Multiple Sclerosis Brain Lesions Research Articles

Close association of water channel AQP1 with amyloid-β deposition in Alzheimer disease brains

Aquaporin-1 (AQP1), a membrane water channel protein, is expressed exclusively in the choroid plexus epithelium in the central nervous system under physiological conditions. However, AQP1 expression is enhanced in reactive astrocytes, accumulating in brain lesions of Creutzfeldt-Jakob disease and multiple sclerosis, suggesting a role of AQP1-expressing astrocytes in brain water homeostasis under pathological conditions. To clarify a pathological implication of AQP1 in Alzheimer disease (AD), we investigated the possible relationship between amyloid-beta (Aβ) deposition and astrocytic AQP1 expression in the motor cortex and hippocampus of 11 AD patients and 16 age-matched other neurological disease cases. In all cases, AQP1 was expressed exclusively in a subpopulation of multipolar fibrillary astrocytes. The great majority of AQP1-expressing astrocytes were located either on the top of or in close proximity to Aβ plaques in AD brains but not in non-AD cases, whereas those independent of Aβ deposition were found predominantly in non-AD brains. By Western blot, cultured human astrocytes constitutively expressed AQP1, and the levels of AQP1 protein expression were not affected by exposure to Aβ1-42 peptide, but were elevated by hypertonic sodium chloride. By immunoprecipitation, the C-terminal fragment-beta (CTFβ) of amyloid precursor protein interacted with the N-terminal half of AQP1 spanning the transmembrane helices H1, H2 and H3. These observations suggest the possible association of astrocytic AQP1 with Aβ deposition in AD brains.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-008-0387-x) contains supplementary material, which is available to authorized users.

Corpora amylacea from multiple sclerosis brain tissue consists of aggregated neuronal cells.

In this report, we describe proteomic analysis of corpora amylacea collected by postmortem laser microdissection from multiple sclerosis (MS) brain lesions. Using low level protein loads (about 30 microg), a combination of two-dimensional electrophoresis with matrix-assisted laser desorption/ionization-time of flight mass spectrometry and database interrogations we identified 24 proteins of suspected neuronal origin. In addition to major cytoskeletal proteins like actin, tubulin, and vimentin, we identified a variety of proteins implicated specifically in cellular motility and plasticity (F-actin capping protein), regulation of apoptosis and senescence (tumor rejection antigen-1, heat shock proteins, valosin-containing protein, and ubiquitin-activating enzyme E1), and enzymatic pathways (glyceraldehyde-3-dehydrogenase, protein disulfide isomerase, protein disulfide isomerase related protein 5, lactate dehydrogenase). Samples taken from regions in the vicinity of corpora amylacea showed only traces of cellular proteins suggesting that these bodies may represent remnants of neuronal aggregates with highly polymerized cytoskeletal material. Our data provide evidence supporting the concept that biogenesis of corpora amylacea involves degeneration and aggregation of cells of neuronal origin.

The value of chemical fat-saturation pulse added to T1-weighted spin-echo sequence in evaluating gadolinium-enhancing brain lesions in multiple sclerosis

This study was undertaken to assess the value of a chemical (spectral) fat-saturation (fat-sat) pulse added to a T1-weighted spin-echo sequence after intravenous administration of paramagnetic contrast agent in detecting enhancing lesions in multiple sclerosis. Twenty patients with relapsing-remitting multiple sclerosis underwent a brain 1.0-Tesla magnetic resonance (MR) scan with T1-weighted spin-echo sequences (24 contiguous para-axial slices with a thickness of 5 mm, pixel size 0.96 mm(2), number of excitations 2, flip angle 90 degrees ) 5 min after intravenous injection of 0.1 mmol/kg of gadodiamide with and without fat-sat, acquired with randomised order of priority. Two readers counted by consensus the number of enhancing lesions and assigned a conspicuity score (low conspicuity=1; high conspicuity=2) to each enhancing lesion during a randomised reading without any visual comparison between the two corresponding images (with and without fat-sat) of the same patient. McNemar and Wilcoxon matched-pair signed-rank tests were used. Seventy-two enhancing lesions without fat-sat and 94 with fat-sat were detected; 22 lesions were visible only with fat-sat, whereas no lesion was detected only without fat-sat (p<0.0001). The conspicuity score was 1.17+/-0.38 (mean+/-standard deviation) and 1.57+/-0.44, respectively (p<0.0001). A fat-sat pulse added to a T1-weighted spin-echo sequence increases significantly the number and conspicuity of contrast-enhancing lesions in patients with relapsing-remitting multiple sclerosis.

