Journal of Neuroimmunology - Articles in Press

The TLR7 agonist, imiquimod, increases IFN-β production and reduces the severity of experimental autoimmune encephalomyelitis - Corrected Proof

Kate O'Brien, Denise Fitzgerald, Abdolmohamad Rostami, Bruno Gran — 2010-02-08

Abstract: Experimental autoimmune encephalomyelitis (EAE) is a well-characterised model of autoimmune inflammatory demyelination. Toll-like receptors (TLRs) recognise microbial components and initiate innate immune responses. We report in this study that TLR7 stimulation by imiquimod, a synthetic analog of ssRNA, suppresses disease severity in a chronic EAE model. Disease suppression is associated with increased IFN-β production in spleens of mice treated with imiquimod. In vitro experiments on pDCs, which express high levels of TLR7 and are potent producers of IFN-β, suggest that an amplification loop involving TLR7 and IFNAR is required for the observed effects.

Glial cell line-derived neurotrophic factor is increased in cerebrospinal fluid but decreased in blood during long-term pain - Corrected Proof

Christopher Lundborg, Mirjana Hahn-Zoric, Björn Biber, Elisabeth Hansson — 2010-02-03

Abstract: Glial cell line-derived neurotrophic factor (GDNF) is involved in inflammation and pain, roles which remain to be delineated clinically.We aimed to evaluate the role of central nervous and peripheral GDNF in long-term pain patients and in controls by analysing intrathecal and blood concentrations of GDNF. Simultaneous measurements of pro-inflammatory cytokines IL-1β, TNF-α and IL-6, anti-inflammatory cytokine IL-10 and chemokine IL-8 served to define inflammatory responses.Generally, blood levels of GDNF were higher than corresponding intrathecal levels. Pain was associated with levels of GDNF that were increased intrathecally, but decreased in blood. IL-8 was uniformly higher in pain patients.

The effect of electroacupuncture on T cell responses in rats with experimental autoimmune encephalitis - Corrected Proof

2010-02-01

Abstract: Successive electroacupuncture (EA) stimulation on Zusanli ST36 acupoints of rats with experimental autoimmune encephalitis (EAE), which is an inflammatory disease mediated by autoreactive T cells, relieved disease severity, inhibited specific T cell proliferation and rebuilt the CD4+ T cell subset balance. In addition, EA-treated rats had significantly higher ACTH concentrations in vivo compared to untreated EAE rats. These results indicated that EA stimulation could relieve the severity of EAE by restoring balance to the Th1/Th2/Th17/Treg Th cell subset responses by stimulating the hypothalamus to increase ACTH secretion.

Substance P downregulates expression of the high affinity IgE receptor (FcεRI) by human mast cells - Corrected Proof

2010-02-01

Abstract: The effect of the neuropeptide substance P (SP) on human mast cell (MC) phenotype is poorly understood. In this study, SP effects on human MC expression of the high affinity IgE receptor (FcεRI) were characterized. SP downregulated expression of FcεRI mRNA and protein by approximately 50% and in a concentration dependent manner, the effect was partially mediated by engagement of the neurokinin-1 receptor (NK1R) and resulted in reduced mast cell activation. Sensitization of MC with IgE prior to SP exposure protected MC from SP-mediated FcεRI downregulation. SP release may inhibit MC responses to allergens and these results may have implications in neuroinflammatiion and stress.

IFN-β reverses the lipopolysaccharide-induced proteome modifications in treated astrocytes - Corrected Proof

2010-02-01

Abstract: Astrocytes have a key role in the pathogenesis of several diseases, including multiple sclerosis, and are proposed as a possible target for immunotherapy.Our earlier study reported that astrocytes treated with IFN-β modified their biomechanical properties possibly due to changes in the expression of the proteins involved in cytoskeleton organization and other important physiological processes.To gain insight into the mechanism underlying IFN-β action during inflammation, we stimulated astrocytes with LPS, a bacterial wall component used as a model for both in vitro and in vivo immunological stimulation of microglia and astrocytes.We showed that IFN-β reverses the effects of LPS on the proteome of astrocytes. To better examine this result, we performed a proteomic analysis of astrocytes treated with LPS or LPS plus IFN-β. Treatment with LPS caused increases both in a series of proteins mainly involved in cytoskeletal changes and in protein degradation, as well as protective enzymes like superoxide dismutase. IFN-β reverses LPS effects on astrocyte proteome, supporting its protective role during inflammatory insults.

