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1.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 35(8): 707-713, 2019 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-31638568

RESUMO

Objective To investigate the relationship between mitochondria and systemic sclerosis (SSc) by analyzing the expression of mitochondrial function-related genes in skin biopsy samples from patients with SSc. Methods Gene chip expression profile of SSc skin biopsy in Gene Expression Omnibus (GEO) database was used, and differently expressed genes (DEGs) related to mitochondrial function were identified by t test and fold change (FC). What's more, functional annotation, functional enrichment and protein interaction network analysis were performed. Results A total of 422 significant DEGs were identified between the SSc group and the normal group. Among them, 23 DEGs were mitochondrial function-related genes. Functional annotation and enrichment analysis of 23 DEGs revealed that abnormally expressed mitochondrial function-related genes mainly affected several biological processes, such as mitochondrial energy supply and cell metabolism. Conclusion The dysregulation of mitochondrial function-related genes in SSc patients affects the function of mitochondria, suggesting that the abnormality of mitochondrial function may be associated with the development of SSc.


Assuntos
Biologia Computacional , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Mitocôndrias , Escleroderma Sistêmico , Perfilação da Expressão Gênica , Humanos , Mitocôndrias/genética , Mitocôndrias/patologia , Escleroderma Sistêmico/genética , Escleroderma Sistêmico/fisiopatologia , Transcriptoma
2.
Clin Exp Rheumatol ; 37 Suppl 119(4): 32-40, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31573470

RESUMO

OBJECTIVES: U1-70K, encoded by the SNRNP70 gene, is a key early immunogen in connective tissue disease. The aim of the study was the genetic analysis of the SNRNP70 gene in mixed connective tissue disease (MCTD), systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) patients. METHODS: SNRNP70 genetic variants were detected using 3730 DNA Analyzer. SNRNP70 rs560811128 G/A (c.476-252 G/A), rs78616533delCT (c.475+130_475+131delCT) and rs117167710 T/C (c.393+326 T/C) variants were genotyped using the technique of sequence-specific hybridisation probe binding assays. SNRNP70 393_47 G/A mutation was detected using TaqMan SNP genotyping assay. RESULTS: We found one novel c.393+47G>A and three, c.476-252 G/A, c.475+130_475+131delCT and c.393+326 T/C, previously recorded variants. The present study revealed that T-G-CT-G haplotype demonstrated significantly higher frequencies in MCTD patients than in SLE and SSc patients. In MCTD patients c.475+130_475+131delCT distribution of genotype was gender-dependent and showed association with thrombo-/leukocytopenia. Mutation at position c.476-252G>A was predicted to possibly have an impact on splicing of the SNRNP70 transcript and it was present only in one MCTD patient. CONCLUSIONS: Our results demonstrated that the T-G-CT-G SNRNP70 haplotype is another proof that MCTD may be distinct from SLE and SSc. The novel c.476-252G>A mutation in SNRNP70 gene created a new acceptor splice site and may potentially alert of splicing of the SNRNP70 transcript.


Assuntos
Lúpus Eritematoso Sistêmico , Doença Mista do Tecido Conjuntivo , Ribonucleoproteína Nuclear Pequena U1 , Escleroderma Sistêmico , Predisposição Genética para Doença/genética , Haplótipos , Humanos , Lúpus Eritematoso Sistêmico/genética , Doença Mista do Tecido Conjuntivo/genética , Ribonucleoproteína Nuclear Pequena U1/genética , Ribonucleoproteína Nuclear Pequena U1/imunologia , Escleroderma Sistêmico/genética , Tomografia Computadorizada por Raios X
3.
Autoimmun Rev ; 18(11): 102396, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31520794

RESUMO

Systemic Sclerosis (SSc) pathogenesis involves multiple immunological, vascular and fibroproliferative abnormalities that contribute to a severe and complex clinical picture. Vasculopathy and fibroproliferative alterations are two hallmark pathological processes in SSc that are responsible for the most severe clinical manifestations of the disease and determine its clinical outcome and mortality. However, the pathogenesis of SSc vasculopathy and of the uncontrolled SSc fibrotic process remain incompletely understood. Recent investigations into the molecular pathways involved in these processes have identified an important role for epigenetic processes that contribute to overall disease progression and have emphasized microRNAs (miRNAs) as crucial epigenetic regulators. MiRNAs hold unique potential for elucidating SSc pathogenesis, improving diagnosis and developing effective targeted therapies for the disease. This review examines the important role that miRNAs play in the development and regulation of vascular and fibroproliferative alterations associated with SSc pathogenesis and their possible participation in the establishment of pathogenetic connections between these two processes. This review also emphasizes that further understanding of the involvement of miRNA in SSc fibrosis and vasculopathy will very likely provide novel future research directions and allow for the identification of groundbreaking therapeutic interventions within these processes. MiR-21, miR- 31, and miR-155 are of particular interest owing to their important involvement in both SSc vasculopathy and fibroproliferative alterations.


