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PubMed2003

Antimyelin antibodies as a predictor of clinically definite multiple sclerosis after a first demyelinating event.

BACKGROUND: Most patients with multiple sclerosis initially present with a clinically isolated syndrome. Despite the fact that clinically definite multiple sclerosis will develop in up to 80 percent of these patients, the course of the disease is unpredictable at its onset and requires long-term observation or repeated magnetic resonance imaging (MRI). We investigated whether the presence of serum antibodies against myelin oligodendrocyte glycoprotein (MOG) and myelin basic protein (MBP) in patients with a clinically isolated syndrome predicts the interval to conversion to clinically definite multiple sclerosis. METHODS: A total of 103 patients with a clinically isolated syndrome, positive findings on cerebral MRI, and oligoclonal bands in the cerebrospinal fluid were studied. At base line, serum samples were collected to test for anti-MOG and anti-MBP antibodies with Western blot analysis, and the lesions detected by cerebral MRI were quantified. Neurologic examinations for relapse or disease progression (defined as conversion to clinically definite multiple sclerosis) were performed at base line and subsequently every three months. RESULTS: Patients with anti-MOG and anti-MBP antibodies had relapses more often and earlier than patients without these antibodies. Only 9 of 39 antibody-seronegative patients (23 percent) had a relapse, and the mean (+/-SD) time to relapse was 45.1+/-13.7 months. In contrast, 21 of 22 patients (95 percent) with antibodies against both MOG and MBP had a relapse within a mean of 7.5+/-4.4 months, and 35 of 42 patients (83 percent) with only anti-MOG antibodies had a relapse within 14.6+/-9.6 months (P<0.001 for both comparisons with antibody-seronegative patients). The adjusted hazard ratio for the development of clinically definite multiple sclerosis was 76.5 (95 percent confidence interval, 20.6 to 284.6) among the patients who were seropositive for both antibodies and 31.6 (95 percent confidence interval, 9.5 to 104.5) among the patients who were seropositive only for anti-MOG antibodies, as compared with the seronegative patients. CONCLUSIONS: Analysis of antibodies against MOG and MBP in patients with a clinically isolated syndrome is a rapid, inexpensive, and precise method for the prediction of early conversion to clinically definite multiple sclerosis. This finding may be important for the counseling and care of patients with a first demyelinating event suggestive of multiple sclerosis.

Adolescent↗
PubMed2002

Tuberous sclerosis-associated lesions of the kidney, brain, and skin are angiogenic neoplasms.

BACKGROUND: Tuberous sclerosis is an autosomal dominant condition characterized by the development of benign neoplasms of the brain, kidney, and skin. Progressive growth and malignant transformation of brain and kidney lesions constitute the major cause of morbidity and mortality in adults with tuberous sclerosis. In addition, growth of skin lesions may be disfiguring to patients. OBJECTIVE: The purpose of this study was to determine whether benign tumors in patients with tuberous sclerosis are angiogenic. METHODS: Brain, kidney, and skin tumors from patients with tuberous sclerosis were stained with CD31, a specific marker of vascular endothelium. In addition, we used Northern blot analysis to demonstrate that renal angiomyolipoma cells express the potent angiogenesis stimulator vascular endothelial growth factor (VEGF). RESULTS: Brain, kidney, and skin neoplasms from patients with tuberous sclerosis are highly angiogenic. Renal angiomyolipoma cells produce the potent angiogenic factor VEGF. CONCLUSION: Benign neoplasms of patients with tuberous sclerosis are highly vascular. Our results provide a rationale for antiangiogenic therapy in the treatment and prevention of tuberous sclerosis-associated neoplasms.

Adult↗
PubMed2006

Antibiotic use and risk of multiple sclerosis.

