163 research outputs found

    HERVs in Multiple Sclerosis — From Insertion to Therapy

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    Genome-wide association studies (GWAS) have not been able to completely elucidate the genetic background of complex diseases. Part of it could lie in repetitive sequences not studied in the GWAS, as those corresponding to Human Endogenous Retroviruses (HERVs). In the present work, we aim to review the potential role of HERVs in the etiology of autoimmune diseases, especially in multiple sclerosis (MS); their potential pathogenic role and their putative consideration as a good target for new treatments. For this purpose, we carried out an in-depth literature review on HERVs, and we integrated our previous findings about HERV-W, HERV-K18, and HERV-Fc1 and MS susceptibility. The study was carried out by a systematic search from electronic databases using the keywords “HERV,” “Multiple sclerosis,” “HERV-W,” “MSRV,” “HERV-K,” “HERV-Fc1,” and “GNbAC1.

    Interleukin-10 haplotypes in Celiac Disease in the Spanish population

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    BACKGROUND: Celiac disease (CD) is a chronic disorder characterized by a pathological inflammatory response after exposure to gluten in genetically susceptible individuals. The HLA complex accounts for less than half of the genetic component of the disease, and additional genes must be implicated. Interleukin-10 (IL-10) is an important regulator of mucosal immunity, and several reports have described alterations of IL-10 levels in celiac patients. The IL-10 gene is located on chromosome 1, and its promoter carries several single nucleotide polymorphisms (SNPs) and microsatellites which have been associated to production levels. Our aim was to study the role of those polymorphisms in susceptibility to CD in our population. METHODS: A case-control and a familial study were performed. Positions -1082, -819 and -592 of the IL-10 promoter were typed by TaqMan and allele specific PCR. IL10R and IL10G microsatellites were amplified with labelled primers, and they were subsequently run on an automatic sequencer. In this study 446 patients and 573 controls were included, all of them white Spaniards. Extended haplotypes encompassing microsatellites and SNPs were obtained in families and estimated in controls by the Expectation-Maximization algorithm. RESULTS: No significant associations after Bonferroni correction were observed in the SNPs or any of the microsatellites. Stratification by HLA-DQ2 (DQA1*0501-DQB1*02) status did not alter the results. When extended haplotypes were analyzed, no differences were apparent either. CONCLUSION: The IL-10 polymorphisms studied are not associated with celiac disease. Our data suggest that the IL-10 alteration seen in patients may be more consequence than cause of the disease

    Genetic variation in NDFIP1 modifies the metabolic patterns in immune cells of multiple sclerosis patients

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    Autoinmunidad; Marcadores genĂ©ticos; Trastornos neurolĂłgicosAutoimmunitat; Marcadors genĂštics; Trastorns neurolĂČgicsAutoimmunity; Genetic markers; Neurological disordersOne of the 233 polymorphisms associated with multiple sclerosis (MS) susceptibility lies within the NDFIP1 gene, and it was previously identified as eQTL in healthy controls. NDFIP1 shows interesting immune functions and is involved in the development of the central nervous system. We aimed at studying the NDFIP1 variant on activation and metabolism of immune cells. NDFIP1 mRNA and protein expression were assessed in PBMCs by qPCR and western blot in 87 MS patients and 84 healthy controls genotyped for rs4912622. Immune activation after PHA stimulation was evaluated by CD69 upregulation, and metabolic function of both basal and PHA-activated lymphocytes was studied by Seahorse Xfp-Analyzer. In minor-allele homozygous controls but not in patients, we found higher NDFIP1 expression, significantly reduced protein levels, and CD69 upregulation in B- and T-cells. PBMCs from minor-allele homozygous controls showed significantly higher basal mitochondrial respiration and ATP production compared to major-allele carriers, while minor-allele homozygous patients showed significantly lower metabolic activity than carriers of the major allele. In conclusion, we describe associations in minor-allele homozygous controls with lower levels of NDFIP1 protein, CD69 upregulation, and raised mitochondrial activity, which are not replicated in MS patients, suggesting a NDFIP1 differential effect in health and disease.This work was supported by the projects PI16/01259 and PI20/01634, integrated in the Plan Nacional de I + D + I, AES 2013–2016 and 2017–2020; funded by the ISCIII and co-funded by the European Regional Development Fund (ERDF) "A way to make Europe”. LEP is recipient of a contract from “REEM: Red Española de Esclerosis MĂșltiple” (RETICS-REEM RD16/0015/0013; www.reem.es). AGJ and JAZ hold contracts from the program “PromociĂłn de empleo joven y garantĂ­a juvenil-CAM” (PEJ2018-003125-A and PEJD-2019-PRE/SAL-16662)