Assuntos
MicroRNAs , Escleroderma Sistêmico/genética , Doenças Vasculares/genética , Animais , Fibrose , Humanos
4.
DNA Cell Biol ; 38(9): 933-944, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31361540

RESUMO

Interstitial lung disease (ILD) is the main reason of death in patients with systemic sclerosis (SSc). The potential microRNA (miRNA)-messenger RNA (mRNA) interaction networks of SSc-ILD from a systematic biological perspective are unclear. To characterize differentially expressed miRNAs (DE-miRNAs) and differentially expressed genes (DEGs) likely related to SSc-ILD, we downloaded the miRNA microarray dataset (GSE81923) and mRNA datasets (GSE76808 and GSE81292) from the Gene Expression Omnibus database. Comprehensive bioinformatic analyses were conducted to predict target genes for DE-miRNAs and generate an miRNA-hub gene network with SSc-ILD. In total, 26 DE-miRNAs were detected in SSc-ILD, among which 2 were upregulated and 24 were downregulated. Additionally, 178 common DEGs (55 upregulated and 123 downregulated) were identified. miRNAs were primarily enriched in pathways involving inflammation and regulation of fibroblasts. The hub genes identified were MMP7, IER2, HBEGF, CCL4, NFKBIA, JUNB, LIF, SERPINE1, FOSL1, and NAMPT. We discovered the miRNA-mediated regulatory network in SSc-ILD using an integrated bioinformatic analysis. The findings provide novel insight and expand our comprehension of the molecular mechanisms participating in the pathogenesis of SSc-ILD, along with identification of new potential diagnostic biomarkers.


Assuntos
Redes Reguladoras de Genes , Fibrose Pulmonar Idiopática/genética , MicroRNAs/genética , Escleroderma Sistêmico/genética , Humanos , Fibrose Pulmonar Idiopática/complicações , Fibrose Pulmonar Idiopática/metabolismo , MicroRNAs/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/metabolismo
5.
Iran J Allergy Asthma Immunol ; 18(2): 173-181, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-31066253

RESUMO

Systemic sclerosis (SSc) is characterized by excessive production of collagens by fibroblasts that leads to vast fibrosis. Resistance to apoptosis is one of the possible underlying mechanisms of fibrosis in these patients. Survivinis involved in inhibition of apoptosis and aberrantly functions in SSc. Since dysregulation of survivin-targeting microRNAs (miRNAs) has frequently been observed in cancer and some autoimmune disorders, this study aimed to investigate their expression status in dermal fibroblasts from SSc patients. DiffuseSSc patients were selected according to American College of Rheumatology criteria. Isolated fibroblasts from 10 SSc and 10 healthy skin biopsies were cultured. After examining purity of the cells, mRNA and miRNAs extraction was performed followed by complementary DNA (cDNA) synthesis. Relative expressions ofsurvivin mRNA, miR-16-5p, miR-320a, miR-218-5p, miR-708-5p and miR-542-3p were analyzed using real time PCR. Survivin mRNA expression was significantly 1.85-fold upregulated in fibroblasts from SSc patients compared with healthy controls (p=0.046). Among the studied miRNAs, miR-542-3p expression was significantly decreased (p=0.033), while enhanced expression of miR-708-5p was observed in SSc fibroblasts (p=0.05) in comparison to healthy subjects. Downregulation of miR-542-3p significantly correlated with survivin overexpression (r=-0.45, p=0.049). Downregulation of miR-542-3p that is correlated with higher surviving expression levels might be a possible cause of apoptosis resistance in SSc fibroblasts, hence providing a new understanding of the disease pathogenesis.


Assuntos
Derme/patologia , Fibroblastos/fisiologia , MicroRNAs/genética , Escleroderma Sistêmico/genética , Survivina/metabolismo , Adulto , Apoptose , Células Cultivadas , Colágeno/metabolismo , Regulação para Baixo , Feminino , Fibrose , Humanos , Masculino , Pessoa de Meia-Idade , Survivina/genética , Regulação para Cima
6.
Iran J Allergy Asthma Immunol ; 18(2): 182-189, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-31066254

RESUMO

Systemic sclerosis is a fibrotic autoimmune disease in which aberrant remodeling of the extracellular matrix in organs disturbs their functionalities. The aim of this study was to investigate the expression of gelatinases on systemic sclerosis. Consequently, a mouse model of systemic sclerosis was employed and the gelatinolytic activity of gelatinases was evaluated on the fibrotic tissues of this model. Two groups of ten mice were considered in this work: a group of systemic sclerosis model and control group. For the generation of systemic sclerosis model, mice received bleomycin, while the control group was subjected to phosphate buffered saline (PBS) reception. Mice were tested for fibrosis by using trichrome staining, hydroxyproline measurement and α-SMA detection in tissue sections. Additionally, the gelatinolytic activity of matrix metalloproteinase 2 and matrix metalloproteinase 9 were measured using gelatin zymography in lungs and skin tissue homogenates. The obtained results indicated that subcutaneous injection of bleomycin-induced fibrosis in skin and lung tissues of mice. Pro and active forms of matrix methaloproteinase 9 were increased in fibrotic lung tissues (p<0.05 and p<0.01, respectively), while, the gelatinolytic activity of MMP2 was unaffected in these tissues. Additionally, in skin tissues of bleomycin-treated animals, both pro and active forms of MMP9 and MMP2 were increased (p<0.05). Pro and active forms of gelatinases increase differently in skin and lung tissues of bleomycin-induced scleroderma.


