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1.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 35(9): 776-782, 2019 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-31750817

RESUMO

Objective To prepare inducible lupus model mice and investigate the effect of nuclear autoantigenic sperm protein (NASP) gene mutation on the autoimmune response of mice with induced systemic lupus erythematosus (SLE). Methods The 3-month wild-type B6 (B6-WT) mice were used as a control group and the NASP mutant B6 (B6-NASPM) mice as an experimental group. Mouse spleen lymphocytes were activated with concanavalin A (ConA), and the DNA was extracted as autoantigen. B6-WT mice and B6-NASPM mice were immunized three times. Serum anti-double stranded DNA (dsDNA) IgG levels were detected by ELISA. Renal lesions were detected by HE staining. Immunohistochemical staining was performed to detect the deposition of IgG and complement C3 in the renal tissues. Flow cytometry was applied to compare the spleen lymphocyte subsets in B6-WT and B6-NASPM mice and to explore the mechanism of NASP gene mutation affecting the immune response in mice. Results Compared with B6-WT mice, B6-NASPM mice showed no significant changes in body weight, kidney index and spleen index; serum anti-dsDNA IgG levels significantly increased; glomerular cell proliferation was obvious and the deposition of IgG and C3 in the renal tissues increased. The proportion of spleen CD3+ T cells and natural killer (NK) cells decreased, while the proportion of CD19+ B cells and regulatory B cells (Breg) increased. Conclusion Mutation in the NASP gene can increase the levels of anti-dsDNA IgG antibodies, promote cell proliferation in the glomerulus of the kidney, deposition of IgG antibodies and complement C3, alter the proportion of immune cells in the spleen and aggravate the autoimmune response in lupus model mice.


Assuntos
Autoantígenos/genética , Autoimunidade , Lúpus Eritematoso Sistêmico/genética , Proteínas Nucleares/genética , Animais , Anticorpos Antinucleares/sangue , Complemento C3/imunologia , Modelos Animais de Doenças , Glomérulos Renais/imunologia , Lúpus Eritematoso Sistêmico/patologia , Camundongos , Mutação , Baço/imunologia
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.
Isr Med Assoc J ; 21(7): 487-490, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31507126

RESUMO

BACKGROUND: Recurrent pericarditis is a state of repetitive inflammation of the pericardium with intervals of remission. The etiology of recurrent pericarditis is still largely unknown, yet most causes are presumed to be immune mediated. Genetic factors, including human leukocyte antigen (HLA) haplotypes, can be involved in dysregulation of the immune system and as a predisposition to several autoimmune conditions, including recurrent pericarditis. Several diseases are frequently associated with such manifestations. They include systemic lupus erythematosus, familial Mediterranean fever, and tumor necrosis factor receptor-associated periodic syndrome. However, idiopathic recurrent pericarditis remains the most frequently observed clinical condition and the conundrum of this disease still needs to be solved.


Assuntos
Doenças Autoimunes/genética , Predisposição Genética para Doença , Pericardite/fisiopatologia , Febre Familiar do Mediterrâneo/genética , Febre Familiar do Mediterrâneo/imunologia , Antígenos HLA/genética , Haplótipos , Humanos , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/imunologia , Pericardite/genética , Pericardite/imunologia , Recidiva
4.
Autoimmun Rev ; 18(10): 102361, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31401343

RESUMO

Systemic lupus erythematosus (SLE) is a severe lifelong multisystem autoimmune disease characterized by the presence of autoantibodies targeting nuclear autoantigens, increased production of type I interferon and B cell abnormalities. Clinical presentation of SLE is extremely heterogeneous and different groups of disease are likely to exist. Recently, childhood-onset SLE (cSLE) cases have been linked to single gene mutations, defining the concept of monogenic or Mendelian lupus. Genes associated with Mendelian lupus can be grouped in at least three functional categories. First, complement deficiencies represent the main cause of monogenic lupus and its components are involved in the clearance of dying cells, a mechanism also called efferocytosis. Mutations in extracellular DNASE have been also identified in cSLE patients and represent additional causes leading to defective clearance of nucleic acids and apoptotic bodies. Second, the study of Aicardi-Goutières syndromes has introduced the concept of type-I interferonopathies. Bona fide lupus syndromes have been associated to this genetic condition, driven by defective nucleic acids metabolism or innate sensors overactivity. Interferon signalling anomalies can be detected and monitored during therapies, such as Janus-kinase (JAK) inhibitors. Third, tolerance breakdown can occur following genetic mutations in B and/or T cell expressing key immunoregulatory molecules. Biallelic mutations in PRKCD are associated to lupus and lymphoproliferative diseases as PKC-δ displays proapoptotic activity and is crucial to eliminate self-reactive transitional B cells. Here we review the literature of the emerging field of Mendelian lupus and discuss the physiopathological learning from these inborn errors of immunity. In addition, clinical and biological features are highlighted as well as specific therapies that have been tested in these genetic contexts.