Human astrocytes express aquaporin‐1 and aquaporin‐4 in vitro and in vivo

Aquaporins (AQP) constitute an evolutionarily conserved family of integral membrane water transport channel proteins. Previous studies indicate that AQP1 is expressed exclusively in the choroid plexus epithelium, while AQP4 is localized on the vascular foot of astrocytes in the central nervous system (CNS) under physiological conditions. To investigate a role of AQP in the pathophysiology of neurological diseases involving astrogliosis we studied the expression of AQP1 and AQP4 in cultured human astrocytes and brain tissues of multiple sclerosis (MS), cerebral infarction and control cases. By reverse transcriptasepolymerase chain reaction and western blot analysis, cultured human astrocytes co-expressed both AQP1 and AQP4 mRNA and proteins, where AQP4 levels were elevated by exposure to interferon-gamma but neither by tumor necrosis factor-alpha nor interleukin-1beta, whereas AQP1 levels were unaffected by any of the cytokines examined. By western blot analysis, AQP1 and AQP4 proteins were detected in the brain homogenates of the MS and non-MS cases, where both levels were correlated with those of glial fibrillary acid protein. By immunohistochemistry, astrocytes with highly branched processes surrounding blood vessels, along with glial scar, expressed intensely AQP1 and AQP4 in MS and ischemic brain lesions, whereas neither macrophages, neurons nor oligodendrocyte cell bodies were immunopositive. These immunohistochemical results indicate that the expression not only of AQP4 but also of AQP1 was enhanced in MS and ischemic brain lesions located predominantly in astrocytes, suggesting a pivotal role of astrocytic AQP in the maintenance of water homeostasis in the CNS under pathological conditions.

Komparacija detektabilnosti mozdanih lezija u multipleks sklerozi pri pregledu magnetnom rezonancijom jacine magnetnog polja 1.0 i 3.0 Tesla

To estimate the relative sensitivity of MR examination for brain lesions in multiple sclerosis at 1.0 Tesla (T) and 3.0 T using identical acquisition conditions. 54 patients with multiple sclerosis were examined both at 1.0T (Siemens Impact Expert) and 3.0T (Philips Intera) using T1-weighted spin echo (T1W-SE) with and without gadolinium contrast injections, T2W SE and fluid attenuated inversion recovery (FLAIR) imaging. Images were examined independently by three experienced neuroradiologists using focal lesion counting. 3.0T scans compared with 1.0T scans demonstrate a 27.3%, increase in the number of detected contrast enhanced lesions and an 22.7% increase in the number of detected lesions on FLAIR MR tomograms. Highfield 3.0T MR imaging demonstrates better sensitivity in the detection of focal brain lesions in multiple sclerosis. This improvement is more apparent in contrast enhanced lesion detection and less noticeable in FLAIR detected lesions.

Insulin‐like growth factor binding proteins: regulation in chronic active plaques in multiple sclerosis and functional analysis of glial cells

