Incidence and prevalence of NMOSD in Australia and New Zealand.

OBJECTIVES: We have undertaken a clinic-based survey of neuromyelitis optica spectrum disorders (NMOSDs) in Australia and New Zealand to establish incidence and prevalence across the region and in populations of differing ancestry. BACKGROUND: NMOSD is a recently defined demyelinating disease of the central nervous system (CNS). The incidence and prevalence of NMOSD in Australia and New Zealand has not been established. METHODS: Centres managing patients with demyelinating disease of the CNS across Australia and New Zealand reported patients with clinical and laboratory features that were suspicious for NMOSD. Testing for aquaporin 4 antibodies was undertaken in all suspected cases. From this group, cases were identified who fulfilled the 2015 Wingerchuk diagnostic criteria for NMOSD. A capture-recapture methodology was used to estimate incidence and prevalence, based on additional laboratory identified cases. RESULTS: NMOSD was confirmed in 81/170 (48%) cases referred. Capture-recapture analysis gave an adjusted incidence estimate of 0.37 (95% CI 0.35 to 0.39) per million per year and a prevalence estimate for NMOSD of 0.70 (95% CI 0.61 to 0.78) per 100 000. NMOSD was three times more common in the Asian population (1.57 (95% CI 1.15 to 1.98) per 100 000) compared with the remainder of the population (0.57 (95% CI 0.50 to 0.65) per 100 000). The latitudinal gradient evident in multiple sclerosis was not seen in NMOSD. CONCLUSIONS: NMOSD incidence and prevalence in Australia and New Zealand are comparable with figures from other populations of largely European ancestry. We found NMOSD to be more common in the population with Asian ancestry.

Stressful life events and the risk of initial central nervous system demyelination.

BACKGROUND: There is substantial evidence that stress increases multiple sclerosis disease activity, but limited evidence on its association with the onset of multiple sclerosis. OBJECTIVE: To examine the association between stressful life events and risk of first demyelinating event (FDE). METHODS: This was a multicentre incident case-control study. Cases ( n = 282 with first diagnosis of central nervous system (CNS) demyelination, including n = 216 with 'classic FDE') were aged 18-59 years. Controls without CNS demyelination ( n = 558) were matched to cases on age, sex and study region. Stressful life events were assessed using a questionnaire based on the Social Readjustment Rating Scale. RESULTS: Those who suffered from a serious illness in the previous 12 months were more likely to have an FDE (odds ratio (OR) = 2.35 (1.36, 4.06), p = 0.002), and when we limited our reference group to those who had no stressful life events, the magnitude of effect became stronger (OR = 5.41 (1.80, 16.28)). The total stress number and stress load were not convincingly associated with the risk of an FDE. CONCLUSION: Cases were more likely to report a serious illness in the previous 12 months, which could suggest that a non-specific illness provides an additional strain to an already predisposed immune system.

Deficiency of CD8+ effector memory T cells is an early and persistent feature of multiple sclerosis.

BACKGROUND: Patients with multiple sclerosis (MS) have a deficiency of circulating CD8+ T cells, which might impair control of Epstein-Barr virus (EBV) and predispose to MS by allowing EBV-infected autoreactive B cells to accumulate in the central nervous system. Based on the expression of CD45RA and CD62L, CD4+ T cells and CD8+ T cells can be subdivided into four subsets with distinct homing and functional properties, namely: naïve, central memory, effector memory (EM) and effector memory re-expressing CD45RA (EMRA) cells. OBJECTIVE: Our aim was to determine which memory subsets are involved in the CD8+ T cell deficiency and how these relate to clinical course. METHODS: We used flow cytometry to analyze the memory phenotypes of T cells in the blood of 118 MS patients and 112 healthy subjects. RESULTS: MS patients had a decreased frequency of EM (CD45RA(-)CD62L(-)) and EMRA (CD45RA(+)CD62L(-)) CD8+ T cells, which was present at the onset of disease and persisted throughout the clinical course. The frequencies of CD4+ EM and EMRA T cells were normal. CONCLUSION: Deficiency of effector memory CD8+ T cells is an early and persistent feature of MS and might underlie the impaired CD8+ T cell control of EBV.

Epstein-Barr virus-specific adoptive immunotherapy for progressive multiple sclerosis.