Assuntos
Predisposição Genética para Doença , Lúpus Eritematoso Sistêmico/classificação , Lúpus Eritematoso Sistêmico/genética , Polimorfismo Genético , Humanos , Lúpus Eritematoso Sistêmico/imunologia
5.
DNA Cell Biol ; 38(10): 1040-1047, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31414895

RESUMO

The helper T cell 9 (Thelper-9, Th9), as a functional subgroup of CD4+T cells, was first discovered in 2008. Th9 cells expressed transcription factor PU.1 and cytokine interleukin-9 (IL-9) characteristically. Recent researches have shown that the differentiation of Th9 cells was coregulated by cytokine transforming growth factor ß, IL-4, and various transcription factors. Th9 cells, as a new player, played an important role in various immune-related diseases, including tumors, inflammatory diseases, parasite infection, and other diseases. In this article, we summarize the related research progress and discuss the possible prospect.


Assuntos
Interleucina-9/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Neoplasias/imunologia , Proteínas Proto-Oncogênicas/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Transativadores/imunologia , Fator de Crescimento Transformador beta/imunologia , Animais , Diferenciação Celular , Fator de Transcrição GATA3/deficiência , Fator de Transcrição GATA3/genética , Fator de Transcrição GATA3/imunologia , Regulação da Expressão Gênica , Humanos , Inflamação , Interleucina-4/genética , Interleucina-4/imunologia , Interleucina-9/genética , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/patologia , Camundongos , Camundongos Knockout , Neoplasias/genética , Neoplasias/patologia , Proteínas Proto-Oncogênicas/genética , Fator de Transcrição STAT6/genética , Fator de Transcrição STAT6/imunologia , Transdução de Sinais , Linfócitos T Auxiliares-Indutores/patologia , Transativadores/genética , Fator de Crescimento Transformador beta/genética
6.
Egypt J Immunol ; 26(1): 101-112, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31333000

RESUMO

Systemic lupus erythematosus (SLE) is a complex autoimmune disease affecting all organ systems due to alterations of both innate and adaptive immune systems. Given the importance of several factors that may be incriminated in deregulation of immune system in SLE, we aimed to study MTNR1ß gene polymorphisms rs10830963 C/G, serum levels of melatonin and pro-inflammatory cytokines; TNF-α, IL-6, and IL-1ß in SLE patients and the correlation of these parameters to SLE disease activity and damage index at time of study. Subjects were subdivided into 2 groups: group I: 40 SLE patients attending Alexandria main university hospital and outpatient clinic, and group II: 40 control cases of apparently healthy individuals matched for age and sex. For all cases, MTNR1ß gene polymorphism rs10830963 was analyzed by quantitative RT-PCR, serum levels of melatonin, TNF-α, IL-6 and IL-1ß were detected by ELISA. Activity index (SLEDAI) and damage index (SLEDDI) were assessed in SLE patients. MTNR1ß gene polymorphism rs10830963 genotype in SLE patients showed that 50% had GG, 35% CG and 15% CC. The control group had significantly lower ratios, 5% had GG, 15% CG and 80% CC (P < 0.001). Serum melatonin level was decreased in SLE patients (P < 0.001). Serum levels of TNF-α, IL-6, and IL-1ß were increased in SLE patients compared to controls (P < 0.001, P < 0.001, P < 0.001 respectively). There was no correlation between serum melatonin level, TNF-α, IL-6, and IL-1ß with SLEDAI or SLEDDI. In conclusion, MTNR1ß gene polymorphism rs10830963 G allele may contribute in SLE pathogenesis. Inflammatory cytokines; TNF-α, IL-6, IL-1ß may have role in SLE disease manifestations. Targeting immunoregulators as melatonin and proinflammatory cytokines in SLE treatment strategy can be a promising way to SLE cure.


