Journal of Neuroimmunology

Editorial Board

2010-01-25

Sphingosine-1-phosphate and its receptors as a possible therapeutic target in autoimmune diseases of the nervous system

Aiden Haghikia, Ralf Gold — 2009-10-30

A common feature of autoimmune diseases of the central (CNS) and the peripheral nervous system (PNS) is the presence of cellular infiltrates composed by different subtypes of immune cells. Some of these cells may directly target parenchymal auto-antigens, others may prepare the wave of inflammation by their secreted inflammatory factors. In this context, various histopathological investigations on acute lesions have suggested different patterns of T lymphocytes and macrophages/monocytes at the site of inflammation in multiple sclerosis (MS), the most common autoimmune disorder of the CNS in young adults (). Similarly, a crucial role for autoreactive immune cells has been attributed to autoimmune neuropathies: the perivascular T cell- and endoneural macrophage-infiltrates have been shown in nerve biopsies of patients suffering from chronic inflammatory demyelinating neuropathy (CIDP), a prominent example of an autoimmune disease of the peripheral nervous system (). There, the blood-nerve-barrier (BNB) may allow access especially at the nerve roots and the nerve terminals; the BNB is not as tightly sealing as the blood-brain-barrier (BBB) (). Thus, after confrontation with a neuritogenic auto-antigen by antigen-presenting cells in secondary lymphoid organs (SLOs), the activated and clonally-expanded auto-antigen primed lymphocytes set out to cross the BNB in a distinct multi-step manner (). Among the concerted mechanisms determining BNB penetration by auto-antigen specific lymphocytes, recognition and attachment to cellular adhesion molecules (CAMs), on vascular endothelial cells constituting the BNB, are crucial steps before approaching the auto-antigen ().

Notch: A new player in MS mechanisms

Maciej Juryńczyk, Krzysztof Selmaj — 2009-09-14

Abstract: Notch is a family of four transmembrane receptors (Notch1–4) that orchestrate differentiation of various cell types, tissues and organs. Recent studies have revealed that Notch, among other processes, regulates immune responses of peripheral T cells, controls oligodendrocyte maturation and myelination of axons and under inflammatory conditions affects activation of macrophages and microglia. Therefore, Notch signaling has been implicated in the differentiation and function of all cell types considered crucial for the development and clinical progression of multiple sclerosis (MS). Importantly, inflammatory/demyelinating lesions in MS and its animal model, autoimmune experimental encephalomyelitis (EAE), abundantly express Notch receptors, their ligands and downstream activation targets. In EAE, in vivo modulation of Notch signaling affects immune responses of myelin-reactive T cells, enhances tissue repair and reduces clinical severity of the disease. In this review, we present recent findings on how Notch signaling may affect function of both immune and glial cells, analyze data implicating the Notch pathway in MS and EAE, and discuss the therapeutic potential of manipulating Notch signaling in MS patients.

Stress induced cognitive deficit is differentially modulated in BALB/c and C57Bl/6 mice: Correlation with Th1/Th2 balance after stress exposure

M.L. Palumbo, M.C. Canzobre, C.G. Pascuan, H. Ríos, M. Wald, A.M. Genaro — 2009-11-30

Abstract: This work shows a comparative study on the effects of chronic mild stress upon learning and memory and immunity, in BALB/c and C57BL/6 mice. Stressed BALB/c, but not C57Bl/6 mice, showed a poor learning performance, morphological alterations in the hippocampus with an increase in oxidative stress. A correlation between poor memory performance and the increase of the Th2/Th1 balance was found. Our results suggest that vulnerability to cognitive deficit associated with stress exposition could be related to a differential regulation of Th1/Th2 cytokine balance, suggesting a better learning performance for individuals that produce Th1 type cytokine after stress exposition.

