activity, and a CXCR7 inhibitor blocked sphere formation by sorted CSCs.Conclusions:These results indicate that CXCR7 inhibitors could block GBM tumour recurrence after IR, perhaps by interfering with CSCs.British Journal of Cancer advance online publication, 14 January 2014; doi:10.1038/bjc.2013.830 www.bjcancer.com.
    British Journal of Cancer 01/2014; · 5.08 Impact Factor
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    Cristina Limatola, Richard M Ransohoff
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    ABSTRACT: Since the initial cloning of fractalkine/CX3CL1, it was proposed that the only known member of the CX3C or δ subfamily of chemotactic cytokines could play some significant role in the nervous system, due to its high expression on neurons. The pivotal description of the localization of the unique CX3CL1 receptor, CX3CR1, on microglial cells, firmed up by the generation of cx3cr1(GFP/GFP) mice, opened the road to the hypothesis of some specific key interactions between microglia and neurons mediated by this pair. This expectation has been indeed supported by recent exciting evidence indicating that CX3CL1-mediated microglia-neuron interaction modulates basic physiological activities during development, adulthood and aging, including: synaptic pruning; promoting survival of neurons and neural precursors; modulating synaptic transmission and plasticity; enhancing synapse and network maturation; and facilitating the establishment of neuropathic pain circuits. Beyond playing such fascinating roles in physiological conditions, CX3CL1 signaling has been implicated in different neuropathologies. Early papers demonstrated that the levels of CX3CL1 may be modulated by various toxic stimuli in vitro and that CX3CL1 signaling is positively or negatively regulated in EAE and MS, in HIV infection and LPS challenge, in epilepsy, in brain tumors, and in other neuropathologies. In this review we focus on the experimental evidence of CX3CL1 involvement in neuroprotection and survey the common molecular and cellular mechanisms described in different brain diseases.
    Frontiers in Cellular Neuroscience 01/2014; 8:229. · 4.47 Impact Factor
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    ABSTRACT: Microglia are myeloid cells of the CNS that participate both in normal CNS function and in disease. We investigated the molecular signature of microglia and identified 239 genes and 8 microRNAs that were uniquely or highly expressed in microglia versus myeloid and other immune cells. Of the 239 genes, 106 were enriched in microglia as compared with astrocytes, oligodendrocytes and neurons. This microglia signature was not observed in microglial lines or in monocytes recruited to the CNS, and was also observed in human microglia. We found that TGF-β was required for the in vitro development of microglia that express the microglial molecular signature characteristic of adult microglia and that microglia were absent in the CNS of TGF-β1-deficient mice. Our results identify a unique microglial signature that is dependent on TGF-β signaling and provide insights into microglial biology and the possibility of targeting microglia for the treatment of CNS disease.
    Nature Neuroscience 12/2013; · 15.25 Impact Factor
  • Birgit Obermeier, Richard Daneman, Richard M Ransohoff
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    ABSTRACT: The interface between the blood circulation and the neural tissue features unique characteristics that are encompassed by the term 'blood-brain barrier' (BBB). The main functions of this barrier, namely maintenance of brain homeostasis, regulation of influx and efflux transport, and protection from harm, are determined by its specialized multicellular structure. Every constituent cell type makes an indispensable contribution to the BBB's integrity. But if one member of the BBB fails, and as a result the barrier breaks down, there can be dramatic consequences and neuroinflammation and neurodegeneration can occur. In this Review, we highlight recently gained mechanistic insights into the development and maintenance of the BBB. We then discuss how BBB disruption can cause or contribute to neurological disease. Finally, we examine how this knowledge can be used to explore new possibilities for BBB repair.
