Showing papers by "Marco Salvetti published in 2008"

B cells and multiple sclerosis.

Abstract: Clonal expansion of B cells and the production of oligoclonal IgG in the brain and cerebrospinal fluid (CSF) of patients with multiple sclerosis (MS) have long been interpreted as circumstantial evidence of the immune-mediated pathogenesis of the disease and suggest a possible infectious cause. Extensive work on intrathecally produced antibodies has not yet clarified whether they are pathogenetically relevant. Irrespective of antibody specificity, however, the processes of antibody synthesis in the CNS of patients with MS are becoming increasingly clear. Likewise, targeting B cells might be therapeutically relevant in MS and other autoimmune diseases that are deemed to be driven predominantly by T cells. Accumulating evidence indicates that in MS, similar to rheumatoid arthritis, B cells aggregate into lymphoid-like structures in the target organ. The process of aggregation is mediated through the expression of lymphoid-homing chemokines. In the brain of a patient with MS, ectopic B-cell follicles preferentially adjoin the pial membrane within the subarachnoid space. Recent findings indicate that substantial numbers of B cells that are infected with Epstein-Barr virus (EBV) accumulate in these intrameningeal follicles and in white matter lesions and are probably the target of a cytotoxic immune response. These findings, which await confirmation, could be an explanation for the continuous B-cell and T-cell activation in MS, but leave open concerns about the possible pathogenicity of autoantibodies. Going beyond the antimyelin-antibody dogma, the above data warrant further work on various B-cell-related mechanisms, including investigation of B-cell effector and regulatory functions, definition of the consistency of CNS colonisation by Epstein-Barr virus-infected B cells, and understanding of the mechanisms that underlie the formation and persistence of tertiary lymphoid tissues in patients with MS and other chronic autoimmune diseases (ectopic follicle syndromes). This work will stimulate new and unconventional ways of reasoning about MS pathogenesis.

Plasmacytoid dendritic cells in multiple sclerosis: intracerebral recruitment and impaired maturation in response to interferon-beta.

Abstract: The roles of plasmacytoid dendritic cells (pDCs) and their response to interferon (IFN)-beta therapy in multiple sclerosis (MS) patients are poorly understood. We identified pDC accumulation in white matter lesions and leptomeninges of MS brains and abundant expression of the Type I IFN-induced protein MxA, mainly in perivascular CD3+ lymphocytes in lesions, indicating Type I IFN production by activated pDCs. The pDC chemoattractant chemerin was detected in intralesional cerebrovascular endothelial cells, and the chemerin receptor was expressed on infiltrating leukocytes, including pDCs. The effect of IFN-beta on pDC phenotype and function was evaluated in MS patients before and during IFN-beta treatment. Although IFN-beta did not modify the frequency and immature phenotype of circulating pDC, they showed lower expression of major histocompatibility complex Class II and blood-dendritic cell antigen 2 molecules and upregulation of CD38 and B7H1 costimulatory molecules. On exposure to CpG (a site where cytosine [C] lies next to guanine [G] in the DNA sequence [the p indicates that C and G are connected by a phosphodiester bond]) oligodeoxynucleotides in vitro, pDCs from IFN-beta-treated MS patients showed reduced expression of the pDC maturation markers CD83 and CD86 molecules; in vitro IFN-beta treatment of pDCs from healthy donors resulted in lower secretion of proinflammatory cytokines, including IFN-alpha, and a decreased ability to stimulate allogeneic T cells in response to maturative stimuli. These data indicate that IFN-beta modulates the immunologic functions of pDC, thus identifying pDCs as a novel target of IFN-beta therapy in MS patients.

Refining genetic associations in multiple sclerosis

Abstract: Genome-wide association studies involve several hundred thousand markers and, even when quality control is scrupulous, are invariably confounded by residual uncorrected errors that can falsely inflate the apparent difference between cases and controls (so-called genomic inflation). As a consequence such studies inevitably generate false positives alongside genuine associations. By use of Bayesian logic and empirical data, the Wellcome Trust Case Control Consortium suggested that association studies in complex disease should involve at least 2000 cases and 2000 controls, at which level they predicted that p values of less than 5×10 −7 would more commonly signify true positives than false positives.

Primary headache and multiple sclerosis: preliminary results of a prospective study.

Abstract: The aim of this study was to explore the association between different types of headache (HA) and the clinical features of multiple sclerosis (MS). The relationship between HA and MS-specific therapies was also analysed. A total of 102 MS patients were recruited at the MS Centre of S. Andrea Hospital in Rome. According to International Headache Society criteria, the lifetime prevalence of primary HA was 61.8%. Migraine was observed more often in young relapsing-remitting MS patients, whilst tension-type HA was associated with older age, male gender and a secondary progressive course. Sixty-four patients had a history of ongoing or past interferon beta (IFNb) exposure. Of these, 17 subjects did not have a history of HA, while 24 complained of an increase in frequency of migraine attacks and 7 reported an IFNb-induced HA. Investigating and treating HA in MS patients starting IFNb therapy may improve MS-specific medication compliance.

Variations of the perforin gene in patients with multiple sclerosis.