Assuntos
Lúpus Eritematoso Sistêmico/genética , Melatonina/sangue , Polimorfismo Genético , Receptor MT2 de Melatonina/genética , Estudos de Casos e Controles , Egito , Humanos , Interleucina-1beta/sangue , Interleucina-6/sangue , Lúpus Eritematoso Sistêmico/sangue , Fator de Necrose Tumoral alfa/sangue
7.
J Clin Pathol ; 72(10): 659-662, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31340988

RESUMO

CTLA-4 (cytotoxic T-lymphocyte-associated protein-4) or CD152 is an inhibitory receptor expressed constitutively on CD4+ CD25+ T regulatory lymphocytes and transiently on activated CD4+ and CD8+ T lymphocytes. Its inhibitory function promotes long-lived anergy in immune cells and prevents autoimmunity. Therefore, it plays a crucial role in T cell-mediated autoimmunity, and thus in susceptibility to autoimmune diseases, including systemic lupus erythematosus (SLE). It is encoded by CTLA4 gene in humans. AtoG polymorphism at position +49 of CTLA4 gene is the only polymorphism which changes amino acid sequence from alanine to threonine in the leader sequence, which may affect the function of CTLA-4. Association of CTLA4 polymorphisms with SLE has been investigated in several reports in different ethnic populations from different countries, which have shown highly inconsistent findings. In this review, we have compiled previous studies which have reported the association of CTLA4 A49G polymorphism in SLE and its geographical distribution.


Assuntos
Antígeno CTLA-4/genética , Lúpus Eritematoso Sistêmico/genética , Polimorfismo de Nucleotídeo Único/genética , Autoimunidade , Predisposição Genética para Doença , Geografia , Humanos , Lúpus Eritematoso Sistêmico/imunologia , Linfócitos T Reguladores/imunologia
8.
Nat Immunol ; 20(8): 1071-1082, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31263277

RESUMO

Systemic lupus erythematosus (SLE) is characterized by the expansion of extrafollicular pathogenic B cells derived from newly activated naive cells. Although these cells express distinct markers, their epigenetic architecture and how it contributes to SLE remain poorly understood. To address this, we determined the DNA methylomes, chromatin accessibility profiles and transcriptomes from five human B cell subsets, including a newly defined effector B cell subset, from subjects with SLE and healthy controls. Our data define a differentiation hierarchy for the subsets and elucidate the epigenetic and transcriptional differences between effector and memory B cells. Importantly, an SLE molecular signature was already established in resting naive cells and was dominated by enrichment of accessible chromatin in motifs for AP-1 and EGR transcription factors. Together, these factors acted in synergy with T-BET to shape the epigenome of expanded SLE effector B cell subsets. Thus, our data define the molecular foundation of pathogenic B cell dysfunction in SLE.


Assuntos
Subpopulações de Linfócitos B/patologia , Metilação de DNA/genética , Epigênese Genética/genética , Lúpus Eritematoso Sistêmico/genética , Subpopulações de Linfócitos B/imunologia , Montagem e Desmontagem da Cromatina/fisiologia , Fatores de Transcrição de Resposta de Crescimento Precoce/genética , Humanos , Lúpus Eritematoso Sistêmico/imunologia , Fator de Transcrição AP-1/genética , Transcriptoma/genética
9.
Immunol Med ; 42(1): 1-9, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31204893

RESUMO

Systemic lupus erythematosus (SLE) is a prototypic systemic autoimmune disease that develops in genetically susceptible individuals in response to environmental factors. SLE and primary immunodeficiency disease (PID) share some clinical manifestations in that certain PIDs present with autoimmune phenomena. Patients with SLE become susceptible to infection via three pathways. First, SLE and PID share some genetic factors, such as complement and mannose-binding lectin genes, which predispose patients to infection. Second, patients with SLE have an inherently high risk of infection because of their intrinsic immunological abnormalities induced by SLE. Third, patients with SLE receiving immunosuppressive treatment are at high risk of infection. Further studies delineating the abnormalities related to both autoimmunity and immunodeficiency would be warranted to identify a new potential drug target for SLE.


