Recent evidence suggests that B- and T-cell interactions may be paramount in relapsing-remitting MS (RRMS) disease pathogenesis. We hypothesized that memory B-cell pools from RRMS patients may specifically harbor a subset of potent neuro-APC that support neuro-Ag reactive T-cell proliferation and cytokine secretion. To test this hypothesis, we compared CD80 and HLA-DR expression, IL-10 and lymphotoxin-alpha secretion, neuro-Ag binding capacity, and neuro-Ag presentation by memory B cells from RRMS patients to naïve B cells from RRMS patients and to memory and naïve B cells from healthy donors (HD). We identified memory B cells from some RRMS patients that elicited CD4(+) T-cell proliferation and IFN-gamma secretion in response to myelin basic protein and myelin oligodendrocyte glycoprotein. Notwithstanding the fact that the phenotypic parameters that promote efficient Ag presentation were observed to be similar between RRMS and HD memory B cells, a corresponding capability to elicit CD4(+) T-cell proliferation in response to myelin basic protein and myelin oligodendrocyte glycoprotein was not observed in HD memory B cells. Our results demonstrate for the first time that the memory B-cell pool in RRMS harbors neuro-Ag specific B cells that can activate T cells.

BACKGROUND: Experimental autoimmune encephalomyelitis (EAE) models are important vehicles for studying the effect of infectious elements such as Pertussis toxin (PTx) on disease processes related to acute demyelinating encephalomyelitis (ADEM) or multiple sclerosis (MS). PTx has pleotropic effects on the immune system. This study was designed to investigate the effects of PTx administered intracerebroventricularly (icv) in preventing downstream immune cell infiltration and demyelination of the spinal cord. METHODS AND FINDINGS: EAE was induced in C57BL/6 mice with MOG(35-55). PTx icv at seven days post MOG immunization resulted in mitigation of clinical motor symptoms, minimal T cell infiltration, and the marked absence of axonal loss and demyelination of the spinal cord. Integrity of the blood brain barrier was compromised in the brain whereas spinal cord BBB integrity remained intact. PTx icv markedly increased microglia numbers in the brain preventing their migration to the spinal cord. An in vitro transwell study demonstrated that PTx inhibited migration of microglia. CONCLUSION: Centrally administered PTx abrogated migration of microglia in EAE mice, limiting the inflammatory cytokine milieu to the brain and prevented dissemination of demyelination. The effects of PTx icv warrants further investigation and provides an attractive template for further study regarding the pleotropic effects of infectious elements such as PTx in the pathogenesis of autoimmune disorders.

OBJECTIVE: Retinal nerve fiber layer (RNFL) abnormalities detected by optical coherence tomography (OCT) are useful markers for axonal loss and visual dysfunction in multiple sclerosis (MS), but their role in routine clinical management is not well-studied. METHODS: Clinical and OCT examinations were performed on 240 patients attending a neurology clinic. Using OCT 5th percentile to define abnormal RNFL thickness, we compared eyes classified by neurologists as having optic atrophy to RNFL thickness, and afferent pupillary defect (APD) to RNFL thickness ratios of eye pairs. RESULTS: Mean RNFL thickness was less in eyes classified by neurologists as having optic atrophy (79.4 +/- 21 mum; n = 63) vs those without (97.0 +/- 15 mum; n = 417; p < 0.001, t test) and in eyes with an APD (84.1 +/- 16 mum; n = 44) than without an APD (95.8 +/- 17 mum; n = 436; p < 0.001). Physicians' diagnostic accuracy for detecting pallor in eyes with an abnormal RNFL thickness was 79% (sensitivity = 0.56; specificity = 0.82). Accuracy for detecting a RAPD in patients with mean RNFL ratio (affected eye to unaffected eye) <0.90 was 73% (sensitivity = 0.30; specificity = 0.86). Ability to detect visual pathway injury via assessment of atrophy and APD differed between neurologists. CONCLUSIONS: OCT reveals RNFL abnormality in many patients in whom eyes are not classified by neurologic examiners as having optic atrophy. Further study is needed to define the role of OCT measures in the context of examinations for optic atrophy and APD by neuroophthalmologists. OCT-measured RNFL thickness is likely to have an important future role in the clinical setting.

