Journal of Neuroimmunology

Title Page/Editorial Board

2010-08-25

2010 Elsevier Awards for Young Investigator

2010-08-25

Erratum to “A journey shared; a task fulfilled” [J. Neuroimmunol. 221(2010)1–3]

Cedric S. Raine — 2010-07-26

Erratum to “A journey shared; a task fulfilled” [J. Neuroimmunol. 221 (2010) 1–3]

Cedric S. Raine — 2010-07-26

Beginning April 2010, the Journal of Neuroimmunology will have at its helm a new Editor-in-Chief, Michael K. Racke, whose charge it will be to lead us to new heights as clinical and molecular technologies continue to develop. For this departing (and yes, somewhat saddened) Editor-in-Chief, the inception, launching, and day-to-day running of our Journal has been an exciting journey, a journey shared for three decades with all who have contributed — authors, reviewers and readers alike. In science, sharing is what it is all about and sharing affects all tasks, the mundane and the scientific.

Orchestrating innate immune responses in multiple sclerosis: Molecular players

Marta Fernández, Xavier Montalban, Manuel Comabella — 2010-05-31

Abstract: Innate immunity is the body's first line of defense against foreign pathogens. Although adaptive immune responses have for long time been considered to play important roles in the etiopathogenesis of autoimmune disorders such as multiple sclerosis (MS), evidence exists that adaptive immunity is not acting in isolation but rather in conjunction with components of the innate immune system. In fact, innate immune responses influence the nature of adaptive immune responses, and many components of innate immunity are used by adaptive immunity as effectors. In this review, we will focus on the role of key players of the innate immune system, including Toll-like receptors, the complement system and cytokines, on MS and its animal model, experimental autoimmune encephalomyelitis. We discuss in vitro and in vivo experimental data showing that the interaction mechanisms operating between adaptive and innate immune systems should be considered to better understand disease etiopathogenesis and the effect of therapies targeting components of the innate immune system.

A murine model of stress controllability attenuates Th2-dominant airway inflammatory responses

2010-05-13

Abstract: Epidemiological and experimental studies suggest a positive correlation between chronic respiratory inflammatory disease and the ability to cope with adverse stress. Interactions between neuroendocrine and immune systems are believed to provide insight toward the biological mechanisms of action. The utility of an experimental murine model was employed to investigate the immunological consequences of stress-controllability and ovalbumin-induced airway inflammation. Pre-conditioned uncontrollable stress exacerbated OVA-induced lung histopathological changes that were typical of Th2-predominant inflammatory response along respiratory tissues. Importantly, mice given the ability to exert control over aversive stress attenuated inflammatory responses and reduced lung pathology. This model represents a means of investigating the neuro-immune axis in defining mechanisms of stress and respiratory disease.

Distinct effects of human glioblastoma immunoregulatory molecules programmed cell death ligand-1 (PDL-1) and indoleamine 2,3-dioxygenase (IDO) on tumour-specific T cell functions

2010-05-21

Abstract: Immunotherapy is a promising new treatment for patients suffering from glioma, in particular glioblastoma multiforme (GBM). However, tumour cells use different mechanisms to escape the immune responses induced by the treatment. As many other tumours, gliomas express or secrete several immunosuppressive molecules that regulate immune cell functions. In this study, we first analysed FasL, HLA-G, IDO, PDL-1 and TGF-β1, -β2 and -β3 expression by transcriptomic microarray analysis in a series of 20 GBM samples and found respectively 15%, 60%, 85%, 30%, 70%, 80% and 35% of positive specimens. mRNA expression was then confirmed in 10 GBM primary cell lines and 2 immortalised cell lines U251 and U87MG. Furthermore, the protein expression of PDL-1, IDO activity and TGF-β2 secretion were found on most of the untreated GBM primary cell lines. Remarkably, treatment with IFN-γ increased the PDL-1 cell surface expression and the IDO activity, but reduced the TGF-β2 secretion of GBM cell lines. We finally analysed the immunosuppressive effects of IDO, PDL-1 and TGF-β1-3 by measuring IFN-γ production and cell cytotoxicity activity of tumour antigen-specific T cells. PDL-1 partially affected the IFN-γ production of antigen-specific T cells in response to GBM primary cell lines, and IDO inhibited lymphocyte proliferation induced by lectins. None of these molecules directly affected the T cell cytotoxicity function. Due to the functional role of PDL-1 and IDO molecules expressed by GBM cells, one could expect that blocking these molecules in the immunotherapy strategies would reinforce the efficiency of these treatments of GBM patients.

