Journal of Neuroimmunology

Editorial Board

2012-06-15

Major histocompatibility complex class I molecules modulate embryonic neuritogenesis and neuronal polarization

2012-04-16

Abstract: We studied cultured hippocampal neurons from embryonic wildtype, major histocompatibility complex class I (MHCI) heavy chain-deficient (KbDb−/−) and NSE-Db (which have elevated neuronal MHCI expression) C57BL/6 mice. KbDb−/− neurons displayed slower neuritogenesis and establishment of polarity, while NSE-Db neurons had faster neurite outgrowth, more primary neurites, and tended to have accelerated polarization. Additional studies with ß2M−/− neurons, exogenous ß2M, and a self-MHCI monomer suggest that free heavy chain cis interactions with other surface molecules can promote neuritogenesis while tripartite MHCI interactions with classical MHCI receptors can inhibit axon outgrowth. Together with the results of others, MHCI appears to differentially modulate neuritogenesis and synaptogenesis.

Antibody to α4 integrin suppresses natural killer cells infiltration in central nervous system in experimental autoimmune encephalomyelitis

Yan Gan, Ruolan Liu, Wei Wu, Roberto Bomprezzi, Fu-Dong Shi — 2012-04-16

Abstract: Natalizumab inhibits the influx of leukocytes into the central nervous system (CNS) via blockade of alpha-4 subunit of very late activation antigen (VLA)-4. The association of natalizumab therapy with progressive multifocal leukoencephalopathy (PML) suggests a disturbance of CNS immune surveillance in a small percentage of Multiple Sclerosis (MS) patients exposed to the medication. Natural killer (NK) cells are known to play an important role in modulating the evolution of different phases of this lymphocyte mediated disease, and we investigated the effects of natalizumab on the NK cell phenotype and infiltration in the CNS in experimental autoimmune encephalomyelitis (EAE), a murine model of MS. Our data show that both resting (from naïve mice) and activated (from EAE mice) NK cells express high levels of VLA-4, and anti-VLA-4 antibody treatment significantly decreases NK cells frequency in the CNS of EAE mice. Moreover, we find that anti-VLA-4 possibly impairs NK cells migratory potential, since unblocked VLA-4 expression levels were downregulated on those NK cells that penetrate the CNS. These data suggest that treatment with antibody to VLA-4 may alter immune surveillance of the CNS by impacting NK cell functions and might contribute to the understanding of the mechanisms leading to the development of PML in some MS patients.

Immune activation, viral gene product expression and neurotoxicity in the HIV-1 transgenic rat

Walter Royal, Li Zhang, Ming Guo, Odell Jones, Harry Davis, Joseph L. Bryant — 2012-04-16

Abstract: The HIV-1 transgenic (TG) rat has been shown to be a useful model of nervous system disease that occurs in human HIV-1 infection. Studies were, therefore, performed to examine characteristics of the immune response in the periphery and brain of the animals and expression of factors in the nervous system that might be associated with neurotoxicity. Activated splenocytes from wild-type (WT) and TG rats were stimulated with either CD3/CD28 or with lipopolysaccharide (LPS) and examined for proliferative responses and for proinflammatory cytokine (IFN-γ, TNF-α and IL-1β) secretion. Brain tissue lysates from the rats were also examined for proinflammatory cytokine levels and tissue sections were stained by immunofluorescence for class II MHC+, ED1+ or Iba1+ (for macrophages and microglial cells), and for GFAP+ (for astrocytes) cells and for co-labeling of these cells for TNF-α. Co-labeling was also performed to identify cells expressing HIV-1 gp160, tat, nef and vif. Finally, on Western blots brain tissue lysates were examined for phosphorylation of Erk1/2, p38, JNK-SAPK and Erk5. TG rat splenocyte proliferative responses were higher than for WT with CD3/CD28-stimulation but lower than WT with LPS stimulation. CD3/CD28-stimulated TG rat splenocytes also secreted higher levels of IFN-γ, TNF-α and IL-1β whereas LPS-stimulated TG rat splenocytes secreted higher levels of only TNF-α than cultures from WT rats. Levels of all three cytokines were higher in brain lysates from TG rats than for WT rats. On immunofluorescence staining of corresponding sections of brain, TG rats contained increased numbers of class II MHC+ and ED1+ cells, and there was also increased co-labeling or these cells as well as astrocytes for TNF-α. Iba1+ cells showed positive staining for all of the HIV proteins whereas astrocytes showed significant positive staining for only nef and vif. Phosphorylation of Erk1/2, p38 and JNK/SAPK was detected for both TG and WT rat tissues with higher levels of phosphorylation forms of these proteins detected in the TG rat brain. Phosphorylation of Erk5, a marker that is associated with specifically neuronal repair, was detected only in TG rat brain. These studies suggest that activated nervous system mononuclear phagocytes and astrocytes expressing HIV-1 gene products in specific patterns are associated with neurodegeneration in the HIV-1 TG rat.