    Nature medicine 12/2013; 19(12):1584-96. · 27.14 Impact Factor
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    ABSTRACT: The presentation of myelopathy in patients with the concomitant diagnosis of cervical stenosis (CS) and multiple sclerosis (MS) complicates both diagnosis and treatment, due to the similarities of presentation and disease progression. There are only a few published case-series that examine this unique patient population. 1) To define the demographic features and presenting symptoms of patients with both MS and CS, and 2) To investigate the immediate and long-term outcomes of surgery in patients with MS and CS. Matched cohort controlled retrospective review of 77 surgical patients in the MS group and 77 surgical patients in the control group. Outcome measures were immediate and long-term postoperative neck pain, radiculopathy, and myelopathy; Nurick Disability and mJOA scores were collected as well. Retrospective review was performed for all patients presenting at one institution between January 1996 and July 2011 with coexisting diagnoses of MS and CS who had presenting symptoms of myelopathy, and who then underwent cervical decompression surgery. Each study patient was individually matched to a control patient of the same gender and age that did not have MS, but that did have cervical spondylotic myelopathy or myeloradiculopathy. Each control patient underwent the same surgical procedure within the same year. 154 patients were reviewed, including 77 MS patients and 77 control patients, for an average follow-up of 58 months and 49 months, respectively. Patients in the control group were more likely to have preoperative neck pain (78% versus 47%; p=0.0001) and preoperative radiculopathy (90% versus 75%; p=0.03) than their counterparts in the MS group. Patients in the MS group had a significantly lower rate of postoperative resolution of myelopathic symptoms in both the short-term (39% in the MS group did not improve versus 23% in the control group; p=0.04) and the long-term (44% in the MS group did not improve versus 19% in the control group; p=0.004). Preoperative myelopathy scores were worse for the MS cohort as compared to the control cohort (1.8 versus 1.2 in the Nurick scale, p<0.0001; 13.7 versus 15.0 in the mJOA scale, p=0.002). This difference in scores became even greater at the last follow up visit with Nurick scores of 2.4 versus 0.9 (p<0.0001) and mJOA scores of 16.3 versus 12.4 (p<0.0001) for the MS and control patients, respectively. Myelopathic patients with coexisting MS and CS improve after surgery, although at a lower rate and to a lesser degree than those without MS. Therefore, surgery should be considered for these patients. MS patients should be informed that 1) myelopathy symptoms are less likely to be alleviated completely or may only be alleviated temporarily due to progression of MS, and 2) that surgery can help alleviate neck pain and radicular symptoms.
    The spine journal: official journal of the North American Spine Society 11/2013; · 2.90 Impact Factor
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    ABSTRACT: Massive neuronal loss is a key pathological hallmark of Alzheimer's disease (AD). However, the mechanisms are still unclear. Here we demonstrate that neuroinflammation, cell autonomous to microglia, is capable of inducing neuronal cell cycle events (CCEs), which are toxic for terminally differentiated neurons. First, oligomeric amyloid-beta peptide (AβO)-mediated microglial activation induced neuronal CCEs via the tumor-necrosis factor-α (TNFα) and the c-Jun Kinase (JNK) signaling pathway. Second, adoptive transfer of CD11b+microglia from AD transgenic mice (R1.40) induced neuronal cyclin D1 expression via TNFα signaling pathway. Third, genetic deficiency of TNFα in R1.40 mice (R1.40-Tnfα(-/-)) failed to induce neuronal CCEs. Finally, the mitotically active neurons spatially co-exist with F4/80+ activated microglia in the human AD brain and that a portion of these neurons are apoptotic. Together our data suggest a cell-autonomous role of microglia, and identify TNFα as the responsible cytokine, in promoting neuronal CCEs in the pathogenesis of AD.