    Tear cytokine profile of glaucoma patients treated with preservative-free or preserved latanoprost

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    Purpose: To determine variations in cytokine levels of glaucoma patients treated either with preservative-free latanoprost or preserved latanoprost, relative to healthy individuals. Methods: Tear samples were collected from 39 healthy subjects, 20 glaucoma patients treated with preserved latanoprost, and 20 patients treated with preservative-free latanoprost. A set of 27 inflammatory cytokines was analyzed in each group, including interleukin (IL)-1ÎČ, IL-1ra, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL9, IL-10, IL-12 (p70), IL-13, IL-15, IL-17, eotaxin, fibroblast growth factor (FGF) basic, granulocyte colony stimulating factor (G-CSF), granulocyte monocyte colony stimulating factor (GM-CSF), interferon (IFN)-Îł, interferon gamma-induced protein (IP)-10, monocyte chemo attractant protein (MCP)-1MCAF, macrophage inflammatory protein (MIP)-1α, MIP-1ÎČ, platelet-derived growth factor (PDGF)-BB, regulated on activation, normal T cell expressed and secreted (RANTES), tumor necrosis factor (TNF)-α and vascular endothelial growth factor (VEGF). Cytokine concentrations were obtained by the Bio-Plex Human Cytokine Immunoassay. Non-invasive tear breakup time (NI-TBUT), tear meniscus height, corneal fluorescein staining, conjunctival hyperemia and ocular surface disease index (OSDI) were assessed in patients treated with preservative-free and preserved latanoprost. Results: The levels of IL-2, IL-5, IL-10, IL-12 (p70), IL-13, IL-15, IL-17, FGF basic, PDGF-BB, and TNF-α were significantly higher in patients receiving preserved latanoprost, compared to normal controls (p 0.05). Ocular surface parameters were not significantly different in both glaucoma groups, and no correlation between these clinical parameters and cytokine levels was observed. Conclusions: Treatment with preserved latanoprost has a direct impact on tear cytokine levels, whereas this effect is not observed upon preservative-free latanoprost instillation

    Changes in retinal OCT and their correlations with neurological disability in early ALS patients, a follow-up study

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    Background: To compare early visual changes in amyotrophic lateral sclerosis (ALS) patients with healthy controls in a baseline exploration, to follow-up the patients after 6 months, and to correlate these visual changes with neurological disability. Methods: All patients underwent a comprehensive neurological and ophthalmological examination. A linear mixed analysis and Bonferroni p-value correction were performed, testing four comparisons as follows: Control baseline vs. control follow-up, control baseline vs. ALS baseline, control follow-up vs. ALS follow-up, and ALS baseline vs. ALS follow-up. Results: The mean time from the diagnosis was 10.80 +/- 5.5 months. The analysis of the optical coherence tomography (OCT) showed: (1) In ALS baseline vs. control baseline, a macular significantly increased thickness of the inner macular ring temporal and inferior areas; (2) in ALS follow-up vs. ALS baseline, a significant macular thinning in the inner and outer macular ring inferior areas; (3) in ALS follow-up vs. ALS baseline, a significant peripapillary retinal nerve fiber layer (pRNFL) thinning in the superior and inferior quadrants; and (4) ALS patients showed a moderate correlation between some OCT pRNFL parameters and Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) score. Conclusion: The OCT showed retinal changes in patients with motoneuron disease and could serve as a complementary tool for studying ALS

    Polymorphisms in the selenoprotein S gene: lack of association with autoimmune inflammatory diseases

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    <p>Abstract</p> <p>Background</p> <p>Selenoprotein S (SelS) protects the functional integrity of the endoplasmic reticulum against the deleterious effects of metabolic stress. <it>SEPS1/SelS </it>polymorphisms have been involved in the increased release of pro-inflammatory cytokines interleukin (IL)-1ÎČ, tumor necrosis factor (TNF)-α and IL-6 in macrophages. We aimed at investigating the role of the <it>SEPS1 </it>variants previously associated with higher plasma levels of these cytokines and of the <it>SEPS1 </it>haplotypes in the susceptibility to develop immune-mediated diseases characterized by an inflammatory component.</p> <p>Results</p> <p>Six polymorphisms distributed through the <it>SEPS1 </it>gene (rs11327127, rs28665122, rs4965814, rs12917258, rs4965373 and rs2101171) were genotyped in more than two thousand patients suffering from type 1 diabetes, rheumatoid arthritis or inflammatory bowel diseases and 550 healthy controls included in the case-control study.</p> <p>Conclusion</p> <p>Lack of association of <it>SEPS1 </it>polymorphisms or haplotypes precludes a major role of this gene increasing predisposition to these inflammatory diseases.</p