Hypogelsolinemia is observed in patients with different states of acute or chronic inflammation such as sepsis, rheumatoid arthritis, and multiple sclerosis. In animal models of sepsis, repletion of plasma gelsolin reduces septic mortality. However, the functions of extracellular gelsolin and the mechanisms leading to its protective nature are poorly understood. Potential mechanisms involve gelsolin's extracellular actin scavenging function or its ability to bind bioactive lipids or pro-inflammatory mediators, which would limit inflammatory responses and prevent tissue damage. Here we report that human plasma gelsolin binds to sphingosine 1-phosphate (S1P), a pleiotropic cellular agonist involved in various immune responses, and to its synthetic structural analog FTY720P. The fluorescence intensity of a rhodamine-B labeled phosphatidylinositol 4,5-bisphosphate binding peptide derived from gelsolin and the optical density of recombinant human plasma gelsolin (rhpGSN) were found to decrease following the addition of S1P or FTY720P. Gelsolin's ability to depolymerize F-actin also decreased progressively with increasing addition of S1P. Transient increases in phosphorylation of extracellular signal-regulated kinase in bovine aortic endothelial cells (BAECs) after S1P treatment were inhibited by rhpGSN. The ability of S1P to increase F-actin content and elastic modulus of primary astrocytes and BAECs was also prevented by rhpGSN. Evaluation of S1P and gelsolin levels in cerebrospinal fluid reveals a low concentration of gelsolin and a high concentration of S1P in samples obtained from patients suffering from lymphatic meningitis. These findings suggest that gelsolin-mediated regulation of S1P bioactivity may be important to maintain immunomodulatory balance at inflammatory sites.

Integrins play an important part in axon growth, but integrin traffic in neurons is poorly understood. Expression of the tenascin-C-binding integrin alpha9 promotes axon regeneration. We have therefore studied the mechanism by which alpha9 integrin and its partner beta1 are trafficked along axons and at the growth cone using adult DRG neurons and PC12 cells. We have focused on the small GTPase Rab11 and its effector Rab coupling protein (RCP), as they are involved in the long-range trafficking of beta1 integrins in other cells. Rab11 colocalizes with alpha9 and other alpha integrins and with beta1 integrin in growth cones and axons, and immunopurified Rab11 vesicles contain alpha9 and beta1. Endocytosed beta1 integrins traffic via Rab11. However, Rab11 vesicles in axons are generally static, and alpha9 integrins undergo bouts of movement during which they leave the Rab11 compartment. In growth cones, alpha9 and beta1 overlap with RCP, particularly at the growth cone periphery. We show that beta1 integrin trafficking during neurite outgrowth involves Rab11 and RCP, and that manipulation of these molecules alters surface integrin levels and axon growth, and can be used to enhance alpha9 integrin-dependent neurite outgrowth. Our data suggest that manipulation of trafficking via Rab11 and RCP could be a useful strategy for promoting integrin-dependent axonal regeneration.

Multiple Sclerosis (MS) annualized relapse rates (ARRs) in trials may be declining due to changes in diagnostic criteria, MS etiology, study criteria, and selection biases. This review examines if there is a trend in the ARR for relapsing-remitting MS patients (RRMS) over time and if so, why. A comprehensive literature search was performed using PubMed, Web of Science(R), and the Cochrane Library using electronic searches, screen scraping for abstracts, and hand searching of references for randomized trials conducted between 1960 and 2008. Out of 72 randomized trials, 56 (77.8%) defined relapse. This study uses 32 placebo relapsing-remitting studies out of the 37 (66.1%) with RRMS. The mean ARR for the treatment arms was 0.68 and the one for the placebo groups was 1.002. The year of publication was negatively associated with the ARR (p = 0.0001). The annual reduction amounts to 0.36 relapses over a 10-year period. Age and duration of symptoms were negatively associated with the ARR. Year of publication was significantly negatively associated with ARR after controlling for covariates. ARRs have fallen with relapse definition, entrance criteria remain important, but time exceeds all these variables and reflects two likely sources, selection of patients for trials by clinicians and rescue of patients truncating the number of multiple relapses. The impact of truncating the number of relapses on the falling rates is important, not only on the ARRs, but also on the impact of informative censoring in drop-outs.

