Journal of Neuroimmunology - Articles in Press

Qualitative and quantitative evidence of anti-glutamic acid decarboxylase-specific intrathecal antibody synthesis in patients with stiff person syndrome - Corrected Proof

S. Jarius, O. Stich, J. Speck, Ch. Rasiah, B. Wildemann, H.M. Meinck, S. Rauer — 2010-09-03

Abstract: Background: The stiff person syndrome (SPS) is a CNS disorder of putative autoimmune aetiology, which is clinically characterized by severe rigidity and spasms. In most cases, SPS is associated with serum antibodies against glutamic acid decarboxylase (GAD-Ab). Recent studies suggested that GAD-Ab might be directly involved in the pathogenesis of SPS. Further support for this hypothesis would come from studies providing qualitative evidence for the presence of GAD-Ab-producing B cell clones within the CNS of patients with SPS.Objective and methods: To address that issue, we (i) analysed paired cerebrospinal fluid (CSF) and serum samples from ten GAD-Ab positive patients with SPS and controls by an antigen-driven affinity blotting technique for the presence of GAD-specific oligoclonal IgG bands (OCBs) in the CSF, and (ii) examined the immunoreactive pattern of CSF and serum IgG to recombinant GAD by immunoblotting. To confirm our results quantitatively, we (iii) assessed anti-GAD antibody reactivity in CSF and serum using ELISA and evaluated the GAD-specific antibody index.Results: GAD-specific oligoclonal bands exclusively or predominately in CSF compared to the corresponding serum were detected in 10/10 patients with GAD-positive SPS but in none of the controls. Immunoblotting revealed stronger staining in the CSF, suggestive of intrathecal IgG synthesis, in 7/10 patients upon visual inspection, and in 8/10 patients upon densitometric analysis. A positive GAD-specific antibody index was found in 9/10 patients.Conclusions: Here we demonstrate for the first time that IgG OCBs in SPS bind GAD. Our findings contribute to the ongoing discussion on whether the autoimmune process against GAD is involved in the pathogenesis of SPS by indicating that anti-GAD-Ab is produced by B cell clones within the CNS.

Photoreceptor cells constitutively express functional TLR4 - Corrected Proof

2010-09-01

Abstract: Toll-like receptor 4 (TLR4) is expressed on a number of cells including neurons in the brain. However, it has yet to be determined if TLR4 is expressed on photoreceptor cells in the retina. In this report, we examined primary photoreceptor cells and an established photoreceptor cell line (661W). We found that functional TLR4 is constitutively expressed on photoreceptor cells, and can be activated by LPS. We conclude that TLR4 on photoreceptor cells could directly contribute to retinal inflammatory diseases and photoreceptor cell survival.

Interleukin-18 deficiency reduces neuropeptide gene expressions in the mouse amygdala related with behavioral change - Corrected Proof

2010-09-01

Abstract: In this study, we examined the effects of IL-18 deficiency on behaviors and gene expression profiles in 6 brain regions. IL-18−/− mice reduced depressive-like behavior and changed gene expressions predominantly in the amygdala compared with wild-type mice. Pathway analysis of the differentially expressed genes ranked behavior as the top-scored biological function. Of note, the absence of IL-18 decreased Avp, Hcrt, Oxt, and Pmch mRNA levels and the number of arginine vasopressin- and oxytocin-positive cells in the amygdala, but not in the hypothalamus. Our results suggest that IL-18-dependent vasopressinergic and oxytocinergic circuitry in the amygdala may regulate depressive-like behaviors in mice.

Increased intramuscular nerve branching and inhibition of programmed cell death of chick embryo motoneurons by immunoglobulins from patients with motoneuron disease - Corrected Proof

2010-09-01

Abstract: Massive programmed cell death (PCD) of developing chick embryo motoneurons (MNs) occurs in a well defined temporal and spatial sequence between embryonic day (E) 6 and E10. We have found that, when administered in ovo, either circulating immunoglobulins G (IgGs) or cerebrospinal fluid from patients with MN disease can rescue a significant number of chick embryo MNs from normally occurring PCD. An increase of branching of intramuscular nerves was also observed that may account for the rescuing effects of pathologic IgGs. Proteomic analysis and further analysis by ELISA indicated that these effects may be mediated by the interaction of circulating human immunoglobulins with proteins of the semaphorin family.

Low dose combination steroids control autoimmune mouse hearing loss - Corrected Proof

Dennis R. Trune, J. Beth Kempton — 2010-08-30

Abstract: The severe side effects of glucocorticoids prevent long term management of hearing loss. Alternative steroid treatments that minimize or eliminate these effects would significantly benefit therapeutic control of hearing disorders. A steroid treatment study of autoimmune mouse hearing loss was conducted to determine the efficacy of combining aldosterone and prednisolone at low doses. An assessment also was made of low dose fludrocortisone, a synthetic mineralocorticoid that also has a slight glucocorticoid effect. MRL/MpJ-Faslpr mice were tested for baseline ABR thresholds at 3months of age and then treated with aldosterone (3.0μg/kg) or prednisolone (1.0mg/kg) to determine the lowest effective dose of each. Other mice were given the two steroids in combination at doses of Pred 0.5mg+Aldo 1.5μg; Pred 1.0mg+Aldo 3.0μg; or Pred 1.5mg+Aldo 5.0μg. Mice were retested with ABR at 1 and 2months to determine the efficacy of the different steroid treatments in controlling hearing loss. Another series of mice were given the synthetic mineralocorticoid fludrocortisone at low (2.8μg/kg) or high (10μg/kg) doses and retested at monthly intervals for 3months. Autoimmune mouse hearing loss developed in untreated controls. This threshold elevation was not prevented by prednisolone at 1mg/kg or by aldosterone at 3μg/kg when each was given alone. However, the two steroids combined at these doses effectively controlled hearing loss. The fludrocortisone treatments also were effective at low doses in preventing or reversing the autoimmune mouse hearing loss. This efficacy of combined steroids at low doses suggests the potential for reducing the side effects of glucocorticoids in the therapeutic control of hearing disorders.

