Journal of Neuroimmunology (J NEUROIMMUNOL)

Publications in this journal

• Article: Differential targeting of immune-cells by Pixantrone in experimental myasthenia gravis

  Marolda R, Ruocco C, Cordiglieri C, Toscani C, Antozzi C, Mantegazza R, Baggi F
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  ABSTRACT: Pixantrone was shown to reduce the severity of clinical manifestation in experimental myasthenia gravis. In the present work we further studied its therapeutic effect. Our results demonstrate that a single administration suppressed AChR-specific immune-responses in primed rats. However, clinical symptoms could be improved only by repeated drug administrations (q7dx6 protocol-8.12mg/kg); this treatment allowed stable serum drug levels for at least 7days, as assessed by a functional T-cell bioassay. Pixantrone exerted strong in vitro inhibitory effect only on proliferating T-cells without impairing dendritic cell differentiation and B-cell viability. Our data further demonstrate that Pixantrone is a promising immunosuppressant drug that should be investigated in myasthenia gravis.
  Journal of Neuroimmunology 03/2013;
• Article: Cell adhesion molecule 1 (CADM1) on mast cells promotes interaction with dorsal root ganglion neurites by heterophilic binding to nectin-3.

  Tadahide Furuno, Man Hagiyama, Miho Sekimura, Keisuke Okamoto, Ryo Suzuki, Akihiko Ito, Naohide Hirashima, Mamoru Nakanishi
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  ABSTRACT: Cell adhesion molecule 1 (CADM1) on mast cells promotes attachment and communication with neurons by homophilic binding. However, we found that mast cell CADM1 was responsible for both the attachment of mast cells to dorsal root ganglia (DRG) neurites and their calcium responses to activated DRG neurites, despite the low expression of CADM1 in DRG. Instead, nectin-3 was expressed on DRG neurons and localized to regions of cell-cell contact. A neutralizing antibody to nectin-3 inhibited both mast cell attachment and subsequent calcium responses. This suggests that heterophilic binding between CADM1 and nectin-3 mediates functional DRG-mast cell interactions in vitro.
  Journal of Neuroimmunology 06/2012; 250(1-2):50-8.
• Article: Anti-MuSK- and anti-AChR-positive myasthenia gravis inducedby D-penicillamine

  Konstantinos Poulas a, Euphrosyni Koutsouraki c, Gregory Kordas a, Anna Kokla b, Socrates J. Tzartos a
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  ABSTRACT: a b s t r a c t Article history: Received 6 November 2011 Received in revised form 17 March 2012 Accepted 16 May 2012 Background: Myasthenia gravis (MG) is an autoimmune disorder of the neuromuscular junction usually caused by antibodies to the nicotinic acetylcholine receptor (AChR) and occasionally to muscle-specific kinase (MuSK). D-penicillamine is a therapeutic agent for several diseases, but can also induce a number of immunemediated disorders, including MG, as a side-effect. In most patients with D-penicillamine-induced MG, anti- AChR antibodies are detected, but the presence of anti-MuSK antibodies has not been reported previously. Case: The case reported was a female patient who presented with myasthenic symptoms after D-penicillamine administration for scleroderma. Results: Both anti-AChR and anti-MuSK antibodies were identified in the patient's serum. The anti-MuSK antibodies were of the IgG4 subclass, as in idiopathic MG. Both types of antibody gradually disappeared after discontinuation of D-penicillamine. A significant improvement in symptoms was observed and the patient gradually became free of MG symptoms, without requiring any treatment for MG. Another four doublepositive (anti-AChR and anti-MuSK antibodies) patients were identified during a retrospective study, but none had been treated with D-penicillamine. Conclusion: D-penicillamine can cause anti-AChR and anti-MuSK antibody-positive MG, a rare phenomenon which is reversed after discontinuation of D-penicillamine treatment.
  Journal of Neuroimmunology 05/2012;
• Article: The microRNAs miR-183 and miR-9-2 target Nurr1 and SOCS2 genes, establishing a negative feedback loop that inhibits inflammation in multiple sclerosis

  Francesca Gilli, Nicole D Navone, Simona Perga, Cristian Cosentino, Cristina Barlassina, Maddalena Arigoni, Raffaele A Calogero, Antonio Bertolotto
  Journal of Neuroimmunology 01/2012; 253(1-2):62.
• Article: Administration of dehydroepiandrosterone ameliorates experimental autoimmune neuritis in Lewis rats.