    Neurobiology of Disease 10/2013; · 5.62 Impact Factor
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    ABSTRACT: Interleukin 17 (IL-17) is a signature cytokine of Th17 cells. We previously reported that deletion of NF-κB activator 1 (Act1), the key transducer of IL-17 receptor signaling, from the neuroectodermal lineage in mice (neurons, oligodendrocytes and astrocytes) results in attenuated severity of experimental autoimmune encephalomyelitis (EAE). Here we examined the cellular basis of this observation. EAE disease course was unaffected by deletion of Act1 in neurons or mature oligodendrocytes, and Act1 deletion in astrocytes only modestly affected disease course. Deletion of Act1 in NG2(+) glia resulted in markedly reduced EAE severity. Furthermore, IL-17 induced characteristic inflammatory mediator expression in NG2(+) glial cells. IL-17 also exhibited strong inhibitory effects on the maturation of oligodendrocyte lineage cells in vitro and reduced their survival. These data identify NG2(+) glia as the major CNS cellular target of IL-17 in EAE. The sensitivity of oligodendrocyte lineage cells to IL-17-mediated toxicity further suggests a direct link between inflammation and neurodegeneration in multiple sclerosis.
    Nature Neuroscience 09/2013; · 15.25 Impact Factor
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    ABSTRACT: Fractalkine, a chemokine anchored to neurons or peripheral endothelial cells, serves as an adhesion molecule or as a soluble chemoattractant. Fractalkine binds CX3CR1 on microglia and circulating monocytes, dendritic cells, and NK cells. The aim of this study is to determine the role of CX3CR1 in the trafficking and function of myeloid cells to the CNS during experimental autoimmune encephalomyelitis (EAE). Our results show that, in models of active EAE, Cx3cr1(-/-) mice exhibited more severe neurologic deficiencies. Bone marrow chimeric mice confirmed that CX3CR1 deficiency in bone marrow enhanced EAE severity. Notably, CX3CR1 deficiency was associated with an increased accumulation of CD115(+)Ly6C(-)CD11c(+) dendritic cells into EAE-affected brains that correlated with enhanced demyelination and neuronal damage. Furthermore, higher IFN-γ and IL-17 levels were detected in cerebellar and spinal cord tissues of CX3CR1-deficient mice. Analyses of peripheral responses during disease initiation revealed a higher frequency of IFN-γ- and IL-17-producing T cells in lymphoid tissues of CX3CR1-deficient as well as enhanced T cell proliferation induced by CX3CR1-deficient dendritic cells. In addition, adoptive transfer of myelin oligodendrocyte glycoprotein35-55-reactive wild-type T cells induced substantially more severe EAE in CX3CR1-deficient recipients when compared with wild-type recipients. Collectively, the data demonstrate that besides its role in chemoattraction, CX3CR1 is a key regulator of myeloid cell activation contributing to the establishment of adaptive immune responses.
    The Journal of Immunology 07/2013; · 5.52 Impact Factor
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    ABSTRACT: Identifying and blocking chemokine inflammatory mediators in pediatric opsoclonus-myoclonus syndrome (OMS) is critical to the treatment of this autoimmune, paraneoplastic, neurological disorder. In a prospective, case-control, clinico-scientific study of children with OMS compared to non-inflammatory neurological controls and other inflammatory neurological disorders, CCL19 (n=369) and CCL21 (n=312) were quantified in CSF and serum, respectively, by ELISA. Both cross-sectional and longitudinal effects of OMS and various immunotherapies were evaluated. Significant upregulation of CCL21 concentration (mean±SD) (+32%) was found in serum of untreated OMS (630±133pg/mL), compared to controls (478±168pg/mL), (p<0.0001). Both corticosteroids and ACTH (corticotropin) significantly lowered CCL21 to control levels, as they did in combination with IVIg, rituximab, cyclophosphamide or other treatments, without additional reduction attributable to the other agents. In a pilot longitudinal study of ACTH-based triple therapy, the mean serum CCL21 concentration fell 59% from elevated to less than 1 SD below controls 1week after high-dose ACTH, gradually returning to the control mean with ACTH tapering by 3weeks and out to 12weeks (p<0.0001). In contrast, CCL19, detectable in CSF, was not significantly altered by OMS or various immunotherapies. In the "high" CCL21 subgroup, higher serum concentrations of CCL22 (+57%) and CXCL13 (+40%), as well as the CSF concentration of BAFF (+64%), also were found. Elevated serum CCL21, not CSF CCL19, correlates with OMS severity and duration in pediatric OMS. Corticosteroids and ACTH were the only immunotherapies evaluated that down-regulated CCL21 production. Validation studies are needed to assess treatment biomarker status.