Defective control of Epstein-Barr virus (EBV) infection by cytotoxic CD8(+) T cells might predispose to multiple sclerosis (MS) by allowing EBV-infected autoreactive B cells to accumulate in the central nervous system. We have treated a patient with secondary progressive MS with in vitro-expanded autologous EBV-specific CD8(+) T cells directed against viral latent proteins. This adoptive immunotherapy had no adverse effects and the patient showed clinical improvement with reduced disease activity on magnetic resonance imaging and decreased intrathecal immunoglobulin production. This is the first report of the use of EBV-specific adoptive immunotherapy to treat MS or any other autoimmune disease.

The physical anthropometry, lifestyle habits and blood pressure of people presenting with a first clinical demyelinating event compared to controls: the Ausimmune study.

INTRODUCTION: Lifestyle factors prior to a first clinical demyelinating event (FCD), a disorder often preceding the development of clinically definite multiple sclerosis (MS), have not previously been examined in detail. Past tobacco smoking has been consistently associated with MS. METHODS: This was a multicentre incident case-control study. Cases (n = 282) were aged 18-59 years with an FCD and resident within one of four Australian centres (from latitudes 27°S to 43°S), from 1 November 2003 to 31 December 2006. Controls (n = 558) were matched to cases on age, sex and study region, without CNS demyelination. Exposures measured included current and past tobacco and marijuana, alcohol and beverage use, physical activity patterns, blood pressure and physical anthropometry. RESULTS: A history of smoking ever was associated with FCD risk (AOR 1.89 (95%CL 1.82, 3.52)). Marijuana use was not associated with FCD risk after adjusting for confounders such as smoking ever but the estimates were imprecise because of a low prevalence of use. Alcohol consumption was common and not associated with FCD risk. No case-control differences in blood pressure or physical anthropometry were observed. CONCLUSIONS: Past tobacco smoking was positively associated with a risk of FCD but most other lifestyle factors were not. Prevention efforts against type 2 diabetes and cardiovascular disease by increasing physical activity and reducing obesity are unlikely to alter MS incidence, and more targeted campaigns will be required.

Genome-wide meta-analysis identifies novel multiple sclerosis susceptibility loci.

OBJECTIVE: To perform a 1-stage meta-analysis of genome-wide association studies (GWAS) of multiple sclerosis (MS) susceptibility and to explore functional consequences of new susceptibility loci. METHODS: We synthesized 7 MS GWAS. Each data set was imputed using HapMap phase II, and a per single nucleotide polymorphism (SNP) meta-analysis was performed across the 7 data sets. We explored RNA expression data using a quantitative trait analysis in peripheral blood mononuclear cells (PBMCs) of 228 subjects with demyelinating disease. RESULTS: We meta-analyzed 2,529,394 unique SNPs in 5,545 cases and 12,153 controls. We identified 3 novel susceptibility alleles: rs170934(T) at 3p24.1 (odds ratio [OR], 1.17; p = 1.6 × 10(-8)) near EOMES, rs2150702(G) in the second intron of MLANA on chromosome 9p24.1 (OR, 1.16; p = 3.3 × 10(-8)), and rs6718520(A) in an intergenic region on chromosome 2p21, with THADA as the nearest flanking gene (OR, 1.17; p = 3.4 × 10(-8)). The 3 new loci do not have a strong cis effect on RNA expression in PBMCs. Ten other susceptibility loci had a suggestive p < 1 × 10(-6) , some of these loci have evidence of association in other inflammatory diseases (ie, IL12B, TAGAP, PLEK, and ZMIZ1). INTERPRETATION: We have performed a meta-analysis of GWAS in MS that more than doubles the size of previous gene discovery efforts and highlights 3 novel MS susceptibility loci. These and additional loci with suggestive evidence of association are excellent candidates for further investigations to refine and validate their role in the genetic architecture of MS.

Interleukin-6 gene promoter-572 C allele may play a role in rate of disease progression in multiple sclerosis.

Multiple sclerosis (MS) is an inflammatory demyelinating disease affecting the central nervous system. Although the exact pathogenesis of MS is unknown, it is generally considered to be an autoimmune disease, with numerous genetic and environmental factors determining disease susceptibility and severity. One important mediator of immune responses and inflammation is interleukin-6 (IL-6). Previously, elevated levels of IL-6 in mononuclear cells in blood and in brain tissue from MS patients have been reported. Various polymorphisms in the promoter region of the IL6 gene have also been linked with IL-6 protein levels. In MS, several small studies have investigated whether two IL6 promoter polymorphisms (-597 G>A and -174 G>C) correlate with MS susceptibility, but with varying results. In the present study, we analyzed these polymorphisms, together with an additional polymorphism (-572 G>C) in 279 healthy controls and 509 patients with MS. We found no significant differences between MS patients and healthy controls for the different -597 or -174 IL6 promoter alleles or genotypes. There was a slight reduction in the percentage of individuals with MS who carried a C allele at position -572, although this was not significant after correction for multiple comparisons. Interestingly, however, the -572 C allele showed a significant correlation with the MS severity score, suggesting a possible role in disease progression.

