ARITANIA SOUSA SANTOS
Projetos de Pesquisa
Unidades Organizacionais
Instituto Central, Hospital das Clínicas, Faculdade de Medicina
LIM/18 - Laboratório de Carboidratos e Radioimunoensaios, Hospital das Clínicas, Faculdade de Medicina
LIM/18 - Laboratório de Carboidratos e Radioimunoensaios, Hospital das Clínicas, Faculdade de Medicina
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- The PTPN22 1858T allele but not variants in the proximal promoter region of IL-21 gene is associated with the susceptibility to type 1 diabetes and the presence of autoantibodies in a Brazilian cohort(2013) MAINARDI-NOVO, D. T. O.; SANTOS, A. S.; FUKUI, R. T.; GAMBERINI, M.; CORREIA, M. R. S.; RUIZ, M. O.; MANGUEIRA, C. L. P.; MATIOLI, S. R.; VASCONCELOS, D. M.; SILVA, M. E. R.Interleukin (IL)-21 and protein tyrosine phosphatase non-receptor 22 (PTPN22) regulate lymphocyte function and have been implicated in the pathogenesis of autoimmune diabetes. We sequenced the proximal promoter of the IL-21 gene for the first time and analysed the PTPN22 1858T polymorphism in type 1A diabetes (T1AD) patients and healthy controls (HC). We correlated the frequencies of islet and extra-pancreatic autoantibodies with genotypes from both loci. The case series comprised 612 T1AD patients and 792 HC. Genotyping of PTPN22 C1858T was performed on 434 T1AD patients and 689 HC. The 448 to +83 base pairs (bp) region of the IL-21 gene was sequenced in 309 Brazilian T1AD and 189 HC subjects. We also evaluated human leucocyte antigen (HLA) DR3/DR4 alleles. The frequencies of glutamic acid decarboxylase (GAD65), tyrosine phosphatase-like protein (IA)-2, anti-nuclear antibody (ANA), thyroid peroxidase (TPO), thyroglobulin (TG), thyrotrophin receptor autoantibody (TRAb), anti-smooth muscle (ASM) and 21-hydroxylase (21-OH) autoantibodies were higher in T1AD patients than in HC. The PTPN22 1858T allele was associated with an increased risk for developing T1AD [odds ratio (OR)=1 center dot 94; P<0 center dot 001], particularly in patients of European ancestry, and with a higher frequency of GAD65 and TG autoantibodies. HLA-DR3/DR4 alleles predominated in T1AD patients. A heterozygous allelic IL-21 gene variant (g.-241 T>A) was found in only one patient. In conclusion, only PTPN22 C1858T polymorphism and HLA-DR3 and/or DR4 alleles, but not allelic variants in the 5-proximal region of the IL-21 gene were associated with T1AD risk. Patients with T1AD had increased frequencies of anti-islet-cell, anti-thyroid, anti-nuclear, anti-smooth muscle and anti-21-OH autoantibodies. The C1858T PTPN22 polymorphism was also associated with a higher frequency of GAD65 and TG autoantibodies.
- Th17 pathway in recent-onset autoimmune diabetes(2018) FORES, Jessica Pereira; CRISOSTOMO, Lindiane Gomes; ORII, Noemia Mie; SANTOS, Aritania Sousa; FUKUI, Rosa Tsuneshiro; MATIOLI, Sergio R.; VASCONCELOS, Dewton de Moraes; SILVA, Maria Elizabeth Rossi daAims: Evaluate the participation of IL-17 pathway in T1D pathogenesis. T helper 17 cells are potent, highly inflammatory cells that produce interleukin 17A (IL-17A), considered a mediator of various immune disorders. However, their role in Type 1 diabetes (T1D) pathogenesis in humans is not totally elucidated. Methods: The expression of IL-17 Receptor A (IL-17RA) in peripheral T lymphocytes and IL-17A serum levels in recent-onset patients with T1D were compared with healthy controls. IL-17A gene variants were evaluated in a greater cohort. Results: Patients with recent-onset T1D (less than 6 months of diagnosis) exhibited lower expression of IL-17RA in CD3 + T (% of cells = 31.3% x 43.6%; p =.041) and CD4+ T cells (11.1% x 25.2%; p =.0019) and lower number of IL-17RA in CD4+ T cells (MFI = 1.16 x 4.56; p =.03) than controls. IL-17RA expression in CDS + T cells and IL-17A serum levels were similar in both groups. The coding regions and boundary intron sequences of IL17A were sequenced. Seventeen allelic variants, including three novel variants in exon 3 (3'UTR n) were identified, but no one was associated with T1D susceptibility, as well as the resulting haplotypes and diplotypes. The expression of IL-17RA was not correlated with metabolic variables (glucose and HbA1 c levels) or pancreatic autoantibodies titers. Conclusions: The lower expression of IL-17RA in CD3 + and CD4 + T cells suggests a reduced effect of IL-17A in immune response of recent-onset T1D patients, at least at peripheral tissues. IL-17A allelic variants were not related with T1D susceptibility.
