Serum Levels of miR-146a in Patients with Psoriasis.

BACKGROUND: Psoriasis is an immune-mediated disease with interactions between genetic and environmental factors. An increasing number of studies are demonstrating the importance of microRNAs (miRNAs) in the pathogenesis of psoriasis. miR-146a, a dominant negative regulator of inflammation, has been consistently reported as overexpressed in the skin and peripheral blood mononuclear cells (PBMCs) of patients with psoriasis. Expression and/or function of this miRNA is highly influenced by genetic variations, some of which have already been associated with susceptibility to psoriasis. OBJECTIVE: We sought to study the importance of miR-146a in patients with moderate-to-severe psoriasis and to understand the impact of rs57095329 and rs2910164 polymorphisms in a psoriatic Portuguese population. METHODS: miR-146a circulating levels were quantified using molecular biology techniques in 99 patients with moderate-to-severe psoriasis (35 female, 64 male; age 47.4 ± 10.9 years) and 78 healthy individuals (52 female, 26 male; age 42.4 ± 10.1 years). miRNA expression was correlated with clinicopathological features as well as with genetic data such as the presence of human leukocyte antigen (HLA)-C*0602 allele and two miR-146a polymorphisms (rs2910164 and rs57095329). RESULTS: miR-146a serum levels were 3.7-fold higher in patients with psoriasis than in controls (p < 0.0001, area under the curve [AUC] 0.75; 95% confidence interval [CI] 0.66-0.83). Of note, miR-146a circulating levels positively correlated with Psoriasis Area and Severity Index (p < 0.05) and body surface area (p < 0.05) indexes. No variations in miR-146a levels were observed with rs2910164 and rs57095329 genotypes. CONCLUSION: Circulating miR-146a levels were upregulated in patients with psoriasis, especially in those with active disease. To the best of our knowledge, this is the largest study with a homogenous psoriasis population, and our data could shed light on the pathogenesis of psoriasis, paving the way for new avenues for disease treatment.

Apolipoprotein E isoforms and susceptibility to genetic generalized epilepsies.

Background: Apolipoprotein E (ApoE) is the main lipoprotein secreted in brain. It has a critical immunomodulatory function, influences neurotransmission and it is involved in repairing damaged neurons. ApoE e4 is an isoform of ApoE with altered function, and was previously associated with early onset epilepsy and refractoriness, both in animal models and in patients with focal epilepsies. There is a limited knowledge on ApoE's role in Genetic Generalized Epilepsies (GGE).Aim: To determine if ApoE isoforms are risk factors for GGE development.Methods: A group of 337 GGE patients (193 F, 144 M, 33.6 ± 14.2 years) was compared with a group of 342 healthy individuals in a case-control genetic association study. ApoE genotyping was performed using PCR-RFLP.Results: The genotypic frequency of ApoE e3/e2 was lower in GGE patients relative to controls (6.5% in GGE vs. 11.7% in controls, p = 0.019, OR (95% CI) = 0.53 (0.305-0.905). No associations with other clinical data such as photosensitivity or age at disease onset were observed.Conclusion: Our results show that ApoE e3/e2 genotype may be a protective factor for GGE development. There is evidence that this genotype could be neuroprotective, preventing oxidative damage and promoting neuronal survival. Although replication studies are warranted, our data suggest that ApoE isoforms have a role in epileptogenic mechanisms regardless of the specific epileptic manifestations.

Brain expression of inflammatory mediators in Mesial Temporal Lobe Epilepsy patients.

Neuroinflammation may be central in epileptogenesis. In this study we analysed inflammatory reaction markers in brain tissue of Mesial Temporal Lobe Epilepsy with Hippocampal Sclerosis (MTLE-HS) patients. TLR4, IL-1ß and IL-10 gene expression as well as the presence of activated HLA-DR+ microglia was evaluated in 23 patients and 10 cadaveric controls. Inflammation characterized by the presence of HLA-DR+ microglia and TLR4, IL-1ß overexpression was evident in hippocampus and anterior temporal cortex of MTLE-HS patients. Anti-inflammatory IL-10 was also overexpressed in MTLE-HS patients. Our results show that hippocampal neuroinflammation extends beyond lesional limits, as far as the anterior temporal cortex.

Vitamin D supplementation effects on FoxP3 expression in T cells and FoxP3+/IL-17A ratio and clinical course in systemic lupus erythematosus patients: a study in a Portuguese cohort.