The role of latitude, ultraviolet radiation exposure and vitamin D in childhood asthma and hayfever: an Australian multicenter study.

Observations of increasing allergy prevalence with decreasing distance from the Equator and positive associations with ambient ultraviolet radiation have contributed to a growing interest in the possible role of vitamin D in the etiology of allergy. The aims of this study were to describe any latitudinal variation in the prevalence of childhood allergy in Australia and to evaluate, in parallel, the individual associations between ultraviolet radiation (UVR)- and vitamin D-related measures and hayfever asthma and both conditions. Participants were population-based controls who took part in a multicenter case-control study, aged 18-61 yr and resident in one of four study regions ranging in latitude from 27°S to 43°S. Data were derived from a self-administered questionnaire, interview and examination by a research officer and biologic sampling. Latitude and longitude coordinates were geocoded from participants' residential locations and climatic data were linked to postcodes of current residence. Stored serum was analyzed for 25-hydroxyvitamin D concentrations and silicone rubber casts of the skin were used as an objective measure of cumulative actinic damage. There was an inverse latitude gradient for asthma (a 9% decrease per increasing degree of latitude); however, this pattern did not persist after adjusting for average daily temperature. There was no association between any of the UVR- or vitamin D-related measures and childhood asthma, but greater time in the sun in winter between the ages 6-15 yr was associated with an increase in the odds of having hayfever [adjusted odds ratios (OR) 1.29; 95% CI 1.01-1.63]. Oral supplementation with cod liver oil in childhood increased the odds of a history of having both asthma and hayfever (2.87; 1.00-8.32). Further investigation of the possible role of early vitamin D supplementation in the development of allergy is warranted. Our results also suggest that solar exposure during childhood may be important in allergic sensitization. Plausible explanations, including biologic mechanisms, exist for both observations.

Decreased CD8+ T cell response to Epstein-Barr virus infected B cells in multiple sclerosis is not due to decreased HLA class I expression on B cells or monocytes.

BACKGROUND: Patients with multiple sclerosis (MS) have a decreased frequency of CD8+ T cells reactive to their own Epstein-Barr virus (EBV) infected B cells. We have proposed that this might predispose to the development of MS by allowing EBV-infected autoreactive B cells to accumulate in the central nervous system. The decreased CD8+ T cell response to EBV results from a general CD8+ T cell deficiency and also a decreased proportion of EBV-specific T cells within the total CD8+ T cell population. Because decreased HLA class I expression on monocytes and B cells has been reported in MS and could influence the generation and effector function of EBV-specific CD8+ T cells, the present study was undertaken to measure the expression of HLA molecules on B cells and monocytes in patients with MS. METHODS: We used flow cytometry to determine the proportions of T cells, natural killer cells, B cells and monocytes in peripheral blood mononuclear cells (PBMC) and to quantify the expression of HLA molecules on T cells, B cells and monocytes of 59 healthy subjects and 62 patients with MS who had not received corticosteroids or immunomodulatory therapy in the previous 3 months. RESULTS: The levels of HLA class I and class II molecules expressed on T cells, B cells and monocytes were normal in patients with MS, with the exception of two patients with secondary progressive MS with very low class II expression on B cells. In confirmation of previous studies we also found that the percentage of CD8+ T cells was significantly decreased whereas the percentage of CD4+ T cells and the CD4:CD8 ratio were significantly increased in patients with MS compared to healthy subjects. CONCLUSIONS: The decreased CD8+ T cell response to EBV-infected B cells in MS patients is not due to decreased HLA class I expression on monocytes or B cells. In a small proportion of patients decreased HLA class II expression on B cells might impair the CD8+ T cell response to EBV by reducing CD4+ T cell help.

Correlations between macrophage/microglial activation marker sTREM-2 and measures of T-cell activation, neuroaxonal damage and disease severity in multiple sclerosis.

