Journal of Neuroimmunology

Editorial Board

2010-03-30

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

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.

Encephalitogenic T-cells increase numbers of CNS T-cells regardless of antigen specificity by both increasing T-cell entry and preventing egress

Jason R. Lees, Julia Sim, John H. Russell — 2010-02-18

Abstract: This study utilized an adoptive transfer model of experimental autoimmune encephalomyelitis (EAE) induction in mice to characterize the mechanisms involved in CNS accumulation of transferred and host T-cells. Using a flow cytometric technique, we examined phenotypic characteristics of CNS T-cells following disease initiation and the role of T-cell activation in CNS invasion and retention. Host T-cell activation increased cell recruitment and EAE severity. CNS antigen specific T-cells were required to induce T-cell retention within the CNS. Once retention was initiated, CNS T-cells were retained regardless of specificity. This study characterizes mechanisms involved in CNS accumulation of T-cells during EAE pathogenesis.

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

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.

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

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.

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

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.

Involvement of phosphodiesterases in autoimmune diseases

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.

Rapamycin inhibits relapsing experimental autoimmune encephalomyelitis by both effector and regulatory T cells modulation

2010-02-12

Abstract: Rapamycin is an oral immunosuppressant drug previously reported to efficiently induce naturally occurring CD4+CD25+FoxP3+ regulatory T (nTreg) cells re-establishing long-term immune self-tolerance in autoimmune diseases. We investigated the effect of rapamycin administration to SJL/j mice affected by PLP139–151-induced relapsing–remitting experimental autoimmune encephalomyelitis (RR-EAE). We found that oral or intraperitoneal treatment at the peak of disease or at the end of the first clinical attack, dramatically ameliorated the clinical course of RR-EAE. Treatment suspension resulted in early reappearance of disease. Clinical response was associated with reduced central nervous system demyelination and axonal loss. Rapamycin induced suppression of IFN-γ, and IL-17 release from antigen-specific T cells in peripheral lymphoid organs. While CD4+FoxP3+ cells were unaffected, we observed disappearance of CD4+CD45RBhigh effector T (Teff) cells and selective expansion of Treg cells bearing the CD4+CD45RBlowFoxP3+CD25+CD103+ extended phenotype. Finally, the dual action of rapamycin on both Teff and Treg cells resulted in modulation of their ratio that closely paralleled disease course. Our data show that rapamycin inhibits RR-EAE, provide evidence for the immunological mechanisms, and indicate this compound as a potential candidate for the treatment of multiple sclerosis.

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

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 parasitism 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.

Reduction of cell proliferation and potentiation of Fas-induced apoptosis by the selective kappa-opioid receptor agonist U50 488 in the multiple myeloma LP-1 cells

Céline Kerros, Isabelle Brood, Brigitte Sola, Philippe Jauzac, Stéphane Allouche — 2010-02-18

Abstract: As opioid receptors modulate proliferation and apoptosis of immune cells, we hypothesized that they could reduce malignant haematopoietic cells. After screening, we selected the human multiple myeloma LP-1 cells which express mu- (MOP-) and kappa-opioid receptors (KOP-R). U50 488 produces a modest but significant decrease in viability associated with an arrest in the G0/G1 phase, but not antagonized by NorBNI and not associated with modulation of p21Cip1, p27Kip1 or p53 expression. In contrast, no effect was observed with dynorphin, U69 593 and morphine.In conclusion, the anti-proliferative effects of U50 488 are not mediated by KOP-R in the LP-1 cells.

Chronic restraint stress during early Theiler's virus infection exacerbates the subsequent demyelinating disease in SJL mice: II. CNS disease severity

2010-02-18

Abstract: Theiler's murine encephalomyelitis virus (TMEV) infection is a well-characterized model of multiple sclerosis (MS). Previous research has shown that chronic restraint stress (RS) during early TMEV infection exacerbates behavioral signs of the disease. The present data suggest that RS-induced increases in CNS inflammation, demyelination, and axonal degeneration may underlie this exacerbation. In addition, we report that males exhibit greater CNS inflammation and higher numbers of demyelinating lesions while females show greater susceptibility to RS-induced exacerbation. These findings indicate that RS during early TMEV infection increases CNS lesion formation during the late phase and suggest that the effects of RS are sex-dependent.

Strain-specific BDNF expression of rat primary astrocytes

Rongtai Wei, Chiao-Mei Lin, Yu-Ying Tu — 2010-02-22

Abstract: By producing brain-derived neurotrophic factor (BDNF), astrocytes play a role in disease resistance. This study was undertaken to investigate whether primary astrocytes derived from LEW/N and F344/N rats differentially express BDNF. LEW/N astrocytes expressed more BDNF mRNA and protein than F344/N astrocytes in basal and valproic acid (VPA)-stimulated conditions. VPA suppresses HDAC enzyme activity without affecting HDAC gene and protein expression in astrocytes of both strains. Blockade of TrkB receptors resulted in similar fold decreases in basal BDNF mRNA levels between two strains. The results suggest that inhibition of HDAC activity and BDNF–TrkB autocrine loop are involved in regulation of astrocytic BDNF transcription, whereas the mechanisms for elevated constitutive gene BDNF expression of LEW/N astrocytes remain to be investigated.