Common variation in the MOG gene influences transcript splicing in humans - Corrected Proof

2010-08-30

Abstract: Multiple sclerosis (MS) is a complex autoimmune disease characterised by demyelinating lesions in the central nervous system (CNS) and myelin oligodendrocyte glycoprotein (MOG), a CNS-restricted protein expressed on the outer cell membrane of oligodendrocytes, has been linked with disease pathogenesis. We have investigated whether expression of MOG in post-mortem human brain tissue is associated with genetic variations in the MOG gene that have previously been associated with genetic susceptibility to MS (520G>A, rs3130253, V145I and 511G>C, rs2857766, V142L). Using quantitative reverse transcriptase PCR (qPCR), we found that the haplotype containing the 520A (rs3130253A, I145) allele is associated with a 1.7-fold increase in splicing of exon 2 to exon 3, which encodes the extracellular and transmembrane domains of MOG. Using predictive algorithms, we found that the 520G>A variant also alters a putative exonic splicing enhancer (ESE) involving the SC35 and SRp55 RNA-binding proteins, supporting the notion that this variation has a regulatory effect. No consistent differences in allele-specific expression were observed for any of the SNPs using the SNaPshot® method. In this exploratory study we have observed that changes in splicing, but not expression levels, are associated with common genetic variation in the MOG gene. Further work is now required to confirm these data and determine whether this altered MOG expression profile, which is predicted to be over-represented in Northern Europeans with MS, is relevant to the pathophysiology of this debilitating disease.

Sex and autoantibody titers determine the development of neuropsychiatric manifestations in lupus-prone mice - Corrected Proof

Hua-Xin Gao, Elena Sanders, Arlene Tan Tieng, Chaim Putterman — 2010-08-27

Abstract: Emotional disturbances are among the most common neuropsychiatric manifestations of SLE, a systemic autoimmune disease with a strong female predominance. In this study, we evaluated young MRL/lpr mice, directly comparing males and females. MRL/lpr females exhibited significant depression as early as 5weeks (at which time elevated levels of autoantibodies were already present), as compared to MRL/lpr males, where depression was noted only at 18weeks. Depression was significantly correlated with autoantibodies against nuclear antigens, NMDA receptor, and ribosomal P. Our results are consistent with a primary role of autoantibodies in the pathogenesis of early neuropsychiatric deficits in this lupus model, which translate into gender-based differences in clinical phenotype.

Natalizumab treatment reduces endothelial activity in MS patients - Corrected Proof

2010-08-26

Abstract: Vascular cell adhesion molecule-1 a ligand for leukocyte very late activating antigen-4 is a key player in leukocyte extravasation in MS lesions. Natalizumab a monoclonal antibody against VLA-4 blocks this interaction. VCAM-1 and its soluble form are up-regulated during endothelial activation in MS.We investigated the effect of Natalizumab on sVCAM-1 and VLA-4 on circulating leukocytes in MS patients.Natalizumab reduced levels of sVCAM-1 compared to controls (256 vs. 597ng/mL). This effect was sustained and only reversed in patients with neutralizing antibodies against Natalizumab. Correspondingly Natalizumab diminished VLA-4 on leukocyte subsets.Our findings indicate that Natalizumab reduces transmigration not only by blocking VLA-4 but also by down-regulating VCAM-1.

Bone marrow mesenchymal stem cell transplantation in patients with multiple sclerosis: A pilot study - Corrected Proof

2010-08-23

Abstract: We explore the safety, and therapeutic benefit of intrathecal injection of ex-vivo expanded autologous bone marrow derived mesenchymal stem cells (BM-MSCs) in 10 patients with advanced multiple sclerosis (MS). Patients were assessed at 3, 6 and 12months. Assessment at 3–6months revealed Expanded Disability Scale Score (EDSS) improvement in 5/7, stabilization in 1/7, and worsening in 1/7 patients. MRI at 3months revealed new or enlarging lesions in 5/7 and Gadolinium (Gd+) enhancing lesions in 3/7 patients. Vision and low contrast sensitivity testing at 3months showed improvement in 5/6 and worsening in 1/6 patients. Early results show hints of clinical but not radiological efficacy and evidence of safety with no serious adverse events.

A novel galectin-1 and interleukin 2 receptor β haplotype is associated with autoimmune myasthenia gravis - Corrected Proof

2010-08-23

Abstract: Galectin-1 (LGALS1) and interleukin receptor 2β (IL2Rβ) are regulators of T-cell activation. Here we evaluated the association of regulatory region polymorphisms of the LGALS1 (rs4820293, rs4820294) and IL2Rβ (rs743777, rs228941) genes in 146 Caucasian myasthenia gravis patients compared to 291 ethnically matched controls. A significant difference was found in the distribution of the rs4820293/rs743777 polymorphism haplotypes (p<0.01). The rs4820293 polymorphism, previously not described to be associated with any disease, does not affect LGALS1 expression in peripheral mononuclear cells and skeletal muscle. Pathway analysis revealed interaction between LGALS1 and IL2Rβ suggesting a role of these proteins in this rare disease.

Aquaporin-4 water channel expression by thymoma of patients with and without myasthenia gravis - Corrected Proof

2010-08-23

Abstract: Background: Neuromyelitis optica (NMO) is a serious idiopathic inflammatory demyelinating disorder characterized by acute transverse myelitis and optic neuritis. A significant proportion of NMO patients are seropositive for NMO-IgG, an autoantibody targeting aquaporin-4 (AQP4) water channel. Paraneoplastic NMO associated various tumors were recently reported.Aim: We studied the expression of AQP4 by thymoma from patients with and without myasthenia gravis (MG).Methods: Thymoma obtained from thymomectomy in patients with and without MG were studied by immunohistochemistry and western blot.Results: Ten thymoma patients (9 with MG) and two control patients without thymoma or MG were studied. Immunohistochemistry revealed AQP4 immunoreactivity in cell membrane of thymoma cells from all ten thymoma specimens whereas thymic tissues from patients without thymoma or MG were negative for AQP4 immunoreactivity. Western blot revealed that lysates of nine of the ten thymoma specimens reacted with anti-human AQP4 antibody with a band of ~30kDa compatible with the molecular weight of AQP4. Interestingly, immunofluorescence revealed that IgG isolated from 2 NMO patients seropositive for NMO-IgG bound to cell membrane of thymoma cells from all ten thymoma specimens while IgG from healthy control subject did not.Conclusion: Thymoma cells of patients with and without MG express AQP4. AQP4 autoantibodies from serum of NMO patients bound to AQP4 expressed on thymoma cell membrane.

Regional topographical differences of canine microglial immunophenotype and function in the healthy spinal cord - Corrected Proof

2010-08-23

Abstract: Differences in the regulation of surface molecule expression and functional activity of microglia, the resident immune effector elements of the central nervous system (CNS), might give important insights into understanding the predilection sites of some diseases within the CNS. Therefore, canine microglial cells in relation to different topographical regions within the healthy CNS were evaluated ex vivo from the brain, cervical, and thoracolumbar spinal cord using density gradient centrifugation and flow cytometry in a homogenous dog population.Immunophenotypical characterization showed physiological regional differences for B7-1, CD14, CD44, CD1c, CD18, CD11b, and CD11c. Both, phagocytosis and ROS generation revealed differences between the brain, cervical, and thoracolumbar spinal cord.Our results emphasize that microglia displays physiological topographical regional differences within the CNS. The dog seems to be an ideal model to further investigate the role of microglia in focal pathological conditions of the spinal cord.