  Xiao-Dong Tan, Ying-Chun Dou, Chang-Wen Shi, Rui-Sheng Duan, Ruo-Peng Sun
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  ABSTRACT: Dehydroepiandrosterone (DHEA) is an abundant adrenal steroid in serum of humans, and has been reported to have anti-inflammatory, anti-proliferative, and certain immune-regulating properties. Experimental autoimmune neuritis (EAN) is a Th1 cell-mediated animal model of Guillain-Barré syndrome (GBS) in humans. In the present study, DHEA was administered subcutaneously to Lewis rats immunized with bovine peripheral myelin (BPM) in Freund's complete adjuvant. Rats treated with DHEA displayed significant delay in onset, decreased inflammatory cell infiltration in the PNS. Benefit was associated with significant decreases in numbers of IFN-gamma and TNF-alpha expressing cells in the PNS, BPM-stimulated T cell proliferation and IFN-gamma, TNF-alpha-secretion in the spleen cells. Only 2 mg DHEA-treated EAN rats decreased peak clinical score. No significant difference of supernatant IL-10 was found among the treatment and control groups. These results suggest that DHEA can ameliorate the severity of EAN by suppressing the proliferation of autoreactive T cell and expression of pro-inflammatory cytokines.
  Journal of Neuroimmunology 02/2009; 207(1-2):39-44.
• Article: Delta9-tetrahydrocannabinol and cannabidiol modulate mitogen-induced tryptophan degradation and neopterin formation in peripheral blood mononuclear cells in vitro.

  Marcel Jenny, Elisabeth Santer, Eberhard Pirich, Harald Schennach, Dietmar Fuchs
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  ABSTRACT: Nanomolar concentrations of Delta9-tetrahydrocannabinol or cannabidiol are demonstrated to enhance mitogen-induced degradation of tryptophan in human peripheral blood mononuclear cells in dependence of CB1- or CB2-receptor activation. In contrast, suppression of this pathway by cannabinoids in the micromolar concentration range was achieved independent of cannabinoid receptor activation. Both cannabinoids also suppressed tryptophan degradation in myelomonocytic THP-1 cells stimulated with lipopolysaccharide. We conclude, that suppression of tryptophan degradation by cannabinoids via indoleamine-2,3-dioxygenase, which is independent of cannabinoid receptor activation, might enhance the availability of tryptophan for serotonin biosynthesis and consequently can be important in the action of cannabinoids to improve mood disturbances.
  Journal of Neuroimmunology 02/2009; 207(1-2):75-82.
• Article: Chronic CXCL10 alters neuronal properties in rat hippocampal culture.

  Jungsook Cho, Thomas E Nelson, Hilda Bajova, Donna L Gruol
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  ABSTRACT: The chemokine CXCL10 is expressed in the central nervous system (CNS) during neuroinflammatory conditions. Neurons express CXCR3, the receptor for CXCL10, and neuronal function has been shown to be altered by acute exposure to CXCL10. Little is known about the effects of chronic exposure to CXCL10 on neuronal function. Results from our studies show that chronic exposure of cultured rat hippocampal neurons to CXCL10 results in altered levels of protein for GABA and glutamate receptors and altered synaptic network activity. These effects of CXCL10 may contribute to altered CNS function that occurs in some chronic neuroinflammatory conditions.
  Journal of Neuroimmunology 02/2009; 207(1-2):92-100.
• Article: TRPA1 and TRPV1 activation is a novel adjuvant effect mechanism in contact hypersensitivity.

  Takahiro Shiba, Takashi Maruyama, Kohta Kurohane, Yusaku Iwasaki, Tatsuo Watanabe, Yasuyuki Imai
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  ABSTRACT: We have revealed that local stimulation of sensory neurons is involved in the adjuvant effect of dibutyl phthalate (DBP) in a fluorescein isothiocyanate-induced mouse contact hypersensitivity model. Transient receptor potential (TRP) A1 and TRPV1 seemed to be candidate DBP targets. Here we directly demonstrated that DBP activates a subset of neurons in mouse dorsal root ganglia responsive to TRPA1 and TRPV1 agonists. TRPA1 and TRPV1 activation was further demonstrated using cultured cells expressing TRP channels. Among structurally different phthalate esters, there is a positive relationship between the activation of TRPA1- or TRPV1-expressing cells and the adjuvant effect.
  Journal of Neuroimmunology 02/2009; 207(1-2):66-74.
• Article: Neuropsychiatric manifestations of systemic lupus erythematosus - A primary disease manifestation.

  Nancy Agmon-Levin, Kivity Shaye, Yehuda Shoenfeld
  Journal of Neuroimmunology 02/2009; 207(1-2):1-2.
• Article: Deletion of the G2A receptor fails to attenuate experimental autoimmune encephalomyelitis.