Assuntos
Gelatinases/metabolismo , Escleroderma Sistêmico/metabolismo , Pele/patologia , Actinas/metabolismo , Animais , Bleomicina , Modelos Animais de Doenças , Feminino , Fibrose , Humanos , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Escleroderma Sistêmico/genética , Regulação para Cima
7.
Biomed Res Int ; 2019: 1484736, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31119153

RESUMO

Background and Objective: Progressive pulmonary fibrosis is the main cause of death in patients with systemic sclerosis (SSc) with interstitial lung disease (ILD) and in those with idiopathic pulmonary fibrosis (IPF). Transforming growth factor-ß (TGF-ß) and NADPH oxidase- (NOX-) derived reactive oxygen species (ROS) are drivers of lung fibrosis. We aimed to determine the role of the epigenetic readers, bromodomain and extraterminal (BET) proteins in the regulation of redox balance in activated myofibroblasts. Methods: In TGF-ß-stimulated fibroblasts, we investigated the effect of the BET inhibitor JQ1 on the mRNA expression of the prooxidant gene NOX4 and the antioxidant gene superoxide dismutase (SOD2) by quantitative RT-PCR, the antioxidant transcription factor NF-E2-related factor 2 (Nrf2) activity by a reporter assay, and intracellular ROS levels by dichlorofluorescein staining. Myofibroblast activation was determined by α-smooth muscle actin immunocytochemistry. The role of specific BET protein isoforms in NOX4 gene regulation was studied by siRNA silencing and chromatin-immunoprecipitation. Results and Conclusions: Affymetrix gene array analysis revealed increased NOX4 and reduced SOD2 expression in SSc and IPF fibroblasts. SOD2 silencing in non-ILD control fibroblasts induced a profibrotic phenotype. TGF-ß increased NOX4 and inhibited SOD2 expression, while increasing ROS production and myofibroblast differentiation. JQ1 reversed the TGF-ß-mediated NOX4/SOD2 imbalance and Nrf2 inactivation and attenuated ROS production and myofibroblast differentiation. The BET proteins Brd3 and Brd4 were shown to bind to the NOX4 promoter and drive TGF-ß-induced NOX4 expression. Our data indicate a critical role of BET proteins in promoting redox imbalance and pulmonary myofibroblast activation and support BET bromodomain inhibitors as a potential therapy for fibrotic lung disease.


Assuntos
Fibrose Pulmonar Idiopática/genética , NADPH Oxidase 4/genética , Proteínas Nucleares/genética , Proteínas de Ligação a RNA/genética , Escleroderma Sistêmico/genética , Fatores de Transcrição/genética , Azepinas/farmacologia , Desdiferenciação Celular/genética , Proliferação de Células/genética , Epigênese Genética , Regulação da Expressão Gênica/genética , Humanos , Fibrose Pulmonar Idiopática/complicações , Fibrose Pulmonar Idiopática/patologia , Pulmão/metabolismo , Pulmão/patologia , Miofibroblastos/metabolismo , Miofibroblastos/patologia , Fator 2 Relacionado a NF-E2/genética , Oxirredução , RNA Interferente Pequeno/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/patologia , Superóxido Dismutase/genética , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/farmacologia , Triazóis/farmacologia
8.
Orv Hetil ; 160(15): 563-572, 2019 Apr.
Artigo em Húngaro | MEDLINE | ID: mdl-30957538

RESUMO

MicroRNAs (miRNAs) are 18-25 nucleotide long, single stranded, endogenous, non-coding small RNAs playing an important role in regulating gene expression at posttranscriptional level. miRNAs control approximately 90% of protein-coding genes, and play a central role in various biological processes including immune cell lineage commitment, differentiation, proliferation, apoptosis and maintenance of immune homeostasis. Changes in the expression of certain miRNAs may lead to the development of many diseases, including systemic autoimmune diseases. In this study, we summarize the biogenesis of miRNAs, their role in regulation of the immune system, and review the latest research findings in systemic lupus erythematosus, primary Sjögren's syndrome, rheumatoid arthritis and systemic sclerosis. In the future, miRNAs may help not only in establishing diagnosis and prognosis but potentially serve as targets for modern therapeutic approaches in autoimmune diseases. Orv Hetil. 2019; 160(15): 563-572.


Assuntos
Artrite Reumatoide/genética , Doenças Autoimunes/genética , Lúpus Eritematoso Sistêmico/genética , MicroRNAs/genética , Escleroderma Sistêmico/genética , Síndrome de Sjogren/genética , Artrite Reumatoide/patologia , Doenças Autoimunes/etiologia , Doenças Autoimunes/imunologia , Regulação da Expressão Gênica , Humanos , Lúpus Eritematoso Sistêmico/patologia , MicroRNAs/imunologia , Escleroderma Sistêmico/patologia , Síndrome de Sjogren/patologia
9.
Nat Commun ; 10(1): 1128, 2019 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-30850660