MGAT5 alters the severity of multiple sclerosis - Corrected Proof

2010-02-01

Abstract: Multiple Sclerosis (MS) is a genetically complex immune mediated, demyelinating disease of the central nervous system. To date no genetic variants have been unambiguously linked to disease severity. We have conducted a genome wide screen, using Affymetrix Genechip® 500K technology, for severity in 1040 MS patients. Two markers within MGAT5, a gene coding for a glycosylation enzyme, were found to be significantly associated with outcome in the screening as well as in an independent population (combined p-values: 2.8×10−6 and 1.5×10−7).

A highly sensitive electrochemiluminescence immunoassay for the neurofilament heavy chain protein - Corrected Proof

2010-02-01

Abstract: Background: The loss of neurological function is closely related to axonal damage. Neurofilament subunits are concentrated in neurons and axons and have emerged as promising biomarkers for neurodegeneration. Electrochemiluminescence (ECL) based assays are known to be of superior sensitivity and require less sample volume than conventional ELISAs.Methods: We developed an ECL based solid-phase sandwich immunoassay to measure the neurofilament heavy chain protein (NfHSMI35) in CSF. We employed commercially available antibodies as previously used in a conventional ELISA (Petzold et al., 2003; Petzold and Shaw, 2007). The optimised and validated assay was applied in a reference cohort and defined patient groups.Results: Analytical sensitivity (background plus three SD) of our assay was 2.4pg/ml. The mean intra-assay coefficient of variation (CV) was 4.8% and the inter-assay CV 8.4%. All measured control and patient samples produced signals well above background. Patients with multiple sclerosis (MS) (median 46.2pg/ml, n=95), amyotrophic lateral sclerosis (ALS) (160.1pg/ml, n=50), mild cognitive impairment/Alzheimer's disease (MCI/AD) (65.6pg/ml, n=20), Guillain–Barre syndrome (GBS) (91.0pg/ml, n=20) or subarachnoid hemorrhage (SAH) (345.0pg/ml, n=20) had higher CSF NfHSMI35 values than the reference cohort (27.1pg/ml, n=73, p<0.0001 for each comparison).Conclusion: The new ECL based assay for NfHSMI35 in CSF is superior in terms of sensitivity, precision and accuracy to previously published methods (Petzold et al., 2003; Shaw et al., 2005; Teunissen et al., 2009). The improved performance and small sample volume requirement qualify this method in experimental settings and clinical trials designed to perform a number of tests on limited amounts of material.

No evidence of association of the rare nsSNP rs35667974 in IFIH1 with multiple sclerosis - Corrected Proof

2010-02-01

Abstract: Studies suggest that different autoimmune diseases share a common genetic background, in particular, an overlap between Multiple Sclerosis (MS) and type 1 diabetes (T1D) susceptibility loci has been established. A recent study found that four rare SNPs in the IFIH1 (interferon induced with helicase C domain 1) were significantly associated with T1D.To establish if these SNPs were also involved in MS susceptibility, we chose to examine the non-synonymous SNP rs35667974/Ile923Val which displayed the strongest effect in T1D and was also shown to lead to a loss of IFIH1 function in an in vitro study. We have performed the first association study to test if this rare variant is involved in MS susceptibility in a very large sample consisting of 3037 MS patients and 10,657 healthy controls recruited from Italy and the UK. This study has 99% power to demonstrate an association at the 5% level with this rare variant. Our analysis shows that the nsSNP rs35667974/Ile923Val does not have a role in susceptibility to MS.