Cytotoxic T-lymphocytes secrete soluble factors that induce caspase-mediated apoptosis in glioblastoma cell lines

Alberto Cagigi, Anna Nilsson, Victor Levitsky, Farideh Sabri — 2010-05-18

Abstract: We have previously shown that factors secreted by activated CTLs induce apoptosis in a panel of glioblastoma lines. In this study, we analyzed the expression of death receptors, activation of caspases and mRNA expression of 96 apoptotic genes in glioblastoma lines either sensitive or resistant to supernatant of activated CTLs. Our results indicate that exposure to supernatant triggers several pathways of caspase activation in glioblastoma lines involved in the initiation of both extrinsic and intrinsic apoptosis. High steady-state levels of Bcl-2 were identified as potentially accounting for the resistance of a proportion of glioblastoma lines to factors secreted by activated CTLs.

Glial cell line-derived neurotrophic factor protects midbrain dopaminergic neurons against lipopolysaccharide neurotoxicity

Bin Xing, Tao Xin, Lingling Zhao, Randy L. Hunter, Yan Chen, Guoying Bing — 2010-05-17

Abstract: Aberrant microglia activation causes dopaminergic neuronal loss and nitric oxide produced by microglia plays a critical role in dopaminergic neuronal degeneration. However, no study has determined if GDNF protects dopaminergic neurons via inhibiting nitric oxide generation in Parkinson's disease animal model. We report that GDNF not only reduces lipopolysaccharide-induced degeneration of dopaminergic neurons, suppresses microglia activation and nitric oxide generation, but also reverses the inhibition of phosphoinositide 3-kinase (PI3K) in dopaminergic neurons and microglia. It suggests that the neuroprotective effect of GDNF on dopaminergic neurons may be related to its suppression of microglia activation-mediated nitric oxide via releasing the inhibition of PI3K in both neurons and microglia.

Binding of recombinant T cell receptor ligands (RTL) to antigen presenting cells prevents upregulation of CD11b and inhibits T cell activation and transfer of experimental autoimmune encephalomyelitis

2010-05-24

Abstract: Recombinant T cell ligands (RTLs) ameliorate experimental autoimmune encephalomyelitis (EAE) in an antigen-specific manner. We evaluated effects of RTL401 (I-As α1β1+PLP-139-151) on splenocytes from SJL/J mice with EAE to study RTL-T cell tolerance-inducing mechanisms. RTLs bound to B, macrophages and DCs, through RTL-MHC-α1β1 moiety. RTL binding reduced CD11b expression on splenic macrophages/DC, and RTL401-conditioned macrophages/DC, not B cells, inhibited T cell activation. Reduced ability of RTL- incubated splenocytes to transfer EAE was likely mediated through macrophages/DC, since B cells were unnecessary for RTL treatment of EAE. These results demonstrate a novel pathway of T cell regulation by RTL-bound APCs.

Paying the circadian toll: The circadian response to LPS injection is dependent on the Toll-like receptor 4

Natalia Paladino, M. Juliana Leone, Santiago A. Plano, Diego A. Golombek — 2010-05-31

Abstract: Systemic low doses of the endotoxin lipopolysaccharide (LPS) administered at CT15 (circadian time 12 corresponds to locomotor activity onset) induce phase delays of locomotor activity rhythms in mice. To evaluate if this effect was mediated by the Toll-like receptor 4 (TLR4), our present aim was to characterize the circadian behavior and LPS-induced circadian response of TLR4 (LPS receptor)-deficient mice (in C57bl/10 and C3H backgrounds). In mutants, we observed a free-running period and a light-induced phase delay similar to the one observed in their corresponding wild-type (WT) littermates. The LPS-induced phase delay, wheel running inhibition and c-Fos/Per-1 immunoreactivity in the paraventricular nuclei observed in WT mice was absent or significantly decreased in the TLR4-deficient mice. In conclusion, we show that LPS-induced circadian responses are mediated by TLR4.