RESUMO

Scleroderma is an autoimmune rheumatic disorder accompanied by severe fibrosis in skin and other internal organs. During scleroderma progression, resident fibroblasts undergo activation and convert to α-smooth muscle actin (α-SMA) expressing myofibroblasts (MFBs) with increased capacity to synthesize collagens and fibrogenic components. Accordingly, MFBs are a major therapeutic target for fibrosis in scleroderma and treatment with blocking MFBs could produce anti-fibrotic effects. TLY012 is an engineered human TNF-related apoptosis-inducing ligand (TRAIL) which induces selective apoptosis in transformed cells expressing its cognate death receptors (DRs). Here we report that TLY012 selectively blocks activation of dermal fibroblasts and induces DR-mediated apoptosis in α-SMA+ MFBs through upregulated DR5 during its activation. In vivo, TLY012 reverses established skin fibrosis to near-normal skin architecture in mouse models of scleroderma. Thus, the TRAIL pathway plays a critical role in tissue remodeling and targeting upregulated DR5 in α-SMA+ MFBs is a viable therapy for fibrosis in scleroderma.


Assuntos
Actinas/genética , Derme/efeitos dos fármacos , Miofibroblastos/efeitos dos fármacos , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/genética , Escleroderma Sistêmico/tratamento farmacológico , Ligante Indutor de Apoptose Relacionado a TNF/farmacologia , Actinas/metabolismo , Adulto , Idoso , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Diferenciação Celular , Colágeno/genética , Colágeno/metabolismo , Derme/metabolismo , Derme/patologia , Modelos Animais de Doenças , Feminino , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/patologia , Fibrose , Regulação da Expressão Gênica , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Miofibroblastos/metabolismo , Miofibroblastos/patologia , Engenharia de Proteínas , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/agonistas , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Escleroderma Sistêmico/genética , Escleroderma Sistêmico/imunologia , Escleroderma Sistêmico/patologia , Transdução de Sinais
10.
Transl Res ; 209: 77-89, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30876809

RESUMO

Systemic sclerosis (SSc, scleroderma) is a complex multisystem disease characterized by autoimmunity, vasculopathy, and most notably, fibrosis. Multiple lines of evidence demonstrate a variety of emerging cellular and molecular pathways which are relevant to fibrosis in SSc. The myofibroblast remains the key effector cell in SSc. Understanding the development, differentiation, and function of the myofibroblast is therefore crucial to understanding the fibrotic phenotype of SSc. Studies now show that (1) multiple cell types give rise to myofibroblasts, (2) fibroblasts and myofibroblasts are heterogeneous, and (3) that a large number of (primarily immune) cells have important influences on the transition of fibroblasts to an activated myofibroblasts. In SSc, this differentiation process involves multiple pathways, including well known signaling cascades such as TGF-ß and Wnt/ß-Catenin signaling, as well as epigenetic reprogramming and a number of more recently defined cellular pathways. After reviewing the major and emerging cellular and molecular mechanisms underlying SSc, this article looks to identify clinical applications where this new molecular knowledge may allow for targeted treatment and personalized medicine approaches.


Assuntos
Escleroderma Sistêmico/patologia , Epigênese Genética , Fibrose , Humanos , Miofibroblastos/patologia , Escleroderma Sistêmico/genética , Escleroderma Sistêmico/imunologia , Transdução de Sinais , Pele/patologia
11.
J Immunol Res ; 2019: 6808061, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30723749

RESUMO

Introduction: Systemic Sclerosis (SSc) is an autoimmune, inflammatory, and multisystemic disease characterized by the presence of autoantibodies and fibrosis. The pathogenesis involves the interaction between immune system cells such as macrophages, NK cells, T cells, and B cells. Killer-cell Immunoglobulin-like Receptors (KIR) are expressed in NK cells and some T cell subsets that recognize HLA class I molecules as ligands and are involved in regulating the activation and inhibition of these cells. The KIR family consists of 14 genes and two pseudogenes; according to the gene content, the genotype could be AA and Bx. The aim of this study was to evaluate the association between KIR/HLA genes and genotypes with SSc and the clinical characteristics. Methods: We included 50 SSc patients and 90 Control Subjects (CS). Genotyping of KIR, HLA-C, -Bw4, and -A ∗ 03/ ∗ 11 was made by SSP-PCR. Results: In SSc patients, a higher frequency of KIR2DL2 (p = 0.0007, p' = 0.011), KIR2DS4del (p = 0.001, p' = 0.021), and HLA-C2 (p = 0.02, p' = 0.09) was found. This is the first study to evaluate the frequency of HLA-A ∗ 03/ ∗ 11 in SSc patients, of which a low frequency was found in both groups. Compound genotypes KIR2DL2+/HLA-C1+ or KIR2DL2+/HLA-C2+ have a higher frequency in SSc patients. The Bx genotype was the most frequent and was associated with risk to SSc (p = 0.007, OR = 3.1, 95% CI = 1.4-7.9, p' = 0.014). The genotypes with a higher iKIR number than aKIR (iKIR > aKIR) were found in all individuals; genotypes with 7-8 iKIR genes were increased in SSc patients. We do not find an association between the KIR genes with the clinical characteristics. Conclusion: The results suggest that KIR2DL2 and 2DS4del could have a risk role in the development of SSc, but not with clinical manifestations.


