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1.
Nat Commun ; 10(1): 4097, 2019 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-31506438

RESUMO

Phenotypic variation of quantitative traits is orchestrated by a complex interplay between the environment (e.g. diet) and genetics. However, the impact of gene-environment interactions on phenotypic traits mostly remains elusive. To address this, we feed 1154 mice of an autoimmunity-prone intercross line (AIL) three different diets. We find that diet substantially contributes to the variability of complex traits and unmasks additional genetic susceptibility quantitative trait loci (QTL). By performing whole-genome sequencing of the AIL founder strains, we resolve these QTLs to few or single candidate genes. To address whether diet can also modulate genetic predisposition towards a given trait, we set NZM2410/J mice on similar dietary regimens as AIL mice. Our data suggest that diet modifies genetic susceptibility to lupus and shifts intestinal bacterial and fungal community composition, which precedes clinical disease manifestation. Collectively, our study underlines the importance of including environmental factors in genetic association studies.


Assuntos
Cruzamentos Genéticos , Dieta , Genes , Estudos de Associação Genética , Característica Quantitativa Herdável , Animais , Animais não Endogâmicos , Anticorpos Antinucleares/genética , Bactérias/crescimento & desenvolvimento , Biodiversidade , Feminino , Fungos/crescimento & desenvolvimento , Predisposição Genética para Doença , Nefrite Lúpica/genética , Nefrite Lúpica/imunologia , Masculino , Camundongos , Microbiota , Mapeamento Físico do Cromossomo , Locos de Características Quantitativas/genética , Baço/metabolismo , Transcriptoma/genética , Sequenciamento Completo do Genoma
2.
Medicine (Baltimore) ; 98(31): e16716, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31374066

RESUMO

The purposes of the study was to validate the relationship between General transcription factor II-I (GTF2I) genetic variants and kidney involvements of systemic lupus erythematosus (SLE) patients in a Chinese Han population.Samples from 400 SLE patients and 400 age- and sex-matched healthy controls were collected and genotyped by improved multiplex ligation detection reaction technique. The relationship between gene polymorphism of rs117026326, rs73366469, and susceptibility, progression of SLE were analyzed.The present study provided evidence that rs117026326 and rs73366469 were both associated with SLE susceptibility (both C vs T: P < .001). The analysis of dominant, recessive disease model provided us with further validation (P < .001). Both gene polymorphisms are associated with a triad of disease manifestations among SLE patients. Patients carrying genotype TT of rs117026326 had lower 24-hour urinary total protein (24 hours UTP, g/24 hours), 24-hour urinary protein level (g/L·24 hours), lower frequency of the proteinuria and lupus nephritis (LN). Patients carrying genotype TT at rs73366469 had higher 24-hour urinary protein level, higher frequency of the proteinuria, LN and positive anti-dsDNA than those with other genotypes.This study identified the involvement of GTF2I gene polymorphisms in development of SLE, particularly in renal involvement.


Assuntos
Nefrite Lúpica/genética , Fatores de Transcrição TFII/genética , Adulto , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , China , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Nefrite Lúpica/urina , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Proteinúria/urina , Adulto Jovem
3.
Int J Mol Sci ; 20(13)2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31266174

RESUMO

It is incompletely understood how self-antigens become targets of humoral immunity in antibody-mediated autoimmune diseases. In this context, alarmins are discussed as an important level of regulation. Alarmins are recognized by various receptors, such as receptor for advanced glycation end products (RAGE). As RAGE is upregulated under inflammatory conditions, strongly binds nucleic acids and mediates pro-inflammatory responses upon alarmin recognition, our aim was to examine its contribution to immune complex-mediated autoimmune diseases. This question was addressed employing RAGE-/- animals in murine models of pristane-induced lupus, collagen-induced, and serum-transfer arthritis. Autoantibodies were assessed by enzyme-linked immunosorbent assay, renal disease by quantification of proteinuria and histology, arthritis by scoring joint inflammation. The associated immune status was determined by flow cytometry. In both disease entities, we detected tendentiously decreased autoantibody levels in RAGE-/- mice, however no differences in clinical outcome. In accordance with autoantibody levels, a subgroup of the RAGE-/- animals showed a decrease in plasma cells, and germinal center B cells and an increase in follicular B cells. Based on our results, we suggest that RAGE deficiency alone does not significantly affect antibody-mediated autoimmunity. RAGE may rather exert its effects along with other receptors linking environmental factors to auto-reactive immune responses.