IL-33 blockade suppresses the development of experimental autoimmune encephalomyelitis in C57BL/6 mice

Mingcai Li, Yan Li, Xiaojin Liu, Xueming Gao, Yaqing Wang — 2012-04-20

Abstract: IL-33 is a recently described member of the IL-1 family that has been reported to have a pathogenic role in several inflammatory diseases. In this study, we evaluated the role of IL-33 in a murine model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE). We showed that the expression of IL-33 and its receptor, ST2, was markedly elevated in the spinal cord of mice during myelin oligodendrocyte glycoprotein (MOG)35–55 peptide-induced EAE. Administration of a blocking anti-IL-33 antibody in mice of EAE during the induction phase significantly inhibited the onset and severity of EAE and reduced MOG35–55-induced IFN-γ and IL-17 production. In contrast, treatment with recombinant IL-33 worsened the disease course of EAE in association with increased induction of both IFN-γ and IL-17. Furthermore, anti-IL-33 treatment caused a remarkable decrease in expression of IL-17, IFN-γ, T-bet and RORγt, and an upregulation of IL-10 and TGF-β in the spinal cord of EAE mice. These results demonstrate that endogenous IL-33 plays a pivotal role in the pathogenesis of EAE and indicate that blockade of IL-33 has a significant protective effect against EAE.

Intravenous tolerance effectively overcomes enhanced pro-inflammatory responses and experimental autoimmune encephalomyelitis severity in the absence of IL-12 receptor signaling

2012-04-23

Abstract: Intravenous (i.v.) administration of autoantigen effectively induces Ag-specific tolerance against experimental autoimmune encephalomyelitis (EAE). We and others have shown enhanced EAE severity in mice lacking IL-12 or its receptor, strongly suggesting an immunoregulatory effect of IL-12 signaling. To examine the role of IL-12 responsiveness in autoantigen-induced tolerance in EAE, we administered autoantigen i.v. in two distinct treatment regimes to wildtype and IL-12Rβ2−/− mice, immunized to develop EAE. Administration at the induction phase suppressed EAE in wildtype and IL-12Rβ2−/− mice however the effect was somewhat less potent in the absence of IL-12Rβ2. Expression of pro-inflammatory cytokines such as IFN-γ, IL-17 and IL-2, was inhibited in wild-type tolerized mice but less so in IL-12Rβ2−/− mice. I.v. antigen was also effective in suppressing disease in both genotypes when given during the clinical phase of disease with similar CNS inflammation, demyelination and peripheral inflammatory cytokine profiles observed in both genotypes. There was however a mild impact of a lack of IL-12 signaling on Treg induction during tolerance induction compared to WT mice in this treatment regime. These findings show that the enhanced severity of EAE that occurs in the absence of IL-12 signaling can be effectively overcome by i.v. autoantigen, indicating that this therapeutic effect is not primarily mediated by IL-12 and that i.v. tolerance could be a powerful approach in suppressing severe and aggressive MS.

Chronically lowering sympathetic activity protects sympathetic nerves in spleens from aging F344 rats

2012-04-30

Abstract: In the present study, we investigated how increased sympathetic tone during middle-age affects the splenic sympathetic neurotransmission. Fifteen-month-old (M) F344 rats received rilmenidine (0, 0.5 or 1.5mg/kg/day, i.p. for 90days) to lower sympathetic tone. Controls for age were untreated 3 or 18M rats. We report that rilmenidine (1) reduced plasma and splenic norepinephrine concentrations and splenic norepinephrine turnover, and partially reversed the sympathetic nerve loss; and (2) increased β-adrenergic receptor (β-AR) density and β-AR-stimulated cAMP production. Collectively, these findings suggest a protective effect of lowering sympathetic tone on sympathetic nerve integrity, and enhanced sympathetic neurotransmission in secondary immune organs.

Exposure to morphine affects the expression of endocannabinoid receptors and immune functions

Qing-Yu Zhang, Min Zhang, Yi Cao — 2012-04-30

Abstract: Compared with control rats, rats under morphine exposure exhibited cannabinoid receptor 2 (CB2-R) upregulation in the spleen and periphery blood mononuclear cells (PBMCs). IgG and IgM values in the plasma were also altered. In morphine abusers, cannabinoid receptors were upregulated in the PBMCs, and the expression of IL-4 mRNA in the PBMCs as well as the IgG and IgM values in the plasma were higher compared with those in healthy people. The expression of cannabinoid receptor 1 and CB2-R in culture cells was directly affected by morphine treatment. These findings indicate that the alteration in cannabinoid receptor expression could be disturbed by morphine exposure, and it may be involved in abnormal immune function.