Background: Mitoxantrone (MTX) is an immunosuppressive drug approved for multiple sclerosis (MS) treatment.Objective: The aim of this study is to evaluate and to compare the clinical and neuroradiological responses to MTX in relapsing-remitting (RR) and secondary progressive (SP) MS patients.Methods: We conducted a retrospective, non-randomized, open-label, observational study to evaluate the clinical and neuroradiological response to the drug in 79 patients with RR MS and 210 patients with SP MS.Results: A statistically significant reduction (p < 0.001) in the number of relapses was observed during MTX treatment and in the year after in both RR and SP MS patients. On the contrary, an opposite behavior in terms of disease progression was found in RR compared with SP MS patients, resulting in a statistically significant improvement of the Expanded Disability Status Scale score during the MTX treatment (p < 0.001) and in the year after (p < 0.001) for RR MS patients compared with a continuous, although mild, worsening of the disability in SP MS patients (p < 0.001). Finally, a significant reduction (p < 0.001) of new Gd-enhanced lesions in both RR and SP MS patients was observed in a subgroup of 224 individuals who underwent a brain MRI evaluation before and after MTX treatment.Conclusions: MTX should be considered as an effective therapeutic option in RR MS patients with evidence of relevant disease activity, but the potential life-threatening adverse events and the overall benefit-risk ratio must be carefully evaluated at individual patient level.

Experimental autoimmune encephalomyelitis (EAE) is a widely used animal model for multiple sclerosis (MS) that can be induced by immunization with myelin antigens such as myelin oligodendrocyte glycoprotein (MOG). The objective of this study was (i) to investigate how matrix metalloproteinase-9 (MMP-9) and NADPH oxidase enzymes are affected in the EAE mouse model and (ii) to know whether peripheral organs also express these enzymes in the EAE model. MOG(33-55) was administered subcutaneously on two sites over the back. Pertussis toxin was administered intraperitoneally immediately after MOG and again two days later. A significant difference was observed in body weights and clinical signs of EAE-induced mice. MMP-9 and NADPH oxidase enzymes were measured in central nervous system (CNS) tissues, peripheral tissues and plasma of EAE-induced mice. The primary findings include the distribution pattern of MMP-9 in CNS and peripheral tissues, and alterations in the enzymatic expression of MMP-9 and NADPH oxidase in the CNS tissues, spleen and plasma of EAE-induced mice. From these results, it can be considered that the spleen as well as the CNS can act as target organs in EAE disease, and plasma MMP-9 and NADPH oxidase may contribute to the pathogenesis of the disease.

The generation of T cell receptor (TCR) sequence diversity can produce 'forbidden' clones able to recognize self-antigens. Here, the structure of the complex between a myelin basic protein peptide (MBP85-99), human leukocyte antigen (HLA)-DR2 (DRB1*1501/DRA) and TCR-Ob.2F3, the dominant autoimmune clone obtained from a multiple sclerosis (MS) patient, has been determined using structural docking simulation and dynamics in silico and compared to the structure of TCR-Ob.1A12 complexes with the same MHC/peptide determined by X-ray crystallography. The two TCRs differ by three amino acids in the CDR3 alpha and beta loops. As the result different hydrogen bonds are formed between the two CDR3beta loops and the peptide in the complexes of the simulated structures, with three hydrogen bonds seen in the TCR-Ob.2F3 complex and five in the TCR-Ob.1A12 complex. The two TCRs, each located near the N-terminal end of the HLA-DR2 binding groove and both had an orthogonal binding axis but they deviated by about 10 degrees . Simulation methods, such as structural docking and molecular dynamics as used here, provide an avenue to understand molecular binding mode efficiently and more rapidly than obtaining multiple crystal structures when a large structural database is already available.

BACKGROUND AND OBJECTIVE: Multiple sclerosis (MS) has been consistently associated with the HLA-DR2 haplotype and particularly with the HLA-DRB1*15 allele. Epistatic interactions between both parental alleles in the DRB1 loci have been shown to modify the MS susceptibility risk. This study investigated the frequencies of various HLA-DRB1 genotypes, their impact on MS susceptibility and their correlation with the clinical severity in a Spanish population. METHODS: A genotype was considered as the combination of the two parental DRB1 alleles. We compared the frequencies of the genotypes in a sporadic MS population (n=380) with those of an unrelated healthy control cohort (n=1088). We correlated the different genotypes with the age at onset, gender distribution, symptoms at onset, course of the disease and progression severity by means of the time to reach the progressive phase and EDSS scores of 3 and 6. RESULTS: We found 81 different genotypes. There were four different MS-predisposing genotypes. Three of them contained the DRB1*15 allele (DRB1*03/15, DRB1*04/15, and DRB1*08/15) and the fourth was homozygote for the DRB1*03 allele. The highest odds ratio was found with the genotype DRB1*08/15 (OR=3.88, 95% CI=1.83-8.26, p<0.01), followed by DRB1*03/03 (OR=3.15, 95% CI=1.93-5.14, p<0.01), DRB1*03/15 (OR=2.72, 95% CI=1.88-3.94, p<0.01) and DRB1*04/15 (OR=2.54, 95% CI=1.64-3.98, p<0.01). The DRB1*01/04 and the DRB1*15/15 genotypes were associated with a shorter time to reach an EDSS score of 6. CONCLUSIONS: Our results show the importance of epistatic interactions among the HLA-DRB1 alleles, modifying the risk for MS as well as its clinical severity.

