Journal of Neuroimmunology - Articles in Press

Alternative splicing of interleukin-7 (IL-7) and interleukin-7 receptor alpha (IL-7Rα) in peripheral blood from patients with multiple sclerosis (MS) - Corrected Proof

2010-03-12

Abstract: IL-7 and IL-7Rα (IL-7R) form a non-redundant ligand receptor system which plays a crucial role in human T cell immunity. Both IL-7 and IL-7R are multi-exonal genes and exhibit alternative splicing. We measured the relative distribution of IL-7 and IL-7R spliced mRNA from patients with MS and healthy individuals and observed extensive alternative splicing of both genes with marked differences in proportional transcript expression levels. We report here for the first time that the IL-7 transcript, lacking exon 4, and not the full length IL-7 represents the dominant IL-7 RNA transcript in human PBMCs and a novel IL-7R splice variant lacking exons 5, 6 and 7.

Thymic involution and proliferative T-cell responses in multiple sclerosis - Corrected Proof

2010-03-11

Abstract: We investigated naïve CD4 T-cell homeostasis in relapsing–remitting multiple sclerosis (RRMS). Quantification of signal joint T-cell receptor excision circles in FACS-isolated CD31hi cells, which correspond closely to CD4 recent thymic emigrants (RTEs), indicates that young patients have reduced generation of CD4 RTEs compared to age-matched controls. In RRMS, compared to controls, CXCR4 analyses indicate age-associated thymic output of progressively immature CD4 RTEs, and Ki-67 data demonstrate altered T-cell proliferative responses that fail to maintain naïve CD4 T-cell numbers with age. Thus, RRMS patients have early thymic involution with compensatory homeostatic peripheral T-cell proliferative responses that may predispose patients to autoreactivity.

Ectopic and high CXCL13 chemokine expression in myasthenia gravis with thymic lymphoid hyperplasia - Corrected Proof

2010-03-11

Abstract: Myasthenia gravis (MG) is an antibody and complement mediated autoimmune disease. Serum CXC chemokine ligand 13 (CXCL13) was found to be elevated in MG patients and high CXCL13 level was associated with severe clinical stages, especially in females with thymic lymphoid hyperplasia. Both protein and mRNA of CXCL13 and CXC chemokine receptor 5 (CXCR5) in the thymic tissues were significantly higher in MG patients with lymphoid hyperplasia than those with thymoma. Our data indicated that serum CXCL13 can be used as an index of disease severity and ectopic thymic expression of CXCL13 might be associated with aberrant cell trafficking to the thymus of MG.

Systemic minocycline differentially influences changes in spinal microglial markers following formalin-induced nociception - Corrected Proof

Kai Li, Kai-Yuan Fu, Alan R. Light, Jianren Mao — 2010-03-08

Abstract: In the present study, intraperitoneal administration of minocycline attenuated enhancing nociceptive behaviors in those rats receiving dual formalin injections (5% formalin followed at 7days later by 1% formalin). The minocycline treatment did not prevent the increase in OX-42 and MHC class I labeling and morphological changes, but significantly attenuated upregulation of phospho-p38 in activated microglia. These results suggest that the later days of microglial activation with upregulated immune markers in the spinal cord contributes to enhancing long-term pain response by a pathway of p38 activation in microglia.

Midregional Proenkephalin A and N-terminal Protachykinin A are decreased in the cerebrospinal fluid of patients with dementia disorders and acute neuroinflammation - Corrected Proof

2010-03-08

Abstract: Midregional Proenkephalin A (MR-PENK A) and N-terminal Protachykinin A (NT-PTA) are stable fragments of the precursor peptides for enkephalins and substance P, respectively. We measured MR-PENK A and NT-PTA concentrations by sensitive chemiluminescence immunoassays in cerebrospinal fluid (CSF) of 19 neurologically healthy controls (NHC), 28 patients with other neurologic disorders (OND), 70 patients with dementia disorders (38 Alzheimer's disease [AD], 8 dementia with Lewy bodies [DLB], 12 frontotemporal dementia [FTD], and 12 patients with vascular dementia [VD]), and 16 patients with acute neuroinflammation (AN). Median concentrations of NT-PTA were decreased in all patient groups compared to NHC showing significant differences between patients with NHC and AN (p<0.001), OND and AN (p<0.001), FTD and AN (p<0.01) and pAD and AN (p<0.05). Median MR-PENK A levels were lower in patients with OND, dementia disorders (including AD, FTD, DLB and VD) and AN compared to NHC subjects, although this differences did not reach statistical significance (p>0.05). A maximum difference of both proneuropeptide fragments was found between NHC subjects and patients with AN, with a more than 2fold decrease in median NT-PTA and a 1.5fold decrease in median MR-PENK A levels. Concentrations of both proneuropeptide fragments were positively correlated in all patients (r=0.77, p<0.001). Our results indicate alterations of the cerebral PENK A- and PTA-system in both, dementia and acute neuroinflammatory disorders. These neuropeptide systems seem to be highly correlated in healthy and pathological status.