Some reports suggest that bacteria, including Chlamydophila pneumoniae, could be involved in the etiology of multiple sclerosis. If that is true, persons who used antibiotics active against these bacteria, compared with nonusers, might be at lower risk of multiple sclerosis. Using a 1993-2000 case-control study nested in the United Kingdom-based General Practice Research Database cohort, the authors identified 163 multiple sclerosis cases who were followed up for at least 3 years before their first symptoms (the index date). Up to 10 controls matched to the cases by age, sex, general practice, and time in the cohort were selected. Exposure to antibiotics was assessed through computerized medical records. Overall antibiotic use or use of antibiotics against C. pneumoniae was not associated with multiple sclerosis risk. However, use of penicillins in the 3 years before the index date decreased the risk of developing a first attack of multiple sclerosis (odds ratio=0.5, 95% confidence interval: 0.3, 0.9 for those who used penicillins for >or=15 days compared with no use). In conclusion, use of antibiotics active against C. pneumoniae was not associated with a decreased risk of short-term multiple sclerosis. The observed lower risk of multiple sclerosis for penicillin users needs to be confirmed in other populations.

Adult↗
PubMed1993

Changes in shapes of surviving motor neurons in amyotrophic lateral sclerosis.

In amyotrophic lateral sclerosis, motor neurons in the spinal cord and brainstem shrink before they die. In 12 cases of sporadic amyotrophic lateral sclerosis, and in 11 control subjects, we have measured the neurons in the second sacral segment and the hypoglossal nucleus, and have calculated a 'shape index' that shows the convexity or concavity of the cell body. (The shape index, SI = 100 x C/P, where C is the circumference of the largest circle that can be inscribed in the neuron and P is the perimeter of the perikaryon, including the bases of the dendrites as seen in a Nissl preparation. The shape index increases with increasing convexity of the cell.) In the ventral horn of segment S2 and in the hypoglossal nucleus, the surviving motor neurons in amyotrophic lateral sclerosis showed significantly decreased size and increased shape index (convexity) of the cell bodies. By contrast, the nucleus of Onuf in segment S2, consisting of neurons that supply the pelvic floor muscles, was preserved in amyotrophic lateral sclerosis. Its cells did not differ significantly in size or convexity between the amyotrophic lateral sclerosis and control groups. In both the hypoglossal and S2 neuronal populations in amyotrophic lateral sclerosis, the sizes of the cells were positively correlated with the numbers of surviving motor neurons. However, there was no correlation of the shape index with numbers of cells. This is interpreted as due to shrinkage of neurons still taking place at the time of death, when the changes in shape were probably largely completed. These observations indicate that the mechanism of neuronal atrophy in amyotrophic lateral sclerosis may involve both reduced protein synthesis and enzymatic degradation of the cytoskeleton within the larger dendrites.

Aged↗
PubMed1994

Erectile dysfunction in multiple sclerosis. Associated neurological and neurophysiological deficits, and treatment of the condition.

Forty-eight men with multiple sclerosis and erectile dysfunction were evaluated. Emphasis was placed on the neurological features and the relationship between impotence and the bladder dysfunction in multiple sclerosis. Erectile failure was invariably associated with pyramidal signs in the lower limbs and with urinary symptoms. All of the men with impotence and marked pyramidal dysfunction in their legs were found by cystometric studies to have bladder hyperreflexia. The severity of the urinary symptoms was related to the degree of pyramidal impairment in the lower limbs. The posterior tibial and the pudendal cortical evoked potentials were abnormal in most of the men with multiple sclerosis and erectile failure. However, recording the pudendal cortical responses in patients with multiple sclerosis and impotence provided no more information than the tibial cortical evoked potentials. The neurological examination findings together with the results of the neurophysiological and cystometric tests suggest that erectile dysfunction in multiple sclerosis is due to spinal lesions situated proximal to the sacral cord. The feasability of papaverine intracorporeal injection therapy for men with multiple sclerosis and impotence was assessed. Papaverine intracorporeal injections produced satisfactory erections in the majority of the impotent men. Erectile failure in patients with multiple sclerosis was successfully managed for up to 2 years, by intracorporeal self-injection therapy.

Adult↗
PubMed1997

The neuroendocrine axis in patients with multiple sclerosis.

