[Show abstract][Hide abstract] ABSTRACT: Aim:
To evaluate whether circulating microparticles (MPs) derived from three cell subtypes (platelets, total leukocytes or monocytes) obtained from multiple sclerosis (MS) patients were modulated depending on the clinical status and to investigate the effect of treatments on MP levels.
Patients & methods:
The MP counts were assessed with flow cytometry.
The platelet-derived MP level was higher in untreated MS patients than controls. Relapsing-remitting patients showed the highest levels in the three subtypes of MP while secondary progressive patients presented similar levels to those of healthy controls. Treatments had significant effects increasing the three subtypes of MP counts.
We suggest that MPs play a role in MS pathogenesis, reflecting disease status with an increment of their shedding during inflammatory periods and turning to baseline during chronic progressive degeneration.
Biomarkers in Medicine 06/2014; 8(5):653-61. DOI:10.2217/bmm.14.9 · 2.65 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Impairment of nerve conduction is common in neurodegenerative and neuroinflammatory diseases such as multiple sclerosis (MS), and measurement of evoked potentials (visual, motor, or sensory) has been widely used for diagnosis and recently also as a prognostic marker for MS. We used a classical genetic approach to identify novel genes controlling nerve conduction. First, we used quantitative trait mapping in F2 progeny of B10/SJL mice to identify EAE31, a locus controlling latency of motor evoked potentials (MEPs) and clinical onset of experimental autoimmune encephalomyelitis. Then, by combining congenic mapping, in silico haplotype analyses, and comparative genomics we identified inositol polyphosphate-4- phosphatase, type II (Inpp4b) as the quantitative trait gene for EAE31. Sequence variants of Inpp4b (C/A, exon 13; A/C, exon 14) were identified as differing among multiple mouse strains and correlated with individual cortical MEP latency differences. To evaluate the functional relevance of the amino acid ex- changes at positions S474R and H548P, we generated transgenic mice carrying the longer-latency allele (Inpp4b474R/548P) in the C57BL/6J background. Inpp4b474R/548P mice exhibited significantly longer cortical MEP latencies (4.5 ` 0.22 ms versus 3.7 ` 0.13 ms; P Z 1.04 10�9), indicating that INPP4B regulates nerve conduction velocity. An association of an INPP4B polymorphism (rs13102150) with MS was observed in German and Spanish MS cohorts (3676 controls and 911 cases) (P Z 8.8 10�3).
American Journal Of Pathology 05/2014; DOI:10.1016/j.ajpath.2014.05.021 · 4.59 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Recombinant interferon β (IFNβ) is a first-line therapy for relapsing-remitting multiple sclerosis (MS), with a proven effect on the inflammatory activity. Neutralising antibodies against IFNβ (NAbs) promote a loss of IFNβ bioactivity in a titre-dependent way and their development was associated with certain human leucocyte antigen (HLA) alleles. We investigated the contribution conferred by HLA alleles on the development of NAbs in independent cohorts of Southern Europe.
Serum NAbs from 610 MS patients with HLA-genotype data were evaluated by cytopathic effect assay: negative tests included at least one negative result (NAb titres<20 NU/mL) after 1 year treatment; NAb-titres ≥20 NU/mL were positive tests and NAb titres ≥150 NU/mL in any test were classified as high-titre positives.
The combined presence of DRB1*07/DQA1*02 with A*26 or B*14 was found in 20% of patients with NAbs at high titres, but only in 5.4% of NAb-negative patients (p=0.00052, OR (95% CI) 4.34 (1.85 to 10.13)). The DRB1*04:01 allele was also more frequently carried by patients with high titres of NAbs (10% vs 4.5%; p=0.046, OR (95% CI) 2.38 (0.93 to 5.92)). The alleles carried at a significantly lower frequency in patients with high persistent NAbs corresponded to the A*11 allele (3.3% vs 13.8%; p=0.023, OR (95% CI) 0.22 (0.02 to 0.87)), as well as the DRB1*03/DQA1*05/DQB1*02 haplotype (16.3% vs 26.8%; p=0.02, OR (95% CI) 0.53 (0.27 to 1.03)) and the DRB1*13/DQA1*01:03/DQB1*06:03 haplotype (2.5% vs 9.1%; p=0.045, OR (95% CI) 0.25 (0.03 to 1.02)).