Annunziata P, De Santi L, Di Rezze S, Millefiorini E, Capello E, Mancardi G, De Riz M, Scarpini E, Vecchio R, Patti F. Clinical features of Sjogren's syndrome in patients with multiple sclerosis. Acta Neurol Scand: DOI: 10.1111/j.1600-0404.2010.01428.x. (c) 2010 John Wiley & Sons A/S. Objectives - To assess the frequency of clinical features of Sjogren's syndrome (SS) in patients with multiple sclerosis (MS) receiving treatment with disease-modifying drugs (DMDs) or naïve to treatment and the possible association with clinical, cerebrospinal fluid (CSF) and magnetic resonance imaging (MRI) parameters. Methods - A multicentre cross-sectional observational study was designed, based on a structured neurologist-administered questionnaire to 440 patients. Results - Twenty-eight of 230 (12%) patients receiving treatment with DMDs (DMDs(+)) and 14 of 210 (6.6%) treatment-naïve patients (DMDs(-)) showed clinical features of SS. Four primary SS were diagnosed, two of which were DMDs(+) and two were DMDs(-). Sicca symptoms were significantly associated with higher EDSS scores (P = 0.018), a low frequency of gadolinium-enhanced MRI-positive lesions (P = 0.018) and cerebral disturbances (P = 0.001). Conclusions - Screening for the clinical features of SS should be performed in patients with MS both receiving treatment with immunomodulatory drugs and without therapy.

Background: Tumor necrosis factor (TNF) inhibitors such as adalimumab are increasingly used in the treatment of ocular inflammatory disease refractory to standard therapies. There is evidence that TNF inhibitors are associated with demyelinating neurologic events. Objective: The authors report a case of optic neuritis and multiple sclerosis developing in association with the use of adalimumab for the treatment of bilateral chronic granulomatous iridocyclitis and multifocal choroiditis. They also review the available literature on cases of optic neuritis occurring in the setting of TNF inhibition. Results: The authors identified 21 cases of optic neuritis associated with TNF inhibition; 36% of cases with available MRI results had evidence of other demyelinating lesions in the CNS. Conclusions: The strong association between TNF inhibitors and CNS demyelination may represent an adverse effect of these drugs. Ophthalmologists should recognize the relationship between TNF inhibitors and demyelinating disease, as it can present initially with visual symptoms.

Object The aim of this retrospective study was to evaluate the predictive value of diffusion tensor (DT) imaging with respect to resectability of intramedullary spinal cord tumors and to determine the concordance of this method with intraoperative surgical findings. Methods Diffusion tensor imaging was performed in 14 patients with intramedullary lesions of the spinal cord at different levels using a 3-T magnet. Routine MR imaging scans were also obtained, including unenhanced and enhanced T1-weighted images and T2-weighted images. Patients were classified according to the fiber course with respect to the lesion and their lesions were rated as resectable or nonresectable. These results were compared with the surgical findings (existence vs absence of cleavage plane). The interrater reliability was calculated using the kappa coefficient of Cohen. Results Of the 14 patients (7 male, 7 female; mean age 49.2 +/- 15.5 years), 13 had tumors (8 ependymomas, 2 lymphomas, and 3 astrocytoma). One lesion was proven to be a multiple sclerosis plaque during further diagnostic workup. The lesions could be classified into 3 types according to the fiber course. In Type 1 (5 cases) fibers did not pass through the solid lesion. In Type 2 (3 cases) some fibers crossed the lesion, but most of the lesion volume did not contain fibers. In Type 3 (6 cases) the fibers were completely encased by tumor. Based on these results, 6 tumors were considered resectable, 7 were not. During surgery, 7 tumors showed a good cleavage plane, 6 did not. The interrater reliability (Cohen kappa) was calculated as 0.83 (p < 0.003), which is considered to represent substantial agreement. The mean duration of follow-up was 12.0 +/- 2.9. The median McCormick grade at the end of follow-up was II. Conclusions These preliminary data suggest that DT imaging in patients with spinal cord tumors is capable of predicting the resectability of the lesion. A further prospective study is needed to confirm these results and any effect on patient outcome.