We investigated the basal and dynamic regulation of the hypothalamo-pituitary-adrenal (HPA), hypothalamo-pituitary-thyroid (HPT) and hypothalamo-pituitary-gonadal axes and prolactin secretion in 52 patients with clinically definite multiple sclerosis. These patients also had gadolinium enhanced brain MRI scans and were divided into relapsing-remitting, secondary progressive and primary progressive subgroups. These subgroups were compared with healthy controls and a group of patients with other neurological diseases. The cortisol diurnal rhythm was preserved in all groups of patients. The time-integrated cortisol response to human corticotropin-releasing hormone (CRH) stimulation was lower in the patients with secondary progressive multiple sclerosis, compared with patients with primary progressive multiple sclerosis and healthy subjects. The time-integrated beta-endorphin response to CRH was greater in the patients with relapsing-remitting multiple sclerosis compared with the others. Feedback regulation assessed by dexamethasone suppression was normal. Serum testosterone was low in 24% of male multiple sclerosis patients and oestradiol was low in 25% of pre-menopausal female multiple sclerosis patients, whereas prolactin and the HPT function were normal. Correlations with C-reactive protein (CRP) and MRI suggest that activation of the HPA axis in multiple sclerosis patients is secondary to an active inflammatory stimulus.

Adult↗
PubMed1997

Increased immunoreactivity to two overlapping peptides of myelin proteolipid protein in multiple sclerosis.

We tested the proliferative responses of peripheral blood mononuclear cells from 61 patients with multiple sclerosis, 56 healthy control subjects and 52 patients with other neurological diseases to seven synthetic peptides of myelin proteolipid protein (PLP) and 19 synthetic peptides of myelin basic protein (MBP). Increased proliferative responses to two overlapping PLP peptides, PLP184-199 and PLP190-209 were found significantly more frequently in blood from patients with relapsing-remitting or secondary progressive multiple sclerosis (52.3%), but not from those with primary progressive multiple sclerosis (18.2%), than in that from healthy control subjects (8.9%) and patients with other neurological diseases (20.8%). Reactivity to these PLP peptides was most frequently seen in blood from patients with multiple sclerosis of 6-15 years duration and with moderate to severe disability (Kurtzke's Expanded Disability Status Scale > 4.0); the blood from 15 of 19 patients in this group reacted to one or both of the peptides. Both peptides could be recognized by short-term T-cell lines specific for whole PLP, and lines specific for one or other of the two overlapping peptides were able to recognize whole PLP, indicating that these peptides can be processed naturally from the intact molecule. This region of PLP is encephalitogenic in a number of strains of mice. Samples from multiple sclerosis patients did not react more frequently to any of the MBP peptides than those from healthy control subjects. The proportions of patients with other neurological diseases whose blood responded to the MBP peptides that most frequently elicited responses in blood from multiple sclerosis patients were significantly lower than the proportions of multiple sclerosis patients and healthy control subjects whose blood responded to these peptides.

Adolescent↗
PubMed1999

Serum gelatinase B, TIMP-1 and TIMP-2 levels in multiple sclerosis. A longitudinal clinical and MRI study.

Metalloproteinases have been implicated in the pathogenesis of multiple sclerosis. We report longitudinal serum levels of gelatinase B and of the tissue inhibitors of matrix metalloproteinases (TIMP), TIMP-1 and TIMP-2, in 21 patients with relapsing multiple sclerosis. Patients had monthly clinical and gadolinium-enhanced MRI follow-up for 10 months. Longitudinal samples in nine healthy controls and cross-sectional samples from 12 patients with inflammatory CNS disease and 15 patients with other neurological diseases were used for comparison. Average serum gelatinase B, TIMP-1 and TIMP-2 levels were significantly higher in multiple sclerosis patients and those with other neurological diseases than in healthy controls. In the patients with multiple sclerosis, gelatinase B levels were significantly higher during clinical relapse compared with periods of clinical stability. Multiple sclerosis patients with high mean serum gelatinase B levels had significantly more T1-weighted gadolinium-enhancing MRI lesions than those with mean levels within the control range. TIMP-1 levels were not different during relapse and between relapses. There was a trend for TIMP-2 levels to be lower during relapse compared with non-relapse periods. For similar levels of serum gelatinase B, associated TIMP-1 levels were significantly lower and TIMP-2 levels significantly higher in multiple sclerosis patients compared with the inflammatory CNS control group. We propose that an abnormality in the inhibitory response to metalloproteinases may play an aetiological role in the chronicity of multiple sclerosis.