LRRK2 is expressed in B-2 but not in B-1 B cells, and downregulated by cellular activation - Corrected Proof

2010-08-23

Abstract: LRRK2, the causal molecule of familial Parkinson's disease, is expressed strongly by one of the B cell subsets, B-2 cells, but not by the other subset, B-1 cells, in the mouse peritoneal cavity, spleen, and peripheral blood. Bone marrow pre-B cells or T cells exhibited little LRRK2 expression. LRRK2 expression was dramatically downregulated upon activation of B-2 cells with various types of stimulation. These results suggest that LRRK2, whose true function has not yet been clarified, may play some important role(s) in the development and function of B cells, particularly the maintenance of B-2 cells in a resting status.

Selective recognition and elimination of nicotinic acetylcholine receptor-reactive B cells by a recombinant fusion protein AChR-Fc in myasthenia gravis in vitro - Corrected Proof

2010-08-20

Abstract: AChR-reactive B cells play a key role in the pathogenesis of myasthenia gravis (MG) by producing autoantibodies. Selective elimination of AChR-reactive B cells will be a promising way to treat MG. Thus, we generated a fusion protein (referred to as AChR-Fc) composed of the human extracellular domain of AChR α1 subunit and the Fc domain of the human IgG1 heavy chain, which could bind both to AChR-reactive BCR and FcγRIIB on the surface of AChR-reactive B cells. Our results showed that AChR-Fc inhibited the proliferation of AChR-specific hybridoma cells, promoted their apoptosis, and mediated cytotoxicity by cross-linking effector cells and complement. Likewise, AChR-Fc significantly reduced the number of AChR-reactive B cells from spleen of Lewis rats immunized with AChR ex vivo.

In vitro and in vivo induction and activation of nNOS by LPS in oligodendrocytes - Corrected Proof

S.Y. Yao, A. Ljunggren-Rose, N. Chandramohan, W.O. Whetsell, S. Sriram — 2010-08-20

Abstract: There are currently four known isoforms of nitric oxide synthase (NOS). Of these, neuronal NOS (nNOS) is known to be present exclusively in neurons, endothelial NOS (eNOS) in vascular endothelium, while the inducible form of NOS (iNOS) is known to be activated in oligodendrocytes, astrocytes and microglia. The fourth isoform, mitochondrial NOS (mtNOS), represents a post-translational modification of nNOS. Using western blotting and real time-PCR, we show induction and activation of nNOS following culture of oligodendrocyte progenitor cells (OPC) with lipopolysaccharide (LPS). Activation of nNOS results in accumulation of peroxynitrite and tyrosine nitration of proteins in oligodendrocytes resulting in reduced cell viability. Injection of LPS in vivo into the corpus callosum of rats leads to the development of extensive demyelination of the white matter tracts. Immunostaining of regions close to the injection site shows the presence of nNOS, but not iNOS, in oligodendrocytes. Neither iNOS nor nNOS was seen in astrocytes in areas of demyelination. These studies suggest that activation of nNOS in oligodendrocytes leads to oligodendrocyte injury resulting in demyelination.

The role of measurement of serum autoantibodies in prediction of pediatric neuropsychiatric systemic lupus erythematosus - Corrected Proof

Gehan A. Mostafa, Dalia H. Ibrahim, Abeer A. Shehab, Azza K. Mohammed — 2010-08-19

Abstract: Neuropsychiatric systemic lupus erythematosus (NPSLE) is one of the most difficult manifestations of lupus to diagnose. Measurement of serum brain antibodies has contributed to early diagnosis and management of NPSLE before development of a debilitating disease. We aimed to assess the value of serum anti-ganglioside M1 antibodies in prediction of NPSLE, in comparison to other antibodies used in routine laboratory diagnosis of NPSLE. In addition, we are the first to study the relationship between these antibodies and cognitive function in lupus patients. Serum anti-ganglioside M1, anti-ribosomal P protein and anti-cardiolipin antibodies were measured in 30 lupus patients without clinical evidence of NPSLE, aged 8–16years, and 30 healthy matched-subjects. Patients were followed-up clinically by monthly neuropsychiatric evaluation and assessment of cognitive function for 12months. Twelve patients developed neuropsychiatric manifestations during follow-up. Of those patients, 83.3%, 50% and 16.7% were seropositive for anti-ganglioside M1, anti-ribosomal P and anti-cardiolipin antibodies, respectively at the time of initial evaluation before clinical presentation of NPSLE. There was a significant positive association between anti-ganglioside seropositivity and cognitive dysfunction (P<0.001). In addition, anti-ganglioside seropositivity had a significant risk for association with cognitive dysfunction (odds ratio: 36; 95% CI: 4.3–302.8). Conclusions: Serum anti-ganglioside M1 antibodies had a higher predictive value for NPSLE than other antibodies used in routine laboratory diagnosis of this disease. Thus, they may be reliable parameters for early diagnosis and management of NPSLE before clinical manifestations ensue. In addition, anti-ganglioside M1 antibodies may play a role in cognitive dysfunction found in some lupus patients.

Intracerebroventricular injection of an agonist-like monoclonal antibody to adenosine A2A receptor has antinociceptive effects in mice - Corrected Proof

2010-08-19

Abstract: Adenosine is a modulator of nociceptive pathways, both at the spinal and supraspinal levels. Adenosine A1 and A2A receptors (A1R, A2AR) are expressed in the basal ganglia where they are the target of caffeine, the most widely use psychoactive drug which acts as an antagonist to both types of receptors. Given the controversial role of A2AR versus A1R in modulating pain in brain areas, mice received intracerebroventricular injection of Adonis, an agonist-like monoclonal antibody with high specificity for the A2AR and were subjected to behavioral tests investigating nociceptive thresholds. We report that Adonis led to a significant dose-dependent increase in hot-plate and tail-flick latencies in mice and that such increase was prevented by caffeine and ZM 241385, a specific A2AR antagonist. The Adonis antinociceptive effects were also inhibited by naloxone, a non selective antagonist for opioid receptors, suggesting that Adonis acts, at least in part, through the stimulation of the endogenous opioid system. These results confirm the A2AR as a target for pain control and Adonis as a potential drug with therapeutic interest.