Assuntos
Síndromes de Imunodeficiência/imunologia , Infecção/etiologia , Lúpus Eritematoso Sistêmico/imunologia , Autoimunidade , Proteínas do Sistema Complemento/imunologia , Suscetibilidade a Doenças , Predisposição Genética para Doença , Humanos , Síndromes de Imunodeficiência/genética , Imunossupressores/efeitos adversos , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/genética , Lectina de Ligação a Manose/genética , Terapia de Alvo Molecular , Risco
10.
Medicine (Baltimore) ; 98(18): e15329, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31045771

RESUMO

RATIONALE: Gain of function (GOF) mutations in PIK3CD gene encoding PI3K p110δ were recently associated with a novel combined immune deficiency characterized by recurrent sinopulmonary infections, CD4 lymphopenia, reduced class-switched memory B cells, lymphadenopathy, cytomegalovirus and/or epstein-Barr virus (EBV) viremia, and EBV-related lymphoma. A subset of affected patients also had elevated serum IgM. PATIENT CONCERNS: We report a patient who was diagnosed with systemic lupus erythematosus (SLE) at a young age and was recently found to carry heterozygous mutations in PIK3CD. The patient not only presented with recurrent sinopulmonary infections, CD4 lymphopenia, lymphadenopathy, EBV viremia, and elevated serum IgM, but also met classification criteria of SLE based on persistent proteinuria and hematuria, leukopenia and anemia, low level of serum complement, and positive autoantibody for antinuclear antibodies. DIAGNOSES: Activated PI3Kδ syndrome. INTERVENTIONS: Oral prednisolone and hydroxychloroquine combined with mycophenolate mofetil was given to the patient. He was currently receiving intravenous immunoglobulin per month in association with hydroxychloroquine, low-dose prednisolone, and mycophenolate mofetil. OUTCOMES: At present, the level of complement restored to normal, hematuria and proteinuria disappeared, and liver function returned to normal. LESSONS: SLE may be a novel phenotype of GOF mutation in PI3CKD gene (GOF PIK3CD).


Assuntos
Classe I de Fosfatidilinositol 3-Quinases/genética , Mutação com Ganho de Função/genética , Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/genética , Lúpus Eritematoso Sistêmico/genética , Adolescente , Anticorpos Antinucleares/sangue , Grupo com Ancestrais do Continente Asiático/genética , Classe I de Fosfatidilinositol 3-Quinases/efeitos dos fármacos , Proteínas do Sistema Complemento/análise , Proteínas do Sistema Complemento/efeitos dos fármacos , Inibidores Enzimáticos/uso terapêutico , Infecções por Vírus Epstein-Barr/diagnóstico , Infecções por Vírus Epstein-Barr/etiologia , Infecções por Vírus Epstein-Barr/imunologia , Glucocorticoides/uso terapêutico , Herpesvirus Humano 4/imunologia , Humanos , Hidroxicloroquina/administração & dosagem , Hidroxicloroquina/uso terapêutico , Imunoglobulinas Intravenosas/uso terapêutico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/etiologia , Lúpus Eritematoso Sistêmico/imunologia , Masculino , Ácido Micofenólico/administração & dosagem , Ácido Micofenólico/uso terapêutico , Fenótipo , Prednisolona/administração & dosagem , Prednisolona/uso terapêutico
11.
Nat Commun ; 10(1): 2201, 2019 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-31101814

RESUMO

Systemic lupus erythematosus (SLE) is the prototypic systemic autoimmune disease. It is thought that many common variant gene loci of weak effect act additively to predispose to common autoimmune diseases, while the contribution of rare variants remains unclear. Here we describe that rare coding variants in lupus-risk genes are present in most SLE patients and healthy controls. We demonstrate the functional consequences of rare and low frequency missense variants in the interacting proteins BLK and BANK1, which are present alone, or in combination, in a substantial proportion of lupus patients. The rare variants found in patients, but not those found exclusively in controls, impair suppression of IRF5 and type-I IFN in human B cell lines and increase pathogenic lymphocytes in lupus-prone mice. Thus, rare gene variants are common in SLE and likely contribute to genetic risk.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Predisposição Genética para Doença , Lúpus Eritematoso Sistêmico/genética , Proteínas de Membrana/genética , Quinases da Família src/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adolescente , Adulto , Animais , Linfócitos B/citologia , Linfócitos B/imunologia , Linfócitos B/metabolismo , Estudos de Casos e Controles , Linhagem Celular , Núcleo Celular/imunologia , Núcleo Celular/metabolismo , Criança , Modelos Animais de Doenças , Feminino , Frequência do Gene , Células HEK293 , Voluntários Saudáveis , Humanos , Fatores Reguladores de Interferon/imunologia , Fatores Reguladores de Interferon/metabolismo , Interferon Tipo I/imunologia , Interferon Tipo I/metabolismo , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/imunologia , Masculino , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutação de Sentido Incorreto , Sequenciamento Completo do Exoma , Quinases da Família src/metabolismo
12.
Nat Commun ; 10(1): 2164, 2019 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-31092820