Association of interleukin 1β polymorphisms and haplotypes with Alzheimer's disease

2012-04-12

Abstract: Our study aimed to associate IL-1β and IL-1RN polymorphisms with AD disease in comparison with elderly control group from São Paulo — Brazil. We genotyped 199 Alzheimer's disease (AD) patients, 165 elderly control and 122 young control samples, concerning VNTR (IL-1RN) and −511C>T and −31T>C (IL-1β) polymorphisms. Our findings revealed that −511C/−31T/2-repetitions VNTR haplotype had a protective effect for AD when compared to EC (p=0.005), whereas −511C/−31C/1-repetition VNTR haplotype was associated as a risk factor for AD (p=0.021). Taken together, we may suggest that there is a relevant role of IL-1 genes cluster in AD pathogenesis in this Brazilian population.

Neuronal antigens recognized by cerebrospinal fluid IgM in multiple sclerosis

2012-04-12

Abstract: Axonal injury is the major cause of disability in patients with multiple sclerosis (MS), but the mechanisms leading to axonal damage are poorly understood. Oligoclonal IgM against lipids predicts an aggressive disease course in MS; however, the antigen that elicits the immune response has not yet been identified. We screened the CSF of 12 patients with MS, 7 patients with neuromyelitis optica (NMO), and 5 controls with non-inflammatory neurological disease (NIND) for the presence of IgM-type antibodies (IgM-Ab) against neuronal surface antigens, and analyzed the relationship between IgM-Ab level and the extent of brain atrophy. The CSF of MS patients displayed significantly higher levels of IgM-Ab compared to NIND or NMO patients. Furthermore, we document for the first time that these IgM-Ab recognize neuronal surface antigens, and that the levels of neuronal-bound IgM-Ab were independent of the IgM concentration and correlate with brain atrophy. Our findings suggest a role for the CSF IgM-Ab in the development of MS pathophysiology.

Serum and CSF measles antibody levels increase over time in patients with multiple sclerosis or clinically isolated syndrome

Cecilia Ahlgren, Anders Odén, Tomas Bergström, Jan Lycke — 2012-04-13

Abstract: In general, measles virus (MV) immunoglobulin G (IgG) antibody titres decline over time. However, we found that serum and CSF MV antibody titres increased with age (slope=0.038, p<0.001 and slope=0.022, p=0.008), respectively, and disease duration (slope=0.031, p=0.002 and slope=0.032, p=0.005), respectively, in patients with multiple sclerosis (MS) or clinically isolated syndrome (CIS). The age dependency of serum antibody levels differed between patients and controls (slope=0.038 versus −0.004, p<0.001). The increasing MV antibody titres over time in MS/CIS patients support a general nonspecific stimulation of B cells and plasma cells that is not confined only to the CNS/CSF compartment.

Increased expression of Toll-like receptors 2 and 4 is associated with poor outcome in intracerebral hemorrhage

2012-04-12

Abstract: Inflammatory response in intracerebral hemorrhage (ICH) is associated with poor outcome and could be a consequence of Toll-like receptor (TLR) activation. We investigated the influence of TLR2 and TLR4 expression on the outcome of ICH patients. Expression levels of TLR2 and TLR4 in monocytes at admission were independently associated with poor functional outcome. On the other hand, TLR2 and TLR4 expression at admission in both monocytes and neutrophils was independently associated with residual lesion volume. In conclusion, increased expression of TLR2 and TLR4 is associated with poor functional outcome and greater residual volume in ICH patients.

HLA-DQA103:02/DQB103:03:02 is strongly associated with susceptibility to childhood-onset ocular myasthenia gravis in Southern Han Chinese

2012-04-16

Abstract: Objective: Our aim was to investigate the correlation between onset age, clinical features and HLA-DQA1/DQB1 genetic variability in myasthenia gravis (MG) patients in Southern Han Chinese.Methods: 205 MG patients and 100 controls were genotyped for HLA-DQA1 and -DQB1 using sequence-based typing (SBT) and analyzed for haplotype frequencies. Anti-acetylcholine receptor (AChR) autoantibodies were measured in all, and muscle-specific tyrosine kinase (MuSK) antibodies were tested in AChR antibody negative patients.Results: HLA-DQA1/DQB1 haplotypes showed association only with childhood-onset MG. Haplotype DQA1*03:02/DQB1*03:03:02 (DQ9) was positively associated with the childhood-onset MG, while haplotype DQA1*02:01/DQB1*02:02 and DQA1*05:01:01/DQB1*02:01:01 (DQ2) were negatively associated with this group. Childhood-onset ocular MG patients had an extremely high phenotype frequency of DQ9 haplotype (90.1% of patients, 34.0% of controls, p≤0.0001, OR=17.8).Conclusions: The childhood-onset ocular MG in Southern Han Chinese may present a particular subgroup of distinct genetic background. Its correlation to the HLA haplotype DQA1*03:02/DQB1*03:03:02 might explain the phenotypic difference of MG between Han Chinese and Caucasians.