Studies in experimental allergic encephalomyelitis, an animal model of multiple sclerosis (MS), suggest that astrocyte-secreted insulin-like growth factor binding protein-2 (IGFBP-2) helps target IGF-1 to IGF-1 receptor-expressing oligodendrocytes and promote remyelination. We examined the presence of IGFBPs 1-6 in astrocytes in normal post-mortem human brain tissue and lesions of MS by means of immunohistochemistry. Under normal conditions all six IGFBPs were detected. Compared to controls, hypertrophic astrocytes at the borders of chronic active MS lesions displayed increased immunoreactivity for IGFBP-2 and IGFBP-4. In vitro studies were performed to analyse the effects of IGFBPs on cellular proliferation of neonatal rat glial cells. Treatment of astrocytes with IGF-1 and -2 enhanced proliferation whereas IGFBP-2 and -4 inhibited cellular growth. Interestingly, combined treatment with IGFBP-2 and IGF-1 potentiated effects on cellular proliferation whereas combined treatment with IGFBP-2 and IGF-2 inhibited growth. Unlike IGFBP-2, IGFBP-4 inhibited proliferation in combined treatment with IGF-1. In contrast, combined treatment with IGFBP-2 and IGF-1 resulted in decreased cell survival of oligodendrocyte precursor cells. Our results suggest that the up-regulation of IGFBP-2 in reactive astrocytes in MS lesions may primarily serve to enhance the IGF-1-mediated mitogenic stimulus for astrocytes rather than supporting oligodendrocyte survival.

Gray and white matter brain atrophy and neuropsychological impairment in multiple sclerosis

The relationship of gray and white matter atrophy in multiple sclerosis (MS) to neuropsychological and neuropsychiatric impairment has not been examined. In 40 patients with MS and 15 age-/sex-matched normal controls, the authors used SPM99 to obtain whole brain normalized volumes of gray and white matter, as well as measured conventional lesion burden (total T1 hypointense and FLAIR hyperintense lesion volume). The whole brain segmentation was corrected for misclassification related to MS brain lesions. To compare the effects of gray matter, white matter, and lesion volumes with respect to brain-behavior relationships, the MS group (disease duration = 11.2 +/- 8.8 years; EDSS score = 3.3 +/- 1.9) underwent neuropsychological assessment, and was compared to a separate, larger group of age-/sex-matched normal controls (n = 83). The MS group had smaller gray (p = 0.009) and white matter volume (p = 0.018), impaired cognitive performance (verbal memory, visual memory, processing speed, and working memory) (all p < 0.0001), and greater neuropsychiatric symptoms (depression, p < 0.0001; dysphoria, p < 0.0001; irritability, p < 0.0001; anxiety, p < 0.0001; euphoria, p = 0.006; agitation, p = 0.02; apathy, p = 0.02; and disinhibition, p = 0.11) vs controls. Hierarchical stepwise regression analysis revealed that whole gray and white matter volumes accounted for greater variance than lesion burden in explaining cognitive performance and neuropsychiatric symptoms. White matter volume was the best predictor of mental processing speed and working memory, whereas gray matter volume predicted verbal memory, euphoria, and disinhibition. Both gray and white brain matter atrophy contribute to neuropsychological deficits in multiple sclerosis.

Age-related gadolinium-enhancement of MRI brain lesions in multiple sclerosis

There is evidence that inflammatory processes in multiple sclerosis (MS) are age-dependent. In this study we evaluated the impact of aging on gadolinium (Gd) enhancement of brain magnetic resonance imaging (MRI) lesions in MS patients. Pre- and post-contrast MRI scans, acquired using a standardized procedure by the same MRI scanner, at least 1 month far from clinical relapse or steroid treatment, were examined in 200 disease-modifying treatment free MS patients. Seventy-three patients (36.5%) showed at least one enhancing lesion. Age at MRI examination ( p = 0.0001), disease duration ( p = 0.002) and EDSS score were significantly ( p = 0.02) lower, whereas relapse rate in the preceding 2 years was higher ( p = 0.003) in patients with enhancing lesions than in patients with unenhancing scans. Multivariate logistic analysis showed that current age was the variable better predicting Gd enhancement ( p = 0.004). The odds ratios were 0.95 (CI: 0.92–0.98) for each year of patient's age and 0.64 (CI: 0.48–0.87) for each age decade. The main changes in enhancement risk occurred after 35 years of age. Multivariate Poisson regression model showed that relapse rate in the preceding 2 years ( p < 0.0001) and current age ( p = 0.0003) were the best predictors of the number of enhancing lesions. This information can be used to increase the statistical power of clinical trials using Gd-enhancing lesions as an outcome measure.