Adult↗
PubMed2000

Oligodendrocyte survival, loss and birth in lesions of chronic-stage multiple sclerosis.

One of the hallmarks of the human demyelinating disease multiple sclerosis is the inability to compensate adequately for the loss of myelin and of oligodendrocytes, the myelin-forming cells of the CNS. Oligodendrocyte precursor cells, a potential source of oligodendrocytes, have been identified in lesions of chronic multiple sclerosis, but it is not known whether they develop into new, fully differentiated oligodendrocytes, capable of remyelination. Sections of post-mortem multiple sclerosis tissue were therefore immunolabelled with antibodies to galactocerebroside (GalC), the first oligodendrocyte-specific molecule to be expressed by differentiating oligodendrocyte precursor cells, and myelin oligodendrocyte glycoprotein (MOG), a marker for mature oligodendrocytes. In total, 23 lesions from 15 subjects with chronic progressive multiple sclerosis were analysed. The immunolabelling revealed that chronic multiple sclerosis lesions contain only small numbers of immature, process-bearing, GalC-positive oligodendrocytes (0-2 cells/mm(2) in 10 micrometer thick sections); they had a relatively large, pale nucleus (maximum diameter: 9.9 +/- 0.9 micrometer). Although they appeared to make contact with surrounding demyelinated axons, most immature oligodendrocytes appeared not to be engaged in myelination. These findings suggest that oligodendrocyte differentiation of precursor cells is a rare event in chronic multiple sclerosis, which is consistent with the general failure of myelin repair during the later stages of this disease. The lesions in the collection, in particular those with recent demyelinating activity, contained another distinct population of oligodendrocytes. It consisted of small, round cells with a small, dense nucleus (maximum diameter: 6.8 +/- 0.8 micrometer) that expressed both GalC and MOG but lacked processes, suggesting that these cells were mature oligodendrocytes that had survived the loss of their myelin sheaths, i.e. they were demyelinated oligodendrocytes. In the most recent lesions in the collection, the demyelinated oligodendrocytes were found in large numbers throughout the centre of the lesion (up to 700 cells/mm(2)), while in the older lesions they were found only at the edges. Moreover, when the borders of these older lesions still contained numerous macrophages, they tended to contain more demyelinated oligodendrocytes than those lacking macrophages. These findings suggest that mature, demyelinated oligodendrocytes gradually disappear from lesion areas with increasing age of the lesion. The present study thus suggests that the failure of myelin repair in at least some cases of chronic multiple sclerosis is due to (i) the loss of demyelinated oligodendrocytes from lesion areas and (ii) the failure of the oligodendrocyte precursor population to expand and generate new oligodendrocytes. Gaining further insight into these processes may prove crucial for the development of remyelination promoting strategies.

Adult↗
PubMed2001

Matrix metalloproteinases and tissue inhibitors of metalloproteinases in cerebrospinal fluid differ in multiple sclerosis and Devic's neuromyelitis optica.

Matrix metalloproteinases (MMPs) are increased in the CSF of patients with multiple sclerosis. Devic's neuromyelitis optica (DNO) is a demyelinating syndrome that involves the optic nerve and cervical cord but differs pathologically from multiple sclerosis. Therefore, we hypothesized that the type of inflammatory reaction that causes MMPs to be elevated in multiple sclerosis would be absent in patients with DNO. CSF was collected from 23 patients with relapsing-remitting or secondary progressive multiple sclerosis, all of whom were experiencing acute symptoms, from seven patients with DNO, and from seven normal volunteers. Diagnoses were made according to current criteria on the basis of clinical manifestations, imaging results and CSF studies. IgG synthesis was increased in the CSF of multiple sclerosis patients but not in that of DNO patients. Zymography, reverse zymography and ELISA (enzyme-linked immunosorbent assay) were used to measure gelatinase A (MMP-2), gelatinase B (MMP-9) and tissue inhibitors of metalloproteinases (TIMPs). Zymograms showed that multiple sclerosis patients had elevated MMP-9 compared with DNO patients and controls (P: < 0.05). TIMP-1 and TIMP-2 levels were similar in all three groups. We conclude that multiple sclerosis patients have higher MMP-9 levels in the CSF than patients with DNO, which supports the different pathological mechanisms of these diseases.