RESUMO

Systemic lupus erythematosus (SLE) is an autoimmune disease, characterised by increased expression of type I interferon (IFN)-regulated genes and a striking sex imbalance towards females. Through combined genetic, in silico, in vitro, and ex vivo approaches, we define CXorf21, a gene of hitherto unknown function, which escapes X-chromosome inactivation, as a candidate underlying the Xp21.2 SLE association. We demonstrate that CXorf21 is an IFN-response gene and that the sexual dimorphism in expression is magnified by immunological challenge. Fine-mapping reveals a single haplotype as a potential causal cis-eQTL for CXorf21. We propose that expression is amplified through modification of promoter and 3'-UTR chromatin interactions. Finally, we show that the CXORF21 protein colocalises with TLR7, a pathway implicated in SLE pathogenesis. Our study reveals modulation in gene expression affected by the combination of two hallmarks of SLE: CXorf21 expression increases in a both an IFN-inducible and sex-specific manner.


Assuntos
Cromossomos Humanos X/genética , Genes Ligados ao Cromossomo X/genética , Interferon Tipo I/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Lúpus Eritematoso Sistêmico/genética , Regiões 3' não Traduzidas/genética , Adulto , Fatores Etários , Estudos de Casos e Controles , Feminino , Genes Ligados ao Cromossomo X/imunologia , Predisposição Genética para Doença , Humanos , Interferon Tipo I/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/genética , Lúpus Eritematoso Sistêmico/imunologia , Masculino , Regiões Promotoras Genéticas/genética , Fatores Sexuais , Receptor 7 Toll-Like/genética
13.
Gene ; 706: 181-187, 2019 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-31082500

RESUMO

Systemic lupus erythematous (SEL) is a heterogeneous, systemic autoimmune disorder which is defined by its autoantibody pattern. Transcriptomic data analysis has shown pathways and immune system responses associated with SLE. Eight up-regulated genes (SOCE, MMP9, CXCL8, JUN, IL1B, NFKBIA, TNF and FOS) have been examined with four interactions among different pathways. These genes are associated with SNPs which have been identified through two datasets from SLE genome-wide association studies (GWAS). In this investigation, the GWAS results were integrated with pathway analysis of transcriptomes and several genes were detected with known SLE-related variations (TYK2, C5, SH2B, IRF5, IL2RA, STAT4, FCGR2A, IL7R, LYN, HLA-DRB and TNFAIP3). Pathway-based analysis on the Wikipathway Human Collection allowed the identification of prioritized variants in the relevant pathways, such as thymic stromal lymphopoietin (TSLP) signaling pathway linked to LYN, IL7R, STAT4 and rs7574865. Analysis of existing transcriptomes and GWAS data identified eight up-regulated candidate genes with more than four relationships among the different pathways associated with SNPs to pinpoint the relevant loci linked to SLE. The results of this investigation have expanded the number of candidate genes related to SLE and have highlighted possible pathways and GWAS-based methods for gene detection. Identification of the fundamental genes would assist in revealing the mechanisms responsible for SLE.


Assuntos
Perfilação da Expressão Gênica/métodos , Lúpus Eritematoso Sistêmico/genética , Estudos de Casos e Controles , Bases de Dados Genéticas , Ontologia Genética , Redes Reguladoras de Genes/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Fatores Reguladores de Interferon/genética , Lúpus Eritematoso Sistêmico/fisiopatologia , Polimorfismo de Nucleotídeo Único/genética , Receptores de IgG/genética , Fator de Transcrição STAT4/genética , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/genética
14.
Lupus ; 28(6): 771-777, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31042126