    Ocular Involvement in Friedreich Ataxia Patients and its Relationship with Neurological Disability, a Follow-up Study

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    Background: This study compared functional and structural visual changes in Friedreich ataxia (FRDA) patients with healthy controls (HC) and correlated these changes with neurological disability. Methods: Eight FRDA Spanish patients and eight HC were selected from 2014 to 2018. Best corrected visual acuity (BCVA), visual field (VF), optic coherence tomography (OCT), and neurological disability measured by “scale for the assessment and rating of ataxia” (SARA) were taken in a basal exploration and repeated after 6 months. A linear mixed analysis and Bonferroni p-value correction were performed. Results: FRDA baseline and follow-up patients showed statistically significant decreases in BCVA, VF, and OCT parameters compared with the HC. Some of the VF measurements and most of the OCT parameters had an inverse mild-to-strong correlation with SARA. Moreover, the analysis of the ROC curve demonstrated that the peripapillary retinal nerve fiber layer (pRNFL) average thickness was the best parameter to discriminate between FRDA patients and HC. Conclusions: The follow-up study showed a progression in OCT parameters. Findings showed a sequential effect in pRNFL, ganglion cell complex (GCC), and macula. The VF and the OCT could be useful biomarkers in FRDA, both for their correlation with neurological disease as well as for their ability to evaluate disease progression

    Influence of the LILRA3 Deletion on Multiple Sclerosis Risk : Original Data and Meta-Analysis

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    Altres ajuts: Junta de AndalucĂ­a (JA)- Fondos Europeos de Desarrollo Regional (FEDER) (grant number CTS2704 to FM).Multiple sclerosis (MS) is a neurodegenerative, autoimmune disease of the central nervous system. Genome-wide association studies (GWAS) have identified over hundred polymorphisms with modest individual effects in MS susceptibility and they have confirmed the main individual effect of the Major Histocompatibility Complex. Additional risk loci with immunologically relevant genes were found significantly overrepresented. Nonetheless, it is accepted that most of the genetic architecture underlying susceptibility to the disease remains to be defined. Candidate association studies of the leukocyte immunoglobulin-like receptor LILRA3 gene in MS have been repeatedly reported with inconsistent results. In an attempt to shed some light on these controversial findings, a combined analysis was performed including the previously published datasets and three newly genotyped cohorts. Both wild-type and deleted LILRA3 alleles were discriminated in a single-tube PCR amplification and the resulting products were visualized by their different electrophoretic mobilities. Overall, this meta-analysis involved 3200 MS patients and 3069 matched healthy controls and it did not evidence significant association of the LILRA3 deletion [carriers of LILRA3 deletion: p = 0.25, OR (95% CI) = 1.07 (0.95-1.19)], even after stratification by gender and the HLA-DRB1*15 : 01 risk allele

    Susceptibility to type 1 diabetes conferred by the PTPN22 C1858T polymorphism in the Spanish population

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    <p>Abstract</p> <p>Background</p> <p>The protein tyrosine phosphatase N22 gene (<it>PTPN22</it>) encodes a lymphoid-specific phosphatase (LYP) which is an important downregulator of T cell activation. A <it>PTPN22 </it>polymorphism, C1858T, was found associated with type 1 diabetes (T1D) in different Caucasian populations. In this study, we aimed at confirming the role of this variant in T1D predisposition in the Spanish population.</p> <p>Methods</p> <p>A case-control was performed with 316 Spanish white T1D patients consecutively recruited and 554 healthy controls, all of them from the Madrid area. The <it>PTPN22 </it>C1858T SNP was genotyped in both patients and controls using a TaqMan Assay in a 7900 HT Fast Real-Time PCR System.</p> <p>Results</p> <p>We replicated for the first time in a Spanish population the association of the 1858T allele with an increased risk for developing T1D [carriers of allele T vs. CC: OR (95%) = 1.73 (1.17–2.54); p = 0.004]. Furthermore, this allele showed a significant association in female patients with diabetes onset before age 16 years [carriers of allele T vs. CC: OR (95%) = 2.95 (1.45–6.01), female patients vs female controls p = 0.0009]. No other association in specific subgroups stratified for gender, HLA susceptibility or age at onset were observed.</p> <p>Conclusion</p> <p>Our results provide evidence that the <it>PTPN22 </it>1858T allele is a T1D susceptibility factor also in the Spanish population and it might play a different role in susceptibility to T1D according to gender in early-onset T1D patients.</p