  Inga Osmers, Sherry S Smith, Brian W Parks, Shaohua Yu, Roshni Srivastava, Jillian E Wohler, Scott R Barnum, Janusz H S Kabarowski
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  ABSTRACT: Lysophosphatidylcholine (LPC) is a chemotactic lysolipid produced during inflammation by the hydrolytic action of phospholipase A(2) enzymes. LPC stimulates chemotaxis of T cells in vitro through activation of the G protein-coupled receptor, G2A. This has led to the proposition that G2A contributes to the recruitment of T cells to sites of inflammation and thus promotes chronic inflammatory autoimmune diseases associated with the generation and subsequent tissue infiltration of auto-antigen-specific effector T cells. However, one study suggests that G2A may negatively regulate T cell proliferative responses to antigen receptor engagement and thereby attenuates autoimmunity by reducing the generation of autoreactive T cells. To address the relative contribution of these G2A-mediated effects to the pathophysiology of T cell-mediated autoimmune disease, we examined the impact of G2A inactivation on the onset and severity of murine experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS). Wild type (G2A(+/+)) and G2A-deficient (G2A(-/-)) C57BL/6J mice exhibited a similar incidence and onset of disease following immunization with MOG(35-55) peptide. Disease severity was only moderately reduced in G2A(-/-) mice. Similar numbers of MOG(35-55) specific T cells were generated in secondary lymphoid organs of MOG(35-55)-immunized G2A(+/+) and G2A(-/-) mice. Comparable numbers of T cells were detected in spinal cords of G2A(+/+) and G2A(-/-) mice. We conclude that the proposed anti-proliferative and chemotactic functions of G2A are not manifested in vivo and therefore therapeutic targeting of G2A is unlikely to be beneficial in the treatment of MS.
  Journal of Neuroimmunology 02/2009; 207(1-2):18-23.
• Article: Depression is an early disease manifestation in lupus-prone MRL/lpr mice.

  Hua-Xin Gao, Sean R Campbell, Min-Hui Cui, Pu Zong, Jong Hee-Hwang, Maria Gulinello, Chaim Putterman
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  ABSTRACT: Many lupus patients develop neuropsychiatric manifestations, including cognitive dysfunction, depression, and anxiety. However, it is not clear if neuropsychiatric lupus is a primary disease manifestation, or is secondary to non-CNS disease. We found that MRL/lpr lupus-prone mice exhibited significant depression-like behavior already at 8 weeks of age, despite normal visual working memory, locomotor coordination and social preference. Moreover, depression was significantly correlated with titers of autoantibodies against DNA, NMDA receptors and cardiolipin. Our results indicate that lupus mice develop depression and CNS dysfunction very early in the course of disease, in the absence of substantial pathology involving other target organs.
  Journal of Neuroimmunology 02/2009; 207(1-2):45-56.
• Article: Changes in circulating dendritic cells and B-cells in patients with multiple sclerosis relapse during corticosteroid therapy.

  Mitosek-Szewczyk Krystyna, Tabarkiewicz Jacek, Radej Sebastian, Belniak Ewa, Bartosik-Psujek Halina, Stelmasiak Zbigniew, Rolinski Jacek
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  ABSTRACT: We studied dendritic, myeloid (mDCs) (BDCA1+/CD19-) and plasmacytoid cells (pDCs) (BDCA2+/CD123+) and B-cells (CD19+) at relapse, after short intravenous methyloprednisolone therapy and 30 days after treatment completion (remission period) and results were compared with a control group of healthy volunteers. We confirmed the decrease in BDCA2+/CD123+ after therapy (p=0.00006) and then an increase (p=0.0032) in comparison to the control group. The level of B CD19+ cells after GC therapy increased compared to the control group (p=0.00809) and had stabilised 30 days after therapy. The effect of methyloprednisolone on DC function and B-cell levels thus changes.
  Journal of Neuroimmunology 02/2009; 207(1-2):107-10.
• Article: Elevated immune response in the brain of autistic patients.

  Xiaohong Li, Abha Chauhan, Ashfaq M Sheikh, Sangita Patil, Ved Chauhan, Xiu-Min Li, Lina Ji, Ted Brown, Mazhar Malik
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  ABSTRACT: This study determined immune activities in the brain of ASD patients and matched normal subjects by examining cytokines in the brain tissue. Our results showed that proinflammatory cytokines (TNF-alpha, IL-6 and GM-CSF), Th1 cytokine (IFN-gamma) and chemokine (IL-8) were significantly increased in the brains of ASD patients compared with the controls. However the Th2 cytokines (IL-4, IL-5 and IL-10) showed no significant difference. The Th1/Th2 ratio was also significantly increased in ASD patients. Conclusion: ASD patients displayed an increased innate and adaptive immune response through the Th1 pathway, suggesting that localized brain inflammation and autoimmune disorder may be involved in the pathogenesis of ASD.
  Journal of Neuroimmunology 02/2009; 207(1-2):111-6.
• Article: Administration of bone marrow stromal cells ameliorates experimental autoimmune myasthenia gravis by altering the balance of Th1/Th2/Th17/Treg cell subsets through the secretion of TGF-beta.