RESUMO

Systemic lupus erythematosus (SLE) is an autoimmune disease with unknown exact etiology. Vitamin D receptor gene ( VDR) and oxidative stress play important roles in the pathogenesis of SLE. Here we investigated the genotypes and allelic frequencies of VDR BsmI polymorphism as well as their relationship with oxidative stress markers in Egyptian SLE children. We conducted a cross-sectional comparative study at Mansoura University Children's Hospital, Egypt from 2014 to 2018 including 100 SLE children and 100 controls. We investigated both groups for VDR BsmI polymorphism using polymerase chain reaction. Oxidative stress was assessed using malondialdehyde, glutathione S-transferase, superoxide dismutase, catalase and total antioxidant capacity. BB genotype frequency was found to be significantly higher in the SLE group ( p = 0.04, odds ratio (95% confidence interval) = 2.5 (1.01-5.9)). However, VDR B allele and b allele showed insignificant differences between SLE patients and controls ( p = 0.36, odds ratio (95% confidence interval) = 1.2 (0.8-1.8)). Lower levels of glutathione S-transferase, superoxide dismutase and total antioxidant capacity were found in the SLE group with statistically significant differences as regards glutathione S-transferase and superoxide dismutase ( p < 0.001). Serum malondialdehyde and catalase levels were significantly higher in the SLE group ( p < 0.001). No significant differences were found between VDR BsmI polymorphism (genotypes and alleles) and oxidative stress markers in the SLE group. In conclusion, BB genotype of VDR BsmI polymorphism is associated with an increased risk of SLE among Egyptian children. Oxidative stress may contribute in pathogenesis of SLE but is not associated with VDR BsmI polymorphism.


Assuntos
Lúpus Eritematoso Sistêmico/genética , Estresse Oxidativo , Polimorfismo Genético , Receptores de Calcitriol/genética , Adolescente , Alelos , Estudos de Casos e Controles , Criança , Estudos Transversais , Egito , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Reação em Cadeia da Polimerase
15.
Clin Sci (Lond) ; 133(9): 1049-1052, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-31064795

RESUMO

Circular RNAs (circRNAs) are a class of non-coding RNAs that regulate gene expression by acting as competitive endogenous RNAs (ceRNAs) and modulating gene transcription. Several studies support the implication of circRNAs in a variety of human diseases, but research on the role of circRNAs in systemic lupus erythematosus (SLE) is lacking. In a study recently published in Clinical Science (2018), Zhang et al. identified hsa_circ_0012919 as a potential biomarker of disease activity in SLE patients. The authors observed different circRNA expression between SLE patients and healthy controls, an association with clinical variables and with the abnormal DNA methylation present in SLE CD4+ T cells. Finally, Zhang et al. demonstrated that hsa_circ_0012919 acts as a miRNA sponge for miR-125a-3p, regulating the gene expression of targets RANTES and KLF13 that are involved in the physiology and pathophysiology of acute and chronic inflammatory processes. These findings support the role of circRNAs in the pathophysiology of SLE.


Assuntos
Lúpus Eritematoso Sistêmico/genética , MicroRNAs/genética , Biomarcadores , Ligante CD27/genética , Linfócitos T CD4-Positivos , Metilação de DNA , Regulação para Baixo , Humanos
16.
Chem Biol Interact ; 306: 110-116, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30991045

RESUMO

MicroRNAs (miRNAs) have been implicated in both biological and pathological processes in patients with systemic lupus erythematosus (SLE). Previous studies have demonstrated dysregulated expression of miR-199-3p, interleukin (IL)-10, and poly (ADP-ribose) polymerase-1 (PARP-1) in SLE. However, the underlying mechanisms of these aberrations have not been fully elucidated. In this study, we investigated the mechanism through which miR-199-3p dysregulation contributed to the pathogenesis of SLE. Altered gene expression was assessed by ChIP analysis. We then silenced the expression of candidate genes using siRNA for functional analysis; mRNA expression, protein levels, and protein expression were determined by qRT-PCR, ELISA, and western blotting, respectively. According to ChIP and qRT-PCR results, miR-199-3p was up-regulated in SLE patients. Moreover, IL-10 was found to be highly expressed in SLE patients by ELISA. Further, PARP1 was significantly down-regulated in SLE patients based on western blotting. Our results also indicated that miR-199-3p inhibits PARP1 expression by activating the ERK1/2 pathway, thereby increasing IL-10 expression. Significantly up-regulated miR-199-3p was inversely related to PARP-1 expression and positively correlated with IL-10 levels in SLE. As miR-199-3p was shown to target PARP-1 to activate the ERK1/2 pathway and promote IL-10 production, restoring physiological miR-199-3p levels could represent a potential therapeutic strategy for SLE treatment.