Antigen-specific therapy of EAE via intranasal delivery of filamentous phage displaying a myelin immunodominant epitope

Idan S. Rakover, Natalia Zabavnik, Rela Kopel, Miri Paz-Rozner, Beka Solomon — 2010-05-26

Abstract: The presence of anti-myelin antibodies (Abs) in patients with early multiple sclerosis (MS) and in MS animal models has led to renewed interest in the role of B cells, plasma cells and their products in the pathogenesis of the disease, and in their therapeutic potential. Here, we present a novel strategy based on filamentous phage display of the myelin oligodendrocyte glycoprotein immunodominant epitope (MOG 36–44) fused to the main coat protein. Filamentous phages are well characterized, both structurally and genetically. We found that the fibrous shape of the phage (1000nm long and 6nm wide) enables penetration into the central nervous system (CNS) when administered nasally. Thus, intranasal treatment of experimental autoimmune encephalomyelitis (EAE) in mice, with phage MOG, showed improved neuronal function, reduced levels of proinflammatory cytokines, particularly monocyte chemoattractant protein 1 (MCP-1), interferon γ (IFN-γ) and IL-6, but no change in IL-10 or IL-12 levels. Moreover, the treatment induced depletion of the autoantibodies against MOG and prevented demyelination resulting in improved clinical scores and the reduced inflammation in the CNS and periphery in EAE mice compared to untreated sick animals.

Reduced stress fever is accompanied by increased glucocorticoids and reduced PGE2 in adult rats exposed to endotoxin as neonates

Renato N. Soriano, Luiz G.S. Branco — 2010-05-24

Abstract: Immune challenges during neonatal period may permanently program immune responses later in life, including endotoxin fever. We tested the hypothesis that neonatal endotoxin exposure affects stress fever in adult rats. In control rats (treated with saline as neonates; nSal) body temperature peaked ∼1.5°C during open-field stress, whereas in rats exposed to endotoxin (lipopolysaccharide, LPS) as neonates (nLPS) stress fever was significantly attenuated. Following stress, plasma corticosterone levels significantly increased from 74.29±7.05ngml−1 to 226.29±9.87ngml−1 in nSal rats, and from 83.43±10.31ngml−1 to 324.7±36.87ngml−1 in nLPS rats. Animals treated with LPS as neonates and adrenalectomized one week before experimentation no longer displayed the attenuated febrile response to stress. This attenuated stress fever caused by an increased corticosterone secretion is likely to be linked to an inhibitory effect of glucocorticoids on cyclooxygenase activity/PGE2 production in preoptic/anteroventral third ventricular region (AV3V) since stress failed to cause a significant increase in PGE2 in nLPS rats, and this effect was reverted by adrenalectomy. Altogether, the present results indicate that endogenous glucocorticoids are key modulators of the attenuated stress fever in adult rats treated with LPS as neonates, and they act downregulating PGE2 production in AV3V. Moreover, our findings also support the notion that neonatal immune stimulus affects programming of stress responses during adulthood, despite the fact that inflammation and stress are two distinct processes mediated largely by different neurobiological mechanisms.

Expression and regulation in the brain of the chemokine CCL27 gene locus

2010-06-04

Abstract: The chemokine CCL27 has chemoattractant properties for memory T cells and has been implicated in skin allergic reactions. The present study reports the expression in the brain of two CCL27 splice variants localized in the cerebral cortex and limbic regions. CCL27-like immunoreactivity was identified mainly in neurons. Variant 1 was found elevated in the olfactory bulbs during allergic inflammation induced by intranasal challenge with allergen. This was accompanied by the presence of T cells in the olfactory bulbs. Intranasal administration of neutralizing antibodies against CCL27 reduced the presence of T cells in the olfactory bulbs suggesting a function in T cell activity in the brain.