Increased urinary free immunoglobulin light chain excretion in patients with multiple sclerosis

2010-02-22

Abstract: Background: Plasma and B cells are implicated in multiple sclerosis (MS) and produce free light chains (FLC) that are excreted in urine.Objective: To confirm that demyelinating diseases (DD) cause increased urinary FLCs.Method: Urinary FLC in 50 patients with DD were compared to 20 patients with posterior uveitis (PU), 19 with AIDS, 34 with rheumatoid arthritis (RA) and 19 normal controls (NC).Result: Subjects with DD, PU, RA and AIDS have higher urinary FLCs than NC (p<0.01). Urinary FLCs did not correlate with gadolinium-enhancing lesions on MRI.Conclusions: Urinary FLCs are raised in DD. Further studies are required to see if they correlate with disease activity.

Cerebrospinal fluid levels of BAFF and APRIL in untreated multiple sclerosis

2010-02-12

Abstract: Objective and subjects: To examine in vivo levels of BAFF (B-cell activating factor of the tumor necrosis factor family) and APRIL (a proliferation-inducing ligand) in both the cerebrospinal fluid (CSF) and serum of 30 naïve MS patients and 79 subjects affected by acute or chronic inflammatory or non-inflammatory neurological diseases.Design: Case-control study.Results: No difference among groups was evidenced in serum BAFF or APRIL levels. By contrast, CSF levels of BAFF in MS (mean 144.3pg/ml±141.2), although not significantly different from those observed in NIND (164.2pg/ml±92.0), acute peripheral OIND (243.1pg/ml±139.0) or chronic OIND (240.2pg/ml±122.5), were significantly higher in acute central OIND patients (1274.0pg/ml±803.8; p<0.001 vs. all groups).Similarly, CSF APRIL levels in MS (1541.0pg/ml±1071.0), NIND (2629.0pg/ml±1669.0), acute peripheral OIND (2834.0pg/ml±1118.) or chronic OIND (2764.0pg/ml±659.7) were not significantly different, while they were significantly higher in acute central OIND (6218.0pg/ml±3790.0; p<0.001 vs. MS and NIND; and p<0.05 vs. acute peripheral OIND).Conclusions: Our results strongly suggest that further investigation is warranted to elucidate the role of BAFF and APRIL in MS and that serum levels of BAFF and APRIL do not reflect CSF levels.

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

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.

A highly sensitive electrochemiluminescence immunoassay for the neurofilament heavy chain protein

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.

MGAT5 alters the severity of multiple sclerosis

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).

Long-term treatment of multiple sclerosis with glatiramer acetate: Natural history of the subtypes of anti-glatiramer acetate antibodies and their correlation with clinical efficacy

2010-02-16

Abstract: A retrospective phase IV study was designed to evaluate the anti-GA antibody subtypes, test their in vitro neutralizing activity and correlate these parameters with the clinical efficacy, in long-term GA treatment of MS patients. Serum samples from 153 MS patients, 126 treated with GA for 2 to 15years (mean 6.6years) and 27 treated for <2years, were collected. Anti-myelin basic protein (MBP) and anti-GA antibodies were measured by specific ELISA. Neutralizing activity was determined by the capacity of the serum to inhibit the proliferation of GA-specific T-cells. Anti-GA antibodies were detected even after very long treatment periods, although at lower levels. Anti-MBP reactivity remained consistently negative. The IgG2 isotype of anti-GA antibodies and the multiple sclerosis severity scale (MSSS) was lower in the long-term treated patients P=0.0003 and 0.016 respectively. The neutralizing activity of anti-GA antibodies was insignificant. Our results indicate that the clinical efficacy of GA treatment could be associated with a decrease in anti-GA IgG2 isotype in long-term GA-treated patients.

Production of immune-modulatory nonclassical molecules HLA-G and HLA-E by tumor infiltrating ameboid microglia/macrophages in glioblastomas: A role in innate immunity?

2010-02-18

Abstract: The possible role of immune-modulatory nonclassical molecules HLA-G and HLA-E in an anti-tumoral response and development of glioblastoma is not well characterized. In this study, we evaluated an expression of HLA-G and HLA-E by activated tumor infiltrating microglia/macrophages. We found production of HLA-G and HLA-E by tumor infiltrating activated microglia/macrophages in a majority of glioblastomas. We speculate that the expression of these molecules by activated microglia/CNS macrophages plays a role in the anti-tumoral immunity in the development of glioblastoma. Mechanisms of microglia–glioblastoma cell interactions with respect to the expression of these molecules deserves further study.

Progesterone treatment reduces disease severity and increases IL-10 in experimental autoimmune encephalomyelitis

M.A. Yates, Y. Li, P. Chlebeck, T. Proctor, A.A. Vandenbark, H. Offner — 2010-02-12

Abstract: Ovarian hormones, including progesterone, are known to have immunomodulatory and neuroprotective effects which may alter the disease course of experimental autoimmune encephalomyelitis (EAE). In the current study, we examined the treatment potential of progesterone beginning at the onset of EAE symptoms. Progesterone treated animals showed reduced peak disease scores and cumulative disease indices, and decreased inflammatory cytokine secretion (IL-2 and IL-17). In addition, increased production of IL-10 was accompanied by increased numbers of CD19+ cells and an increase in CD8+ cells. Decreased chemokine and chemokine receptor expression in the spinal cord also contributed to decreased lesions in the spinal cord.