CD163‐positive perivascular macrophages in the human CNS express molecules for antigen recognition and presentation

Perivascular macrophages (PVM) constitute a subpopulation of resident macrophages in the central nervous system (CNS) that by virtue of their strategic location at the blood-brain barrier potentially lend themselves to a variety of important functions in both health and disease. Functional evidence suggests that PVM play a supportive role during experimental autoimmune encephalomyelitis in rodents. However, the function of PVM in the human CNS remains poorly characterized. We first set out to investigate the validity of the antibody EDhu1, which recognizes human CD163, to specifically identify human PVM. Second, we wanted to gain insight into the function of PVM in antigen recognition and presentation and therefore we studied the expression of DC-SIGN, mannose receptor, MHC class II, and several costimulatory molecules by PVM in the normal and inflamed human CNS (multiple sclerosis (MS) brain lesions). Conventional immunohistochemistry and double-labeled immunofluorescence techniques were used. We show that CD163 specifically reveals PVM in the normal human CNS. In MS lesions, CD163 staining reveals expression on foamy macrophages and microglia, besides an upregulation of the amount of PVM stained. In contrast, mannose receptor expression is restricted to PVM in both normal and inflamed brain tissue. Furthermore, we show that a subpopulation of PVM in the human brain express several molecules involved in antigen recognition, presentation, and costimulation. Therefore PVM, which occupy a strategic location at the BBB, are equipped to recognize antigen and present it to T cells, supporting a role in the regulation of perivascular inflammation in the human CNS.

Serum Levels of Anti-Myelin Antibodies in Relapsing-Remitting Multiple Sclerosis Patients during Different Phases of Disease Activity and Immunomodulatory Therapy

Antibodies against myelin oligodendrocyte antigens have been found in the immunoreactive brain lesions of Multiple Sclerosis (MS) patients. Recently it has been proposed that these antibodies can be used as a prognostic marker in the course of disease. However, the serum levels of these autoantibodies during different phases of disease activity or after an immunomodulatory therapy have been poorly investigated. In this study the serum levels of anti-myelin oligodendrocyte glycoprotein (MOG) (directed against the epitopes 1–26 and 15–40) and anti-myelin basic protein (MBP) antibodies were sequentially measured in the same MS patient either in relapse or remission phases. We found that MS patients in the relapse phase had higher serum anti-MOG (peptides 1–26 and 15–40) and anti-MBP antibody levels than controls. In addition, the levels of anti-MOG 1–26 were also elevated during the relapse as compared with the remission phase but no significant changes were found in the levels of anti-MOG 15–40 of anti-MBP antibodies. We also evaluated the effect of interferon-beta (β) therapy on anti-myelin antibodies. 1-year of interferon-β treatment did not induce any changes in the levels of anti-MOG and anti-MBP antibodies. In conclusion, these data indicate that the use of peripheral levels of autoantibodies against MOG and MBP as marker of multiple sclerosis might be complicated by the phase of disease activity and by the epitope of the MOG protein used.

RANTES: a genetic risk marker for multiple sclerosis.

Regulated upon activation, normal T-cell expressed and secreted (RANTES) is a beta-chemokine and has been detected in brain lesions of multiple sclerosis (MS) patients. Considering its potential role in MS, we screened two functional polymorphisms in the proximal promoter region of the RANTES in MS patients versus controls. We examined 140 postmortem brain samples from subjects with a primary diagnosis of MS, and peripheral blood samples from 216 control subjects. The RANTES-28C/G and -403G/A promoter polymorphisms were examined. All subjects were non-Hispanic Caucasians. MS cases differed from controls showing a significant association with the 403G/A polymorphism (odds ratio, 2.359, [1.465-3.799]; P=0.0001), but not the -28C/G (P=NS) polymorphism. There was a significant association of the -28G allele with both early onset (P=0.031) and longer survival (P=0.006). There is a significant but complex association of the RANTES gene with MS.