Proliferative and protective effects of SurR9-C84A on differentiated neural cells - Corrected Proof

Sara Baratchi, Rupinder K. Kanwar, Chun Hei Antonio Cheung, Jagat R. Kanwar — 2010-08-16

Abstract: Targeting survivin has the ability to inhibit apoptosis and regulate mitosis for the protection of neuronal cells, and it offers several advantages for neuronal repair and protection. We found that the BIR motif mutant of survivin (SurR9-C84A) can bind to microtubules and regulate their stability, induce cell division, increase proliferation and activate the expression of cell cycle and neuronal markers in differentiated SK-N-SH and HCN-2 neurons. We further showed the protective effects of SurR9-C84A against post differentiation retinoic acid induced neurotoxicity. These abilities of SurR9-C84A offer a great potential for future neuronal repair therapy.

Enhanced Th17 phenotype in individuals with generalized anxiety disorder - Corrected Proof

2010-08-16

Abstract: The generalized anxiety disorder (GAD) is often a debilitating chronic condition, characterized by long-lasting anxiety that is not focused on any object or situation. Besides being clearly linked to increased susceptibility to infectious diseases, anxiety is also known to contribute to the pathogenesis of many inflammatory/autoimmune disorders. The present work aimed to explore the T cell profile following in vitro activation in cultures obtained from a group of individuals with GAD, comparing them with healthy control individuals. Our results demonstrated that cell cultures from GAD group proliferated less following T cell activation as compared with the control group. The analysis of the cytokine profile revealed Th1 and Th2 cytokine deficiencies in the anxious group, as compared with the control subjects. On the other hand, this cellular and humoral immune damage was followed by enhanced production of Th17-derived cytokines. In particular, the levels of TNF-α and IL-17 were significantly higher in cell cultures containing activated T cells from GAD individuals. Therefore, besides a deficiency on Th1 phenotype, an elevated proinflammatory status of these individuals might be related to both glucocorticoid immune resistance and lower IL-10 levels produced by activated T cells. In conclusion, our results demonstrated a T cell functional dysregulation in individuals with GAD, and can help to explain the mechanisms of immune impairment in these subjects and their relationship with increased susceptibility to infections and autoimmune diseases.

Involvement of IFN-γ and perforin, but not Fas/FasL interactions in regulatory T cell-mediated suppression of experimental autoimmune encephalomyelitis - Corrected Proof

Tara Beeston, Trevor R.F. Smith, Igor Maricic, Xiaolei Tang, Vipin Kumar — 2010-08-13

Abstract: Autoaggressive, myelin-reactive T cells are involved in multiple sclerosis and its prototype experimental autoimmune encephalomyelitis (EAE) in mice. A peripheral negative feedback mechanism involving regulatory CD4+ and CD8+T cells (Treg) operates to suppress disease-mediating T cell responses. We have recently characterized a novel population of Qa-1a-restricted, TCR-peptide-reactive CD8αα+TCRαβ+ Treg that induce apoptotic depletion of the encephalitogenic Vβ8.2 cells in vivo and provide protection from EAE. Here we have used mice deficient in perforin, Fas/FasL and IFN-γ molecules to investigate their role in Treg-mediated regulation of EAE. Data show that Fas/FasL interactions are not involved, but regulation mediated by Treg is dependent on the presence of IFN-γ and the perforin pathway. These data provide a molecular mechanism of Treg-mediated killing of the pathogenic T cells and have important implications in the design of immune interventions for demyelinating disease.

Anti-SOX1 antibodies in patients with paraneoplastic and non-paraneoplastic neuropathy - Corrected Proof

2010-08-12

Abstract: Anti-SOX1 antibodies have been described to be positive in patients with paraneoplastic Lambert–Eaton myasthenic syndrome and, in a lower amount, in patients with anti-Hu positive paraneoplastic neurological syndromes, and with SCLC alone, respectively. We found 5/32 patients with paraneoplastic neuropathy and, surprisingly, 4/22 patients with neuropathy of unknown origin positive for anti-SOX1 antibodies, whereas no patient with inflammatory neuropathy and no healthy controls showed any reactivity (p=0.007). All patients with neuropathy of unknown origin where followed up for four years without diagnosis of a tumour so far. Anti-SOX1 antibodies are associated with paraneoplastic neuropathies and may define another group of non-paraneoplastic, immune-mediated neuropathies.

GAD antibodies associated neurological disorders: Incidence and phenotype distribution among neurological inflammatory diseases - Corrected Proof

2010-08-10

Abstract: We investigated the prevalence and the clinical association of high titer of antibodies against glutamic acid decarboxylase (hGADAb) among unselected patients with inflammatory/autoimmune disorders of the nervous system. By indirect immunofluorescence examination of samples from 1435 patients, we identified 7 cases (0.48%) with hGADAb. Although stiff-person plus syndrome was the commonest clinical accompaniment, most of the patients presented with a combination of different symptoms, including psychiatric disturbances and intestinal motility disorders. Diagnosis delay and chronic evolution were common findings. In two cases persistently high values of hGADAb over the years were observed. The rarity and the phenotype heterogeneity of hGADAb clinical association should not discourage clinicians from antibody screening, at least in selected cases, as an early immunotherapy can change the otherwise chronic progression of this complex disorder spectrum.

Association to the Glypican-5 gene in multiple sclerosis - Corrected Proof

2010-08-09

Abstract: Multiple sclerosis (MS) is an inflammatory, demyelinating disease affecting the central nervous system. MS-associated variants have been reported at both HLA and non-HLA loci, the latter including chromosome 13q31–32 and the Glypican-5 and Glypican-6 genes.In order to further explore the 13q31–32 region in MS, we genotyped 33 SNPs in 1355 Norwegian MS patients and 1446 Norwegian controls. An intronic SNP in the Glypican-5 gene (rs9523787) showed association with MS (pcorr=0.006). Thus, this study supports that MS susceptibility at 13q31–32 may localize to the Glypican-5 gene, which should lead to further fine-mapping, replication and functional studies of this gene.