50% of the studied MS patients carried some of the five independently associated HLA allele/allele combinations described in this work. This relevant percentage of patients could benefit a therapeutic decision.
Journal of Medical Genetics 04/2014; 51(6). DOI:10.1136/jmedgenet-2014-102348 · 6.34 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The levels of soluble tumor necrosis factor receptor II (sTNF-RII) were determined in serum of 161 untreated multiple sclerosis (MS) patients with different clinical forms and 46 healthy controls (HC) by ELISA. Our results show that serum sTNF-RII levels were significantly increased in patients with primary progressive MS (PPMS) compared with other MS forms and HC. Although sTNF-RII levels significantly increased over a 2-year follow-up period in a subgroup of PPMS patients, they could not discriminate between patients with and without disability progression. Additional studies are needed to further implicate sTNF-RII in patients with PPMS.
Journal of neuroimmunology 04/2014; 271(1-2). DOI:10.1016/j.jneuroim.2014.04.001 · 2.47 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: AIM2-like receptors (ALRs) are a family of nucleic acid sensors essential for innate immune responses against viruses and bacteria. We performed an evolutionary analysis of ALR genes (MNDA, PYHIN1, IFI16, and AIM2) by analyzing inter- and intra-species diversity. Maximum-likelihood analyses indicated that IFI16 and AIM2 evolved adaptively in primates, with branch specific-selection at the catarrhini lineage for IFI16. Application of a population-genetics phylogenetics approach also allowed identification of positive selection events in the human lineage. Positive selection in primates targeted sites located at the DNA binding interface in both IFI16 and AIM2. In IFI16 several sites positively selected in primates and in the human lineage were located in the PYD domain, which is involved in protein-protein interaction and is bound by a human cytomegalovirus immune evasion protein. Finally, positive selection was found to target nuclear localization signals in IFI16 and the spacer region separating the two HIN domains. Population genetic analysis in humans revealed that an IFI16 genic region has been a target of long-standing balancing selection, possibly acting on two nonsynonymous polymorphisms located in the spacer region. Data herein indicate that ALRs have been repeatedly targeted by natural selection. The balancing selection region in IFI16 carries a variant with opposite risk effect for distinct autoimmune diseases, suggesting antagonistic pleiotropy. We propose that the underlying scenario is the result of an ancestral and still ongoing host-pathogen arms race and that the maintenance of susceptibility alleles for autoimmune diseases at IFI16 represents an evolutionary trade-off.
[Show abstract][Hide abstract] ABSTRACT: In patients with relapsing-remitting multiple sclerosis (RRMS), a scoring system based on new magnetic resonance imaging (MRI) active lesions, relapses and sustained disability progression after a 1-year treatment with IFNβ predicted patient disability progression over time; however, this score had not been tested in patients receiving glatiramer acetate (GA).
The objective of this study was to evaluate whether this previous scoring system can also be applied to patients treated with GA.
This was a prospective, longitudinal study of 151 RRMS patients treated with GA. Their scores were constructed, based on the clinical and MRI activity after 1 year of therapy. Regression analysis was performed, in order to identify the response variables.
The total possible score range was 0-3. Patients with a score of ≥ 2 and those with clinical activity (with or without MRI activity) during their first year of treatment were at increased risk of continuing with relapses and/or sustained disability in the next 2 years (odds ratio (OR): 38.8; p < 0.0001 and OR: 7.8; p < 0.009, respectively).
In RRMS patients treated with GA, a combination of clinical activity measures may have prognostic value for identifying patients with disease activity in the next 2 years of therapy.