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with multi-organ inflammation, linked to loss of immune tolerance to self-antigens and the production of a diversity of autoantibodies, with a negative impact on the patients' quality of life. Regulatory T cells have been reported as deficient in number and function in SLE patients. However, some authors also described an enrichment of this cell type. The hypothesis that certain forms of autoimmunity may result from a conversion of Treg cells into a Th17 cell phenotype has been suggested by some studies. In fact, in SLE patients' sera, the IL-17 levels were observed as abnormally high when compared with healthy individuals. Environmental factors, such as vitamin D, that is considered a potential anti-inflammatory agent, combined with genetic and hormonal characteristics have been associated with SLE phenotype and with disease progression. The aim of this study was to evaluate the effect of vitamin D supplementation on FoxP3 expression and IL-17A-producing T cells, through FoxP3+/IL-17A ratio. Additionally, disease evolution, serum vitamin D levels, serum autoantibodies levels and calcium metabolism (to assure safety) were also studied. We assessed 24 phenotypically well-characterized SLE patients. All patients were screened before vitamin D supplementation and 3 and 6 months after the beginning of this treatment. Peripheral blood lymphocyte's subsets were analysed by flow cytometry. Serum 25(OH)D levels significantly increased under vitamin D supplementation (p = 0.001). The FoxP3+/IL-17A ratio in SLE patients after 6 months of vitamin D supplementation was higher than that in the baseline (p < 0.001). In conclusion, this study demonstrated that vitamin D supplementation provided favourable, immunological and clinical impact on SLE.

Age of onset of mesial temporal lobe epilepsy with hippocampal sclerosis: the effect of apolipoprotein E and febrile seizures.

PURPOSE: Mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) is the most frequent pharmaco-resistant epilepsy. It has been associated with febrile seizures (FS) in childhood. Its aetiology remains unclear but genetic factors are involved. Apolipoprotein E (ApoE) is the main lipoprotein secreted in brain. It has a critical immunomodulatory function, influences neurotransmission and it is involved in repairing damaged neurons. ApoE ϵ4 is an isoform of ApoE with altered protein function, previously associated with refractoriness and early onset epilepsy. This study was undertaken to determine if ApoE isoforms are risk factors for MTLE-HS and influence clinical characteristics. METHODS: A group of 188 MTLE-HS patients (101 F, 87 M, mean age = 44.7 ± 11.6 years, 100 with FS antecedents) was studied and compared with a group of 342 healthy individuals in a case-control genetic association study. Data were analysed with Pearson Chi-squared Test or Student's t test, as appropriated. RESULTS: No differences in ApoE ϵ4 allelic frequencies between MTLE-HS patients and controls or between MTLE-HS subgroups were observed. Nevertheless, ApoE ϵ4 carriers had an earlier MTLE-HS onset (11.0 ± 7.9 years in ApoE ϵ4 carriers vs. 14.4 ± 11.2 years in ApoE ϵ4 non-carriers p < 0.05). Additionally, we observed that MTLE-HS patients with FS antecedents had a statistically significant early disease onset (11.5 ± 8.7 years in FS+ vs. 16.0 ± 12.1 years in FS-, p < 0.01). CONCLUSIONS: Our data show that ApoE ϵ4 and FS may not participate directly in etiopathogenic mechanisms of MTLE-HS but could hasten the disease development in predisposed individuals.

CC chemokine receptor polymorphism CCR5Δ32 in Portuguese Behçet's disease patients.

OBJECTIVES: To investigate whether CCR5 deletion is associated with susceptibility to Behçet's disease (BD) in a Portuguese population. METHODS: A total of 122 BD patients and 227 ethnically-matched controls were studied. Genotyping of the CCR5Δ32 polymorphisms was performed using polymerase chain reaction product sizing. RESULTS: No significant differences were observed in the allelic frequencies of CCR532 between patients and controls (OR=0.820; p=0.512). Stratification for gender and for the presence of HLA-B*51 did not reveal any significant differences. CONCLUSIONS: These results indicate that CCR5Δ32 is unlikely to contribute to susceptibility to BD in Portuguese patients. This may be explained by the known functional redundancy of this signalling system.

The role of KIR2DS1 in multiple sclerosis--KIR in Portuguese MS patients.