BACKGROUND: Soluble triggering receptor expressed on myeloid cells-2 (sTREM-2) is a marker of macrophage and microglial activation and is increased in the cerebrospinal fluid (CSF) in multiple sclerosis (MS). OBJECTIVE: To determine the relationships among sTREM-2, T cell activation, neuroaxonal damage and clinical features of MS. METHODS: Enzyme-linked immunosorbent assays were used to measure the levels of sTREM-2, soluble CD27 (sCD27, a marker of T cell activation), neurofilament light chain (NfL) and phosphorylated neurofilament heavy chain (pNfH) in the CSF of 42 patients with MS (including nine with clinically isolated syndrome) and 15 patients with other neurological diseases (OND) and in the serum of 164 patients with MS, 87 patients with OND and 62 healthy controls. RESULTS: sTREM-2 was significantly elevated in the CSF (p = 0.012), but not in the serum, in MS compared to OND. In MS, CSF sTREM-2 correlated positively with CSF sCD27 (p = 0.005), CSF NfL (p = 0.0001), CSF pNfH (p = 0.0006), Expanded Disability Status Scale (EDSS) score (p = 0.0079) and MS Severity Score (MSSS) (p = 0.0006). CONCLUSION: In MS the level of sTREM-2 in the CSF is related to measures of T cell activation (sCD27), neuroaxonal damage (NfL and pNfH), disability (EDSS) and disease severity (MSSS).

Sustained Clinical Improvement in a Subset of Patients With Progressive Multiple Sclerosis Treated With Epstein-Barr Virus-Specific T Cell Therapy.

Background: Increasing evidence indicates a role for Epstein-Barr virus (EBV) in the pathogenesis of multiple sclerosis (MS). EBV-infected autoreactive B cells might accumulate in the central nervous system because of defective cytotoxic CD8+ T cell immunity. We have previously reported results of a phase I clinical trial of autologous EBV-specific T cell therapy in MS 6 months after treatment. Objective: To investigate longer-term outcomes in MS patients who received autologous EBV-specific T cell therapy. Methods: We assessed participants 2 and 3 years after completion of T cell therapy. Results: We collected data from all 10 treated participants at year 2 and from 9 participants at year 3. No serious treatment-related adverse events were observed. Four participants had at least some sustained clinical improvement at year 2, including reduced fatigue in three participants, and reduced Expanded Disability Status Scale score in two participants. Three participants experienced a sustained improvement in at least some symptoms at year 3. More sustained improvement was associated with higher EBV-specific CD8+ T cell reactivity in the administered T cell product. Conclusion: Autologous EBV-specific T cell therapy is well-tolerated, and some degree of clinical improvement can be sustained for up to 3 years after treatment.

Latitudinal variation in incidence and type of first central nervous system demyelinating events.

Increasing prevalence and variable geographic patterns of occurrence of multiple sclerosis suggest an environmental role in causation. There are few descriptive, population-level, data on whether such variability applies to first demyelinating events (FDEs). We recruited 216 adults (18-59 years), with a FDE between 1 November 2003 and 31 December 2006 in a multi-center incident case-control study in four locations on the south-eastern and eastern seaboard of Australia, spanning latitudes 27 degrees south to 43 degrees south. Population denominators were obtained from the Australian Bureau of Statistics censuses of 2001 and 2006. Age and sex adjusted FDE incidence rates increased by 9.55% (95% confidence interval (CI) 7.37-11.78, p < 0.001) per higher degree of latitude. The incidence rate gradient per higher degree of latitude varied by gender (male: 14.69% (95% CI 9.68-19.94, p < 0.001); female 8.13% (95% CI 5.69-10.62, p < 0.001)); and also by the presenting FDE type: optic neuritis 11.39% (95% CI 7.15-15.80, p < 0.001); brainstem/cerebellar syndrome 9.47% (95% CI 5.18-13.93, p < 0.001); and spinal cord syndrome 5.36% (95% CI 1.78-9.06, p = 0.003). Differences in incidence rate gradients were statistically significant between males and females (p = 0.02) and between optic neuritis and spinal cord syndrome (p = 0.04). The male to female ratio varied from 1 : 6.7 at 27 degrees south to 1 : 2.5 at 43 degrees south. The study establishes a positive latitudinal gradient of FDE incidence in Australia. The latitude-related factor(s) influences FDE incidence variably according to subtype and gender, with the strongest influence on optic neuritis presentations and for males. These descriptive case analyses show intriguing patterns that could be important for understanding the etiology of multiple sclerosis.

Hypothesis: bipolar disorder is an Epstein-Barr virus-driven chronic autoimmune disease - implications for immunotherapy.