Tumor necrosis factor-α impairs the recovery of synaptic transmission from hypoxia in rat hippocampal slices

Laura Batti, John J. O'Connor — 2009-11-27

Abstract: Cerebral ischaemia is a common occurrence in a range of pathological conditions, including stroke and traumatic brain injury. Two of the components in ischaemia are tissue hypoxia and the release of pro-inflammatory agents such as TNF-α. The role of TNF-α in an ischaemic/hypoxic episode is still controversial, although deleterious effects of pro-inflammatory cytokines in the area of injury are well documented. One of the prime adaptive mechanisms in response to hypoxia is the cellular activation of adenosine 1 receptors (A1Rs), which inhibits excitatory synaptic transmission. In the present study we have examined the effect of TNF-α application on synaptic transmission during hypoxic exposure and re-oxygenation using extracellular recordings in the CA1 region of the rat hippocampal slice. Hypoxia caused a reversible depression of the field EPSP (29.6±9.7% of control, n=5), which was adenosine A1 receptor-dependent (85.7±4.3%, in the presence of DPCPX (200nM), the adenosine A1 receptor antagonist). DPCPX inhibited the maintenance of long-term potentiation obtained 30min post hypoxia (143.8±8.2% versus 96.4±10.6% respectively, 1h post tetanus; n=5; p<0.005). In TNF-α (150pM) treated slices hypoxic depression was similar to controls but a reduction in fEPSP slope was observed during re-oxygenation (66.8±1.4%, n=5). This effect was reversed by pre-treatment with SB 203580 (1µM), a p38 MAP kinase inhibitor (91.8±6.9%, n=5). These results demonstrate a novel p38 MAPK dependent role for TNF-α in attenuating synaptic transmission after a hypoxic episode.

Modulating dendritic cells (DC) from immunogenic to tolerogenic responses: A novel mechanism of AZA/6-MP

2009-11-26

Abstract: Azathioprine (Aza), 6-Mercaptopurine (6-MP) and 6-Thioguanine (6-TG) are thiopurine drugs widely used as immunosuppressants/anti-inflammatory agents in organ transplantation and chemotherapy. Aza is well tolerated and effective in modifying the course of MS. Here we investigated the action of 6-MP on human dendritic cells (DCs). We described for the first time that 6-MP impairs in vitro differentiation of DCs, has an inhibitory effect during DC activation processes inducing a functionally less immunogenic phenotype. Moreover, 6-MP significantly reduces DC IL-23 production and CCR7 expression, at the same time induces IL-10 augmentation. All these findings add a novel action mechanism in Aza immune modulation.

Peroxisome proliferator-activated receptor-γ agonists suppress iNOS expression induced by LPS in rat primary Schwann cells

2009-11-27

Abstract: In bacterial-induced peripheral nervous system (PNS) inflammation, Schwann cells (SCs) are activated, producing inducible nitric oxide synthase (iNOS), contributed to the pathogenesis of demyelinating disease, such as multiple sclerosis. Peroxisome proliferator-activated receptor-gamma (PPAR-γ) has been shown to play a protective role in cellular inflammatory responses. Here we showed that LPS-induced iNOS biosynthesis was in a concentration and time-dependent manner. In LPS-treated primary SCs, retreatment with PPAR-γ agonist remitted the increase of iNOS, p38 phosphorylation and TLR4, MyD88, augmented the expression of PPAR-γ and localization in nuclear. Coadministration of GW 9662 reversed the effect of PPAR-γ agonists. These results suggest that PPAR-γ agonists, 15d-PGJ2 and pioglitazone, had the anti-inflammatory effects.

Role of opioid receptor like-1 receptor in modulation of endocrine, immunological, and behavioral responses to the T-cell superantigen staphylococcal enterotoxin A

Elyse M. Mallimo, Mike A. Ansonoff, John E. Pintar, Alexander W. Kusnecov — 2009-11-16

Abstract: Opioid receptor like-1 receptor (ORL1) is selective for orphaninFQ/nociceptin (OFQ/N), a peptide linked to stress. Since immunologic stimuli exert stressor-like effects, the neuroendocrine and behavioral effects of the T-cell superantigen staphylococcal enterotoxin A (SEA) were tested in ORL1−/− and ORL1+/+ wildtype 129S6 mice. Within 2h of SEA challenge both genotypes showed elevated corticosterone, but only wildtypes were elevated after 4h, and had altered hypothalamic CRH mRNA. Although amygdaloid CRH and TNFα mRNA was increased by SEA, this did not vary with genotype. Interestingly, gustatory neophobia due to SEA challenge was augmented in ORL1−/− mice, although object neophobia tested 4days later was abrogated. These results suggest differential requirements for ORL1 in the mediation of neuroimmune effects exerted at different times after an immune challenge.

Mast cell adhesion induces cytoskeletal modifications and programmed cell death in oligodendrocytes

2009-11-11

Abstract: In this paper we show that rat peritoneal mast cells (RPMC) adhere to rat oligodendrocytes (ODC) in culture and switch on a bi-directional signal affecting both adhering cell and its target. Following heterotypic interaction, RPMC release granule content and ODC show morphological changes and enter the apoptotic programme. Altogether, these findings indicate that the interaction of MC with ODC could play a role in the mechanism of CNS damage induced by the inflammatory reaction.