Killer Immunoglobulin-like Receptor (KIR) genes may influence both resistance and susceptibility to different autoimmune diseases, but their role in the pathogenesis of Multiple Sclerosis (MS) is still unclear. We investigated the influence of KIR genes on MS susceptibility in 447 MS Portuguese patients, and also whether genetic interactions between specific KIR genes and their HLA class I ligands could contribute to the pathogenesis of MS. We observed a negative association between the activating KIR2DS1 gene and MS (adjusted OR=0.450, p=0.030) independently from the presence of HLA-DRB1*15 allele. The activating KIR2DS1 receptor seems to confer protection against MS most probably through modulation of autoreactive T cells by Natural Killer cells.

Effects of highly conserved major histocompatibility complex (MHC) extended haplotypes on iron and low CD8+ T lymphocyte phenotypes in HFE C282Y homozygous hemochromatosis patients from three geographically distant areas.

Hereditary Hemochromatosis (HH) is a recessively inherited disorder of iron overload occurring commonly in subjects homozygous for the C282Y mutation in HFE gene localized on chromosome 6p21.3 in linkage disequilibrium with the human leukocyte antigen (HLA)-A locus. Although its genetic homogeneity, the phenotypic expression is variable suggesting the presence of modifying factors. One such genetic factor, a SNP microhaplotype named A-A-T, was recently found to be associated with a more severe phenotype and also with low CD8(+)T-lymphocyte numbers. The present study aimed to test whether the predictive value of the A-A-T microhaplotype remained in other population settings. In this study of 304 HH patients from 3 geographically distant populations (Porto, Portugal 65; Alabama, USA 57; Nord-Trøndelag, Norway 182), the extended haplotypes involving A-A-T were studied in 608 chromosomes and the CD8(+) T-lymphocyte numbers were determined in all subjects. Patients from Porto had a more severe phenotype than those from other settings. Patients with A-A-T seemed on average to have greater iron stores (p = 0.021), but significant differences were not confirmed in the 3 separate populations. Low CD8(+) T-lymphocytes were associated with HLA-A*03-A-A-T in Porto and Alabama patients but not in the greater series from Nord-Trøndelag. Although A-A-T may signal a more severe iron phenotype, this study was unable to prove such an association in all population settings, precluding its use as a universal predictive marker of iron overload in HH. Interestingly, the association between A-A-T and CD8(+) T-lymphocytes, which was confirmed in Porto and Alabama patients, was not observed in Nord-Trøndelag patients, showing that common HLA haplotypes like A*01-B*08 or A*03-B*07 segregating with HFE/C282Y in the three populations may carry different messages. These findings further strengthen the relevance of HH as a good disease model to search for novel candidate loci associated with the genetic transmission of CD8(+) T-lymphocyte numbers.

Epilepsy, hippocampal sclerosis and febrile seizures linked by common genetic variation around SCN1A.

Epilepsy comprises several syndromes, amongst the most common being mesial temporal lobe epilepsy with hippocampal sclerosis. Seizures in mesial temporal lobe epilepsy with hippocampal sclerosis are typically drug-resistant, and mesial temporal lobe epilepsy with hippocampal sclerosis is frequently associated with important co-morbidities, mandating the search for better understanding and treatment. The cause of mesial temporal lobe epilepsy with hippocampal sclerosis is unknown, but there is an association with childhood febrile seizures. Several rarer epilepsies featuring febrile seizures are caused by mutations in SCN1A, which encodes a brain-expressed sodium channel subunit targeted by many anti-epileptic drugs. We undertook a genome-wide association study in 1018 people with mesial temporal lobe epilepsy with hippocampal sclerosis and 7552 control subjects, with validation in an independent sample set comprising 959 people with mesial temporal lobe epilepsy with hippocampal sclerosis and 3591 control subjects. To dissect out variants related to a history of febrile seizures, we tested cases with mesial temporal lobe epilepsy with hippocampal sclerosis with (overall n = 757) and without (overall n = 803) a history of febrile seizures. Meta-analysis revealed a genome-wide significant association for mesial temporal lobe epilepsy with hippocampal sclerosis with febrile seizures at the sodium channel gene cluster on chromosome 2q24.3 [rs7587026, within an intron of the SCN1A gene, P = 3.36 × 10(-9), odds ratio (A) = 1.42, 95% confidence interval: 1.26-1.59]. In a cohort of 172 individuals with febrile seizures, who did not develop epilepsy during prospective follow-up to age 13 years, and 6456 controls, no association was found for rs7587026 and febrile seizures. These findings suggest SCN1A involvement in a common epilepsy syndrome, give new direction to biological understanding of mesial temporal lobe epilepsy with hippocampal sclerosis with febrile seizures, and open avenues for investigation of prognostic factors and possible prevention of epilepsy in some children with febrile seizures.