Humans↗
PubMed2002

Oligodendrocyte precursor cells in the demyelinated multiple sclerosis spinal cord.

Lesions appearing in the CNS of patients in the chronic phase of the inflammatory, demyelinating disease multiple sclerosis often fail to repair, resulting in neurological dysfunction. This failure of remyelination appears, in many cases, to be due not to the destruction of the local oligodendrocyte precursor population, a source for new myelin-forming cells, but to the failure of the precursor cells to proliferate and differentiate, at least in brain lesions. The spinal cord is also a prominent site for lesions in multiple sclerosis, but nothing is known about the fate of the oligodendrocyte precursor population in this area. The present study has therefore analysed spinal cord samples with demyelination from 16 subjects with longstanding multiple sclerosis for the presence of oligodendrocyte precursor cells. Immunolabellings of 10 microm thick sections with the O4/anti-galactocerebroside (GalC) antibody combination, to visualize O4-positive, GalC-negative oligodendrocyte precursor cells, revealed that such cells were prevalent in many spinal cord lesions, with densities of up to 35 cells/mm(2). Six of the spinal cord lesions contained < or =3 O4-positive, GalC-negative cells/mm(2), but such cells were widespread in brain lesions from these multiple sclerosis cases that were available for study (8-26 cells/mm(2)). The density of the O4-positive, GalC-negative oligodendrocyte precursor cells in all spinal cord and brain lesions studied thus far (n = 41) decreased significantly with declining numbers of debris-laden macrophages. In addition, lesions lacking macrophages tended to be derived from the older patients and there was a negative correlation between the density of the oligodendrocyte precursor cells and clinical age of the multiple sclerosis subject at death, and disease duration. The analysis further revealed that lesions from subjects with primary progressive and secondary progressive multiple sclerosis contained, on average, similar numbers of oligodendrocyte precursor cells/mm(2) and that immature oligodendrocytes were only present in significant numbers in lesions with high precursor densities. Taken together, the present data suggest that there is a gradual reduction in the size of the O4-positive, GalC- negative oligodendrocyte precursor population with increasing age of the lesion, that the generation of new oligodendrocytes becomes increasingly more impaired and that lesions are not repopulated to a significant extent by migratory oligodendrocyte precursor cells present in the adjacent unaffected tissue. Hence, strategies intended to promote endogenous remyelination in multiple sclerosis patients should focus on both enhancing the long-term survival of oligodendrocyte precursor cells and on stimulating these cells to proliferate and differentiate into remyelinating oligodendrocytes.

Adult↗
PubMed2002

Oligoclonal expansion of memory CD8+ T cells in cerebrospinal fluid from multiple sclerosis patients.

Multiple sclerosis is a chronic inflammatory demyelinating disease of the CNS. Although the aetiology of multiple sclerosis is still unknown, it is widely believed that T cells play a central role in its pathogenesis. To identify and characterize disease-relevant T cells, we analysed CD4+ and CD8+ T cells freshly isolated from the CSF and peripheral blood of 36 multiple sclerosis patients for their T-cell receptor variable beta (TCRBV) chain repertoire. In most patients, we found significant overexpression of individual TCRBV chains on CD8+ T cells from CSF compared with peripheral blood. In contrast, only a few multiple sclerosis patients showed differences between the two compartments in TCRBV expression on CD4+ T cells. The overexpression of specific TCRBV chains on CD8+ T cells was found to be stable over several months in selected patients and involved mainly T cells with a memory phenotype. In two patients studied, individual TCRBV chain overexpression was found to be caused by the expansion of T cell populations with identical or highly similar rearranged T-cell receptor beta- and alpha-chain sequences, which were not found among peripheral blood CD8+ T cells. Our findings demonstrate selective enrichment of memory CD8+ T cells in the CSF of multiple sclerosis patients, suggesting a role for these CD8+ T cells in the pathogenesis of multiple sclerosis. Our study provides a basis for future trials to identify disease-associated antigens and disease pathogenesis in multiple sclerosis.