Differential expression of interferon-γ receptor on human glial cells in vivo and in vitro

Sadayuki Hashioka, Andis Klegeris, Claudia Schwab, Sheng Yu, Patrick L. McGeer — 2010-05-31

Abstract: Although significant effects of interferon-γ (IFN-γ) on glial cells are well documented, information on the expression level and localization of glial IFN-γ receptors (IFN-γ-R) in the human central nervous system (CNS) is sparse. To examine the glial expression of IFN-γ-R in the human CNS, immunohistochemistry and quantitative analyses were performed on Alzheimer disease hippocampus, Parkinson disease substantia nigra, amyotrophic lateral sclerosis spinal cord and corresponding areas from non-neurological cases. Almost all IFN-γ-R-positive (IFN-γ-R+) cells corresponded to GFAP-positive (GFAP+) astrocytes, while none of IFN-γ-R+ cells corresponded to IBA1-positive (IBA1+) microglia or MBP-positive (MBP+) oligodendrocytes in these neurological cases. We observed a similar pattern of glial IFN-γ-R expression in non-neurological cases. Also, we quantitatively analyzed the IFN-γ-R expression by cultured human glial cells using immunocytochemistry and reverse transcription polymerase chain reaction (RT-PCR). In contrast to in vivo results, almost all IFN-γ-R+ cells were IBA1+ in microglial cultures, GFAP+ in astrocytic cultures and MBP+ in oligodendrocytic cultures. Moreover, no significant difference in IFN-γ-R mRNA expression was found for these glial cell types by RT-PCR. These results suggest that the microglial and oligodendrocytic expression levels of IFN-γ-R are much lower than the astrocytic expression levels in the human CNS in vivo, whereas all three types of glial cells constitutively express IFN-γ-R when cultured in vitro.

Glatiramer acetate reduces Th-17 inflammation and induces regulatory T-cells in the CNS of mice with relapsing–remitting or chronic EAE

2010-05-31

Abstract: The aim of this study was to identify cell populations relevant to pathogenesis and repair within the injured CNS in mice that recovered from experimental autoimmune encephalomyelitis (EAE). We demonstrate that in two EAE models, with either relapsing–remitting or chronic course, T-cells and resident activated microglia manifested extensive IL-17 expression, with apparent localization within regions of myelin loss. In mice treated with glatiramer acetate (GA, Copaxone®), even when treatment started after disease exacerbation, CNS inflammation and Th-17 occurrence were drastically reduced, with parallel elevation in T-regulatory cells, indicating the immunomodulatory therapeutic consequences of GA treatment in situ.

Myelin ingestion by macrophages promotes their motility and capacity to recruit myeloid cells

2010-06-04

Abstract: Myelin-laden macrophages reside within the CNS, the CSF and in the CNS-draining lymph nodes during MS and EAE, suggesting migration of these macrophages between these compartments and interaction with other cells. Since chemokines and their receptors are pivotal for leukocyte trafficking, we addressed whether myelin ingestion affects chemotaxis of mouse macrophages in vitro. Myelin ingestion enhanced expression of CCR7 and CXCR3 on macrophages and migration towards CCL21 and CXCL10. Furthermore, myelin-laden macrophages released chemoattractants resulting in enhanced migration of myeloid cells in vitro. Our data demonstrate that myelin-laden macrophages have increased motility and suggest trafficking between anatomical compartments in vivo.

Neural cell adhesion molecule — Description of a CSF ELISA method and evidence of reduced levels in selected neurological disorders

2010-06-02

Abstract: Neural cell adhesion molecule (NCAM) is important for neuronal growth and repair. Here we describe the development and validation of a sensitive ELISA for NCAM using commercially available reagents. The measurable range of NCAM ELISA is 16–500ng/mL, with a constant coefficient-of variation and good parallelism between the reference standard curve and CSF. CSF NCAM was measured in 36 benign-intracranial hypertension, 51 multiple sclerosis, 27 neuropathy, 37 Alzheimer's disease, 12 cognitive impairment, 15 motoneurone disease, 13 meningitis, 17 encephalitis, and 17 control cases. Significant reductions were found between controls and multiple sclerosis, Alzheimer's disease and meningitis.