Role of endothelin receptors in the control of central nervous system parasitism in Trypanosoma cruzi infection in rats - Corrected Proof

2010-02-01

Abstract: Endothelin has been implicated in the pathogenesis of experimental and human Chagas disease. In the present study, we investigated whether the treatment with bosentan, an antagonist of both ETA/ETB endothelin receptors, modified parasite load and inflammation in the central nervous system (CNS) of Trypanosoma cruzi-infected rats. The cerebellum was the most affected region in the CNS with marked parasitemia and inflammation. Treatment with bosentan enhanced parasitemia and CNS parasitism, but control of infection was eventually attained. There was also an increase in the levels of the cytokines TNF-α, IL-10, IFN-γ, CCL2/MCP-1, CCL3/MIP-1α and CCL5/RANTES in the brain of infected animals at days 9, 13 and 18 after infection. Overall, bosentan has some effects on the expression of certain cytokines and this may be related to the initial enhanced parasite load. Altogether, our data suggest that endothelin action via ETA and ETB receptors may play a role in the initial resistance of the CNS to T. cruzi infection in rats.

Long-term follow up of thymus in patients with myasthenia gravis - Corrected Proof

2010-01-29

Abstract: We examined transversely the thymus of 33 myasthenia gravis (MG) patients followed up for more than 5years and found three thymomas. One was found 21years after thymoma resection (Masaoka I, WHO Type B2 thymoma) and extended thymectomy. The other two were non-thymomatous at onset, and they were not treated with extended thymectomy. Therapeutic guidelines should mention the importance of follow-up in MG thymus.

Involvement of phosphodiesterases in autoimmune diseases - Corrected Proof

2010-01-25

Abstract: We have previously shown that several phosphodiesterase (PDE) subtypes are up-regulated in muscles and lymph node cells (LNC) of rats with experimental autoimmune myasthenia gravis (EAMG). In the present study we investigated PDE expression during the course of EAMG and experimental allergic encephalomyelitis (EAE) and found that the up-regulated expression of selected PDE subtypes in both experimental models is correlated with disease severity. In EAMG, PDE expression is correlated also with muscle damage. A similar up-regulation of PDE was also observed in the respective human diseases, MG and multiple sclerosis (MS). Our findings suggest that change in PDE expression levels is a general phenomenon in autoimmune diseases and may also be used as a marker for disease severity.

Ovariectomy, a model of menopause in rodents, causes a premature aging of the nervous and immune systems - Corrected Proof

I. Baeza, N.M. De Castro, L. Giménez-Llort, M. De la Fuente — 2010-01-22

Abstract: Ovariectomy in rodents is a good model for mimicking human ovarian hormone loss. This work studies the consequences of ovariectomy on the nervous and immune systems in the context of biological aging. Ovariectomy accelerates the process of aging by impairing the sensorimotor abilities (with loss of muscular vigor and impaired equilibrium and traction capacities) and the exploratory capacities (with reduction of vertical exploratory activity). It also leads to a premature immunosenescence with regard to chemotaxis index, lymphoproliferative response and natural killer activity, parameters investigated in the spleen and axillary nodes. Therefore, ovariectomy deteriorates homeostasis and may be a model of premature aging.

Minocycline attenuates experimental autoimmune encephalomyelitis in rats by reducing T cell infiltration into the spinal cord - Corrected Proof

Maria Nikodemova, JangEun Lee, Zsuzsanna Fabry, Ian D. Duncan — 2010-01-21

Abstract: We investigated the anti-inflammatory effects of minocycline in EAE, an animal model of MS. Minocycline, administered for two weeks after the clinical onset, significantly decreased the cumulative and mean clinical scores of EAE. This was associated with the reduction of both CD4+ and CD8+ T cell numbers in the spinal cord and the downregulation of LFA-1 on T cells without affecting the cytokine production profile. The predominant cytokine produced by T cells in the spleen was IFN-γ whereas in the CNS it was IL-17. Our results indicate that minocycline regulates T cell infiltration into the CNS without modifying the dominant cytokine production.

Protective autoimmunity and protein localization - Corrected Proof

Borros M. Arneth — 2010-01-15

Abstract: The influence of the immune system was originally thought to be harmful regarding injuries and infarctions of the brain. Recently, there has been increasing evidence for the protective, positive effects of cells of the immune system on brain tissue. From an evolutionary biology standpoint, this hypothesis is more compelling than viewing the immune system only as a harmful influence. Herein we emphasize how physiological activation of immune cells following tissue damage and/or by infarcts of brain tissue can lead to an activation of T-lymphocytes. These activated T-lymphocytes are then regarded to perform several protective effects.