The hypothalamic endocannabinoid system participates in the secretion of oxytocin and tumor necrosis factor-alpha induced by lipopolysaccharide - Corrected Proof

2010-03-08

Abstract: This study investigated the participation of the hypothalamic endocannabinoid system in the response to lipopolysaccharide (LPS) challenge evaluating oxytocin (OXT) and tumor necrosis factor-alpha (TNF-a) plasma levels in vivo and their release from hypothalamic fragments in vitro. LPS increased OXT and TNF-α release through anandamide-activation of hypothalamic cannabinoid receptor CB1, since the antagonist AM251 blocked this effect. Anandamide, through its receptors, also increased hypothalamic nitric oxide (NO) which inhibited OXT release, ending the stimulatory effect of the endocannabinoid. Our findings reveal a hypothalamic interaction between oxytocin, endocannabinoid and NO-ergic systems providing a regulation of the hypothalamic–neurohypophyseal axis under basal and stress conditions.

Inhibition of C5a receptor alleviates experimental CNS lupus - Corrected Proof

2010-03-08

Abstract: To investigate the role of C5a generated on complement activation in brain, the lupus model, MRL/lpr mice were treated with C5a receptor(R) antagonist (ant). Neutrophil infiltration, ICAM, TNF-α and iNOS mRNA expression, neuronal apoptosis and the expression of p-JNK, pSTAT1 and p-Erk were reduced and p-Akt increased on C5aR inhibition in MRL/lpr brains. MRL/lpr serum caused increased apoptosis in neurons showing that lupus had a direct effect on these cells. C5aRant pretreatment prevented the lupus serum induced loss of neuronal cells. Our findings demonstrate for the first time that C5a/C5aR signaling plays an important role in the pathogenesis of CNS lupus.

TNF-α, IL-1β, IL-6, and cinc-1 levels in rat brain after meningitis induced by Streptococcus pneumoniae - Corrected Proof

2010-03-04

Abstract: Bacterial meningitis caused by Streptococcus pneumoniae is associated with a significant mortality rate and persisting neurologic sequelae, including sensory–motor deficits, seizures, and impairment of learning and memory. The presence of proliferating bacteria within the subarachnoid and ventricular space compartments triggers an intense inflammatory host response at killing the invading microorganism. Proinflammatory mediators released in the process, including tumor necrosis factor alpha (TNF-α), interleukin (IL)-1β, and IL-6, were shown to contribute to the development of brain injury in bacterial meningitis. Thus, the aim of this study was to verify the levels of the TNF-α, IL-1β, IL-6, and CINC-1 in the rat brain after pneumococcal meningitis. The animals underwent a magna cistern tap receiving either 10µL of sterile saline as a placebo or an equivalent volume of a S. pneumoniae suspension at the concentration of 5×109cfu/mL. The placebo group was killed immediately after the induction and the meningitis group at 0, 6, 12, 24, 48, and 96h after induction. The brains were removed followed by the isolation of the hippocampus and prefrontal cortex for determining TNF-α, IL-1β, IL-6, and CINC-1 levels. In the hippocampus we found increased levels of the TNF-α only at 6h (p<0.01; F=3.777); CINC-1 levels increased at 6 and 24h (p<0.001; p<0.05; F=15.05); and IL-6 and IL-1β levels were not altered. In the prefrontal cortex, the TNF-α levels were found to be increased only at 6h (p<0.05; F=4.921); IL-6 (p<0.05; F=11.69) and IL-1β (p<0.001; F=132.0) levels were found to be increased only at 24h after meningitis induction; and CINC-1 levels were found to be increased at 6, 12, and 24h (p<0.01; p<0.01; p<0.01; F=16.86) after meningitis induction. Our data suggest that cytokine/chemokine levels can be putative biomarkers of brain damage in the first hours of the pneumococcal meningitis.