Induction of vascular endothelial growth factor receptor-3 mRNA in glial cells following focal cerebral ischemia in rats - Corrected Proof

2010-08-09

Abstract: To identify whether vascular endothelial growth factor receptor (VEGFR)-3, a receptor for VEGF-C and VEGF-D, is involved in pathophysiology of stroke, we investigated the spatiotemporal regulation of VEGFR-3 mRNA after transient focal cerebral ischemia. Most of the increase in VEGFR-3 expression in the ischemic core could be attributed to brain macrophages, whereas VEGFR-3 in the peri-infarct penumbra region was predominantly expressed in reactive astrocytes. A subpopulation of VEGFR-3-expressing brain macrophages was positive for NG2 proteoglycan and showed proliferative activity. In addition, in vitro model of stroke revealed no significant induction of VEGFR-3 in activated microglial cells, indicating that infiltrating exogenous macrophages expressed VEGFR-3 after focal ischemia. These data suggest that VEGFR-3 may be involved in the glial reaction and possibly in the recruitment of monocytic macrophages during ischemic insults.

Laquinimod interferes with migratory capacity of T cells and reduces IL-17 levels, inflammatory demyelination and acute axonal damage in mice with experimental autoimmune encephalomyelitis - Corrected Proof

2010-08-04

Abstract: We investigated the effect of laquinimod on inflammatory demyelination, axonal damage, cytokine profiles and migratory capacities of lymphocytes in C57BL/6 mice with active EAE induced with MOG35–55 peptide. The mice were treated at disease induction and after disease onset. Spinal cords were assessed histologically. Cytokines and adhesive properties were analyzed in splenocytes. Preventive and therapeutic laquinimod treatment reduced clinical signs, inflammation, and demyelination. VLA-4-mediated adhesiveness and pro-inflammatory cytokines such as IL-17 were down-regulated in treated animals. Within lesions, treated mice showed similar axonal densities, but less acute axonal damage than controls. Laquinimod might thus protect myelin and axons by decreasing pro-inflammatory cytokines and impairing the migratory capacity of lymphocytes.

Chronic exposure to the chemokine CCL3 enhances neuronal network activity in rat hippocampal cultures - Corrected Proof

M. Kuijpers, K.L.I. van Gassen, P.N.E. de Graan, D. Gruol — 2010-08-03

Abstract: We examined the effect of chronic CCL3 treatment on the properties of cultured rat hippocampal neurons to gain an understanding of the neuronal effects of CCL3 during neuroinflammatory disorders. Western blot assays showed that chronic exposure to CCL3 altered the level of specific neuronal and glial proteins and that CCL3 had no effect on neuronal survival. CCL3 treatment also altered intracellular Ca2+ dynamics and increased Ca2+ levels in hippocampal neurons, measured by fura-2 imaging techniques. Additionally, chronic CCL3 increased NMDA-evoked Ca2+ signals in the hippocampal neurons and increased NMDA receptor levels. These CCL3-induced neuroadaptive changes could play an important role in the CNS dysfunction associated with CNS disorders with a neuroinflammatory component.

Two HLA class I genes independently associated with multiple sclerosis - Corrected Proof

2010-08-03

Abstract: Objective: The risk of multiple sclerosis (MS) is influenced by HLA-DRB1, while protective effects have been proposed for HLA-A*02 and HLA-C*05. Our aim was to further understand the role of HLA class I in MS through a comprehensive investigation.Methods: 1529 MS patients and 1814 controls from Sweden and Norway were genotyped for HLA-DRB1, HLA-A, and HLA-C. Simultaneous analysis of all alleles while adjusting for confounding was achieved using logistic regression.Results: We observed independent effects of all three genes. We confirm the HLA-A*02 (OR=0.73, p=9.2×10−4) association and report a novel effect of HLA-C*08 (OR=1.85, p=0.0093).Conclusions: The HLA class I region contains two factors modulating MS risk, characterized by independent associations with HLA-A and HLA-C.

Analysis of glial secretome: The long pentraxin PTX3 modulates phagocytic activity of microglia - Corrected Proof

Hyejin Jeon, Shinrye Lee, Won-Ha Lee, Kyoungho Suk — 2010-08-02

Abstract: Microglia, as the phagocytes of the central nervous system, play an important role in the recognition, engulfment, and clearance of apoptotic cells and invading microbes. Proteins secreted from activated glial cells may affect microglial phagocytic activity. Secreted proteins of mixed glial cells stimulated with lipopolysaccharide (LPS) and interferon-γ (IFN-γ) for 24h were identified for the first time by liquid chromatography and tandem mass spectrometric analysis. Several proteins were newly identified as a glia-secreted protein. Among the proteins identified by the mixed glia secretome analysis, pentraxin 3 (PTX3) secretion was most highly induced by LPS/IFN-γ stimulation. Expression of PTX3 mRNA was detected in primary microglia and astrocyte cultures as well as glial cell lines. Glial secretion of PTX3 and its inflammatory induction was confirmed by Western blot analysis of conditioned media of mixed glial cultures. PTX3 did not influence LPS-induced nitric oxide production or neurotoxicity of BV-2 microglial cells. Most importantly, PTX3 selectively modulated microglial phagocytosis activity; it promoted engulfment of zymosan particles, while it inhibited uptake of apoptotic cells. Our results indicate that glia-derived PTX3 may modulate phagocytic functions of microglia, and this may have important implications in the regulation of microglial activity in health and disease.

A unique antibody gene signature is prevalent in the central nervous system of patients with multiple sclerosis - Corrected Proof

2010-07-26

Abstract: B cells isolated from the CSF of patients with multiple sclerosis (MS) have a unique accumulation of somatic hypermutation within the B cell receptor, termed the antibody gene signature (AGS). The focus of this study was to investigate whether the AGS could also be detected in MS brain tissue. Genetic analysis of B cells isolated from post-mortem CNS tissue samples from four MS brains demonstrated that signature enriched B cells are present at the site of tissue injury as well as in the circulating CSF.

Therapeutic effects of resveratrol during acute periods following experimental ischemic stroke - Corrected Proof

Jin A. Shin, Hyunah Lee, Yoo-Kyoung Lim, Yaekyu Koh, Ji Ha Choi, Eun-Mi Park — 2010-07-26

Abstract: We defined whether resveratrol administration during the acute phase of ischemic stroke reduces brain injury in mice. Infarct volumes were decreased significantly in both sexes with different doses of resveratrol (5mg/kg for males and 1mg/kg for females) administered 3h after ischemic stroke. Administration of resveratrol 6h after insult was also effective to decrease infarct volumes. Resveratrol suppressed expressions of IL-1β and TNF-α, microglial activation, and ROS production in the ischemic cortex. The findings suggest that the suppression of inflammation is partly associated with the neuroprotective effects of resveratrol, and resveratrol can be developed as a therapeutic drug for acute ischemic stroke.

