Therapeutic dosing of FTY720 reduces naïve T cells and TCM, but not TEM, in blood, without affecting T cell function. This is presumably because naive T cells and TCM express the homing receptor CCR7, allowing recirculation to secondary lymphoid tissues on a regular basis and, thus, trapping of the cells by FTY720 in lymph nodes.

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T cells are considered to play a pivotal role in orchestrating the self-reactive immune responses in multiple sclerosis (MS). Programmed death 1 (PD-1) is a member of the B7/CD28 superfamily of costimulatory molecules exerting inhibitory functions on T cells. Recently, an intronic 7146G/A polymorphism within the PD-1 gene was described and suggested to be associated with autoimmunity. We investigated whether this genetic polymorphism is a genetic modifier for risk and progression of MS. Blood samples from 939 German MS patients (mean age, 39 years; range, 13-71; 566 patients [60%] with relapsing-remitting MS, 279 (30%) with secondary, and 94 (10%) with primary progressive MS) and 272 healthy white controls were tested. Genotyping was performed by polymerase chain reaction and restriction enzyme digestion; results were confirmed by automatic sequencing. A significant association of the mutated allele with a progressive disease course was detected (44% 7146G vs 56% 7146A, chi(2) p = 0.002). Consequences of the PD-1 mutation for T-cell function were assessed ex vivo in some patients using microsphere-stimulated peripheral blood lymphocytes and purified CD4 cells. Importantly, PD-1-mediated inhibition of T-cell cytokine secretion (interferon-gamma) is impaired in patients carrying the PD-1 polymorphism. In conclusion, our data suggest that PD-1 polymorphism is a genetic modifier of the progression of MS, possibly through inducing a partial defect in PD-1-mediated inhibition of T-cell activation.

MicroRNA (miRNA) are a class of post-transcriptional regulators of gene expression targeting mRNA for translational repression and/or degradation. We analyzed the expression of 365 miRNA in lymphocytes in relapsing-remitting MS patients, and show the first evidence for distinct miRNA expression profiles in CD4 1 , CD81 and B cells in MS when compared with those in healthy volunteers. MiR-17-5p, which is involved in autoimmunity, was up-regulated in CD4 1 cells from MS patients. This was correlated with alterations in the expression of potential target genes of miR-17-5p, i.e. phosphatase and tensin homology and phosphatidyl-inositol-3-kinase regulatory subunit 1, which were down-regulated upon stimulation of CD4 1 cells with anti-CD3/CD28 in vitro. Functional experiments with a synthetic inhibitor of miR-17 supported the link between miRNA expression and the altered target gene expression. Moreover, we found distinct responses of deregulated miRNA to stimulation, i.e. miR-17-5p and miR-193a were strongly upregulated, in contrast to the down-regulation of miR-497, miR-1 and miR-126. Other deregulated miRNA did not respond to the stimulation probably due to other, non-T-cell activation related, mechanisms in their mode of action. Our findings support the role of miRNA-dependent regulatory mechanisms in the immunopathogenesis of MS.Key words: Autoimmune disease . Expression . Lymphocytes . MicroRNA . MS Supporting Information available onlineIntroduction MS results from a combination of environmental and genetic factors [1]. Genetic evidence suggests the existence of multiple susceptibility factors underlying MS. In the last couple of years, genomewide association studies have started to provide more information on genes that contribute to the risk of developing MS [2][3][4]. Large-scale transcriptional analysis with microarray technology has provided further insights into the molecular mechanisms of pathogenesis of MS. This approach has yielded several candidate genes responsible for the heterogeneous expression of the disease [5]. However, gene regulation is influenced by post-genomic regulatory mechanisms, e.g. micro-RNA (miRNA). MiRNA are small, endogenous non-coding RNA of approximately 22 nucleotides. They are transcribed in the nucleus, and after processing and export into the cytoplasm, they silence expression of target genes in a sequence-specific manner [6]. Repression of target genes is due to translational repression (imperfect sequence match) or mRNA cleavage (perfect match). MiRNA are key regulators of a wide variety of biological processes, e.g. cell proliferation and differentiation, apoptosis, signal transduction and organ development [7][8][9] It has been shown that miRNA are important in the homeostasis and function of the immune system [14][15][16][17]. Zhou et al. [18] showed that miR-150 is up-regulated during B-and T-cell maturation. Furthermore, Wu [19] reported different expression profiles of miRNA in antigen-specific naive, effector and memory CD8 1 T cells. In two recent reports [20,21...

This study provides Class I evidence that in some patients with MS receiving immunizations, concurrent fingolimod treatment in comparison to placebo decreases vaccination-induced immune responses.