Assuntos
Frequência do Gene , Genes MHC Classe I , Genótipo , Receptores KIR/genética , Escleroderma Sistêmico/genética , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Técnicas de Genotipagem , Humanos , Masculino , México , Pessoa de Meia-Idade , Fatores de Risco , Adulto Jovem
12.
Genes (Basel) ; 10(2)2019 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-30678304

RESUMO

: Systemic sclerosis (SSc) is a complex multi-system autoimmune disease characterized by immune dysregulation, vasculopathy, and organ fibrosis. Skin fibrosis causes high morbidity and impaired quality of life in affected individuals. Animal models do not fully recapitulate the human disease. Thus, there is a critical need to identify ex vivo models for the dermal fibrosis characteristic of SSc. We identified genes regulated by the pro-fibrotic factor TGFß in human skin maintained in organ culture. The molecular signature of human skin overlapped with that which was identified in SSc patient biopsies, suggesting that this model recapitulates the dermal fibrosis characteristic of the human disease. We further characterized the regulation and functional impact of a previously unreported gene in the setting of dermal fibrosis, COL22A1, and show that silencing COL22A1 significantly reduced TGFß-induced ACTA2 expression. COL22A1 expression was significantly increased in dermal fibroblasts from patients with SSc. In summary, we identified the molecular fingerprint of TGFß in human skin and demonstrated that COL22A1 is associated with the pathogenesis of fibrosis in SSc as an early response gene that may have important implications for fibroblast activation. Further, this model will provide a critical tool with direct relevance to human disease to facilitate the assessment of potential therapies for fibrosis.


Assuntos
Colágeno/metabolismo , Miofibroblastos/metabolismo , Escleroderma Sistêmico/metabolismo , Actinas/genética , Actinas/metabolismo , Células Cultivadas , Colágeno/genética , Fibrose , Humanos , Miofibroblastos/efeitos dos fármacos , Miofibroblastos/patologia , Escleroderma Sistêmico/genética , Escleroderma Sistêmico/patologia , Pele/metabolismo , Pele/patologia , Fator de Crescimento Transformador beta/farmacologia
13.
PLoS One ; 13(12): e0209343, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30586461

RESUMO

BACKGROUND: The TNFSF13B (TNF superfamily member 13b) gene encodes BAFF, a cytokine with a crucial role in the differentiation and activation of B cells. An insertion-deletion variant (GCTGT→A) of this gene, leading to increased levels of BAFF, has been recently implicated in the genetic predisposition to several autoimmune diseases, including multiple sclerosis, systemic lupus erythematosus, and rheumatoid arthritis. Based on the elevated levels of this cytokine found in patients with giant cell arteritis (GCA) and systemic sclerosis (SSc), we aimed to assess whether this functional variant also represents a novel genetic risk factor for these two disorders. METHODS: A total of 1,728 biopsy-proven GCA patients from 4 European cohorts, 4,584 SSc patients from 3 European cohorts and 5,160 ethnically-matched healthy controls were included in the study. The single nucleotide polymorphism (SNP) rs374039502, which colocalizes with the genetic variant previously implicated in autoimmunity, was genotyped using a custom TaqMan assay. First, association analysis was conducted in each independent cohort using χ2 test in Plink (v1.9). Subsequently, different case/control sets were meta-analyzed by the inverse variance method. RESULTS: No statistically significant differences were found when allele distributions were compared between cases and controls for any of the analyzed cohorts. Similarly, combined analysis of the different sets evidenced a lack of association of the rs374039502 variant with GCA (P = 0.421; OR (95% CI) = 0.92 (0.75-1.13)) and SSc (P = 0.500; OR (95% CI) = 1.05 (0.91-1.22)). The stratified analysis considering the main clinical subphenotypes of these diseases yielded similar negative results. CONCLUSION: Our data suggest that the TNFSF13B functional variant does not contribute to the genetic network underlying GCA and SSc.


Assuntos
Fator Ativador de Células B/genética , Predisposição Genética para Doença , Arterite de Células Gigantes/genética , Escleroderma Sistêmico/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia , Estudos de Casos e Controles , Estudos de Coortes , Europa (Continente) , Feminino , Redes Reguladoras de Genes/genética , Técnicas de Genotipagem , Arterite de Células Gigantes/patologia , Humanos , Mutação INDEL , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Escleroderma Sistêmico/patologia
14.
Genome Med ; 10(1): 97, 2018 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-30572963

RESUMO

BACKGROUND: In recent years, research has consistently proven the occurrence of genetic overlap across autoimmune diseases, which supports the existence of common pathogenic mechanisms in autoimmunity. The objective of this study was to further investigate this shared genetic component. METHODS: For this purpose, we performed a cross-disease meta-analysis of Immunochip data from 37,159 patients diagnosed with a seropositive autoimmune disease (11,489 celiac disease (CeD), 15,523 rheumatoid arthritis (RA), 3477 systemic sclerosis (SSc), and 6670 type 1 diabetes (T1D)) and 22,308 healthy controls of European origin using the R package ASSET. RESULTS: We identified 38 risk variants shared by at least two of the conditions analyzed, five of which represent new pleiotropic loci in autoimmunity. We also identified six novel genome-wide associations for the diseases studied. Cell-specific functional annotations and biological pathway enrichment analyses suggested that pleiotropic variants may act by deregulating gene expression in different subsets of T cells, especially Th17 and regulatory T cells. Finally, drug repositioning analysis evidenced several drugs that could represent promising candidates for CeD, RA, SSc, and T1D treatment. CONCLUSIONS: In this study, we have been able to advance in the knowledge of the genetic overlap existing in autoimmunity, thus shedding light on common molecular mechanisms of disease and suggesting novel drug targets that could be explored for the treatment of the autoimmune diseases studied.