BAFF aids generation of IgG anti-ganglioside antibodies in response to Campylobacter jejuni lipo-oligosaccharide

2009-11-09

Abstract: Ganglioside mimicry of Campylobacter jejuni lipo-oligosaccharide (LOS) can induce the production of IgG anti-ganglioside antibodies, but the generation mechanism has yet to be clarified. B-cell activating factor belonging to the TNF family (BAFF) helped murine B cells produce anti-ganglioside antibodies against C. jejuni LOS. In splenocyte culture, however, anti-ganglioside antibodies were produced in the presence of a soluble transmembrane activator and calcium-modulating and cyclophilin ligand interactor immunoadhesin (TACI-Ig), a receptor for BAFF. TACI-Ig adenoviral vectors failed to decrease production of anti-ganglioside antibodies in mice sensitized with C. jejuni LOS and did not alter IgG subclasses, evidence that BAFF aids but is not essential for the generation of IgG anti-ganglioside antibodies in response to C. jejuni LOS.

Circulating brain-reactive autoantibodies and behavioral deficits in the MRL model of CNS lupus

S. Williams, B. Sakic, S.A. Hoffman — 2009-11-18

Abstract: Brain-reactive autoantibodies (BRAA) are hypothesized to play a role in the neuropsychiatric manifestations that accompany systemic lupus erythematosus (SLE). The present study tests the proposed relation between circulating BRAA and behavioral deficits in lupus-prone MRL/lpr mice. Two age-matched cohorts born at different times were used to test the relationship in the context of altered disease severity. Significant correlations between autoimmunity and behavior were detected in both cohorts. These results are the first to report correlations between behavior and autoantibodies to integral membrane proteins of brain, supporting the hypothesis that BRAA contribute to the behavioral dysfunction seen in lupus.

Evaluation of capsular and acapsular strains of S. aureus in an experimental brain abscess model

Nilufer Esen, Gail Wagoner, Napoleon Philips — 2009-11-11

Abstract: Brain abscesses are mainly caused by either direct or indirect inoculation of gram positive bacteria including Stapylococcus aureus (S. aureus) or Streptococcus species into the central nervous system. In the present study, we aimed to compare potential changes in brain abscess pathogenesis induced by two different strains of S. aureus, namely the laboratory strain RN6390 and the clinical isolate Reynolds. Although the Reynolds strain was expected to be more resistant to eradication by the host, due to the existence of a polysaccharide capsule, and subsequently to be more virulent, instead we found parenchymal damage and mortality rates to be more prominent following RN6390 infection. In contrast, the Reynolds strain proliferated faster and induced early expression of the chemokine CXCL2, matrix metalloproteinase-9 (MMP-9), and complement 3a and C5. Furthermore, there were early and more abundant infiltration of PMNs, T cells and erythrocyte extravasation in brain abscesses induced by the Reynolds strain. However, several immune parameters were not different between the two strains during the later stages of the disease. These results suggest that capsular S. aureus can modulate innate immunity and complement system activation differently than the acapsular strain RN6390, and the early changes induced by Reynolds strain may have an important impact on survival.

The HIV-1 transgenic rat as a model for HIV-1 infected individuals on HAART

2009-11-16

Abstract: HIV-1 viral replication is limited in patients given highly active anti-retroviral therapy (HAART); however, HIV-1 viral proteins are still present. We demonstrate that the developing HIV-1Tg rat, which expresses all of the HIV-1 viral genes except the gag–pol replication genes, maintains lower body weight compared with the F344 control rat. Although HIV-1Tg rats eat and drink less than the control animals, they are not anorexic and show no evidence of anhedonia. At 19months (mo) of age, HIV-1Tg rats begin to show clinical signs of wasting that progress to death. Using real-time RT-PCR, we compared the expression of the HIV viral proteins Tat, gp120, nef, and vif, in the HIV-1Tg rats at 2–3mo of age with those at 10–11mo of age. RNA levels of viral protein in the spleens of younger rats were significantly greater than those in the older rats (P<0.01). Conversely, viral protein mRNA levels in the spinal cord, cerebellum, and striatum were significantly greater in the older rats than in the younger animals (P<0.01). In the prefrontal cortex, Tat and nef expression was significantly greater at 2–3mo of age than at 10–11mo of age (P<0.05). These findings indicate that there may be age-dependent differential expression of various HIV viral proteins, with a switch from peripheral immune organs to the CNS, even when the animals are still pre-symptomatic. Our study also demonstrates that this non-infectious rat can be a useful model simulating HIV-1 infected individuals that are on HAART.