Clinical implication of peripheral CD4+CD25+ regulatory T cells and Th17 cells in myasthenia gravis patients

2010-05-18

Abstract: Myasthenia gravis (MG) is an autoimmune disorder generally mediated by antibodies against the acetylcholine receptors (AChR) of the skeletal muscles. CD4 T cells help B cells to produce antibodies through their production of cytokines or chemokines. In this study, we evaluated the frequency of regulatory (Treg) and IL-17 producing CD4 T-cell subsets (Th17) in peripheral blood mononuclear cells (PBMCs) of patients with MG. The transcription factor, forkhead transcription factor (Foxp3), is essential for T-cell regulatory function, and the orphan nuclear receptor, RORγT, is important in Th17 cell differentiation. In MG patients, Foxp3 mRNA expression in PBMCs was lower than those in healthy subjects (p=0.007), while there was no significant difference of RORγT mRNA expression between MG patients and healthy subjects. Glucocorticoid-induced tumour-necrosis-factor receptor-related protein (GITR) is expressed predominantly on CD4+CD25+ Treg cells. We found that the number of GITR+CD4+CD25+ T cells in peripheral lymphocytes in MG patients was lower than that in healthy subjects (P<0.01). In addition, there was a significant positive correlation between the change of the frequency of GITR+CD4+CD25+ T cells and the changing rate in quantitative myasthenia gravis scores (%) (p=0.03). Furthermore, there was a significant negative correlation between the change of the percentage of GITR+CD4+CD25+ T cells (% lymphocytes) and the changing rate of daily PSL doses (%) (P=0.002). The relative RORγT levels in PBMCs negatively correlated with the Th1/Th2 ratio in CD4+ cells in MG patients (p=0.014). In conclusion, our findings suggest that Th17 cells affect the production of autoantibodies through their influence on the Th1- and Th2-cytokine balance in PBMCs of MG patients. On the other hand, Treg cells are suggested to be involved in the clinical condition or severity of MG disease.

Neurosarcoidosis presenting as an anterior horn syndrome

2010-05-19

Abstract: We report a 43year old man who developed progressive weakness of all extremities with fasciculation over four months. Neurological examination was consistent with an anterior horn syndrome. CSF examination showed elevated opening pressure and a lymphocytic pleocytosis. The diagnosis of sarcoidosis was confirmed by muscle and lacrimal gland biopsies. He was treated with the combination of corticosteroids and intravenous immunoglobulin with almost complete resolution of his symptoms a few weeks after discharge. We hypothesize that meningeal granulomatous inflammation compressed the exiting anterior roots which resulted in motor dysfunction with preservation of peripheral sensory fibers.

FOXP3+ T regulatory cells in idiopathic inflammatory myopathies

Anne Waschbisch, Nicholas Schwab, Tobias Ruck, Max-Philipp Stenner, Heinz Wiendl — 2010-06-01

Abstract: FOXP3+ T regulatory cells (Tregs) are considered key players in the maintenance of immune homeostasis. Here we studied the presence and potential role of FOXP3+ Tregs in myositis. CD3 and FOXP3 expression in dermatomyositis, polymyositis and inclusion body myositis was assessed by immunohistochemistry and real-time PCR. FOXP3+ Tregs were found in close proximity to effector cells and their numbers correlated with the degree of inflammation. Despite divergent pathogenetic concepts, we observed no differences in the frequency of FOXP3 immunoreactive cells or FOXP3 mRNA expression between different myositis entities. Functional assays using human myoblasts as targets of CD8+ cells demonstrate that Tregs are capable to inhibit the lytic activity of cytotoxic cells. Our data suggest that FOXP3 Tregs serve to counterbalance muscle destruction by cytotoxic T cells in myositis.

A method for simple and accurate identification of the multiple sclerosis associated allele HLA-DRB1*1501 in neuroscience research laboratories

E. Cisneros, M. Moraru, R. de Pablo, C. Vilches — 2010-05-24

Abstract: Research on multiple sclerosis (MS) frequently requires typing for allele HLA-DRB1*1501, which the complexities of the HLA system can restrict to specialised histocompatibility laboratories. To overcome this limitation, we have implemented a simple, robust and highly specific method for DRB1*1501 detection. One single-tube polymerase-chain reaction (PCR) per DNA sample allows for detecting DR2 individuals. The spare PCR products of these are then sequenced to identify allele DRB1*1501 by comparison with the official, publicly accessible HLA database. This approach, much simpler than previously available methods, should facilitate research on MS by making accurate identification of DRB1*1501 accessible to neuroscience laboratories.