Sphingomyelinase dependent apoptosis of dendritic cells following treatment with amyloid peptides - Corrected Proof

2010-01-11

Abstract: Amyloid peptides are formed during inflammation and modify the function of immune cells. The present study explored the effect of amyloid β-peptide (Aβ1–42) and islet amyloid polypeptide (IAPP) on bone marrow derived dendritic cells (DCs). DCs were treated with Aβ1–42 or IAPP with subsequent assessment of ceramide formation, caspase 8 and 3 activity, DNA fragmentation and phosphatidylserine exposure. In addition, TNFα secretion was assessed in lypopolysaccharide (LPS)-stimulated Aβ1–42- or IAPP-treated DCs. Within 24h Aβ1–42 and IAPP triggered ceramide formation, caspase 8 and caspase 3 activation, DNA fragmentation and annexin V binding in DCs obtained from wild type mice, whereas in DCs from sphingomyelinase deficient (asm−/−) mice and in wild type DCs treated with sphingomyelinase inhibitor amitriptyline all these effects were strongly impaired. Moreover, ceramide formation was also reduced in wild type DCs in which acid sphingomyelinase (Asm) was silenced with Asm-targeted siRNA. Finally, Aβ1–42 and IAPP treatment was further followed by a decline of TNFα formation in wild type DCs. In conclusion, amyloid peptides induce DC apoptosis presumably through activation of acid sphingomyelinase resulting in production of ceramide.

Noradrenaline reuptake inhibitors inhibit expression of chemokines IP-10 and RANTES and cell adhesion molecules VCAM-1 and ICAM-1 in the CNS following a systemic inflammatory challenge - Corrected Proof

Joan B. O'Sullivan, Karen M. Ryan, Andrew Harkin, Thomas J. Connor — 2010-01-11

Abstract: Evidence suggests that noradrenaline has a tonic anti-inflammatory action in the central nervous system (CNS) via its ability to inhibit expression of inflammatory mediators from glial cells. Consequently it is suggested that noradrenaline may play an endogenous neuroprotective role in CNS disorders where inflammatory events contribute to pathology. Infiltration of peripheral immune cells into the brain is driven by increased chemokine and cell adhesion molecule (CAM) expression, and is known to exacerbate neuroinflammation and thereby contribute to the disease process in a number of neurodegenerative disease states. Here we demonstrate that treatment of rats with the noradrenaline reuptake inhibitors (NRIs) desipramine and atomoxetine, agents that increase extracellular noradrenaline in the CNS, suppressed chemokine and cell adhesion molecule (CAM) expression in rat brain following a systemic challenge with bacterial lipopolysaccharide (LPS). Specifically, these agents reduced expression of the chemokines, interferon-inducible protein-10 (IP-10, CXCL-10) and regulated upon activation normal T-cell expressed and secreted (RANTES, CCL-5), and the CAMs, vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule (ICAM-1) in cortex and hippocampus. The inhibitory action of NRIs on chemokines and CAM expression was mimicked by in vitro exposure of cultured glial cells to noradrenaline, but not to the NRIs themselves. These data indicate that the suppressive action of NRIs on chemokine and CAM expression that occurs in vivo is due to increased noradrenaline availability at glial cells, as opposed to a direct action of the drugs on glial cells per se. These results support the theory that noradrenaline has anti-inflammatory properties, and agents that increase noradrenaline availability in vivo can play a role in combating brain inflammation by reducing expression of chemokines and CAMs; molecules that facilitate leucocyte influx into the CNS.

Increased expression of B cell-associated regulatory cytokines by glatiramer acetate in mice with experimental autoimmune encephalomyelitis - Corrected Proof

2009-12-25

Abstract: B cells are of increasing importance as a target for multiple sclerosis treatment. Here we show that GA treatment of mice with experimental autoimmune encephalomyelitis (EAE) biases cytokine production by B cells towards cytokines associated with regulation in MS including interleukin (IL)-4, -10 and -13 and reduces pro-inflammatory IL-6, IL-12, and TNF alpha levels. GA also down-regulates expression of B cell-activating factor (BAFF) of the TNF family and a proliferation-inducing ligand (APRIL), as well as the BAFF receptor in mice with EAE. Thus, GA impacts both B cell survival and B cell cytokine production during CNS inflammatory disease in an EAE model.