Abstract: Perforin is involved in cell-mediated cytotoxicity and mutations of its gene (PRF1) cause familial hemophagocytic lymphohistiocytosis (FLH2). PRF1 sequencing in 190 patients with multiple sclerosis and 268 controls detected two FLH2-associated variations (A91V, N252S) in both groups and six novel mutations (C999T, G1065A, G1428A, A1620G, G719A, C1069T) in patients. All together, carriers of these variations were more frequent in patients than in controls (phenotype frequency: 17 vs 9%, P=0.0166; odds ratio (OR)=2.06, 95% confidence interval (CI): 1.13–3.77). Although A91V was the most frequent variation and displayed a trend of association with multiple sclerosis (MS) in the first population of patients and controls (frequency of the 91V allele: 0.076 vs 0.043, P=0.044), we used it as a marker to confirm PRF1 involvement in MS and assessed its frequency in a second population of 966 patients and 1520 controls. Frequency of the 91V allele was significantly higher in patients than in controls also in the second population (0.075 vs 0.058%, P=0.019). In the combined cohorts of 1156 patients and 1788 controls, presence of the 91V allele in single or double dose conferred an OR=1.38 (95% CI=1.10–1.74). These data suggest that A91V and possibly other perforin variations indicate susceptibility to MS.

Heritability of neurocognitive functioning in the elderly: evidence from an Italian twin study

Abstract: Background: the genetic and environmental origins of individual differences in specific cognitive abilities in the elderly are poorly understood. One reason is the lack of studies performed in cohorts with normal cognitive functions. Objective:toestimatetherelativecontributionsofgeneticandenvironmentalfactorsindetermininginter-individualvariation in neurocognitive abilities in the Italian population. Design: cross-sectional analysis of twin data. Setting: a sample of older twins with normal cognition from the population-based Italian Twin Registry (ITR). Subjects: twin pairs resident in Rome and born between 1926 and 1940, identified through the ITR in 2002. The final study population included 93 twin pairs. Methods: subjects underwent neuropsychological tests providing information about different cognitive domains. The contributions of genetic and environmental effects were assessed using standard univariate twin modelling based on linear structural equations. Results: the best-fitting model incorporated additive genetic (A) and unique environmental (E) sources of variance for the following tests: Mini-Mental State Examination (A = 55%), Raven (A = 56%), Attentional Matrices (A = 79%), Copying Drawings (A = 69%) and Story Recall (A = 54%). For Phonological and Semantic Verbal Fluency, the best model included non-additive (D) and unique environmental influences (D = 62 and 54%, respectively). Cigarette smoking was estimated to be negatively associated with the score of Phonological Verbal Fluency. For Token test, the inter-individual variance was entirely due to environmental factors not shared by the twins. Conclusion: our data showed that most of the specific cognitive abilities are moderately to highly heritable, and that the environmental factors of relevance for these abilities are those causing within-family differences.

A sequence variation in the MOG gene is involved in multiple sclerosis susceptibility in Italy.

Abstract: Several studies suggest that the histocompatibility complex (HLA) class I region harbours genes modulating multiple sclerosis (MS) susceptibility independently from the effect of class II alleles. A candidate gene in this region is MOG, encoding the myelin oligodendrocyte glycoprotein. A significant association with the missense variation V142L (rs2857766) was previously reported in a small sample of 50 Italian MS patients. We confirmed this result in two independent Italian sample sets consisting of 878 MS patients and 890 matched controls (P=6.6 × 10−4) and 246 trio families (P=1.5 × 10−3). The comparison of genotype frequencies suggested a dominant-protective effect of L142. In the combined sample sets L142 conferred an odds ratio (OR)=0.70 (95% confidence interval (CI): 0.60–0.82) that remained similar after accounting for HLA-DRB1*15 carrier status. The association with MOG V142L was still significant after conditioning for all DRB1 alleles (P=0.035). Eleven additional single nucleotide polymorphisms in the MOG gene (namely −1077T/C, −910T/C, −875A/G, −93T/C, S5S, Indel L22, V145I, +814C/T, +900A/G, +1024A/T, +1059C/T), two microsatellites in the MOG 5′ flanking (MOGCA) and 3′ untranslated (MOGTAAA) regions and four microsatellites in the HLA-class I region, from HLA-B to HFE, (namely MIB, D6S265, D6S1683 and D6S2239) were tested by transmission disequilibrium test in 199 trio families. None of these polymorphisms or of their haplotypic combinations showed a significant transmission distortion, in the absence of V142L. In conclusion, MOG V142L, or an untested variant in tight-linkage disequilibrium with it, is an independent MS susceptibility-modulating factor in the HLA class I region.

Early relapses after the first dose of natalizumab in active multiple sclerosis patients.

Abstract: Background Natalizumab is prescribed in Italy in patients who experienced at least two clinical relapses during a 12-month therapy with other approved immunomodulatory agents Results In 7 of 35 patients selected on the basis of these recommendations, we have observed clinical relapses occurring within 24 h after the first dose of natalizumab Conclusion The mechanism by which a first injection of natalizumab may precipitate a clinical relapse in patients with MS is unknown We speculate that natalizumab can promote the release of inflammatory mediators from lymphocytes present in the central nervous system at the time of the first infusion, thus favoring the clinical manifestation of a pre-existing active lesion