[Show abstract][Hide abstract] ABSTRACT: The defective generation or function of regulatory T (Treg) cells in autoimmune disease contributes to chronic inflammation and tissue injury. We report the identification of FoxA1 as a transcription factor in T cells that, after ectopic expression, confers suppressive properties in a newly identified Treg cell population, herein called FoxA1(+) Treg cells. FoxA1 bound to the Pdl1 promoter, inducing programmed cell death ligand 1 (Pd-l1) expression, which was essential for the FoxA1(+) Treg cells to kill activated T cells. FoxA1(+) Treg cells develop primarily in the central nervous system in response to autoimmune inflammation, have a distinct transcriptional profile and are CD4(+)FoxA1(+)CD47(+)CD69(+)PD-L1(hi)FoxP3(-). Adoptive transfer of stable FoxA1(+) Treg cells inhibited experimental autoimmune encephalomyelitis in a FoxA1-and Pd-l1-dependent manner. The development of FoxA1(+) Treg cells is induced by interferon-β (IFN-β) and requires T cell-intrinsic IFN-α/β receptor (Ifnar) signaling, as the frequency of FoxA1(+) Treg cells was reduced in Ifnb(-/-) and Ifnar(-/-) mice. In individuals with relapsing-remitting multiple sclerosis, clinical response to treatment with IFN-β was associated with an increased frequency of suppressive FoxA1(+) Treg cells in the blood. These findings suggest that FoxA1 is a lineage-specification factor that is induced by IFN-β and supports the differentiation and suppressive function of FoxA1(+) Treg cells.
Nature medicine 02/2014; DOI:10.1038/nm.3485 · 27.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Biomarkers can be thought of as multifaceted indicators of healthy status or of pathological disorders. The study of multiple sclerosis can benefit from the use of biomarkers because of the disease's inherent heterogeneity. Biomarkers in multiple sclerosis might assist with diagnosis, prediction of disease course, or identification of response outcome to treatments. Despite the need for biomarkers and extensive research to identify them, validation and clinical application of biomarkers is still an unmet need in multiple sclerosis, and large gaps remain between exploratory biomarkers proposed in many studies, validated biomarkers, and biomarkers that are integrated into routine clinical practice.
The Lancet Neurology 01/2014; 13(1):113-126. DOI:10.1016/S1474-4422(13)70233-3 · 21.90 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Genome-wide association studies (GWASs) perform per-SNP association tests to identify variants involved in disease or trait susceptibility. However, such an approach is not powerful enough to unravel genes that are not individually contributing to the disease/trait, but that may have a role in interaction with other genes as a group. Pathway analysis is an alternative way to highlight such group of genes. Using SNP association P-values from eight multiple sclerosis (MS) GWAS data sets, we performed a candidate pathway analysis for MS susceptibility by considering genes interacting in the cell adhesion molecule (CAMs) biological pathway using Cytoscape software. This network is a strong candidate, as it is involved in the crossing of the blood-brain barrier by the T cells, an early event in MS pathophysiology, and is used as an efficient therapeutic target. We drew up a list of 76 genes belonging to the CAM network. We highlighted 64 networks enriched with CAM genes with low P-values. Filtering by a percentage of CAM genes up to 50% and rejecting enriched signals mainly driven by transcription factors, we highlighted five networks associated with MS susceptibility. One of them, constituted of ITGAL, ICAM1 and ICAM3 genes, could be of interest to develop novel therapeutic targets.Genes and Immunity advance online publication, 16 January 2014; doi:10.1038/gene.2013.70.