- Progression of Type 1 Diabetes: Circulating MicroRNA Expression Profiles Changes from Preclinical to Overt Disease(2022) SANTOS, Aritania Sousa; FERREIRA, Ludmila Rodrigues Pinto; SILVA, Amanda Cabral da; ALVES, Lais Isidoro; DAMASCENO, Jullian Gabriel; KULIKOWSKI, Leslie; CUNHA-NETO, Edecio; SILVA, Maria Elizabeth Rossi daAims/Hypothesis. The role of microRNAs (miRNAs) in type 1 diabetes (T1D) pathogenesis and progression has been described but remains elusive. Objectives. To evaluate the potential biological involvement of miRNA expression in the immune response and beta cell function in T1D. Methods.We screened 377 serum miRNAs of 110 subjects divided into four groups: healthy individuals (control group) and patients at different stages of T1D progression, from the initial immunological manifestation presenting islet autoantibodies (AbP group) until partial and strong beta cell damage in the recent (recent T1D group) and long-term T1D, with 2 to 5 years of disease (T1D 2-5y group).Results. The results revealed 69 differentially expressed miRNAs (DEMs) in relation to controls. Several miRNAs were correlated with islet autoantibodies (IA2A, GADA, and Znt8A), age, and C-peptide levels, mainly from AbP, and recent T1D groups pointing these miRNAs as relevant to T1D pathogenesis and progression. Several miRNAs were related to metabolic derangements, inflammatory pathways, and several other autoimmune diseases. Pathway analysis of putative DEM targets revealed an enrichment in pathways related to metabolic syndrome, inflammatory response, apoptosis and insulin signaling pathways, metabolic derangements, and decreased immunomodulation. One of the miRNAs' gene targets was DYRK2 (dual-specificity tyrosine-phosphorylation-regulated kinase 2), which is an autoantigen targeted by an antibody in T1D. ROC curve analysis showed hsa-miR-16 and hsa-miR-200a-3p with AUCs greater than for glucose levels, with discriminating power for T1D prediction greater than glucose levels. Conclusions/Interpretation. Our data suggests a potential influence of DEMs on disease progression from the initial autoimmune lesion up to severe beta cell dysfunction and the role of miRNAs hsa-miR-16 and hsa-miR-200a-3p as biomarkers of T1D progression.
- Lack of association between IL27 gene variants and type 1 diabetes susceptibility(2013) SANTOS, Aritania S.; MELO, Maria E.; CRISOSTOMO, Lindiane C.; FUKUI, Rosa T.; MATIOLI, Sergio R.; SILVA, Maria Elizabeth R.Background: Recently, a new subpopulation of T cells, the Th17 subset, has been implicated in autoimmune diseases. Its development is influenced by IL-27, expressed in macrophages or dendritic cells. IL-27 blockage delays the onset of diabetes in non obese diabetes mouse, but its role in type 1 diabetes (T1D) in human has not been reported yet. The aim of this study was identify variants in the entire coding regions of IL-27 gene, including the 5' proximal region, and their possible association with the disease. Methods: Those regions were amplified by polymerase chain reaction followed by automatic sequencing and restriction fragments length polymorphisms. The cohort involved 614 individuals - 318 patients with T1D (19.6 +/- 11.2 y, 129 M/189F) and 296 healthy control subjects (30.3 +/- 13.2 y, 131 M/165F). Results: We identified eight allelic variants in the 5' proximal and coding regions of IL-27 gene, including two new variants: the c.-324 C > T in the 5' proximal region and the c.521 G > C in exon 5. None of these variants compromised transcription factor binding sites or the protein structure. The frequency of the alleles and genotypes of IL-27 variants did not differ between T1D patients and controls. There was no association between IL27 variants with gender, ethnicity, age at diagnosis of diabetes or presence of pancreatic and extrapancreatic autoantibodies. Conclusion: Our findings suggest that allelic variants in IL27 are not associated with susceptibility to T1D in a Brazilian population.