Axonal and oligodendrocyte-localized IgM and IgG deposits in MS lesions

2012-04-25

Abstract: Background: Recent findings support the important role of antibodies in multiple sclerosis (MS) physiopathology. Thus, local IgG synthesis is a hallmark of the disease, and intrathecal IgM synthesis associates with a poor disease outcome.Methodology: The aim of this study was to investigate the presence of IgM and IgG in demyelinating lesions using high sensitivity immunohistochemistry techniques in necropsies from fourteen MS patients, four controls without neurological disease and four cases with non MS CNS inflammatory disease.Results: IgG and IgM were absent in controls. Conversely, we found IgM in about 50% and IgG in 75% of MS patients. The presence of IgM and IgG antibodies was independent of disease duration, clinical disease type or lesion stage. IgM and IgG were present in acute, chronic active and chronic inactive lesions. Double immunofluorescence showed that IgM and IgG were detected on axons and oligodendrocytes in demyelinated areas. Moreover, we observed immunoglobulin deposits on oligodendrocytes in NAWM in some cases. IgG and IgM colocalized with complement C3b on demyelinated axons and oligodendrocytes and antibody–antigen immunocomplexes were detected in foamy macrophages in active lesion areas. These findings were absent from cases of non-neurological disease and cases with non-MS CNS inflammatory disease.Significance of the study: These observations provide further evidence on the role of antibodies, complement and macrophages in plaque development, and strongly suggest they can induce axonal injury, an important cause of disability in MS. They may provide novel therapeutic strategies to limit tissue degeneration in the disease.

Active Aβ vaccination fails to enhance amyloid clearance in a mouse model of Alzheimer's disease with Aβ42-driven pathology

Anna Nemirovsky, Jenny Shapiro, Rona Baron, Alex Kompaniets, Alon Monsonego — 2012-04-12

Abstract: Aβ vaccination has been shown to induce remarkable clearance of brain amyloid plaques in mouse models of Alzheimer's disease (AD). However, the extent to which antibody-mediated Aβ clearance is affected by predominant formation of Aβ42 over Aβ40 is unclear. Here we demonstrate for the first time that in a mouse model carrying the human APP mutations KM670/671NL and the human PS1 mutation P166L, Aβ vaccination does not result in plaque clearance. This was in spite of the strong T- and B-cell immune responses evoked under the DR1501 genetic background and the activation of microglia at sites of Aβ plaques. Our findings suggest the existence of antibody-resistant forms of Aβ deposits in the brain consisting of primarily Aβ42, and shed light on the mechanisms of antibody-dependent amyloid clearance as well as novel therapeutic strategies for AD.

Journal of Neuroimmunology

Editorial Board

Major histocompatibility complex class I molecules modulate embryonic neuritogenesis and neuronal polarization

Antibody to α4 integrin suppresses natural killer cells infiltration in central nervous system in experimental autoimmune encephalomyelitis

Immune activation, viral gene product expression and neurotoxicity in the HIV-1 transgenic rat

IL-33 blockade suppresses the development of experimental autoimmune encephalomyelitis in C57BL/6 mice

Intravenous tolerance effectively overcomes enhanced pro-inflammatory responses and experimental autoimmune encephalomyelitis severity in the absence of IL-12 receptor signaling

Chronically lowering sympathetic activity protects sympathetic nerves in spleens from aging F344 rats

Exposure to morphine affects the expression of endocannabinoid receptors and immune functions

Association of interleukin 1β polymorphisms and haplotypes with Alzheimer's disease

Neuronal antigens recognized by cerebrospinal fluid IgM in multiple sclerosis

Serum and CSF measles antibody levels increase over time in patients with multiple sclerosis or clinically isolated syndrome

Increased expression of Toll-like receptors 2 and 4 is associated with poor outcome in intracerebral hemorrhage

HLA-DQA1*03:02/DQB1*03:03:02 is strongly associated with susceptibility to childhood-onset ocular myasthenia gravis in Southern Han Chinese

Axonal and oligodendrocyte-localized IgM and IgG deposits in MS lesions

Active Aβ vaccination fails to enhance amyloid clearance in a mouse model of Alzheimer's disease with Aβ42-driven pathology

HLA-DQA103:02/DQB103:03:02 is strongly associated with susceptibility to childhood-onset ocular myasthenia gravis in Southern Han Chinese