Intérêt du recalage automatique des IRM cérébrales dans le suivi des scléroses en plaques

Magnetic resonance imaging (MRI) has transformed management of patients with multiple sclerosis. The exact contribution of brain MRI remains a subject of debate, but it is generally considered to provide a more specific and more sensitive outcome measure for monitoring purposes and for testing new therapies. The choice of MRI techniques, and measurement reproducibility for multiple sclerosis brain lesions are not defined with precision for routine practice. There are many sources of error when comparing successive images which can be overcome to some extent with repositioning and image processing techniques. We evaluated the impact of image repositioning on treatment decision-making for twelve relapsing remitting patients. Brain MRIs were performed every three months for a one-year period. Two neurologists interpreted the non-repositioned and repositioned images giving their analysis of changes in the lesions visualized on the T2 sequences and their therapeutic decisions. For the first neurologist, analysis of the non-repositioned images yielded six patients whose lesions had worsened while for the repositioned images there were only three. For the second neurologist, four patients had more lesions with the non-repositioned images and only three with repositioning. The subjective interpretations were the same for the two neurologists when they used repositioned images. Comparison by two neurologists of non-repositioned and repositioned MRI, with no other image processing, affected the analysis and in certain cases propositions for treatment.

Chlamydia pneumoniae infection associated with enhanced MRI spinal lesions in multiple sclerosis.

Cerebrospinal fluid (CSF) from 66 patients with multiple sclerosis (MS) and 25 patients with other neurological diseases (OND) were examined for the infection of Chlamydia pneumoniae by culture, polymerase chain reaction (PCR) assay, and determination of antibodies to C. pneumoniae. PCR was positive not only in 9 of 28 (32%) patients with MS but also in 2 patents with inflammatory disorders in 15 (13%) OND controls (p = 0.18). Viable C. pneumoniae was isolated from one patient with MS and one with paraneoplastic encephalomyelitis. C. pneumoniae could be detected only in cell-containing CSF. In MS, enhanced spinal magnetic resonance imaging (MRI) lesions were detected in all of four PCR-positive patents but none of five PCR-negative patients, and the difference was significant (p = 0.0079). However, no correlation was found between enhanced brain MRI lesions and CSF C. pneumoniae DNA. Elevated titers of anti-C. pneumoniae IgG were detected in CSF in 13 of 66 (20%) patients with MS and 1 of 25 (4%) OND controls (p = 0.064). CNS C. pneumoniae infection is not uncommon in MS as well as in other inflammatory disorders of the nervous system. The association of active spinal lesions with Chlamydia in CSF collected by lumber puncture suggests the detection of a recent infection. On the other hand, the lack of association of active MS brain lesions with CSF Chlamydia and the presence of PCR-positive patents who are clinically stable and have no enhancing MRI lesions imply the existence of a chronic infectious process.

Moderating Effects of Coping on the Relationship Between Stress and the Development of New Brain Lesions in Multiple Sclerosis

Objective Many patients with multiple sclerosis (MS) report that stress can trigger disease exacerbations. Considerable research has supported a relationship between stress and both clinical exacerbation and the development of new brain lesions. However, these relationships are not always consistent either within patients or across patients, suggesting the presence of moderators. This study examined the hypothesis that coping moderates the subsequent relationship between stress and the development of new brain lesions in MS. Methods Thirty-six patients (mean age = 44.4; 22 women, 14 men) with relapsing forms of MS were assessed once every 4 weeks for 28–100 weeks. New brain lesions were identified using monthly Gd+ MRI. Stress was measured within 24 hours before MRI using a modified version of the Social Readjustment Rating Scale that assessed Conflict and Disruption in Routine. Coping was measured at baseline using the Coping with Health Injuries and Problems questionnaire, which produces four scales: distraction, instrumental, palliative, and emotional preoccupation. Data were analyzed using mixed effects logistic regression to account for within-subject correlations. Analyses were lagged such that stress assessments predicted new Gd+ MRI brain lesions 8 weeks later. Results As reported previously, stress was significantly related to the development of new Gd+ brain lesions 8 weeks later (OR = 1.62, p = .009). Greater use of distraction was found to be a significant moderator of the relationship between stress and new Gd+ lesions (OR = 0.69, p = .037) such that greater use of distraction was associated with a decreased relationship between stress and new Gd+ lesions. Increased instrumental coping was marginally associated with a decreased relationship between stress and new Gd+ lesions (OR = 0.77, p = .081), while increased emotional preoccupation was marginally associated with an increased relationship between stress and new Gd+ lesions (OR = 1.46, p = .088). There was no significant moderating effect for palliative coping (p = .27) and no significant main effects for any coping variables and the subsequent development of new Gd+ brain lesions (p values > .21). Conclusions These findings provide modest support for the hypothesis that coping can moderate the relationship between stress and the MS disease activity. Several limitations in this study are discussed. While these findings suggest areas of potentially fruitful research, readers are cautioned that these are preliminary results; inferences regarding the clinical importance of these findings are premature.