Cognitive efficiency is associated with endogenous cytokine levels in patients with chronic hepatitis C - Corrected Proof

2010-02-25

Abstract: The etiology of cognitive dysfunction in chronic hepatitis C (CHC) infection is unknown. Among the possibilities is cytokine activation, which has been associated with cognitive dysfunction in other chronic conditions. The purpose of this study was to investigate the relationship between endogenous IFN-α, IL-6, and TNF-α and cognitive functioning in CHC patients. Seventy-eight veterans with CHC underwent cognitive testing and measurement of serum cytokines. In patients with detectable IFN-α, higher levels of IL-6 and TNF-α were related to poorer cognitive functioning. Findings suggest CHC patients with immune responses characterized by elevated IFN-α may be at risk for cognitive difficulties.

Antibodies to gangliosides and ganglioside complexes in Guillain–Barré syndrome and Fisher syndrome: Mini-review - Corrected Proof

Kenichi Kaida, Susumu Kusunoki — 2010-02-22

Abstract: Antiganglioside antibodies play a pathogenic role in the pathophysiology of Guillain–Barré syndrome (GBS) and Fisher syndrome (FS). Antiganglioside antibody-mediated nerve injury is likely to result from nerve damage through complement activation or dysfunction of molecules such as voltage-gated sodium and calcium channels. Clustered epitopes of complexes of two gangliosides in the cell membrane can be targeted by serum antibodies in GBS and FS and may regulate the accessibility and avidity of antiganglioside antibodies. The glycolipid environment or the specific distribution of target gangliosides in the peripheral nervous system may also influence the pathogenic effect of antiganglioside antibodies in GBS and FS. Structural and functional analyses of glycoepitopes of ganglioside complexes in membranes will provide new vistas on antibody–antigen interaction in GBS and shed light on microdomain function mediated by carbohydrate–carbohydrate interactions, which may lead to novel treatments for GBS and FS.

Effect of carbamylated erythropoietin on major histocompatibility complex expression and neural differentiation of human neural stem cells - Corrected Proof

2010-02-17

Abstract: The expression of major histocompatibility complex (MHC) on human neural stem cells (hNSCs) is tightly related to the fate of these cells in transplantation, therefore strategies to relieve rejection and promote graft survival are necessary to be applied. This study investigated the effect of carbamylated erythropoietin (CEPO) on MHC expression and differentiation of hNSCs with or without IFN-γ incubation. Results showed that low levels of MHC molecules were expressed on hNSCs and increased by IFN-γ. CEPO enhanced MHC-I antigens in both proliferative and differentiated hNSCs, but decreased MHC-II antigens in differentiated hNSCs and those cells exposed to IFN-γ. Furthermore, CEPO promoted neural differentiation of hNSCs and outgrowth of neurites. Western blot analysis revealed activation of Stat3, Stat5 and Akt during these processes. These results suggest that CEPO may have immunoregulatory function in hNSCs besides its neuroprotection.

NF-κB1 contributes to T cell-mediated control of Toxoplasma gondii in the CNS - Corrected Proof

2010-02-16

Abstract: In this study, the role of NF-κB1 was examined during toxoplasmosis. While wildtype BALB/c mice generated protective responses, NF-κB1−/− mice developed Toxoplasmic encephalitis, characterized by increased parasite burden and necrosis in the brain. Susceptibility was primarily associated with a local decrease in the number of CD8+ T cells and IFN-γ production, while accessory cell function appeared intact in NF-κB1−/− mice. Consistent with these findings, T cell transfer studies revealed that NF-κB1−/− T cells provided SCID mice less protection than wildtype T cells. These results demonstrate an intrinsic role for NF-κB1 in T cell-mediated immunity to Toxoplasma gondii.

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

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

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

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

2010-02-01

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

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

2010-02-01

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

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

2010-01-29

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

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

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

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

Chemokines and chemokine receptors in the nervous system - Corrected Proof

2007-05-11