Assuntos
Doenças Autoimunes/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Artrite Reumatoide/genética , Doença Celíaca/genética , Diabetes Mellitus Tipo 1/genética , Estudo de Associação Genômica Ampla , Humanos , Anotação de Sequência Molecular , Escleroderma Sistêmico/genética
15.
Rheumatology (Oxford) ; 57(9): 1675-1684, 2018 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-29905853

RESUMO

Objectives: To investigate the mechanism of 2-methoxyestradiol (2-ME) in inhibiting hypoxia-induced collagen synthesis of fibroblasts in SSc. Methods: The expressions of hypoxia-inducible factor 1 alpha (HIF-1α) and connective tissue growth factor (CTGF) in skin specimens derived from SSc patients and healthy volunteers were examined by immunohistochemistry. HIF-1α was knocked down by lentiviral transduction, and SSc dermal fibroblasts cultured under normoxic (21% O2) or hypoxic (1% O2) condition were treated with PI3K inhibitor LY294002, rapamycin or 2-ME (25 µM). The protein levels of HIF-1α, CTGF, collagen I, p-Akt and p-mTOR were examined by western blotting or immunofluorescence. Apoptosis and cell cycle of fibroblasts were assessed by flow cytometry and by measuring caspase 3 activity, and cell proliferation was evaluated by Cell Counting Kit-8. Results: The expressions of HIF-1α and CTGF were increased in skins of SSc patients compared with healthy controls. Hypoxia up-regulated the protein levels of HIF-1α, CTGF and collagen I in SSc fibroblasts. In contrast, 2-ME inhibited PI3K/Akt/mTOR pathway and down-regulated protein levels of HIF-1α, CTGF and collagen I. Knockdown of HIF-1α reduced expressions of CTGF and collagen I, which were further down-regulated by 2-ME intervention. Moreover, 2-ME promoted the apoptosis and inhibited the proliferation of SSc fibroblasts by arresting the cell cycle at the G2/M phase. Conclusion: 2-ME reduced the production of CTGF and collagen I in SSc fibroblasts induced by hypoxia through PI3K/Akt/mTOR/HIF-1α signalling and inhibited the proliferation of fibroblasts. These findings suggested that 2-ME could be employed as a promising antifibrotic therapy for SSc.


Assuntos
Colágeno Tipo I/biossíntese , Estradiol/análogos & derivados , Regulação da Expressão Gênica , Subunidade alfa do Fator 1 Induzível por Hipóxia/biossíntese , Proteínas Proto-Oncogênicas c-akt/genética , Escleroderma Sistêmico/genética , Serina-Treonina Quinases TOR/genética , 2-Metoxiestradiol , Proliferação de Células , Células Cultivadas , Colágeno Tipo I/efeitos dos fármacos , Fator de Crescimento do Tecido Conjuntivo/biossíntese , Fator de Crescimento do Tecido Conjuntivo/efeitos dos fármacos , Estradiol/farmacologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/patologia , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/biossíntese , RNA/genética , Escleroderma Sistêmico/tratamento farmacológico , Escleroderma Sistêmico/metabolismo , Transdução de Sinais , Pele/metabolismo , Pele/patologia , Serina-Treonina Quinases TOR/biossíntese , Moduladores de Tubulina/farmacologia
16.
Cell Mol Biol (Noisy-le-grand) ; 64(5): 46-51, 2018 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-29729713

RESUMO

This study explored whether the functional protein tyrosine phosphatase nonreceptor 22 (PTPN22) G788A (R263Q) polymorphism is associated with susceptibility to autoimmune diseases. A meta-analysis was conducted using 23 comparative studies with a total of 16,719 patients and 17,783 controls. The meta-analysis showed an association between the A allele of the PTPN22 G788A polymorphism and decreased risk of autoimmune diseases in all subjects (p < 0.001). Analysis after stratification by ethnicity indicated that the PTPN22 788A allele was significantly associated with autoimmune diseases in Europeans (p < 0.001) but not in Latin Americans. Meta-analysis by autoimmune disease type showed a significant negative association between the PTPN22 788A allele and systemic lupus erythematous (SLE) (p = 001), rheumatoid arthritis (RA) (p = 0.008), ulcerative colitis (UC) (p = 0.016), but not Crohn's disease (CD). A single study for each showed no association between the PTPN22 788A allele and systemic sclerosis, giant cell arteritis, Henoch-schonlein purpura, uveitis, and Grave's disease. This meta-analysis demonstrates that the PTPN22 G788A polymorphism confers protection against SLE, RA, and UC, supporting evidence of association of the PTPN22 gene with a subgroup of autoimmune diseases.