Excess neutrophil infiltration during cytomegalovirus brain infection of interleukin-10-deficient mice - Corrected Proof

2010-07-26

Abstract: Wild-type mice control murine cytomegalovirus (MCMV) brain infection, but identical infection is lethal to animals deficient in interleukin (IL)-10. Here, we report that MCMV-infected IL-10 knockout (KO) mice displayed a marked increase in neutrophil infiltration into the infected, IL-10-deficient brain when compared to wild-type animals. Enhanced microglial cell activation, determined by MHC class II up-regulation, overexpression of CXCL2, and elevated P-selectin mRNA levels were observed. In vivo blocking of CXCL2 attenuated neutrophil infiltration and significantly improved the outcome of infection. Collectively, these data indicate that the absence of IL-10 results in pathologic neutrophil infiltration into MCMV-infected brains.

Restoration of microglial function by granulocyte-colony stimulating factor in ALS model mice - Corrected Proof

2010-07-26

Abstract: We studied the effects of G-CSF on microglial reactions in mutant SOD1 (mSOD1)-Tg (G93A) ALS model mice. Following hypoglossal axotomy, the numbers of neurons and microglia expressing GDNF were significantly lower in mSOD1-Tg mice than in non-transgenic (NTG) littermates. This decrease in the number of neurons after axotomy and a decrease in the number of large myelinated axons in mSOD1-Tg mice over the disease course were improved by G-CSF, which also increased microglial recruitment. Impaired migration of cultured mSOD1-Tg microglia to MCP-1 was recovered following G-CSF treatment. Restoration of microglial responses by G-CSF may contribute to its neuroprotective effects.

Dominance of E. coli phagocytosis over LPS in the inflammatory response of microglia - Corrected Proof

Vishanthan Sivagnanam, Xiaoping Zhu, Lyanne C. Schlichter — 2010-07-23

Abstract: CNS bacterial infections are prevalent in neonates, the immune-compromised and elderly. During peripheral infections, macrophages employ multiple pattern recognition receptors (PRRs) to respond to pathogens, but less is known about brain microglia. We assessed microglial expression of PRRs, compared responses to whole E. coli and LPS, and tested the hypothesis that bacteria modulate the response to LPS. LPS increased the microglial phagocytic capacity, and changed expression of CD14, CR3, Fcgr1, Fcgr3a, TLR4, MARCO, MHCII, NOD2, TLR9 and SR-A, differently from stimulation with whole E. coli. Importantly, when added with LPS, E. coli dominated the microglial responses for 11/13 genes examined.

A Lecinoxoid, an oxidized phospholipid small molecule, constrains CNS autoimmune disease - Corrected Proof

2010-07-22

Abstract: Oxidized phospholipids (Ox-PLs) are generated in abundance at sites of inflammation. Recent studies have indicated that Ox-PLs may also exhibit anti-inflammatory activities. In this study, we investigated the beneficial effect of VB-201, a pure synthetic Ox-PL analog that we synthesized, on the development of a central nervous system (CNS) autoimmune inflammatory disease, in vivo. Oral administration of VB-201 ameliorated the severity of experimental autoimmune encephalomyelitis (EAE) induced by myelin oligodendrocyte glycoprotein (MOG) peptide MOG35-55, and restrained the encephalogenicity of MOG35-55-specific T-cells. Our data presents a novel prospect for the role of Ox-PL analogs in CNS inflammatory diseases.

Measurement of anti-beta amyloid antibodies in human blood - Corrected Proof

2010-07-21

Abstract: The human IgG repertoire contains endogenous antibodies against beta amyloid (Aβ) that may be relevant to the pathogenesis and treatment of Alzheimer's disease. There have been widely disparate estimates of the levels of these antibodies in human plasma. We identify factors that have contributed to these disparities and describe improved methods for measuring anti-Aβ antibodies in blood. These methods include isolating immunoglobulin by thiophilic chromatography and using chaotropic salts to dislodge weakly bound antibodies without significantly reducing the binding of specific anti-Aβ antibodies. Using these methods, we show that human blood contains polyvalent IgG antibodies that bind to Aβ with relatively low avidity and specificity, as well as IgG antibodies that bind to linear and conformational epitopes on amyloid monomers and aggregates with moderate to high avidity.

Central NOS inhibition differentially affects vasopressin gene expression in hypothalamic nuclei in septic rats - Corrected Proof

2010-07-21

Abstract: Our aim was to investigate the effect of central NOS inhibition on hypothalamic arginine vasopressin (AVP) gene expression, hormone release and on the cardiovascular response during experimental sepsis. Male Wistar rats were intracerebroventricularly injected with the non-selective NO synthase (NOS) inhibitor (L-NAME) or aminoguanidine, a selective inhibitor of the inducible isoform (iNOS). After 30min, sepsis was induced by cecal ligation and puncture (CLP) causing an increase in heart rate (HR), as well as a reduction in median arterial pressure (MAP) and AVP expression ratio (AVPR), mainly in the supraoptic nucleus. AVP plasma levels (AVPp) increased in the early but not in the late phase of sepsis. L-NAME pretreatment increased MAP but did not change HR. It also resulted in an increase in AVPp at all time points, except 24h, when it returned to basal levels. AVPR, however remained reduced in both nuclei. Aminoguanidine pretreatment resulted in increased MAP in the early phase and higher AVPR in the supraoptic, but not in the paraventricular nucleus, while AVPp remained elevated at all time points. We suggest that increased central NO production, mainly inducible NOS-derived, reduces AVP gene expression differentially in supraoptic and paraventricular nuclei, and that this may contribute to low AVP plasma levels and hypotension in the late phase of sepsis.

Altered miRNA expression in T regulatory cells in course of multiple sclerosis - Corrected Proof

2010-07-20

Abstract: Objectives: Multiple sclerosis (MS) is a chronic inflammatory response against constituents of the central nervous system. It is known that regulatory T cells (Tregs) play a key role in the autoimmune balance and their improper function may facilitate the expansion of autoaggressive T cell clones. Recently, microRNAs (miRNAs) have been involved in autoimmune disorders and their loss-of-function in immune cells was shown to facilitate systemic autoimmune disorders. Here, we analyzed the miRNA expression profile in Tregs from MS-RR.Methods: We assessed miRNA genome-wide expression profile by microarray analysis on CD4+CD25+high T cells from 12 MS relapsing–remitting patients in stable condition and 14 healthy controls. Since CD4+CD25+high T cells comprise both T regulatory cells (CD4+CD25+highCD127dim/−) and T effector cells (CD4+CD25+highCD127+), we performed a quantitative RT-PCR on CD4+CD25+highCD127dim/− and CD4+CD25+highCD127+ cells isolated from the same blood sample.Results: We found 23 human miRNAs differentially expressed between CD4+CD25high bona fide Treg cells from MS patients vs. healthy donors, but, conversely, among the deregulated miRNAs, members of the miR-106b-25 were found down-regulated in MS patients when compared to healthy donors in CD4+CD25highCD127dim/− T regulatory cells. More interesting, the ratio between Treg/Teff showed an enrichment of these microRNA in T regulatory cells derived from patients if compared to healthy controls.Conclusion: miR-106b and miR-25 were previously shown to modulate the TGF-β signaling pathway through their action on CDKN1A/p21 and BCL2L11/Bim. TGF-β is involved in T regulatory cells differentiation and maturation. Therefore, the deregulation of this miRNA cluster may alter Treg cells activity in course of MS, by altering TGF-β biological functions.