Anti-acetylcholinesterase antibodies associate with ocular myasthenia gravis

2009-11-30

Abstract: In MG, anti-AChR or anti-MuSK abs impair neuromuscular transmission. Partial inhibition of AChE can ameliorate symptoms, while a complete block causes a cholinergic blockade. We found anti-AChE abs in 115/240 MG patients, with no correlation with sex, age at onset, thymus pathology, presence of anti-AChR or anti-MuSK antibodies. We found a correlation with the ocular form of the disease, and with milder forms of MG not requiring immunosuppressants; moreover, when we considered only those patients who were off AChEI therapy, we found that ocular patients were positive for anti-AChE abs, while generalized patients were negative. According to an experimental model, we hypothesize that anti-AChE abs could contribute to ptosis through an inhibition of the sympathetic innervation of the tarsal muscle.

Dysregulated Epstein-Barr virus infection in patients with CIDP

2009-11-26

Abstract: Ubiquitous viruses have frequently been proposed as a cause or trigger of chronic immune-mediated diseases. Infections are reported to be temporally associated with clinical exacerbations in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). We examined immunological parameters of herpesvirus infections in untreated patients with CIDP compared to demographically matched controls. Patients with CIDP were uniformly seropositive for EBV-specific IgG and the disease was associated with a moderately enhanced IgG reactivity to EBV-encoded antigens expressed during both B cell transformation and productive viral replication. Moreover, cellular EBV copy numbers were 3-fold increased in patients with CIDP. In contrast, humoral immune responses to other herpesviruses (HCMV, HSV) as well as virus-specific IgM responses were unchanged in CIDP. These data indicate that host–pathogen interactions during chronic EBV infection are dysregulated in treatment-naïve patients with CIDP.

Serum levels of complement C4 fragments correlate with disease activity in multiple sclerosis: Proteomic analysis

2009-11-18

Abstract: To detect serum biomarkers associated with disease activity in relapsing–remitting multiple sclerosis (MS). We studied serum low-molecular peptide profiling of MS patients and normal controls comprehensively by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Serum level of 1741Da peptide was increased at the time of clinical relapse in patients than in normal controls and returned toward normal during remission. Tandem mass spectrometry analysis revealed that the peptide was a fragment of complement C4 (NGFKSHALQLNNRQI). This fragment peptide could be a possible marker of disease activity. It may reflect complement activation in the pathogenesis of MS.

Association of TLR4 Asp299Gly and Thr399Ile polymorphisms with Guillain-Barré syndrome in Northern Indian population

2009-11-16

Abstract: Molecular mimicry between Campylobacter jejuni lipopolysaccharide and host gangliosides induces an immune response leading to axonal damage and Guillain-Barré syndrome (GBS). TLR polymorphisms are associated with many autoimmune diseases. The role of the TLR4 gene in GBS susceptibility largely remains unknown. We investigated TLR4 polymorphism in GBS. One hundred and twenty GBS patients and 150 healthy controls were included. TLR4 (Asp299Gly and Thr399Ile) genes were studied by PCR-RFLP. TLR4 (Asp299Gly) polymorphism was significantly associated with GBS (p, 0.045; OR, 8.75; 95% CI, 1.05–72.88); only acute motor axonal neuropathy (AMAN) was associated with Gly299Gly homozygote (p, 0.027; OR, 12.40; 95% CI, 1.33–115.77) and Thr399Ile (p, 0.019; OR, 3.42; 95% CI, 1.22–9.54) heterozygote, and TLR4–399Ile allele (p, 0.045; OR, 2.63; 95% CI, 1.02–6.75) compared to controls. In conclusion, TLR4 (Asp299Gly) polymorphism is associated with an increased susceptibility to GBS. Besides Asp299Gly, AMAN subtype is also associated with Thr399Ile polymorphism.