Assuntos
Artrite Reumatoide/genética , Colite Ulcerativa/genética , Resistência à Doença/genética , Lúpus Eritematoso Sistêmico/genética , Polimorfismo de Nucleotídeo Único , Proteína Tirosina Fosfatase não Receptora Tipo 22/genética , Artrite Reumatoide/etnologia , Artrite Reumatoide/imunologia , Artrite Reumatoide/patologia , Estudos de Casos e Controles , Colite Ulcerativa/etnologia , Colite Ulcerativa/imunologia , Colite Ulcerativa/patologia , Doença de Crohn/etnologia , Doença de Crohn/genética , Doença de Crohn/imunologia , Doença de Crohn/patologia , Grupo com Ancestrais do Continente Europeu , Expressão Gênica , Estudos de Associação Genética , Genótipo , Arterite de Células Gigantes/etnologia , Arterite de Células Gigantes/genética , Arterite de Células Gigantes/imunologia , Arterite de Células Gigantes/patologia , Doença de Graves/etnologia , Doença de Graves/genética , Doença de Graves/imunologia , Doença de Graves/patologia , Hispano-Americanos , Humanos , Lúpus Eritematoso Sistêmico/etnologia , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/patologia , Púrpura de Schoenlein-Henoch/etnologia , Púrpura de Schoenlein-Henoch/genética , Púrpura de Schoenlein-Henoch/imunologia , Púrpura de Schoenlein-Henoch/patologia , Escleroderma Sistêmico/etnologia , Escleroderma Sistêmico/genética , Escleroderma Sistêmico/imunologia , Escleroderma Sistêmico/patologia , Uveíte/etnologia , Uveíte/genética , Uveíte/imunologia , Uveíte/patologia
17.
PLoS One ; 13(5): e0196559, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29718973

RESUMO

Transforming growth factor-ß (TGF-ß) plays a crucial role in the pathogenesis of Systemic Sclerosis (SSc) and other fibrotic disorders. TGF-ß-mediated c-Abl and Src kinase activation induces strong profibrotic cascade signaling. The purpose of this study was to test in vivo the antifibrotic activity of Bosutinib (SKI-606), a second generation c-Abl and Src kinase inhibitor, on TGF-ß induced cutaneous and pulmonary fibrosis. For this purpose, we employed the TBRIcaCol1a2Cre transgenic mice expressing an inducible constitutively active TGF-ß receptor 1 constitutively activated by Col1a promoter-mediated Cre recombinase. The mice were treated parenterally with 2.5, 5.0 or 10.0 mg/kg/day of Bosutinib for 42 days. Skin and lungs from control and Bosutinib-treated mice (n = 6 per group) were assessed by histopathology, measurement of tissue hydroxyproline content, PCR analysis of tissue fibrosis associated gene expression, and evidence of myofibroblast activation. Mice with constitutive TGF-ß-1 signaling displayed severe cutaneous and pulmonary fibrosis. Bosutinib administration decreased collagen deposition and hydroxyproline content in the dermis and lungs in a dose-dependent manner. Bosutinib also reversed the marked increase in profibrotic and myofibroblast activation-associated gene expression. These results demonstrate that constitutive TGF-ß-1-signaling-induced cutaneous and pulmonary fibrosis were abrogated in a dose-related manner following parenteral administration of the c-Abl and Src tyrosine kinase inhibitor, Bosutinib. These results indicate that Bosutinib may be a potential therapeutic agent for tissue fibrosis in SSc and other fibroproliferative disorders.


Assuntos
Compostos de Anilina/farmacologia , Nitrilos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Fibrose Pulmonar/tratamento farmacológico , Quinolinas/farmacologia , Escleroderma Sistêmico/tratamento farmacológico , Fator de Crescimento Transformador beta1/metabolismo , Animais , Hidroxiprolina/metabolismo , Mesilato de Imatinib/farmacologia , Pulmão/patologia , Camundongos , Camundongos Transgênicos , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas c-abl/antagonistas & inibidores , Receptor do Fator de Crescimento Transformador beta Tipo I , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Escleroderma Sistêmico/genética , Escleroderma Sistêmico/patologia , Transdução de Sinais/efeitos dos fármacos , Pele/patologia , Quinases da Família src/antagonistas & inibidores
18.
Rheumatol Int ; 38(3): 489-498, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29356883

RESUMO

Systemic sclerosis (SSc), an autoimmune disease of connective tissue, is characterized by inflammation, fibrosis, and vessel endothelial damage. Products of Integrin subunit beta 2 (ITGB2) and selectin L (SELL) genes participate in several functional pathways of immune system. The aim of this investigation was to survey the transcript level of ITGB2 and SELL genes as well as methylation status of CpG sites in promoter region of differently expressed gene in PBMCs of SSc patients. PBMCs were isolated from whole blood of 50 SSc patients and 30 healthy controls. Total RNA and DNA contents of PBMCs were extracted. Gene expression was analyzed by real-time PCR using the SYBR Green PCR Master Mix. To investigate the methylation status of CpG sites, DNA samples were treated by bisulfite, amplified through nested PCR, and sequenced through Sanger difficult sequencing method. ITGB2 gene in PBMCs of SSc patients was overexpressed significantly in comparison to healthy controls. However, no altered SELL expression was observed. Three CpG sites of 12, 13 and 14 were significantly hypomethylated in patients group, despite overall methylation status of ITGB2 gene promoter revealed no significant difference between study groups. There was no statistically significant correlation between methylation status of ITGB2 promoter and the gene expression in patients. Regarding to lack of correlation of increased expression of ITGB2 with its promoter hypomethylation in SSc patients, our study suggests that upregulation of ITGB2 in PBMCs from SSc patients is probably due to another mechanism other than methylation alteration.