Moderating effects of coping on the relationship between stress and the development of new brain lesions in multiple sclerosis.

Many patients with multiple sclerosis (MS) report that stress can trigger disease exacerbations. Considerable research has supported a relationship between stress and both clinical exacerbation and the development of new brain lesions. However, these relationships are not always consistent either within patients or across patients, suggesting the presence of moderators. This study examined the hypothesis that coping moderates the subsequent relationship between stress and the development of new brain lesions in MS. Thirty-six patients (mean age = 44.4; 22 women, 14 men) with relapsing forms of MS were assessed once every 4 weeks for 28-100 weeks. New brain lesions were identified using monthly Gd+ MRI. Stress was measured within 24 hours before MRI using a modified version of the Social Readjustment Rating Scale that assessed Conflict and Disruption in Routine. Coping was measured at baseline using the Coping with Health Injuries and Problems questionnaire, which produces four scales: distraction, instrumental, palliative, and emotional preoccupation. Data were analyzed using mixed effects logistic regression to account for within-subject correlations. Analyses were lagged such that stress assessments predicted new Gd+ MRI brain lesions 8 weeks later. As reported previously, stress was significantly related to the development of new Gd+ brain lesions 8 weeks later (OR = 1.62, p =.009). Greater use of distraction was found to be a significant moderator of the relationship between stress and new Gd+ lesions (OR = 0.69, p =.037) such that greater use of distraction was associated with a decreased relationship between stress and new Gd+ lesions. Increased instrumental coping was marginally associated with a decreased relationship between stress and new Gd+ lesions (OR = 0.77, p =.081), while increased emotional preoccupation was marginally associated with an increased relationship between stress and new Gd+ lesions (OR = 1.46, p =.088). There was no significant moderating effect for palliative coping (p =.27) and no significant main effects for any coping variables and the subsequent development of new Gd+ brain lesions (p values >.21). These findings provide modest support for the hypothesis that coping can moderate the relationship between stress and the MS disease activity. Several limitations in this study are discussed. While these findings suggest areas of potentially fruitful research, readers are cautioned that these are preliminary results; inferences regarding the clinical importance of these findings are premature.

γ/δ T Cells in Multiple Sclerosis: Chemokine and Chemokine Receptor Expression

γ/δ T cells are enriched in multiple sclerosis (MS) brain lesions and have been postulated to contribute to the pathogenesis of the disease. Increased expression of the chemokine receptors CCR5 and CXCR3 on T cells and raised amounts of the chemokines RANTES and IP-10 have been noted in the CSF and brain tissue of MS patients, but the contribution of γδ T cells to these increases is unknown. We therefore compared intracellular RANTES and IP-10 production as well as CCR5, CXCR3, and CXCR1 expression by γδ T cells derived from the blood and CSF of patients with MS and healthy controls (HC). We observed higher RANTES production by MS γδ than by αβ T cell lines. Most of the MS as well as the HC γδ and αβ T cell lines expressed CXCR3, while expression of CXCR1 was low. Interestingly, MS γδ T cell lines, compared to lines from HC, expressed lower levels of CCR5. Furthermore, CSF-derived γδ T cells had even lower CCR5 expression than blood-derived ones. The higher RANTES production by MS γδ T cell lines, together with a lower expression of CCR5, may reflect an autoregulatory loop, caused by an increased production of its ligands (RANTES, MIP-1α, and MIP-1β) or due to other pro-inflammatory cytokines. Alternatively, we show that lower CCR5 expression could also reflect the result of repeated in vivo stimulation of γδ T cells by autoantigens.