    Cytokine 06/2013; · 2.52 Impact Factor

Publication Stats

20k Citations
2,834.29 Total Impact Points

Institutions

  • 1998–2014
    • Lerner Research Institute
      Cleveland, Ohio, United States
  • 2013
    • Southern Illinois University School of Medicine
      • Department of Neurology
      Springfield, IL, United States
    • University of New Mexico
      Albuquerque, New Mexico, United States
    • Shanghai Jiao Tong University
      Shanghai, Shanghai Shi, China
    • University of Texas at San Antonio
      • Department of Biology
      San Antonio, TX, United States
  • 2011–2013
    • Barrow Neurological Institute
      Phoenix, Arizona, United States
    • Universitätsklinikum Freiburg
      • Institute of Neuropathology
      Freiburg, Lower Saxony, Germany
    • Mayo Clinic - Rochester
      • Department of Neurology
      Rochester, MN, United States
    • University of Washington Seattle
      • Division of General Internal Medicine
      Seattle, WA, United States
  • 1989–2013
    • Cleveland Clinic
      • • Department of Immunology
      • • Neurological Institute
      • • Department of Neurosciences
      • • Head and Neck Institute
      • • Research Institute
      • • Department of Molecular Biology
      Cleveland, Ohio, United States
    • Cleveland Medical Devices Inc.
      Cleveland, Ohio, United States
  • 2012
    • Osaka University
      • Experimental Immunology Group
      Ibaraki, Osaka-fu, Japan
  • 2009–2011
    • University of California, Irvine
      • Department of Molecular Biology and Biochemistry
      Irvine, CA, United States
    • Nagoya University
      • Division of Otorhinolaryngology
      Nagoya-shi, Aichi-ken, Japan
    • Rowe Neuroscience Institute
      Lenexa, Kansas, United States
  • 2008–2011
    • University of Southern California
      • Department of Pathology
      Los Angeles, California, United States
    • Massachusetts General Hospital
      • Department of Neurology
      Boston, MA, United States
    • Comprehensive Cancer Centers of Nevada
      Las Vegas, Nevada, United States
    • Sapienza University of Rome
      • Department of Physiology and Pharmacology "Vittorio Erspamer"
      Roma, Latium, Italy
  • 2010
    • Case Western Reserve University
      • Department of Neurosciences
      Cleveland, OH, United States
    • University of Rome Tor Vergata
      Roma, Latium, Italy
    • Pierre and Marie Curie University - Paris 6
      Lutetia Parisorum, Île-de-France, France
  • 2005–2009
    • University of Nebraska at Omaha
      • Department of Pharmacology and Experimental Neuroscience
      Omaha, NE, United States
    • University of Miami Miller School of Medicine
      • Department of Neurology
      Miami, FL, United States
    • Universität Bern
      Berna, Bern, Switzerland
  • 2007
    • Case Western Reserve University School of Medicine
      Cleveland, Ohio, United States
  • 2006
    • University of California, San Francisco
      • Division of Hospital Medicine
      San Francisco, CA, United States
    • Concordia University–Ann Arbor
      Ann Arbor, Michigan, United States
  • 1995–2006
    • Multiple Sclerosis Research Center of New York
      New York City, New York, United States
  • 1995–2005
    • University of Lodz
      • Department of Neurobiology
      Łódź, Łódź Voivodeship, Poland
  • 2004
    • University of Vienna
      • Brain Research Institute
      Vienna, Vienna, Austria
  • 2001
    • Glostrup Hospital
      • Department of Neurology
      Copenhagen, Capital Region, Denmark
  • 1996
    • Bristol-Myers Squibb
      New York City, New York, United States
  • 1992
    • University of Vermont
      • Department of Neurological Sciences
      Burlington, VT, United States