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Multiple sclerosis (MS) is a chronic debilitating disease, in which T-cells are considered to play a pivotal role. CD28 is the quintessential costimulatory molecule on T-cells and its expression declines progressively with repeated stimulations, leading to the generation of CD28(-) T-cells. Our aim was to examine whether CD4(+)CD28(-) T-cells were enriched in MS patients, and characterize the phenotype of this subset in MS patients and healthy controls (HC). All these changes could provide these CD4(+)CD28(-) T-cell characteristics that might be involved in the pathogenesis of MS, turning this T-cell subset into a potential target for future therapeutic strategies., (Copyright © 2011 Elsevier B.V. All rights reserved.)

The effect of HLA alleles on the outcome of multiple sclerosis (MS) has been widely investigated; however, results are conflicting and no consistent correlation has been established. This study evaluated the association between the HLA DR2 haplotype in patients with primary progressive MS (PPMS) and the effect of alleles on progression. An association was found between PPMS and the DR2 and DRB1*1501 and DQB1*0602 alleles. Severe morbidity was found in DRB1*1501-positive PPMS patients. This exploratory study raises new hypotheses for future research and emphasizes the need to investigate possible candidate genes other than HLA that may contribute towards heterogeneity in the course of the disease.

Some polymorphisms in the FCRL3 gene, a member of the Fc-receptor like family, have been associated with several autoimmune diseases and recently with multiple sclerosis (MS). We performed a case-control study of three SNPs in FCRL3 gene in 645 MS patients and 786 controls, all Caucasians from the South of Spain. Genotype and allele frequencies of two SNPs (rs7528684/FCRL3_3 and rs7522061/N28D), which were in high linkage disequilibrium (r(2) = 0.87), differed between MS cases and controls. The C allele of FCRL3_3 was found to be protective for MS (per allele OR = 0.81, 95% C.I. = 0.70-0.94; P-value = 0.007) as was the G variant of N28D, but no association was found for rs11264799/FCRL3_4. Haplotype analysis confirmed these associations with highly consistent effect sizes for haplotypes carrying the C allele of FCRL3_3.

To determine the gene expression of IFNAR1, IFNAR2 and MxA protein and the association with IFNbeta treatment response in MS patients. MS patients treated with IFNbeta had a significant decrease in IFNAR1 and IFNAR2 expression, and a significant increase in MxA compared to non-treated patients and healthy controls. Also, those patients who had a good response to treatment had a significant decrease in IFNAR1 and IFNAR2 expression compared to non-responders, non-treated patients and healthy controls. IFNbeta influences the expression of its receptors, and is greater in patients who respond to IFNbeta treatment. This down-regulation could be indicative of the response to IFNbeta.

We investigated the role of three polymorphisms in the IFNAR1 (SNPs 18417 and -408) and IFNAR2 (SNP 11876) genes in multiple sclerosis (MS) susceptibility and in the IFNbeta treatment response in a group of 147 patients and 210 controls undergoing interferon therapy during the last 2 years. Only the 18417 and the 11876 SNPs showed an association with disease susceptibility (p=0.001 and 0.035, respectively) although no differential genotype distribution were observed between interferon responders and non-responder MS patients. No alteration of the expression level of IFNAR-1 was observed with respect to the -408 genotypes or to interferon treatment response. These data suggest a role for the IFNAR pathway in susceptibility to MS.

The -330 IL2 gene promoter polymorphism has been associated with multiple sclerosis (MS) [J. Neuroimmunol. 119 (2001) 101], but the basis underlying this association remains unknown to date. In the present work, we have found that IL2 promoter-luciferase constructs, transfected in Jurkat cell line, showed twofold higher levels of gene expression in the -330 G allele. However, the transcriptional effect of this polymorphism in lymphocytes showed that the G allele was related to lower expression of IL2. This difference increased in the patient group. Divergence between in vivo and in vitro influence of the -330 IL2 promoter polymorphic site suggests the existence of additional unknown polymorphisms affecting gene regulation. Our data show an increased IL2 expression among GT and TT genotypes previously associated with susceptibility to MS.