Epstein-Barr virus antibodies in serum and cerebrospinal fluid from Multiple sclerosis, Chronic Inflammatory Demyelinating Polyradiculoneuropathy and Amyotrophic Lateral Sclerosis

2010-05-31

Abstract: Elevated anti-Epstein-Barr virus (EBV) antibody levels are present in serum of Multiple sclerosis (MS) patients but literature lacks of studies comparing anti-EBV antibody levels between MS and other neurological diseases. We evaluate anti-VCA IgG and IgM, anti-EBNA1 IgG, anti-Cytomegalovirus IgG and IgM titres in serum and cerebrospinal fluid (CSF) of 267 MS, 50 Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP) and 88 Amyotrophic Lateral Sclerosis (ALS) patients. We found increased titres of anti-EBV-IgG in serum and CSF of MS subjects as compared to CIDP and ALS patients thus providing additional evidence for a possible involvement of EBV in MS.

Results of a phase I study in patients suffering from secondary-progressive multiple sclerosis demonstrating the safety of the amino acid copolymer PI-2301 and a possible induction of an anti-inflammatory cytokine response

2010-05-14

Abstract: PI-2301 is an immunomodulator that could be an alternative therapy for MS. A placebo-controlled, multiple-ascending dose, double-blind study was performed in patients with secondary-progressive MS. Treatment was given subcutaneously once weekly for 8weeks, followed by a 4-week open-label treatment period with active drug. The most common adverse event was transient injection site reactions. Non-significant trend for increases in serum levels of IL-3, IL-13, and CCL22 over time were suggestive of a beneficial TH2 immune response in subjects dosed with PI-2301 at 3 and 10mg. MRI data indicated a non-significant trend for a reduction of lesion numbers in subjects treated with 1 and 3mg PI-2301.

IGHV4-39 deletion polymorphism does not associate with risk or outcome of multiple sclerosis

2010-05-17

Abstract: The restricted use of immunoglobulin heavy chain variable (IGHV) family 4 gene segments by clonally expanded B cells in brain lesions and cerebrospinal fluid (CSF) of multiple sclerosis (MS) patients is well documented. Specifically, the overrepresentation of gene IGHV4-39 has been highlighted in multiple studies. To investigate the role of IGHV4-39 in MS, we screened 193 MS cases, representing the extremes of clinical outcome (benign and malignant), and 187 controls for a previously reported germline deletion polymorphism containing IGHV4-39. We did not reveal a genetic association linking this polymorphism to MS risk or progression.

Cytokine mRNA profile of Epstein–Barr virus-stimulated highly differentiated T cells in multiple sclerosis: A pilot study

2010-05-17

Abstract: The reason why EBV-specific cellular immune responses are abnormal in multiple sclerosis (MS) patients is still missing. In this exploratory pilot study, we assessed IL-1β, IL-2, IL-4, IL-6, IL-10, IL-17, IFN-γ, TGF-β1 and FOXP3 mRNA expression in EBV-stimulated highly differentiated T cells (THD) of MS patients and healthy controls (HC). We found increased levels of IFN-γ and IL-4 mRNA in CD8+ THD cells of MS patients. All the other tested molecules were expressed similarly in MS patients and HC. Interestingly, increased IFN-γ and IL-4 suggest that the control of EBV replication may be insufficient in MS patients.

Up-regulation of MHC class I and class II in the skeletal muscles of myasthenia gravis

2010-05-24

Abstract: The up-regulation of MHC in muscles is thought to be associated with inflammatory myopathies. The expression of MHC class I and class II was examined in muscles of myasthenia gravis (MG). MG muscle specimens from all 5 patients with thymoma and 2 of 5 without thymoma showed MHC class I up-regulation and 3 of 5 with thymoma showed MHC class II. The up-regulation of MHC in MG muscles is thus considered to be a common phenomenon. MG muscles expressed not only MHC class I but also class II, and these muscles could thus act as immunoregulating cells in MG.

Single nucleotide polymorphism in the MMP-9 gene is associated with susceptibility to develop multiple sclerosis in an Italian case-control study

2010-05-17

Abstract: To investigate the role of the matrix metalloproteinase-9 gene (MMP-9) in multiple sclerosis (MS), we analyzed the functional −1562C/T and −90 (CA)n repeat polymorphisms in 243 Italian patients with MS and 173 healthy controls. A significant increase of the −1562T allele carriers was found in patients with MS compared to controls. Moreover, haplotype analysis showed that the haplotype formed by the −1562T allele and the L allele ((CA)≤20) was over-represented in patients with MS versus controls. These results suggest that a genetic polymorphism of the MMP-9 promoter region may influence the susceptibility to MS.