Clinical, electrophysiological and pathologic correlations in a severe murine experimental autoimmune neuritis model of Guillain–Barré syndrome - Corrected Proof

Robin H. Xia, Nejla Yosef, Eroboghene E. Ubogu — 2009-12-25

Abstract: Severe murine experimental autoimmune neuritis (sm-EAN) in SJL/J mice is a recently described, but incompletely characterized mouse model of Guillain–Barré syndrome (GBS). Electrophysiological and pathologic characterization during the disease course is a necessary prerequisite to designing mechanistic studies that may be relevant to GBS pathogenesis. Sm-EAN is a monophasic disorder with electrophysiological evidence for a diffuse demyelinating polyneuropathy with axonal loss at peak severity. Regression analyses demonstrated strong correlations between neuromuscular severity scores and electrophysiological parameters during the disease course. Progressive multi-focal or diffuse demyelination with axonal loss was observed pathologically in sciatic nerves in association with mononuclear cell infiltrates (F4/80+ macrophages>CD3+ T-lymphocytes>CD19+ B-lymphocytes), peaking at maximal severity. Regression analyses demonstrated strong correlations between severity scores and inflammatory cell counts. The correlative data imply that mononuclear infiltration, as well as demyelination and axonal loss are directly related to the observed neuromuscular weakness in sm-EAN. The high induction rates, as well as pathologic similarities with AIDP make sm-EAN a robust model to study the pathogenesis of human peripheral nerve inflammation using objective outcome measures.

Chemical destruction of brain noradrenergic neurons affects splenic cytokine production - Corrected Proof

2009-12-25

Abstract: The neurotransmitter noradrenaline (NA) plays a pivotal role in immune regulation. Here we used the selective neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) to investigate the impact of central NA depletion on cytokine production by splenic monocytes/macrophages and T cells. Intraperitoneal administration of DSP-4 in adult rats induced a substantial reduction of noradrenergic neurons in the locus coeruleus and the A5 cell group. The degeneration of brainstem noradrenergic neurons was accompanied by a significant decrease in the production of interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α by lipopolysaccharide-stimulated splenocytes. In addition, upon T cell receptor stimulation with anti-CD3, isolated splenocytes of DSP-4 treated animals produced significantly less interferon (IFN)-γ but not IL-2 and IL-4. The proportion of monocytes/macrophages and T cells in the spleen remained unaffected by the neurotoxin treatment, however, the percentage of natural killer cells decreased significantly. The findings suggest that a certain level of central noradrenergic tone is required for normal functioning of peripheral immune cells.

Oxidative stress in Egyptian children with autism: relation to autoimmunity - Corrected Proof

Gehan A. Mostafa, Eman S. El-Hadidi, Doaa H. Hewedi, Mohammed M. Abdou — 2009-12-25

Abstract: We are the first to study the relationship between oxidative stress (by measuring plasma F2-isoprostane, as a marker of lipid peroxidation, and glutathione peroxidase, as an antioxidant enzyme) and autoimmunity (as indicated by serum antineuronal antibodies) in a group of 44 Egyptian autistic children and 44 healthy matched-children. Our results showed that oxidative stress was found in 88.64% of autistic children. Oxidative stress, resulting from elevated plasma F2-isoprostane and/or reduced glutathione peroxidase, had significant risk for antineuronal positivity, which was found in 54.5% of autistic children, (odds ratio: 12.38 and 6.43, respectively, confidence interval: 1.37–112.10 and 1.21–34.19, respectively). Conclusions: the strong association between oxidative stress and autoimmunity in autistic children may indicate the possible role of oxidative stress, through induction of autoimmunity, in some autistic patients. Therefore, studies considering the role of antioxidants and immunotherapy in amelioration of autistic manifestations are recommended.