Bipolar disorder (BD) is a chronic disease characterised by episodes of major depression and episodes of mania or hypomania, with a worldwide prevalence of 2.4%. The cause of BD is unknown. Here, I propose the hypothesis that BD is a chronic autoimmune disease caused by Epstein-Barr virus (EBV) infection of autoreactive B cells. It is postulated that EBV-infected autoreactive B cells accumulate in the brain where they provide costimulatory survival signals to autoreactive T cells and differentiate into plasma cells producing pathogenic autoantibodies targeting brain components such as the N-methyl-D-aspartate receptor. It is also proposed that the accumulation of EBV-infected autoreactive B cells in the brain is a consequence of a genetically determined defect in the ability of CD8+ T cells to control EBV infection. The theory is supported by studies indicating that autoimmunity, EBV infection and CD8+ T-cell deficiency all have roles in the pathogenesis of BD. According to the hypothesis, BD should be able to be treated by EBV-specific T-cell therapy and to be prevented by vaccination against EBV in early childhood. Exposure to sunlight or appropriate artificial light should also be beneficial in BD by augmenting CD8+ T-cell control of EBV infection.

Correlation Between Anti-Myelin Proteolipid Protein (PLP) Antibodies and Disease Severity in Multiple Sclerosis Patients With PLP Response-Permissive HLA Types.

The most prominent pathological features of multiple sclerosis (MS) are demyelination and neurodegeneration. The exact pathogenesis of MS is unknown, but it is generally regarded as a T cell-mediated autoimmune disease. Increasing evidence, however, suggests that other components of the immune system, particularly B cells and antibodies, contribute to the cumulative CNS damage and worsening disability that characterize the disease course in many patients. We have previously described strongly elevated T cell reactivity to an extracellular domain of the most abundant CNS myelin protein, myelin proteolipid protein (PLP) in people with MS. The current paper addresses the question of whether this region of PLP is also a target of autoantibodies in MS. Here we show that serum levels of isotype-switched anti-PLP181-230 specific antibodies are significantly elevated in patients with MS compared to healthy individuals and patients with other neurological diseases. These anti-PLP181-230 antibodies can also live-label PLP-transfected cells, confirming that they can recognize native PLP expressed at the cell surface. Importantly, the antibodies are only elevated in patients who carry HLA molecules that allow strong T cell responses to PLP. In that subgroup of patients, there is a positive correlation between the levels of anti-PLP181-230 antibodies and the severity of MS. These results demonstrate that anti-PLP antibodies have potentially important roles to play in the pathogenesis of MS.

Reduced IκB-α Protein Levels in Peripheral Blood Cells of Patients with Multiple Sclerosis-A Possible Cause of Constitutive NF-κB Activation.

NF-κB signaling pathways are dysregulated in both the central nervous system (CNS) and peripheral blood cells in multiple sclerosis (MS), but the cause of this is unknown. We have recently reported that peripheral blood mononuclear cells (PBMC) of patients with MS have increased constitutive activation and translocation of the transcription factor NF-κB to the nucleus compared to healthy subjects. NF-κB can be activated through either canonical or non-canonical pathways. In the canonical pathway, activation of NF-κB is normally negatively regulated by the inhibitor IκB. We therefore hypothesized that the increased activation of NF-κB could be caused by reduced IκB-α in the cells of patients with MS, possibly due to increased activity of the IκB kinase (IKK) complex, which regulates IκB-α. Alternatively, changes to the activity of key molecules in the non-canonical pathway, such as IKKα, could also lead to increased NF-κB activation. We therefore used Western blotting to detect IκB-α levels and ELISA to investigate NF-κB DNA binding activity and phosphorylation of IKKα and IKKß in samples from PBMC of MS patients and controls. The level of full-length IκB-α protein in the cytosolic fraction of PBMC of MS patients was significantly reduced compared to healthy subjects, with significantly more evidence of multiple low molecular weight putative degradation products of IκB-α present in MS patients compared to healthy subjects. Conversely, the level of NF-κB DNA binding activity was increased in whole cell lysates from MS patients. Both IKKα and IKKß showed increased overall activity in MS compared to healthy subjects, although not all of the MS patients showed increased activity compared to the healthy subjects, suggesting that there may be several different mechanisms underlying the constitutive activation of NF-κB in MS. Taken together, these findings suggest that there may be multiple points at which the NF-κB pathway is dysregulated in MS and that decreased levels of the full-length IκB-α protein are a major component in this.

Epstein-Barr Virus in Multiple Sclerosis: Theory and Emerging Immunotherapies.