Microarray analysis reveals osteopontin as important player in MS

How does one attempt to find immunomodulatory proteins that are important in the autoimmune disease multiple sclerosis (MS)? In the past, investigators often proceeded from one candidate to the next and progress was slow. Now, microarray analysis, which allows investigators to examine thousands of genes at a time, has been applied to studies of MS and a striking result has been obtained. Chabas et al. [1xThe influence of the pro-inflammatory cytokine osteopontin on autoimmune demyelinating disease. Chabas, D et al. Science. 2001; 294: 1731–1735Crossref | PubMed | Scopus (632)See all References][1] have found that the proinflammatory cytokine osteopontin might play an important role in the development of progressive MS.MS is the most common neurodegenerative disease, with a global incidence of 0.1%. It is particularly prevalent in the Northern hemisphere and there is evidence of an infectious environmental etiology, although its nature is not at all clear. MS is characterized by relapsing episodes of neurological impairment, followed by remissions. In approximately one-third of patients, the disease evolves to follow a progressive course. Current treatment involves anti-inflammatory steroids and, more recently, interferon β (IFN-β). This was first used as an anti-viral agent (given the possibility of viral involvement) and then found to decrease the number of attacks and limit brain damage as assessed by magnetic-resonance imaging. However, the effects of IFN-β are only partial and not understood, and there is a pressing need for better therapies.The aim of the present study was to search for proteins that might play a role in the pathogenesis of MS. The study began with an analysis of the expression of 517 genes in the brains of rats with experimental autoimmune encephalomyelitis (EAE), a well-studied animal model of MS. Customized oligonucleotide microarrays containing these genes were used for screening, revealing that the level of transcripts for osteopontin was elevated. In parallel, high-throughput sequencing of cDNAs from MS brain lesions and control brains was carried out. This revealed that several genes are expressed highly in the MS brain, with the gene encoding osteopontin being the most prominent cytokine-encoding gene. This finding was of interest because osteopontin is a proinflammatory cytokine that promotes the activation of T helper 1 (Th1) cells by inducing the expression of cytokines, such as interleukin-12 and IFN-γ. The authors then probed MS tissues immunohistochemically for the expression of osteopontin, and again found its level to be elevated. Next, the role of osteopontin in EAE was examined using osteopontin-knockout mice. Disease severity in these mice was reduced significantly and in particular, the progression of disease was influenced, such that remission from disease was much more evident in the knockout mice. Finally, Th2 responses were much more pronounced in T cells from the osteopontin-knockout mice compared with wild-type mice with EAE.Because of the role played by osteopontin in inflammation and Th1 responses, the authors speculate that it could be important for the pathogenesis of demyelinating disease. In particular, the secretion of osteopontin by neurons might modulate inflammation and demyelination, and thereby influence the clinical severity of disease. Therefore, inhibiting the actions of osteopontin might be useful for the treatment of progressive MS.