Peripheral origin of IL-1β production in the rodent hippocampus under in vivo systemic bacterial lipopolysaccharide (LPS) challenge and its regulation by P2X7 receptors - Corrected Proof

C. Csölle, B. Sperlágh — 2009-12-21

Abstract: In this study we showed that in vivo bacterial lipopolysaccharide (LPS) challenge elevated IL-1β level in the rodent hippocampus. Antagonists of P2X receptors inhibited LPS-induced IL-1β level with a pharmacological profile similar to that of P2X7R and their inhibitory effect was attenuated in the absence of P2X7R. In wild-type mice, LPS overexpressed mRNA encoding P2X4 and P2X7 receptors in the hippocampus and caused also a remarkable increase in the levels of IL-1β in the serum. The hippocampal increase of IL-1β has substantially alleviated when contamination of circulating blood cells was excluded by transcardial perfusion, indicating the peripheral origin of hippocampal IL-1β elevation. These results point to the key role of the endogenous activation of peripheral P2X7R in the level of IL-1β in rodent hippocampus under systemic bacterial endotoxin challenge.

An epitope from Acanthamoeba castellanii that cross-react with proteolipid protein 139-151-reactive T cells induces autoimmune encephalomyelitis in SJL mice - Corrected Proof

Chandirasegaran Massilamany, David Steffen, Jay Reddy — 2009-12-14

Abstract: We report here that an epitope (aa, 83-95) derived from Acanthamoeba castellanii (ACA) induces clinical signs of experimental autoimmune encephalomyelitis (EAE) in SJL/J mice reminiscent of the disease induced with myelin proteolipid protein (PLP) 139-151. By using IAs/tetramers, we demonstrate that both ACA 83-95 and PLP 139-151 generate antigen-specific cross-reactive CD4 T cells and the T cells secrete identical patterns of cytokines and induce EAE with a similar severity. These results may provide insights into the pathogenesis of multiple sclerosis and ACA-induced granulomatous encephalitis.

Anti-ganglioside complex IgM antibodies in multifocal motor neuropathy and chronic immunemediated neuropathies - Corrected Proof

Eduardo Nobile-Orazio, Claudia Giannotta, Chiara Briani — 2009-12-14

Abstract: Anti-ganglioside complexes (GSCs) IgG antibodies have been reported in patients with Guillain–Barré (GBS) or Fisher syndrome but little is known on their presence in multifocal motor neuropathy (MMN) or other chronic immune-mediated neuropathies. We examined 24 patients with MMN, 34 with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), 23 with neuropathy associated with IgM monoclonal gammopathy (PN+IgM), 13 with GBS, 34 with motor neuron disease (MND), 24 with other neuropathies and 20 normal subjects. Patients' sera were tested by ELISA for IgM reactivity to GM1, GM2, GD1a, GD1b and GT1b and with GSCs made by any combination of two of these gangliosides. In all GM1 positive patients with MMN (11), PN+IgM (1), CIDP (1) and POEMS (1), binding to GM1 was abolished or consistently reduced when tested in GSCs also containing GD1a or other gangliosides. This only occurred in one of the three GM1 positive MND patients. In a patient with PN-IgM and anti-GM2 and GD1a IgM, both reactivities were reduced when tested in GSCs also containing GM1. New reactivities were found in a patient with CIDP and anti-GD1b IgM who presented an additional reactivity to GT1b/GM1 and GT1b/GM2 GSCs, and in one with PN-IgM who had reactivity to GM2/GD1b but not to individual gangliosides. Testing for IgM antibodies to GSCs rarely permitted to identify new reactivities in chronic immune neuropathies. IgM binding to gangliosides was however often modified in GSCs suggesting that these reactivities may be affected by contiguous gangliosides possibly influencing their pathogenicity.

HLA-DRB1 allele heterogeneity influences multiple sclerosis severity as well as risk in Western Australia - Corrected Proof

2009-12-14

Abstract: Susceptibility to multiple sclerosis (MS) has been consistently associated with the Human Leukocyte Antigen (HLA)-DRB1⁎1501 genotype, however effects on disease severity and clinical outcome have varied in different populations. We present the results of a high-resolution HLA-DRB1 genotyping and genotype–phenotype correlation study in a large West Australian MS cohort. Our findings indicate that in this population, which is of largely Anglo-Celtic and Northern European origin, HLA-DRB1⁎1501 is not only a strong determinant of disease risk but may also be associated with disease severity as measured by the Multiple Sclerosis Severity Score (MSSS), with the MSSS increasing by an estimated 0.51 per DRB1⁎1501 allele. We also found evidence that the HLA-DRB1⁎1201 allele is associated with less severe disease.