Adolescent↗
PubMed2002

Cognitive function and fMRI in patients with multiple sclerosis: evidence for compensatory cortical activation during an attention task.

Mild cognitive impairment has frequently been reported for patients in the early stages of multiple sclerosis. The aim of the present study was to measure whether altered cortical activation during a sustained attention task occurs along with limited extent of neuropsychological problems. Expanded brain activation of multiple sclerosis patients with normal motor function compared with healthy controls during a finger tapping paradigm has previously been reported. Compensatory brain activation in patients with multiple sclerosis compared with normal controls may also be observed when the subjects are performing cognitive functions. In 21 patients with clinically definite relapsing-remitting multiple sclerosis, a psychometric assessment was performed using the Wechsler Memory Scale (WMS) and the Multiple Sclerosis Functional Composite Score (MSFC). In addition, functional MRI was performed during a Paced Visual Serial Addition Task (PVSAT), a visual analogue of the Paced Auditory Serial Addition Task (PASAT). All patients were within 3 years of diagnosis and were not suffering from a relapse at the time of investigation. The multiple sclerosis patients were compared with a control group of 21 healthy volunteers matched for handedness, age, years of education and sex. With regard to psychometric results, the WMS general memory score showed statistically significant differences between patients and controls. We did not find differences for either the MSFC or the PASAT scores. A group analysis of the functional imaging data during the PVSAT revealed different activation patterns for patients compared with control subjects. In healthy volunteers, the main activation was found in the frontal part of the right gyrus cinguli (Brodmann area 32). In patients, the main activation was detected at the right hemispheric frontal cortex (Brodmann areas 6, 8 and 9). In addition, the left hemispheric Brodmann area 39 was activated. We interpret the different patterns of activation, accompanied with intact performance in a sustained attention task of our multiple sclerosis sample compared with healthy controls, as the consequence of compensatory mechanisms. This is an expression of neuronal plasticity during early stages of a chronic disease.

Adolescent↗
PubMed2003

Altered expression patterns of group I and II metabotropic glutamate receptors in multiple sclerosis.

Recent evidence supports a role for glutamate receptors in the pathophysiology of multiple sclerosis. In the present study, we have focused specifically on the expression of metabotropic glutamate receptors (mGluRs) in multiple sclerosis brain tissue. The expression of group I (mGluR1alpha and mGluR5) and group II (mGluR2/3) mGluRs was studied using immunohistochemistry in tissue from 12 multiple sclerosis cases and seven non-neurological controls. The expression patterns of both group I and II mGluRs in multiple sclerosis tissue differed significantly from those in control tissue. Strong mGluR1alpha immunoreactivity was observed in axons of the subcortical white matter, particularly in the centre of actively demyelinating lesions and in the borders of chronic active lesions. mGluR1alpha axonal immunopositivity was also found in normal appearing multiple sclerosis white matter, but axons in control white matter were generally negative. mGluR1alpha axonal labelling was associated with the presence of non-phosphorylated neurofilaments and beta-amyloid precursor protein, which are sensitive markers for axonal injury and disturbed axonal transport. Changes in mGluR immunoreactivity were also observed in glia. A diffuse increase in the expression of mGluR5 and mGluR2/3 was detected in reactive astrocytes in multiple sclerosis lesions. However, only a subpopulation of reactive astroglial cells expressed mGluR1alpha. In addition, labelling with antibodies to mGluR2/3 and, to a lesser extent labelling with antibodies to mGluR1alpha, was detected in a population of cells of the microglial/macrophage lineage that displayed a macrophage-like morphology. Our data suggest that mGluRs, like ionotropic glutamate receptors, play a role in the complex processes that are associated with the progressive brain damage in multiple sclerosis, including both glial activation and pathological changes in axons.