CCR7 is expressed in astrocytes and upregulated after an inflammatory injury - Corrected Proof

2010-07-20

Abstract: Neurodegenerative or autoimmune diseases are frequently regulated by chemokines and their receptors, controlling both glial activation and immune cell infiltration. CCL19 and CCL21 have been described to mediate crucial functions during CNS pathological states, regulating both immune cell traffic to the CNS and communication between glia and neurons. Here, we describe the expression pattern and cellular sources of CCR7, receptor of CCL19 and CCL21, in the normal mouse brain. Moreover, we found that CCR7 is upregulated in reactive astrocytes upon intracerebral LPS, regulating early glial reactivity through its ligands CCL19 and CCL21. Our results indicate that CCR7 is playing an important role for the intercellular communication during the inflammatory activation in the CNS.

Glatiramer acetate-reactive T lymphocytes regulate oligodendrocyte progenitor cell number in vitro: Role of IGF-2 - Corrected Proof

2010-07-16

Abstract: Glatiramer acetate (GA) is an immunomodulator approved for therapy of relapsing–remitting multiple sclerosis (RRMS), but recent findings indicate that it may also have additional, neurotrophic effects. Here, we found that supernatants from human GA-reactive T lymphocytes potentiated oligodendrocyte numbers in rodent and human oligodendrocyte progenitor (OPC) cultures. Effects of Th2-polarized lines were stronger than Th1-polarized cells. Microarray and ELISA analyses revealed that neurotrophic factors induced in Th2- and Th1-polarized GA-reactive lines included IGF-2 and BMP-7 respectively, and functional studies confirmed IGF-2 as trophic for OPCs. Our results support the concept that GA therapy may result in supportive effects on oligodendrocytes in RRMS patients.

Androgens suppress antigen-specific T cell responses and IFN-γ production during intracranial LCMV infection - Corrected Proof

Adora A. Lin, Sara E. Wojciechowski, David A. Hildeman — 2010-07-12

Abstract: Intracranial (i.c.) lymphocytic choriomeningitis virus (LCMV) infection of mice results in T cell-driven anorexia and weight loss, which is diminished in males compared to females. We investigated sex-specific effects on antigen-presenting cells (APCs) and T cells after i.c. LCMV infection. Numbers of LCMV-specific T cells, APC activation, and levels of inflammatory cytokines and chemokines in CSF were decreased in males compared to females. Orchidectomy enhanced these immune parameters in males, while dihydrotestosterone treatment of orchidectomized males and intact females decreased some of these parameters. These data suggest that qualitative and quantitative effects of androgens on APCs and T cells may contribute to the well-known, but poorly understood sex differences in immunity and autoimmunity.

Plasmacytoid dendritic cells in multiple sclerosis: Chemokine and chemokine receptor modulation by interferon-beta - Corrected Proof

2010-07-12

Abstract: Plasmacytoid dendritic cells (pDCs) are present in peripheral blood, leptomeninges and demyelinating lesions in patients with multiple sclerosis (MS). The ability of pDCs to produce chemokines and express the chemokine receptor CCR7 in MS is not known.We studied pDCs in MS patients and healthy subjects. The ability of pDCs to up-regulate CCR7 was significantly increased in untreated MS patients as compared to healthy subjects. IFN-beta treatment significantly inhibited TLR9 agonist-specific secretion of chemokines, which are ligands for CCR5-positive Th1 cells (CCL3, CCL4, and CCL5), and impaired TLR9 agonist-induced up-regulation of CCR7 and IFN-alpha in MS patients. This finding represents a new immunomodulatory effect of IFN-beta in patients with multiple sclerosis.

Eosinophil-induced neurotoxicity: The role of eosinophil cationic protein/RNase 3 - Corrected Proof

Susanna Navarro, Ester Boix, Claudi M. Cuchillo, M. Victòria Nogués — 2010-07-12

Abstract: We analyze the effect of ECP on primary cultures of cerebellar granule cells (CGCs) and astrocytes in an effort to understand the role of ECP in the eosinophil-induced neurotoxicity. We have shown that ECP induces dose-dependent cell death in both CGCs and astrocytes. The effect of ECP action on cell morphology is consistent with apoptosis for both cell types. The apoptotic mechanism involves ECP binding on the cell surface and an increase in the free cytosolic Ca2+ concentration. It is associated with the activation of caspase-3, -8 and -9, processes that are also involved in the apoptosis induced either by stroke or other neurodegenerative conditions. Our results open new insights to clarify the neurotoxic effects associated to ECP in the hypereosinophilic syndrome.

α-Melanocyte-stimulating hormone modulates lipopolysaccharide plus interferon-γ-induced tumor necrosis factor-α expression but not tumor necrosis factor-α receptor expression in cultured hypothalamic neurons - Corrected Proof

2010-07-12

Abstract: In a previous work we showed that the melanocortin alpha-melanocyte-stimulating hormone (α-MSH) exerts anti-inflammatory action through melanocortin 4 receptor (MC4R) in vivo in rat hypothalamus. In this work, we examined the effect of α-MSH on the expression of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) and their receptors in primary cultured rat hypothalamic neurons. We also investigated α-MSH's possible mechanism/s of action. α-MSH (5μM) decreased TNF-α expression induced by 24h administration of a combination of bacterial lipopolysaccharide (LPS, 1μg/ml) plus interferon-γ (IFN-γ, 50ng/ml). Expression of TNF-α and IL-1β receptors TNFR1, TNFR2 and IL-1RI, was up-regulated by LPS+IFN-γ whereas α-MSH did not modify basal or LPS+IFN-γ-induced-TNFRs or IL-1RI expression. Both α-MSH and LPS+IFN-γ treatments increased CREB activation. α-MSH did not modify NF-κB activation induced by LPS+IFN-γ in hypothalamic neurons. In conclusion, our data show that α-MSH reduces TNF-α expression in hypothalamic neurons by a mechanism which could be mediated by CREB. The regulation of inflammatory processes in the hypothalamus by α-MSH might help to prevent neurodegeneration resulting from inflammation.