Assuntos
Antígenos CD18/genética , Metilação de DNA , Selectina L/genética , Regiões Promotoras Genéticas , Escleroderma Sistêmico/genética , Antígenos CD18/metabolismo , Estudos de Casos e Controles , Ilhas de CpG , Humanos , Selectina L/metabolismo , Leucócitos Mononucleares/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Escleroderma Sistêmico/diagnóstico , Escleroderma Sistêmico/metabolismo , Regulação para Cima
19.
Autoimmun Rev ; 17(3): 267-275, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29369808

RESUMO

We studied the clinical correlations and epitopes of autoantibodies directed to a novel autoantigen, Bicaudal D (BICD2), in systemic sclerosis (SSc) and reviewed its relationship to centromere protein A (CENP-A). 451 SSc sera were tested for anti-BICD2 using a paramagnetic bead immunoassay and then univariate and multivariate logistic regression was used to study the association between anti-BICD2 and demographic and clinical parameters as well as other SSc-related autoantibodies. Epitope mapping was performed on solid phase matrices. 25.7% (116/451) SSc sera were anti-BICD2 positive, of which 19.0% had single specificity anti-BICD2 and 81.0% had other autoantibodies, notably anti-CENP (83/94; 88.3%). Compared to anti-BICD2 negative subjects (335/451), single specificity anti-BICD2 subjects were more likely to have an inflammatory myopathy (IM; 31.8% vs. 9.6%, p=.004) and interstitial lung disease (ILD; 52.4% vs. 29.0%, p=.024). Epitope mapping revealed a serine- and proline-rich nonapeptide SPSPGSSLP comprising amino acids 606-614 of BICD2, shared with CENP-A but not CENP-B. We observed that autoantibodies to BICD2 represent a new biomarker as they were detected in patients without other SSc-specific autoantibodies and were the second most common autoantibody identified in this SSc cohort. Our data indicate that the major cross-reactive epitope is associated with anti-CENP-A but, unlike anti-CENP, single specificity anti-BICD2 antibodies associate with ILD and IM.


Assuntos
Autoanticorpos/imunologia , Proteína Centromérica A/imunologia , Escleroderma Sistêmico/genética , Estudos de Coortes , Feminino , Humanos , Pessoa de Meia-Idade , Fenótipo , Escleroderma Sistêmico/imunologia
20.
PLoS One ; 13(1): e0189498, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29293537

RESUMO

Gene-level analysis of ImmunoChip or genome-wide association studies (GWAS) data has not been previously reported for systemic sclerosis (SSc, scleroderma). The objective of this study was to analyze genetic susceptibility loci in SSc at the gene level and to determine if the detected associations were shared in African-American and White populations, using data from ImmunoChip and GWAS genotyping studies. The White sample included 1833 cases and 3466 controls (956 cases and 2741 controls from the US and 877 cases and 725 controls from Spain) and the African American sample, 291 cases and 260 controls. In both Whites and African Americans, we performed a gene-level analysis that integrates association statistics in a gene possibly harboring multiple SNPs with weak effect on disease risk, using Versatile Gene-based Association Study (VEGAS) software. The SNP-level analysis was performed using PLINK v.1.07. We identified 4 novel candidate genes (STAT1, FCGR2C, NIPSNAP3B, and SCT) significantly associated and 4 genes (SERBP1, PINX1, TMEM175 and EXOC2) suggestively associated with SSc in the gene level analysis in White patients. As an exploratory analysis we compared the results on Whites with those from African Americans. Of previously established susceptibility genes identified in Whites, only TNFAIP3 was significant at the nominal level (p = 6.13x10-3) in African Americans in the gene-level analysis of the ImmunoChip data. Among the top suggestive novel genes identified in Whites based on the ImmunoChip data, FCGR2C and PINX1 were only nominally significant in African Americans (p = 0.016 and p = 0.028, respectively), while among the top novel genes identified in the gene-level analysis in African Americans, UNC5C (p = 5.57x10-4) and CLEC16A (p = 0.0463) were also nominally significant in Whites. We also present the gene-level analysis of SSc clinical and autoantibody phenotypes among Whites. Our findings need to be validated by independent studies, particularly due to the limited sample size of African Americans.


Assuntos
Grupo com Ancestrais do Continente Africano/genética , Grupo com Ancestrais do Continente Europeu/genética , Estudo de Associação Genômica Ampla , Escleroderma Sistêmico/genética , Humanos , Polimorfismo de Nucleotídeo Único
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