Adult↗
PubMed2004

Childhood infections and risk of multiple sclerosis.

Multiple sclerosis has been hypothesized to be the result from an aberrant immune response possibly triggered by delayed exposure to a common childhood infection. Because the vast majority of previous studies testing this hypothesis have been based on a history of childhood infections recalled years to decades later in adulthood, we investigated whether age at six common childhood infections was associated with risk of multiple sclerosis, using information recalled in the childhood of a historical cohort of school children in Denmark. Cases included all individuals with multiple sclerosis in the country born between 1940 and 1975, who had attended school in the capital, Copenhagen. Controls were age- and sex-matched peers. School health records were obtained for all subjects. The records contained information on measles, pertussis, scarlet fever, birth order, sibship size, social class of the father, school years, and name of school and attended school classes for children born since 1940 (n(cases) = 455, n(controls) = 1801). For children born since 1950, the records also contained information on rubella, varicella and mumps (n(cases) = 182, n(controls) = 690). Neither age at infection with measles, rubella, varicella, mumps, pertussis and scarlet fever (upper age limit, 14 years) nor the cumulative number of these infections between the ages of 10 and 14 years was associated with the risk of multiple sclerosis. In addition, the risk of multiple sclerosis was not associated with birth order or social class. No clustering of multiple sclerosis in school classes was observed. Our findings suggest that measles, rubella, mumps, varicella, pertussis and scarlet fever, even if acquired late in childhood, are not associated with increased risk of multiple sclerosis later in life.

Adolescent↗
PubMed2005

Autoreactive CD8+ T cells in multiple sclerosis: a new target for therapy?

Multiple sclerosis afflicts more than 1 million individuals worldwide and is widely considered to be an autoimmune disease. Traditionally, CD4(+) T helper cells have almost exclusively been held responsible for its immunopathogenesis, partly because certain MHC class II alleles clearly predispose for developing multiple sclerosis and also, because of their importance in inducing experimental autoimmune encephalomyelitis (EAE), the animal model for multiple sclerosis. However, several strategies that target CD4(+) T cells beneficially in EAE have failed to ameliorate disease activity in multiple sclerosis, and some have even triggered exacerbations. Recently, the potential importance of CD8(+) T cells has begun to emerge. Physiologically, CD8(+) T cells are essential for detecting and eliminating abnormal cells, whether infected or neoplastic. In multiple sclerosis, genetic associations with MHC class I alleles have now been established, and CD8(+) as well as CD4(+) T cells have been found to invade and clonally expand in inflammatory central nervous system plaques. Recent animal models induced by CD8(+) T cells show interesting similarities to multiple sclerosis, in particular, in lesion distribution (more inflammation in the brain relative to the spinal cord), although not all of the features of the human disease are recapitulated. Here we outline the arguments for a possible role for CD8(+) T cells, a lymphocyte subset that has long been underrated in multiple sclerosis and should now be considered in new therapeutic approaches.

Animals↗
PubMed2005

Expression of the immune-tolerogenic major histocompatibility molecule HLA-G in multiple sclerosis: implications for CNS immunity.