Effect of IFN-ß therapy on the frequency and function of CD4+CD25+ regulatory T cells and Foxp3 gene expression in relapsing–remitting multiple sclerosis (RRMS): A preliminary study

Afshin Namdar, Behroz Nikbin, Mojde Ghabaee, Asghar Bayati, Maryam Izad — 2009-11-23

Abstract: Interferon-ß (IFN-ß) is an immunomodulatory drug of choice to control relapsing–remitting multiple sclerosis (RR-MS), although its function is still unclear. A reduced suppressive function of CD4+CD25+ regulatory T cells (Treg) has been shown in RR-MS patients. In this study, to understand the effect of IFN-ß on CD4+CD25+ regulatory T cells, we analyzed the frequency and function of these cells and Foxp3 gene expression before and after treatment.We evaluated the frequency and function of CD4+CD25+Foxp3+ regulatory T cells by flow cytometry and co-culture inhibition test respectively and gene expression of Foxp3 by real-time PCR in a longitudinal follow-up study in 18 relapsing–remitting MS patients. Our data revealed that IFN-ß significantly improved frequency and suppressive function of Treg cells (P<0.05) without any significant effect on gene expression of Foxp3 after 6months. The results of the present study indicate that IFN-ß therapy in some of patients with RR-MS may restore function of regulatory T cells and control the unchecked immune cascade activity. Larger longitudinal studies on more MS patients are required to confirm our findings.

An atypical case of X-linked lymphoproliferative disease revealed as a late cerebral lymphoma

2009-11-11

Abstract: X-linked lymphoproliferative disease (XLP) is an inherited immunodeficiency, partially characterized by a defect in cytotoxicity to Epstein-Barr virus. This viral infection is therefore often fatal in affected boys, whilst a variety of immune disorders or proliferative diseases may occur in surviving patients.We report an atypical case of a 41year-old male who presented with a primitive B-cell cerebral lymphoma, revealing an XLP.This presentation was unusual because of its late onset, the broad spectrum of the familial characteristics, its initial presentation as a cerebral lymphoma, and the occurrence of B-cell alymphocytosis associated with a-gamma-globulinemia.

Cerebrospinal fluids containing anti-HSP70 autoantibodies from multiple sclerosis patients augment HSP70-induced proinflammatory cytokine production in monocytic cells

Shin-ichi Yokota, Susumu Chiba, Hiroyasu Furuyama, Nobuhiro Fujii — 2009-11-18

Abstract: Anti-heat shock protein 70 (HSP70) autoantibodies are found in cerebrospinal fluids (CSF) from patients with multiple sclerosis. These autoantibodies cross-reacted not only with HSP70 and heat shock cognate protein 70 (HSC70), but also with a bacterial homologue, DnaK. CSF with a high anti-HSP70 autoantibody titer enhanced HSP70-induced proinflammatory cytokine and chemokine production in the human monocytic cell line, THP-1. Thus, anti-HSP70 autoantibodies in the CSF of multiple sclerosis patients may play a pathophysiological role in enhancing inflammation.

Clonally expanded plasma cells in the cerebrospinal fluid of patients with central nervous system autoimmune demyelination produce “oligoclonal bands”

2009-11-10

Abstract: Clonally expanded plasma cells (cePC) and oligoclonal IgG (oligoclonal bands, OCB) in the cerebrospinal fluid (CSF) suggest an involvement of B cell mechanisms in autoimmune CNS demyelination. Due to their CSF-restricted occurrence, OCB are commonly believed to be the products of B cells inside the borders of the blood brain barrier. A comparison of CSF cell Ig transcriptomes and CSF-Ig proteomes recently demonstrated, that in multiple sclerosis patients CSF cells are the origin of CSF immunoglobulins. We expand these findings by applying anti-idiotypic antibodies to detect specific heavy chain CDR3 idiotopes of cePC-produced antibodies amongst OCB in the CSF of a patient each with MS and acute disseminated encephalomyelitis.

Intratumoral IL-7 delivery by mesenchymal stromal cells potentiates IFNγ-transduced tumor cell immunotherapy of experimental glioma

2009-11-16

Abstract: The present study reports regression of pre-established experimental rat gliomas as a result of combining peripheral immunization using interferon gamma (IFNγ) transduced autologous tumor cells with local intratumoral delivery of interleukin 7 (IL-7) by mesenchymal stromal cells. IL-7 alone significantly decreased the tumor area and this effect was enhanced with IFNγ immunization. A higher density of intratumoral T-cells was observed in animals receiving combined therapies compared to rats receiving either cytokine alone suggesting that the therapeutic effect is dependent on a T-cell response.