Additive effects of combination treatment with anti-inflammatory and neuroprotective agents in experimental autoimmune encephalomyelitis - Corrected Proof

Sienmi Du, Francisco Sandoval, Pauline Trinh, Rhonda R. Voskuhl — 2009-12-14

Abstract: We studied the effects of combination treatment with an anti-inflammatory agent, interferon (IFN)-β, and a putative neuroprotective agent, an estrogen receptor (ER)-β ligand, during EAE. Combination treatment significantly attenuated EAE disease severity, preserved axonal densities in spinal cord, and reduced CNS inflammation. Combining ERβ treatment with IFNβ reduced IL-17, while it abrogated IFNβ-mediated increases in Th1 and Th2 cytokines from splenocytes. Additionally, combination treatment reduced VLA-4 expression on CD4+ T cells, while it abrogated IFNβ-mediated decreases in MMP-9. Our data demonstrate that combination treatments can result in complex effects that could not have been predicted based on monotherapy data alone.

Cognitive impairment following high fat diet consumption is associated with brain inflammation - Corrected Proof

2009-12-09

Abstract: C57Bl/6 mice were administered a high fat, Western diet (WD, 41% fat) or a very high fat lard diet (HFL, 60% fat), and evaluated for cognitive ability using the Stone T-maze and for biochemical markers of brain inflammation. WD consumption resulted in significantly increased body weight and astrocyte reactivity, but not impaired cognition, microglial reactivity, or heightened cytokine levels. HFL increased body weight, and impaired cognition, increased brain inflammation, and decreased BDNF. Collectively, these data suggest that while different diet formulations can increase body weight, the ability of high fat diets to disrupt cognition is linked to brain inflammation.

High prevalence of autoantibodies against phosphoglycerate mutase 1 in patients with autoimmune central nervous system diseases - Corrected Proof

2009-12-08

Abstract: We identified the autoantibody against phosphoglycerate mutase 1 (PGAM1), which is a glycolytic enzyme, in sera from multiple sclerosis (MS) patients by proteomics-based analysis. We further searched this autoantibody in sera from patients with other neurological diseases. The prevalence of the anti-PGAM1 antibody is much higher in patients with MS and neuromyelitis optica (NMO) than in those with other neurological diseases and in healthy controls. It was reported that the anti-PGAM1 antibody is frequently detected in patients with autoimmune hepatitis (AIH). Results of our study suggest that the anti-PGAM1 antibody is not only a marker of AIH but also a nonspecific marker of central nervous system autoimmune diseases.

Unmasking of PML by HAART: Unusual clinical features and the role of IRIS - Corrected Proof

Navdeesh Sidhu, J. Allen McCutchan — 2009-12-07

Abstract: For patients with HIV/AIDS, highly active antiretroviral therapy (HAART) is currently the only effective therapy for progressive multifocal leukoencephalopathy (PML), a viral-induced demyelinating disease caused by polyomavirus JC. Immune reconstitution inflammatory syndrome (IRIS) following initiation of HAART can cause paradoxical clinical deterioration in patients with established PML. Because the onset of PML follows soon after initiation of HAART in some cases (unmasking), we investigated the role IRIS plays in unmasked PML. We reviewed records of 20 PML cases seen from 1997–2006 at the UCSD HIV primary care clinic. Eight cases presented with PML symptoms within 6months of initiating HAART (referred to hereafter as unmasked PML), six patients were diagnosed with PML before initiating HAART, and six were diagnosed more than 6months after starting HAART. Patients with unmasked PML constituted 40% of our series, had relatively long survival, and commonly (50%) had lesions exclusively in the posterior fossa, a localization not previously reported with such a high prevalence. Only 3 of the 8 patients with unmasked PML had IRIS reactions as evidenced by contrast enhancement around lesions on MRI, suggesting that IRIS is not necessary for the pathogenesis of this syndrome.