Anti-Heat Shock Protein 70 antibody levels are increased in myasthenia gravis and Guillain-Barré syndrome

2010-05-31

Abstract: Myasthenia gravis (MG) is an autoimmune disorder where patients develop autoantibodies towards skeletal muscle proteins (e.g. acetylcholine receptor and muscle specific kinase), causing weakness in striated muscles. Ocular MG (OMG) represents a subtype of (MG) affecting only the periocular muscles. The pathogenesis of this phenotype remains unclear. Heat Shock Protein 70 (Hsp70) plays a role in immune regulation. Antibodies against this protein are associated with several autoimmune diseases, and its biological significance has been shown in vivo. We have therefore examined the concentration of anti-Hsp70 antibodies in sera from 35 OMG patients and 94 patients with generalized MG (GMG) using ELISA assays. The antibody concentrations were compared to those in patients with multiple sclerosis (MS), Guillain-Barré syndrome (GBS) and to healthy controls.MG patients had significantly higher anti-Hsp70 antibody concentrations than both MS patients and healthy controls. GBS patients had higher antibody levels than all other groups. No difference in antibody levels was found when comparing OMG and GMG. Our results suggest that patients with MG and GBS have a previous or current increased exposure to Hsp70 antigens. The similarity between GMG and OMG strengthens the hypothesis that OMG represents a systemic disease, similar to GMG.

Gene expression profiling in nerve biopsy of vasculitic neuropathy

2010-06-14

Abstract: To investigate molecular mechanisms of peripheral nerve vasculitis, gene expression patterns in archived frozen sural nerve biopsies from patients with vasculitic neuropathy were compared to control nerves by DNA microarray technology. There was a striking upregulation of mRNA of genes involved in immune system processes. Of special interest was the activation of immunoglobulin genes, such as IGLJ3, IGHG3, IGKC, and IGL, and of several chemokines, such as CXCL9 or CCR2. Genes involved in vascular proliferation or remodelling such as CXC31 and AIF were also upregulated. Among the downregulated genes were the Krüppel-Like Transcription Factors KLF2, KLF4 and the nuclear orphan receptor NR4A1 genes known to be involved in endothelial cell activation. Thus, this gene expression profile analysis revealed that in peripheral nerve vasculitis a prominent activation of immune response related genes as well as genes involved in vascular proliferation is taken place, while genes inhibiting endothelial cell activation are down regulated. These data point to interesting mechanistic clues to the molecular pathogenesis of vasculitic neuropathies.

Stimulus-dependent requirement of ion channels for microglial NADPH oxidase-mediated production of reactive oxygen species

Tom Schilling, Claudia Eder — 2010-05-31

Abstract: Reactive oxygen species (ROS) produced by activated microglial cells play a pivotal role in the pathogenesis of neuro-degenerative and neuro-inflammatory diseases. Here we demonstrate that the pro-inflammatory lipid lysophosphatidylcholine (LPC) is capable of inducing microglial ROS production, which is mediated by the activity of NADPH oxidase. Inhibition of TRPV1 non-selective cation channels abolished ROS production in LPC-stimulated microglia, whereas inhibitors of K+ channels, H+ channels and Cl− channels had no significant effects. In contrast, activity of all four ion channel types was required for PMA-induced NADPH oxidase-mediated ROS generation, suggesting a differential, stimulus-dependent regulation of microglial ROS production by ion channel activity.

Prognostic significance and mechanism of Treg infiltration in human brain tumors

2010-05-31

Abstract: Regulatory T cells (Tregs) accumulate in tumors and can contribute to the dismal immune responses observed in these tumors. We reported that the percentage of tumor infiltrating Tregs is strongly correlated with the WHO grade of the brain tumor. We now report on the clinical follow-up of this patient cohort (n=83). Subgroup analyses in patients with glioblastomas (n=29) showed a moderate, not significant, inverted association between Tregs and survival. We further show that Tregs in glioblastomas, in contrast to other tumor infiltrating effector lymphocytes, highly express the CCR4 chemokine receptor. Moreover, the CCR4 ligand CCL22 is secreted by glioblastomas and may explain the specific Treg accumulation seen in these tumors.