Regulatory T cells in myositis — Good Samaritans at the site of inflammation? - Corrected Proof

Bernd C. Kieseier, Reinhard Hohlfeld — 2010-07-12

Regulatory T cells (Tregs) are the main guardians against autoimmunity. Knowledge about these fundamentally important cells has literally exploded during the past years. Establishment and maintenance of self-tolerance is a complex process that includes both central (thymic) and peripheral check points (). Alterations in these critical steps of immunoregulation could induce suboptimal suppression of activated pathogenic immune cells eventually leading to autoimmunity (). With the discovery of a specific subtype of CD4+CD25+ suppressor T cells, nowadays termed regulatory T cells or Tregs, a major cellular component of immune regulation and dysregulation was identified (). Based on data gathered in various animal models and on the discovery of forkhead box protein P3 (Foxp3) as a fundamental Treg-associated transcription factor, it is now commonly accepted that Tregs are crucial for the maintenance of self-tolerance throughout life (). Tregs suppress harmful immune responses against both foreign and self antigens and are of critical importance in controlling the number and function of autoreactive T cells (). The importance of Tregs for tolerance and protection against autoimmunity has been corroborated by various studies involving targeted deletions or mutations of molecules relevant or Treg function. A genetic defect in, or inducible ablation of the Foxp3 gene causes a scurfy autoimmune phenotype in mice (). Similarly, mutations in the FOXP3 gene in humans can result in an aggressive and fatal autoimmune disorder known as immunodysregulation, polyendocrinopathy, enteropathy, X-linked syndrome, or IPEX ().

Nicotinic acetylcholine receptor activation reduces skeletal muscle inflammation of mdx mice - Corrected Proof

2010-07-08

Abstract: Mdx mice develop an inflammatory myopathy characterized at different ages by myonecrosis with scattered inflammatory infiltrates followed by muscular regeneration and later persistent fibrosis. This work aimed to verify the putative anti-inflammatory role of nicotinic acetylcholine receptor (nAChR) in the mdx muscular lesion. Mitigation of myonecrosis and decreased TNFα production were accompanied by increased numbers of F4/80 macrophages expressing nAChRα7. In vivo treatment with nicotine attenuated muscular inflammation characterized by reduced metalloprotease MMP-9 activity, TNFα and NFkB content and increased muscular regeneration. Our data indicate that nAChR activation influences local inflammatory responses in the muscular lesion of mdx mice.

Dual regulation of mu opioid receptors in SK-N-SH neuroblastoma cells by morphine and interleukin-1β: Evidence for opioid-immune crosstalk - Corrected Proof

Shekher Mohan, Randall L. Davis, Udaya DeSilva, Craig W. Stevens — 2010-07-08

Abstract: Treatment of SK-N-SH cells with morphine and interleukin-1beta (IL-1β) produced dual regulation of the mRNA for the human mu opioid receptor (MOR) protein. Morphine produced a decrease in the MOR mRNA while IL-1β increased it, as assessed by real-time quantitative PCR. These data were consistent with immunocytochemical studies of treated and untreated cells. Morphine-mediated down-regulation of MOR was blocked by naltrexone and IL-1β-induced up-regulation of MOR was blocked by interleukin-1 receptor type 1 antagonist. Immune-opioid crosstalk was examined by IL-1β and morphine co-treatment. These data are the first to show dual regulation of MOR in neuroblastoma cells.

Distinct macrophage subpopulations regulate viral encephalitis but not viral clearance in the CNS - Corrected Proof

2010-07-05

Abstract: Intranasal application of vesicular stomatitis virus (VSV) induces acute encephalitis characterized by a pronounced myeloid and T cell infiltrate. The role of distinct phagocytic populations on VSV encephalitis was therefore examined in this study. Ablation of peripheral macrophages did not impair VSV encephalitis or viral clearance from the brain, whereas, depletion of splenic marginal dendritic cells impaired this response and enhanced morbidity/mortality. Selective depletion of brain perivascular macrophages also suppressed this response without altering viral clearance. Thus, two anatomically distinct phagocytic populations regulate VSV encephalitis in a non-redundant fashion although neither population is essential for viral clearance in the CNS.

Regulation of suppressing and activating effects of mesenchymal stem cells on the encephalitogenic potential of MBP68–86-specific lymphocytes - Corrected Proof

2010-07-05

Abstract: Mesenchymal stem cells (MSCs) possess immunosuppressive potential and are proposed as a tool for cell therapy, however under certain circumstance they could change to become immunostimulating. It is therefore of great importance to better understand the MSCs' immune plasticity. Here we used different doses of MSCs to co-culture with MBP68–86-specific T cells and found that MSCs exerted a suppressive effect on the encephalitogenic ability of MBP68–86-specific T cells at high MSC density (MSC/effector ratio ≥1:10). Whereas at lower MSC/effector ratios (≤1:50), MSCs shifted towards stimulatory activity. Thus the limited amounts of MSCs for application should be considered.

Specific and efficient anti-Aβ42 antibodies induced by sixteen tandem repeats of Aβ9 - Corrected Proof

Lili Cui, Xuemei Huang, Jiapeng Wang, Yingjiu Zhang — 2010-07-05

Abstract: To reduce the risk of an adverse T cell-mediated immune response to Aβ42, three (Aβ9)16-based recombinant immunogens were designed to immunize mice. Compared with Aβ42, they elicited significantly stronger anti-Aβ42 antibody responses and mainly resulted in IgG1 and IgG2b anti-Aβ42 antibodies. These (Aβ9)16-induced antibodies exhibited stronger abilities not only to inhibit Aβ42 aggregation and to disassemble Aβ42 aggregation, but also to inhibit and neutralize Aβ42-induced cytotoxicity in vitro though they showed higher specificities to Aβ42 monomers and Aβ42 oligomers. These results suggested that (Aβ9)16 was a promising candidate for the safe and effective primary immunogen against Aβ42.

Evidence for VAV2 and ZNF433 as susceptibility genes for multiple sclerosis - Corrected Proof

2010-07-02

Abstract: In a genome wide association study consisting of 592 German multiple sclerosis (MS) patients and 825 controls we were able to replicate the association of the HLA region with MS independently of previous case control studies. No SNPs outside the HLA region reached a genome wide level of significance. Nevertheless, we found suggestive evidence for an association of MS with variants in two new genes, the VAV2 gene and the gene for ZNF433.