- Prevalence of Inflammatory Pathways Over Immuno-Tolerance in Peripheral Blood Mononuclear Cells of Recent-Onset Type 1 Diabetes(2022) SANTOS, Aritania Sousa; CUNHA-NETO, Edecio; GONFINETTI, Nelson Vinicius; BERTONHA, Fernanda Bernardi; BROCHET, Pauline; BERGON, Aurelie; MOREIRA-FILHO, Carlos Alberto; CHEVILLARD, Christophe; SILVA, Maria Elizabeth Rossi daBackgroundChanges in innate and adaptive immunity occurring in/around pancreatic islets had been observed in peripheral blood mononuclear cells (PBMC) of Caucasian T1D patients by some, but not all researchers. The aim of our study was to investigate whether gene expression patterns of PBMC of the highly admixed Brazilian population could add knowledge about T1D pathogenic mechanisms. MethodsWe assessed global gene expression in PBMC from two groups matched for age, sex and BMI: 20 patients with recent-onset T1D (<= 6 months from diagnosis, in a time when the autoimmune process is still highly active), testing positive for one or more islet autoantibodies and 20 islet autoantibody-negative healthy controls. ResultsWe identified 474 differentially expressed genes between groups. The most expressed genes in T1D group favored host defense, inflammatory and anti-bacterial/antiviral effects (LFT, DEFA4, DEFA1, CTSG, KCNMA1) and cell cycle progression. Several of the downregulated genes in T1D target cellular repair, control of inflammation and immune tolerance. They were related to T helper 2 pathway, induction of FOXP3 expression (AREG) and immune tolerance (SMAD6). SMAD6 expression correlated negatively with islet ZnT8 antibody. The expression of PDE12, that offers resistance to viral pathogens was decreased and negatively related to ZnT8A and GADA levels. The increased expression of long non coding RNAs MALAT1 and NEAT1, related to inflammatory mediators, autoimmune diseases and innate immune response against viral infections reinforced these data ConclusionsOur analysis suggested the activation of cell development, anti-infectious and inflammatory pathways, indicating immune activation, whereas immune-regulatory pathways were downregulated in PBMC from recent-onset T1D patients with a differential genetic profile.
- CD226 rs763361 Is Associated with the Susceptibility to Type 1 Diabetes and Greater Frequency of GAD65 Autoantibody in a Brazilian Cohort(2014) MATTANA, Teresa Cristina Colvara; SANTOS, Aritania Sousa; FUKUI, Rosa Tsuneshiro; MAINARDI-NOVO, Debora Teixeira Oliveira; COSTA, Vinicius Silva; SANTOS, Rosa Ferreira; MATIOLI, Sergio Russo; SILVA, Maria Elizabeth Rossi daCD226 rs763361 variant increases susceptibility to type 1 diabetes (T1D) in Caucasians. There is no data about CD226 variants in the very heterogeneous Brazilian population bearing a wide degree of admixture. We investigated its association with T1D susceptibility, clinical phenotypes, and autoimmune manifestations (islet and extrapancreatic autoantibodies). Casuistry. 532 T1D patients and 594 controls in a case-control study. Initially, CD226 coding regions and boundaries were sequenced in a subset of 106 T1D patients and 102 controls. In a second step, two CD226 variants, rs763361 (exon 7) and rs727088 (3' UTR region), involved with CD226 regulation, were genotyped in the entire cohort. C-peptide and autoantibody levels were determined. No new polymorphic variant was found. The variants rs763361 and rs727088 were in strong linkage disequilibrium. The TT genotype of rs763361 was associated with TID risk (OR = 1.503; 95% CI = 1.135-1.991; P = 0.0044), mainly in females ( P = 0.0012), greater frequency of anti-GAD autoantibody (31.9% x 24.5%; OR = 1.57; CI = 1.136-2.194; P = 0.0081), and lower C-peptide levels when compared to those with TC + CC genotypes (0.41 +/- 0.30 ng/dL versus 0.70 +/- 0.53 ng/dL P = 0.0218). Conclusions. The rs763361 variant of CD226 gene (TT genotype) was associated with susceptibility to T1D and with the degree of aggressiveness of the disease in T1D patients from Brazil. Ancestry had no effect.