HLA-G is a non-classical major histocompatibility complex (MHC) class I antigen with highly limited tissue distribution under non-pathological conditions. Although capable of acting as a peptide-presenting molecule, its strong immune-inhibitory properties identify HLA-G as a mediator of immune tolerance with specific relevance at immune-privileged sites such as trophoblast or thymus. To assess the role of HLA-G in CNS immunity, we investigated its expression in brain specimens from patients with multiple sclerosis (n = 11), meningitis (n = 2) and Alzheimer's disease (n = 2) and non-pathological CNS controls (n = 6). Furthermore, cultured human microglial cells and CSF of patients with multiple sclerosis and controls were assessed. Furthermore, CSF from MS patients and controls, as well as cultured human microglial cells were assessed. Using several HLA-G specific mAb and immunohistochemistry, HLA-G protein was found strongly expressed in brain specimens from patients with multiple sclerosis while it was rarely detectable in the non-pathological control specimens. In multiple sclerosis brain specimens, HLA-G immunoreactivity was observed in acute plaques, in chronic active plaques, in perilesional areas as well as in normal appearing white matter. In all areas microglial cells, macrophages, and in part endothelial cells were identified as the primary cellular source of expression. HLA-G was also found in other disease entities (meningitis, Alzheimer's specimens) where expression correlated to activation and MHC class II expression on microglial cells. Importantly, ILT2, a receptor for HLA-G, was also found in multiple sclerosis brain specimens thus emphasizing the relevance of this inhibitory pathway in vivo. HLA-G mRNA and protein expression and regulation could also be corroborated on cultured human microglial cells in vitro. Further, expression of HLA-G in the CSF of multiple sclerosis patients and controls was analysed by flow cytometry and ELISA. Monocytes represented the main source of cellular HLA-G expression in the CSF. Corresponding to the observations with the tissue specimens, CSF mean levels of soluble HLA-G were significantly higher in multiple sclerosis than in non-inflammatory controls (171 +/- 31 versus 39 +/- 10 U/ml; P = 0.0001). The demonstration of HLA-G and its receptor ILT2 on CNS cells and in areas of microglia activation implicate HLA-G as a contributor to the fundamental mechanisms regulating immune reactivity in the CNS. This pathway may act as an inhibitory feedback aimed to downregulate the deleterious effects of T-cell infiltration in neuroinflammation.

Adult↗
PubMed2005

Chemokines in multiple sclerosis: CXCL12 and CXCL13 up-regulation is differentially linked to CNS immune cell recruitment.

Understanding the mechanisms of immune cell migration to multiple sclerosis lesions offers significant therapeutic potential. This study focused on the chemokines CXCL12 (SDF-1) and CXCL13 (BCA-1), both of which regulate B cell migration in lymphoid tissues. We report that immunohistologically CXCL12 was constitutively expressed in CNS parenchyma on blood vessel walls. In both active and chronic inactive multiple sclerosis lesions CXCL12 protein was elevated and detected on astrocytes and blood vessels. Quantitative PCR demonstrated that CXCL13 was produced in actively demyelinating multiple sclerosis lesions, but not in chronic inactive lesions or in the CNS of subjects who had no neurological disease. CXCL13 protein was localized in perivascular infiltrates and scattered infiltrating cells in lesion parenchyma. In the CSF of relapsing-remitting multiple sclerosis patients, both CXCL12 and CXCL13 were elevated. CXCL13, but not CXCL12, levels correlated strongly with intrathecal immunoglobulin production as well as the presence of B cells, plasma blasts and T cells. About 20% of CSF CD4+ cells and almost all B cells expressed the CXCL13 receptor CXCR5. In vitro, CXCL13 was produced by monocytes and at much higher levels by macrophages. CXCL13 mRNA and protein expression was induced by TNFalpha and IL-1beta but inhibited by IL-4 and IFNgamma. Together, CXCL12 and CXCL13 are elevated in active multiple sclerosis lesions and CXCL12 also in inactive lesions. The consequences of CXCL12 up-regulation could be manifold. CXCL12 localization on blood vessels indicates a possible role in leucocyte extravasation, and CXCL12 may contribute to plasma cell persistence since its receptor CXCR4 is retained during plasma cell differentiation. CXCL12 may contribute to axonal damage as it can become a neurotoxic mediator of cleavage by metalloproteases, which are present in multiple sclerosis lesions. The strong linkage of CXCL13 to immune cells and immunoglobulin levels in CSF suggests that this is one of the factors that attract and maintain B and T cells in inflamed CNS lesions. Therefore, both CXCL13 and CXCR5 may be promising therapeutic targets in multiple sclerosis.

Acute Disease↗