New treatments for multiple sclerosis (MS) focused on B cells have created an atmosphere of excitement in the MS community. B cells are now known to play a major role in disease, demonstrated by the highly impactful effect of a B cell-depleting antibody on controlling MS. The idea that a virus may play a role in the development of MS has a long history and is supported mostly by studies demonstrating a link between B cell-tropic Epstein-Barr virus (EBV) and disease onset. Efforts to develop antiviral strategies for treating MS are underway. Although gaps remain in our understanding of the etiology of MS, the role, if any, of viruses in propagating pathogenic immune responses deserves attention.

CTLA-4 single-nucleotide polymorphisms in a Caucasian population with schizophrenia.

Associations between a single-nucleotide polymorphism (SNP) in exon 1 of the cytotoxic T-lymphocyte antigen-4 (CTLA4) gene and schizophrenia in a Korean population have been previously described. The current study investigated whether a similar link occurs in a Caucasian population with schizophrenia. One hundred and twenty-two age- and sex-matched pairs of people with DSM-III-R diagnosis of schizophrenia and healthy controls were included in this study. Three previously described SNPs (from the promoter, exon 1 and 3' UTR) of the CTLA4 gene were analysed. In the entire sample, we detected no allelic or genotypic association for any of the three SNPs. Given documented gender differences in incidence of schizophrenia, we conducted separate analyses of male and female participants. In males, both the promoter region SNP (-318C/T) and the 3' UTR SNP demonstrated nominally significant association with schizophrenia. The 3' UTR SNP remained significant following correction for multiple testing (permuted P=0.046). In addition, all possible haplogenotypes showed significant association with disease in males with two--both containing the 3' UTR SNP--remaining significant following correction for the genotypic tests of all SNPs and haplogenotypes in males. These results suggest a role for the 3' UTR SNP and/or variants in high linkage disequilibrium with this SNP in the pathogenesis of schizophrenia.

PLP1 Mutations in Patients with Multiple Sclerosis: Identification of a New Mutation and Potential Pathogenicity of the Mutations.

PLP1 is located on the X-chromosome and encodes myelin proteolipid protein (PLP), the most abundant protein in central nervous system myelin. Generally, point mutations in PLP1 result in X-linked dysmyelinating disorders, such as Pelizaeus-Merzbacher disease (PMD) or spastic paraplegia type 2 (SPG2). However, several case studies have identified patients with missense point mutations in PLP1 and clinical symptoms and signs compatible with a diagnosis of multiple sclerosis (MS). To investigate if PLP1 mutations occur relatively frequently in MS, we sequenced the coding regions of PLP1 in 22 female MS patients who had developed disease after the age of 40 and in 42 healthy women, and identified a missense mutation in exon 2 of PLP1 resulting in a Leu30Val mutation in the protein in one of the MS patients. mCherry-tagged plasmids containing wild type or mutant PLP1 sequences of PLP, including two known PMD/SPG2-related mutations as positive controls, were constructed and transfected into Cos-7 cells. In comparison with cells transfected with wild type PLP1, all mutations caused significant accumulation of PLP in the endoplasmic reticulum of the cells and induction of the unfolded protein response-a mechanism that leads to apoptosis of cells expressing mutant proteins. Additionally, in silico analysis of the binding of peptides containing the Leu30Val mutation to the human leukocyte antigen (HLA) molecules carried by the patient harboring this mutation suggested that the mutation could produce several novel immunogenic epitopes in this patient. These results support the idea that mutations in myelin-related genes could contribute to the development of MS in a small proportion of patients.

Increased constitutive activation of NF-κB p65 (RelA) in peripheral blood cells of patients with progressive multiple sclerosis.

The NF-κB signalling pathway plays an important role in controlling cellular immune responses, inflammation and apoptosis. In multiple sclerosis (MS), there is evidence of dysregulation of NF-κB signalling in patients with a relapsing-remitting disease course, but thus far there is little information on whether it is also dysregulated in patients with progressive disease. We hypothesised that patients with progressive MS would have more activation of NF-κB than relapsing-remitting MS patients. Using several different methods, we showed that there was more nuclear translocation of p65 in cells from progressive MS patients, particularly in T cells and monocytes. In addition, the amount of p65 translocated to the nucleus in cells of patients with progressive MS was not increased upon non-specific activation of the cells with the mitogen Con A. These results suggest that NF-κB dysregulation occurs in patients with progressive MS patients, as well as those with relapsing-remitting MS.