Assuntos
Interleucina-10/biossíntese , Lúpus Eritematoso Sistêmico/metabolismo , MicroRNAs/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Poli(ADP-Ribose) Polimerase-1/metabolismo , Adulto , Feminino , Células HEK293 , Humanos , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/genética , Masculino , Pessoa de Meia-Idade , Adulto Jovem
17.
Best Pract Res Clin Haematol ; 32(1): 74-88, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30927978

RESUMO

Autoimmune diseases (ADs) are associated with an increased risk not only of lymphoproliferative disorders but also of myeloid malignancies. The excess risk of myelodysplastic syndromes and/or acute myeloid leukemia is observed across several AD types, including systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disorders, multiple sclerosis, among others. The risk of developing myeloid neoplasms (MNs) is dependent on several variables, including the specific AD type, chronicity and severity of the AD, type and duration of exposure of disease modifying anti-rheumatic drugs or cytotoxics/immunosuppressives, and genetic predisposition risk. Putative triggering factors linking AD to elevated MN risk include AD-directed medications, shared genetic susceptibilities between the two disease entities, and chronic immune stimulation or bone marrow infiltration by the AD. Molecular mechanisms underpinning leukemogenesis remain largely speculative and warrant further investigation. Leukemias arising in patients with AD are not always 'therapy-related' in that MNs may develop in certain AD subtypes even among patients with no prior therapy exposure. Only a few studies have attempted to determine factors associated with MN development in AD but failed to demonstrate consistent characteristic clinical or paraclinical features. These reports have failed to demonstrate a clear correlation between individual agent exposure and subsequent leukemia development due to the low rates of therapy exposure compounded by the rarity of MN occurrence. Notwithstanding, the leukemogenic potential is best documented with agents such as azathioprine, cyclophosphamide, and mitoxantrone; this risk of MN development does not appear to be shared by biologic approaches such as anti-tumor necrosis factors-alpha inhibitors. In this article, we discuss plausible biologic mechanisms underlying MN pathogenesis in AD and review the data available on the development of MNs in patients with AD.


Assuntos
Artrite Reumatoide , Ciclofosfamida/efeitos adversos , Predisposição Genética para Doença , Imunossupressores/efeitos adversos , Leucemia Mieloide Aguda , Lúpus Eritematoso Sistêmico , Mitoxantrona/efeitos adversos , Síndromes Mielodisplásicas , Segunda Neoplasia Primária , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/genética , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Ciclofosfamida/uso terapêutico , Humanos , Imunossupressores/uso terapêutico , Leucemia Mieloide Aguda/induzido quimicamente , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/patologia , Mitoxantrona/uso terapêutico , Síndromes Mielodisplásicas/induzido quimicamente , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/metabolismo , Síndromes Mielodisplásicas/patologia , Segunda Neoplasia Primária/genética , Segunda Neoplasia Primária/metabolismo , Segunda Neoplasia Primária/patologia
18.
J Immunol Res ; 2019: 1547578, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30984790

RESUMO

Aims: This study is aimed at exploring the relation between IL-33 single-nucleotide polymorphisms (SNPs) and the risk of systemic lupus erythematosus (SLE). Methods: SNPStats (online software) was used to test the Hardy-Weinberg equilibrium in controls. Generalized multifactor dimensionality reduction (GMDR) was adopted to screen the preferable interaction between IL-33 SNPs and current smoking. Results: Logistic regression analysis based on the fundamental data of age, gender, BMI, current smoking, and alcohol drinking showed that both rs1929992-G and rs1891385-C alleles were correlated with an increasing risk of SLE, the ORs (95% CI) of which were 1.62 (1.21-2.05) and 1.64 (1.22-2.10), respectively. One two-locus model (rs1929992×current smoking) had a testing accuracy of 60.11% (P = 0.0010). Through an overall multidimensional model, optimum cross-validation consistency was obtained. The analysis indicated that current smoking status influenced the SLE risk depending on the genotypes at rs1929992. Pairwise LD analysis indicated that haplotype rs1929992G-rs7044343T was statistically related to the elevating risk of SLE (P < 0.05). Those subjects with the G-T haplotype had a higher SLE risk than those with other haplotypes, after correction with factors, including gender, alcohol drinking, age, BMI, and current smoking. Conclusions: The rs1929992-G and rs1891385-C allele, interaction between the rs1929992 gene and current smoking, and haplotype rs1929992G-rs7044343T were all risk factors of SLE.