- Increased Expression of Circulating microRNA 101-3p in Type 1 Diabetes Patients: New Insights Into miRNA-Regulated Pathophysiological Pathways for Type 1 Diabetes(2019) SANTOS, Aritania S.; NETO, Edecio Cunha; FUKUI, Rosa T.; FERREIRA, Ludmila R. P.; SILVA, Maria Elizabeth R.MicroRNAs (miRs) are master regulators of post-transcriptional gene expression, and they are often dysregulated in individuals suffering from diabetes. We investigated the roles of miR-101-3p and miR-204-5p, both of which negatively regulate insulin secretion and cell survival and are highly expressed in pancreatic b cells, in the context of type 1 diabetes (T1D) pathogenesis. Using quantitative real time PCR, we evaluated serum levels of miR-101-3p and miR-204-5p in four groups, including recent-onset T1D patients (T1D group; n = 50), individuals with normal glucose levels expressing one islet autoantibody (Ab) (single Ab group; n = 26) ormultiple autoantibodies (multiple Ab group; n = 12), and healthy controls (control group; n = 43). An in silico analysis was performed to identify potential target genes of these miRNAs and to delineate enriched pathways. The relative expression of serum miR-101-3p was approximately three times higher in the multiple Ab and T1D groups than that in the single Ab and control groups (p < 0.0001). When considering all groups together, miR-101-3p expression was positively correlated with the level of islet autoantibodies GADA (r = 0.267; p = 0.0027) and IA-2A (r = 0.291; p = 0.001), and the expression of the miRNA was not correlated with levels of ZnT8A (r = 0.125; p = 0.183). miR-101-3p expression did not correlate with HbA1c (r = 0.178; p = 0.052) or glucose levels (r = 0.177; p = 0.051). No significant differences were observed in miR-204-5p expression among the analyzed groups. Computational analysis of the miR-101-3p target gene pathways indicated a potential activation of the HGF/c-Met, Ephrin receptor, and STAT3 signaling pathways. Our study demonstrated that the circulating levels of miR-101-3p are higher in T1D patients and in individuals with normal glucose levels, testing positive for multiple autoantibodies, indicating that miR-101-3p precedes loss of glucose homeostasis. The pathogenic role of miR-101-3p in T1D may involve multiple molecular pathways.
- Protective effect of interleukin-23A (IL23A) haplotype variants on type 1A diabetes mellitus in a Brazilian population(2013) COSTA, V. S.; SANTOS, A. S.; FUKUI, R. T.; MATTANA, T. C. C.; MATIOLI, S. R.; SILVA, M. E. R.The Interleukin 23 (IL-23) has a central role in autoimmunity. Allelic variants of p19 subunit of IL-23 (IL23A) and IL-23 receptor. (IL23R) genes and increased IL-23 serum concentrations were associated with autoimmune diseases. We therefore searched for variants of IL23A and IL23R that could predispose to Type 1 diabetes (T1D). The coding regions and boundary intron sequences of IL23A were sequenced. Variants of IL23A and of IL23R were also genotyped. Pancreatic and extrapancreatic autoantibodies and IL-23 serum levels were determined. The cohort involved 370 patients with T1D and 351 healthy control subjects. We observed only one coding IL23A variant (rs11171806 G > A) out of the 6 described in databases. As the G alleles of rs11171806 and rs2066808 variants of IL23A gene were in strong linkage disequilibrium (D' = 0.825 for controls, p < 2.0 x 10(-6) and D' = 0.902, p < 2.0 x 10(-17) for patients), further analyses were performed with the haplotypes. The GG haplotype was more frequent in controls (16.7%) than in T1D patients (9.5%), conferring a protection to T1D (OR = 0.53; pc = 0.0003). No association was found between IL23A allelic variants with age at diagnosis of diabetes, C-peptide levels or frequency of autoantibodies. IL23R variants (rs10889677 and rs11209026) frequency and IL-23 serum concentrations were similar between groups. The GG haplotype of IL23A variants (rs11171806 and rs2066808) was protective against T1D. IL23R variants (rs11209026 and rs10889677) were not associated with T1D. IL-23 serum concentrations did not differ between groups.