Tetravalent Aβ1–15 vaccine reduces TCR-positive cell infiltration and up-regulates p75 in Tg2576 brains compared to Aβ42 vaccine - Corrected Proof

Hui Li, Juntao Zou, Zhibin Yao, Jing Yu, Huaqiao Wang, Jie Xu — 2009-12-04

Abstract: In order to investigate the effect of Aβ vaccines on T cell infiltration into the brain, we immunized Tg2576 mice with two adenovirus vaccines containing tetravalent Aβ1–15 (4×Aβ15) or Aβ42. TCR-positive cells were found in the ventricle, parenchyma, and surrounding the vasculature, especially concentrating in the periventricular parenchyma, the reticular part of the substantia nigra and the corpus striatum. Compared to the Aβ42 group, TCR-positive cells in the tetravalent (4×) Aβ15 group were significantly decreased. Both vaccines down-regulated neurotrophic and inflammatory factors, but the 4×Aβ15 vaccine up-regulated TrkA and p75 compared with the Aβ42 vaccine. The results suggest that the 4×Aβ15 vaccine might be safer and more beneficial than the Aβ42 vaccine.

Role of the innate immune system in the pathogenesis of multiple sclerosis - Corrected Proof

Roopali Gandhi, Alice Laroni, Howard L. Weiner — 2009-11-23

Abstract: Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease with heterogeneous clinical presentations and course. MS is considered to be a T cell mediated disease but in recent years contribution of innate immune cells in mediating MS pathogenesis is being appreciated. In this review, we have discussed the role of various innate immune cells in mediating MS. In particular, we have provided an overview of potential anti-inflammatory or pro-inflammatory function of DCs, microglial Cells, NK cells, NK-T cells and gamma delta T cells along with their interaction among themselves and with myelin. Given the understanding of the role of the innate immune cells in MS, it is possible that immunotherapeutic intervention targeting these cells may provide a better and effective treatment.

Herpes simplex type I (HSV-1) infection of the nervous system: Is an immune response a good thing? - Corrected Proof

Christopher D. Conrady, Douglas A. Drevets, Daniel J.J. Carr — 2009-10-12

Abstract: Herpes simplex virus type 1 (HSV-1) can induce a robust immune response initially thru the activation of pattern recognition receptors and subsequent type I interferon production that then shapes, along with other innate immune components, the adaptive immune response to the insult. While this response is necessary to quell virus replication, drive the pathogen into a “latent” state, and likely hinder viral reactivation, collateral damage can ensue with demonstrable cell death and foci of tissue pathology in the central nervous system (CNS) as a result of the release of inflammatory mediators including reactive oxygen species. Although rare, HSV-1 is the leading cause of frank sporadic encephalitis that, if left untreated, can result in death. A greater understanding of the contribution of resident glial cells and infiltrating leukocytes within the CNS in response to HSV-1 invasion is necessary to identify candidate molecules as targets for therapeutic intervention to reduce unwarranted inflammation coinciding with the maintenance of the anti-viral state.

Analyses of cerebrospinal fluid in the diagnosis and monitoring of multiple sclerosis - Corrected Proof

2009-09-27

Abstract: The laboratory evaluation of cerebrospinal fluid (CSF) has been routinely employed as a diagnostic test in the diagnosis of neuroimmunological disorders such as multiple sclerosis (MS). Recently, CSF analyses in MS have garnered renewed interest as a tool for monitoring disease activity and prognosis. With the identification of patients that are very early in their disease course, namely patients with a radiologically isolated (RIS) or a clinically isolated syndrome (CIS), the true value of these evaluations has yet to be fully explored. Ultimately, the hope is that biomarkers within this compartment will be identified that will identify etiologic factors of MS and other inflammatory disorders of the central nervous system.In this review we discuss the history of CSF diagnostic tests and the most recent methodological advances. We also outline the potentially important diagnostic role and possible limitations of these tests.

Chemokines and chemokine receptors in the nervous system - Corrected Proof

2007-05-11