Assuntos
Predisposição Genética para Doença , Interleucina-33/genética , Lúpus Eritematoso Sistêmico/genética , Polimorfismo de Nucleotídeo Único , Fumar/efeitos adversos , Adulto , Consumo de Bebidas Alcoólicas , Alelos , Grupo com Ancestrais do Continente Asiático , Feminino , Frequência do Gene , Estudos de Associação Genética , Genótipo , Haplótipos , Humanos , Lúpus Eritematoso Sistêmico/etnologia , Masculino , Pessoa de Meia-Idade , Análise de Regressão , Fatores de Risco
19.
Lupus ; 28(6): 740-747, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31018759

RESUMO

OBJECTIVE: The aim of this study is to determine whether the functional interferon regulatory factor 5 ( IRF5) polymorphism rs2004640 is associated with susceptibility to systemic lupus erythematosus (SLE) in multiple ethnic populations. METHODS: A meta-analysis was conducted on the T allele of the IRF5 rs2004640 polymorphism in all study participants as well as each ethnic population. RESULTS: Twenty research articles that included 28 comparative studies of 20,892 patients and 24,930 controls were included in the meta-analysis. The Asian population had a much lower prevalence of the T allele than any other study population at 28%, and the European population had the highest prevalence of the T allele at 52%. Meta-analysis showed an association between the IRF5 rs2004640 polymorphism and SLE in all participants (odds ratio = 1.472, 95% confidence interval = 1.370-1.582, p < 0.001). Analysis after stratification by ethnicity indicated that the IRF5 rs2004640 T allele is significantly associated with SLE in Europeans, Asians, Latin Americans and Arabs. CONCLUSIONS: This meta-analysis confirms that the IRF5 rs2004640 polymorphism is associated with SLE susceptibility in different ethnic groups, and that its prevalence is ethnicity dependent.


Assuntos
Fatores Reguladores de Interferon/genética , Lúpus Eritematoso Sistêmico/genética , Polimorfismo Genético , Alelos , Ásia/epidemiologia , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , Grupos Étnicos/genética , Europa (Continente)/epidemiologia , Grupo com Ancestrais do Continente Europeu/genética , Frequência do Gene , Predisposição Genética para Doença , Humanos , América Latina/epidemiologia , Lúpus Eritematoso Sistêmico/epidemiologia , Prevalência
20.
Lupus ; 28(6): 748-754, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31023128

RESUMO

OBJECTIVE: This study aimed to assess IL-24 levels and their association with clinical manifestations in patients with systemic lupus erythematosus (SLE). METHODS: There were 75 patients with SLE and 58 healthy controls recruited in this study. Serum levels of IL-24 were measured by enzyme-linked immunosorbent assays, and mRNA levels of IL-24 were tested by quantitative real-time polymerase chain reaction . The area under the curve of the receiver operating characteristic (ROC) curve was used for diagnostic ability of the inflammatory cytokine. RESULTS: Serum IL-24 levels were significantly higher in SLE patients than that in healthy controls. SLE patients with nephritis had higher IL-24 levels than those without nephritis. Active SLE patients showed higher expression of IL-24 as compared to less active disease patients. The mRNA levels of IL-24 were much higher in SLE patients. Correlation analysis showed significant correlation between serum IL-24 levels and SLE disease activity index. In addition, ROC analysis may suggest good ability of serum IL-24 in differentiating SLE. CONCLUSION: The inflammatory cytokine correlated with SLE disease activity, and may be involved in this disease pathogenesis.


Assuntos
Interleucinas/sangue , Lúpus Eritematoso Sistêmico/sangue , Adulto , Estudos de Casos e Controles , Ensaio de Imunoadsorção Enzimática , Feminino , Predisposição Genética para Doença , Humanos , Interleucinas/genética , Lúpus Eritematoso Sistêmico/genética , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/genética , Curva ROC , Reação em Cadeia da Polimerase em Tempo Real , Índice de Gravidade de Doença
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