Optic neuritis in multiple sclerosis

Purpose: To review the clinical features, natural history, potential pathogenic mechanisms, differential diagnosis, and management of optic neuritis in multiple sclerosis. Methods: Relevant literature regarding optic neuritis in multiple sclerosis from 1970 to the present was reviewed. Results: Optic neuritis is an acute inflammatory optic neuropathy. It is the most common type of optic neuropathy causing acute visual loss in young adults (peak age at 30-40 years), especially among women. Patients usually present with an acute reduction of visual acuity, orbital pain exacerbated by eye movements, dyschromatopsia, and an afferent papillary defect, with or without swelling of the optic nerve head. Visual field testing most often reveals central defects, but others, such as centrocecal, can also occur. Magnetic resonance image (MRI) scanning of the brain should be undertaken in all cases of acute optic neuritis for diagnostic and prognostic purposes. The brain lesions of multiple sclerosis are commonly seen as T2 ovoid high-signal white matter lesions on MRI scans of the brain located in perivenular regions perpendicular to ventricles with variable enhancement. For atypical presentations of optic neuritis, additional laboratory tests, such as cerebrospinal fluid analysis, serologic tests, and visual evoked potentials, prove to be useful in the diagnosis and subsequent management of the patient. The recommended treatment for optic neuritis is intravenous steroids, as shown in the Optic Neuritis Treatment Trial (ONTT). Conclusion: Optic neuritis is often the initial presentation of multiple sclerosis. Recent advances in the understanding of the immune basis for multiple sclerosis has led to earlier and more effective treatment of this disease.

BDNF and gp145trkB in multiple sclerosis brain lesions: neuroprotective interactions between immune and neuronal cells?

Recent immunohistological and imaging studies emphasize the crucial role of axonal injury in determining the extent of permanent neurological deficits in patients with multiple sclerosis. We have recently shown that human immune cells are capable of producing the neurotrophin brain-derived neurotrophic factor (BDNF), which can prevent axonal and neuronal damage after various pathological insults. BDNF imported into the CNS by immune cells would thus be an attractive candidate for mediating neuroprotective effects in multiple sclerosis. The aim of the present study was to perform a detailed immunohistochemical analysis of the expression of BDNF and its receptor truncated trkB tyrosine kinase receptor (gp145trkB) in a series of multiple sclerosis brain lesions. Our data show that various types of neurones throughout the brain are BDNF immunopositive in multiple sclerosis patients as well as in controls. Furthermore, in multiple sclerosis lesions, BDNF is primarily present in immune cells (T cells, macrophages/microglia) and reactive astrocytes. The number of BDNF immunopositive cells correlates with lesional demyelinating activity. The BDNF receptor gp145trkB is found in neurones in the immediate vicinity of multiple sclerosis plaques as well as in reactive astrocytes within the lesion, but not in immune cells. Our results demonstrate that both BDNF and gp145trkB are expressed in multiple sclerosis lesions. This suggests that BDNF and gp145trkB are involved in immune-mediated neuroprotective interactions in multiple sclerosis, and supports the concept that immune cells produce both damaging and protective factors in multiple sclerosis lesions.

CCR1+/CCR5+ Mononuclear Phagocytes Accumulate in the Central Nervous System of Patients with Multiple Sclerosis

Mononuclear phagocytes (monocytes, macrophages, and microglia) are considered central to multiple sclerosis (MS) pathogenesis. Molecular cues that mediate mononuclear phagocyte accumulation and activation in the central nervous system (CNS) of MS patients may include chemokines RANTES/CCL5 and macrophage inflammatory protein-1alpha/CCL3. We analyzed expression of CCR1 and CCR5, the monocyte receptors for these chemokines, on circulating and cerebrospinal fluid CD14+ cells, and in MS brain lesions. Approximately 70% of cerebrospinal fluid monocytes were CCR1+/CCR5+, regardless of the presence of CNS pathology, compared to less than 20% of circulating monocytes. In active MS lesions CCR1+/CCR5+ monocytes were found in perivascular cell cuffs and at the demyelinating edges of evolving lesions. Mononuclear phagocytes in early demyelinating stages comprised CCR1+/CCR5+ hematogenous monocytes and CCR1-/CCR5- resident microglial cells. In later stages, phagocytic macrophages were uniformly CCR1-/CCR5+. Cultured in vitro, adherent monocytes/macrophages up-regulated CCR5 and down-regulated CCR1 expression, compared to freshly-isolated monocytes. Taken together, these findings suggest that monocytes competent to enter the CNS compartment derive from a minority CCR1+/CCR5+ population in the circulating pool. In the presence of ligand, these cells will be retained in the CNS. During further activation in lesions, infiltrating monocytes down-regulate CCR1 but not CCR5, whereas microglia up-regulate CCR5.