  Qing-Fei Kong, Bo Sun, Sha-Sha Bai, Dong-Xu Zhai, Guang-You Wang, Yu-Mei Liu, Shu-Juan Zhang, Rui Li, Wei Zhao, Yan-Yan Sun, Na Li, Qi Wang, Hai-Sheng Peng, Lian-Hong Jin, Hu-Lun Li
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  ABSTRACT: Bone marrow stromal cells (BMSCs) are strong candidates for cell therapy against human autoimmune diseases. Intravenous administration of syngenic BMSCs to EAMG-model rats effectively ameliorated the disease, partially through a TGF-beta-dependent mechanism. The proliferative ability of T or B cells from EAMG rats was inhibited by BMSCs at proper cocultured ratios. And the imbalance of Th1, Th2, Th17 and Treg cell subsets accompanied with the development of EAMG was corrected by the administration of BMSCs. These results provide further insights into the pathogenesis of MG, EAMG, and other immune-mediated diseases, and support a potential role for BMSCs in their treatment.
  Journal of Neuroimmunology 02/2009; 207(1-2):83-91.
• Article: Interferon alpha and neuromuscular disorders.

  Joerg-Patrick Stübgen
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  ABSTRACT: Interferon-alpha (IFNalpha) is a potent extracellular protein mediator of host defense and homeostasis. IFNalpha has well-established direct antiviral, antiproliferative and immunomodulatory properties. The worldwide, increasing and long-term use of IFNalpha, particularly for the treatment of chronic hepatitis C virus infection, has drawn attention to the development or exacerbation of numerous autoimmune phenomena, including a variety of neuropathy syndromes, neuromuscular junction disorders and myopathies. Management entailed withdrawal of IFNalpha therapy with supportive, immunomodulatory, and symptomatic treatment as clinically indicated. The mechanisms of IFNalpha-induced autoimmunity are incompletely understood, and likely vary depending on the inherent differences in the pathogenesis of the immune disorder on a background of patient genetic susceptibility. In addition, there is preliminary evidence from case reports and open-label studies that the immunomodulatory effects of IFNalpha may have potential as a treatment option for a spectrum of immune-mediated neuromuscular diseases, but further studies are needed.
  Journal of Neuroimmunology 02/2009; 207(1-2):3-17.
• Article: The analysis of IL-1 beta and its naturally occurring inhibitors in multiple sclerosis: The elevation of IL-1 receptor antagonist and IL-1 receptor type II after steroid therapy.

  Irena Dujmovic, Katia Mangano, Tatjana Pekmezovic, Cinzia Quattrocchi, Sarlota Mesaros, Nebojsa Stojsavljevic, Ferdinando Nicoletti, Jelena Drulovic
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  ABSTRACT: The aim of our investigation was to analyze the pattern of interleukin-1 (IL-1) family compounds: IL-1 beta, IL-1 receptor accessory protein (Acp), IL-1 receptor antagonist (IL-1Ra) and IL-1 receptor type II (IL-1RII) in the serum and cerebrospinal fluid (CSF) from 67 multiple sclerosis (MS) patients and 31 controls. We found significantly elevated CSF levels of IL-1 beta, IL-1Ra and Acp in MS patients compared to controls (p=0.001), while IL-1 beta and Acp were significantly elevated in MS sera (p=0.001). IL-1Ra and/or IL-1 RII increased in sera of all 10 investigated patients after the steroid treatment for relapse. Our findings suggest the important beneficial role of the induction of IL-1 RII and IL-1Ra in MS.
  Journal of Neuroimmunology 02/2009; 207(1-2):101-6.
• Article: Complement inhibitor prevents disruption of sodium channel clusters in a rabbit model of Guillain-Barré syndrome.

  Vongsavanh Phongsisay, Keiichiro Susuki, Kenjiro Matsuno, Takuyu Yamahashi, Saori Okamoto, Kei Funakoshi, Koichi Hirata, Motoo Shinoda, Nobuhiro Yuki
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  ABSTRACT: Complement-mediated disruption of voltage-gated sodium channels at the nodes of Ranvier acts in the development of acute motor axonal neuropathy. Nafamostat mesilate, a synthetic serine protease inhibitor, used in clinical practice for more than 20 years, has anti-complement activity. Acute motor axonal neuropathy rabbits obtained by GM1 ganglioside sensitization were or were not given nafamostat mesilate intravenously. Complement deposition and sodium channel disruption in the spinal anterior roots were significantly less frequent in the treated rabbits than in the controls. Nafamostat mesilate inhibited complement deposition and prevented sodium channel disruption. This provided the rationale for a clinical trial.
  Journal of Neuroimmunology 01/2009; 205(1-2):101-4.