The purpose of the study was to evaluate the prevalence of insomnia in multiple sclerosis patients with comorbid depression, associations between psychological symptoms, multiple sclerosis symptoms and insomnia, and to test effects of a 16-week protocol-based psychotherapy intervention for depression on insomnia symptoms. Participants with multiple sclerosis and depression (n = 127) were randomized to telephone administered cognitive behavioral therapy and telephone administered supportive emotion-focused therapy. Multiple sclerosis functional limitation was measured at baseline. Depression, insomnia, anxiety and quality of life were evaluated at pre treatment, mid treatment (8 weeks), and post treatment (16 weeks). Prevalence of insomnia >/=3 times per week was 78% at pre treatment and 43% at post treatment. Insomnia at baseline was associated with depression, multiple sclerosis related mood symptoms and anxiety. Middle of the night awakenings were associated with swallowing and speech problems. Improvements in insomnia were associated with improvement in depression and anxiety. Participants with residual insomnia were more likely to have major depressive disorder, greater multiple sclerosis severity, elevated anxiety and lower mental components of quality of life. Results demonstrate rates of insomnia in patients with comorbid multiple sclerosis and depression are higher than those reported in the general multiple sclerosis population and additional insomnia treatment is indicated beyond the treatment of comorbid psychological disorders.

OBJECTIVE: To assess the cost of walking in individuals with multiple sclerosis and to investigate its relationship with dyspnoea and fatigue. METHODS: In 46 individuals with multiple sclerosis and in 36 healthy controls, the cost of walking was measured during the 6-min walk test. Perceived breathlessness after walking was rated on a visual analogue scale and corrected for the distance walked. The subjects' perceived effect of fatigue was assessed by means of the Modified Fatigue Impact Scale. RESULTS: The cost of walking was significantly higher in individuals with multiple sclerosis than in controls; however, individuals with multiple sclerosis with normal walking speeds had normal costs of walking. The cost of walking was directly related to the degree of disability, but not to breathlessness perception and fatigue. Individuals with an Expanded Disability Status Scale score greater than 2.5 were highly likely to show an increased cost of walking. Breathlessness perception was higher than in controls and was related to fatigue. CONCLUSION: Individuals with multiple sclerosis, even with mild disability and not requiring any assistive devices, may have an increase in cost of walking. This suggests that an aerobic training programme should be considered in these patients. Energy expenditure when walking is not a determinant of fatigue or exertional dyspnoea in individuals with multiple sclerosis and low levels of disability.

OBJECTIVE: To use the International Classification of Functioning, Disability and Health (ICF) to describe and compare patient-reported disability in Guillain-Barré syndrome survivors and persons with multiple sclerosis, and to identify relevant environmental factors. METHODS: Cross-sectional survey of 77 survivors of Guillain-Barré syndrome in the community. Their Guillain-Barré syndrome-related problems were linked with ICF categories (second level) using an open-ended questionnaire, consensus between health professionals and the "linking rules", and compared with similar data collected previously for 101 persons with multiple sclerosis. RESULTS: Guillain-Barré syndrome survivors were male (59%) and older than persons with multiple sclerosis (mean age 55 vs 49 years). Of 170 ICF categories, 113 were relevant for Guillain-Barré syndrome survivors (mean number 30 vs 18 for persons with multiple sclerosis). The linked categories for Guillain-Barré syndrome included: body function 27 (56%) compared with 48 (42%) for persons with multiple sclerosis; body structure 11 (68%) vs 16 (34%); activities and participation 48 (70%) and 68 (58%); and for environmental factors 27 (71%) compared with 38 (51%) for persons with multiple sclerosis. The main areas linked in the activities and participation domain were mobility, major life areas and interpersonal relationships; and environmental factors included support and relationships, attitudes and products and technology. CONCLUSION: This is the first study to use ICF in Guillain-Barré syndrome survivors and towards development of the ICF Core Set for Guillain-Barré syndrome from a broader international perspective. : :

The aim of this study was to evaluate whether age of onset of multiple sclerosis is related to use of combined oral contraceptives and/or timing of childbirth. The results showed that use of combined oral contraceptives and childbirth before the first multiple sclerosis symptom was correlated to a higher mean age at the onset of the disease.

ABSTRACT The precise aetio-pathology of multiple sclerosis (MS) remains elusive. However, important recent advances have been made and several therapies have been licensed for clinical use. Many of these were developed, validated or tested in the animal model, experimental autoimmune encephalomyelitis (EAE). This systematic review aims to assess whether the current disease modifying treatments and those that are the closest to the clinic are justified on the basis of the results of EAE studies. We discuss some aspects of the utility and caveats of EAE as a model for MS drug development.