Genes and immunity 01/2014; 15(2). DOI:10.1038/gene.2013.70 · 2.91 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Abstract Inducible heat shock protein (HSP)70 (HSP70-1A and HSP70-1B proteins) is a chaperone responsible for assisting proper protein folding. Following stress conditions, HSP70 is highly up-regulated to mediate cytoprotective functions. In addition, HSP70 is able to trigger innate and adaptive immune responses that promote the immune recognition of antigens and to act as a cytokine when it is released. The data in the literature are controversial with regard to expression studies in peripheral blood mononuclear cells (PBMCs). In the present study, we aimed to examine if alterations of HSP70-1A/B expression are involved in the autoimmune pathogenesis of multiple sclerosis (MS). We determined both mRNA and protein expression in PBMCs of MS patients and healthy donors (HDs). We found a baseline increased expression of the HSPA1A gene in PBMCs from MS patients compared with HDs. Gene expression findings were associated with an increased protein expression of HSP70-1A/B in T lymphocytes (CD4+ and CD8+) and monocytes from MS patients under basal conditions that may reflect the immunological activation occurring in MS patients. We also provided evidence that heat shock (HS) stimulus induced HSP70-1A/B protein expression in HDs and MS patients, and that HS-induced HSP70-1A/B protein expression in monocytes correlated with the number of T2 lesions at baseline in MS patients. However, after lipopolysaccharide inflammatory stimulus, monocytes from MS patients failed to induce HSP70-1A/B protein expression. Our data hint at altered immune responses in MS and may indicate either a state of chronic stress or increased vulnerability to physiological immune responses in MS patients.
[Show abstract][Hide abstract] ABSTRACT: We aimed to investigate the ability of natalizumab (NTZ)-treated patients to assume treatment-associated risks and the factors involved in such risk acceptance.
From a total of 185 patients, 114 patients on NTZ as of July 2011 carried out a comprehensive survey. We obtained disease severity perception scores, personality traits' scores, and risk-acceptance scores (RAS) so that higher RAS indicated higher risk acceptance. We recorded JC virus status (JCV+/-), prior immunosuppression, NTZ treatment duration, and clinical characteristics. NTZ patients were split into subgroups (A-E), depending on their individual PML risk. Some 22 MS patients on first-line drugs (DMD) acted as controls.
No differences between treatment groups were observed in disease severity perception and personality traits. RAS were higher in NTZ than in DMD patients (p<0.01). Perception of the own disease as a more severe condition tended to predict higher RAS (p=0.07). Higher neuroticism scores predicted higher RAS in the NTZ group as a whole (p=0.04), and in high PML-risk subgroups (A-B) (p=0.02). In low PML-risk subgroups (C-E), higher RAS were associated with a JCV+ status (p=0.01). Neither disability scores nor pre-treatment relapse rate predicted RAS in either group.
Risk acceptance is a multifactorial phenomenon, which might be partly explained by an adaptive process, in light of the higher risk acceptance amongst NTZ-treated patients and, especially, amongst those who are JCV seropositive but still have low PML risk, but which seems also intimately related to personality traits.
PLoS ONE 12/2013; 8(12):e82796. DOI:10.1371/journal.pone.0082796 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The most significant data presented at the 28th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), held in France in October 2012, have been summarised in the fifth edition of the Post-ECTRIMS Experts Meeting, held in Madrid in October 2012. This led to the drafting of this review, which has been published in three parts. This third part of the Post-ECTRIMS review presents the findings from the latest studies conducted with disease-modifying treatments, more specifically with glatiramer acetate, laquinimod, ponesimod, BG-12, teriflunomide, daclizumab, natalizumab and secukinumab (AIN457). Likewise, we also address the reasons that justify the search for innovative treatments for multiple sclerosis, with antigen-specific therapy, cell therapy and therapy aimed at promoting remyelination being highlighted among other future therapeutic strategies. Access to new pharmacological agents and the complexity of the therapy of multiple sclerosis in the future will require new design strategies and directions in clinical trials, including the use of surrogate markers, new statistical applications, superiority, inferiority or equivalence clinical trials and adaptable designs.
Revista de neurologia 10/2013; 57(7):317-329. · 0.83 Impact Factor