Assuntos
Artrite Experimental/imunologia , Autoanticorpos/metabolismo , Nefrite Lúpica/imunologia , Receptor para Produtos Finais de Glicação Avançada/deficiência , Animais , Artrite Experimental/genética , Autoanticorpos/sangue , Linfócitos B/imunologia , Colágeno/efeitos adversos , Modelos Animais de Doenças , Centro Germinativo/imunologia , Nefrite Lúpica/genética , Camundongos , Receptor para Produtos Finais de Glicação Avançada/imunologia , Terpenos/efeitos adversos
4.
Scand J Immunol ; 90(5): e12810, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31325389

RESUMO

MicroRNAs (miRNAs) play a vital role in the occurrence and development of many human diseases, including systemic lupus erythematosus (SLE). SLE is an autoimmune disease characterized by the production of autoantibodies against nuclear antigens and multiorgan involvement. Study of miRNAs involved in SLE provides new insights into the pathogenesis of SLE and might lead to the identification of new therapeutic interventions. The aim of this study was to investigate the effect of miR-183 injection on the progression of SLE by using MRL/lpr mouse model. The expression levels of miR-183 and mTOR mRNA were detected by quantitative real-time PCR assay. The effect of miR-183 on the course of spontaneous disease progression in the MRL/lpr mice was examined by intraperitoneal injection of miR-183 into mice and followed by monitoring lifespan, anti-dsDNA antibody levels, urinary albumin levels, blood urea nitrogen (BUN) levels, and Tregs and Th17 cell population. We found that miR-183 injection resulted in reduction of anti-DNA antibody and immune complex component levels, restoration of Tregs and Th17 cell population and prolongation of survival. Our findings suggest that miR-183 injection may serve as an effective therapeutic treatment for delaying or easing pathologic features of SLE.


Assuntos
Nefrite Lúpica/terapia , MicroRNAs/genética , MicroRNAs/uso terapêutico , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/genética , Adulto , Albuminúria/urina , Animais , Anticorpos Antinucleares/sangue , Nitrogênio da Ureia Sanguínea , Modelos Animais de Doenças , Feminino , Humanos , Nefrite Lúpica/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , RNA Mensageiro/genética , Linfócitos T Reguladores/imunologia , Serina-Treonina Quinases TOR/metabolismo , Células Th17/imunologia
5.
Lupus ; 28(8): 995-1002, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31184250

RESUMO

BACKGROUND: Pediatric-onset SLE (pSLE) is a multisystem autoimmune disease. Recently, the ficolin-2 (FCN2) gene has emerged as a potential candidate gene for susceptibility to SLE. OBJECTIVES: The objective of this study was to evaluate the association of the FCN2 gene polymorphisms at positions -986 (G/A), -602 (G/A), -4 (A/G) and SNP C/T (rs3124954) located in intron 1, with susceptibility to pSLE in Egyptian children and adolescents. METHODS: This was a multicenter study of 280 patients diagnosed with pSLE, and 280 well-matched healthy controls. The FCN2 promoter polymorphisms at -986 G/A (rs3124952), -602 G/A (rs3124953), -4 A/G (rs17514136) and SNP C/T (rs3124954) located in intron 1 were genotyped by polymerase chain reaction, while serum ficolin-2 levels were assessed using enzyme-linked immunosorbent assay. RESULTS: The frequencies of the FCN2 GG genotype and G allele at -986 and -602 positions were significantly more represented in patients with pSLE than in controls (p < 0.001). Conversely, the FCN2 AA genotype and A allele at position -4 were more common in patients than in controls (p < 0.001). Moreover, patients carrying the FCN2 GG genotype in -986 position were more likely to develop lupus nephritis (odds ratio: 2.6 (95% confidence interval: 1.4-4.78); p = 0.006). The FCN2 AA genotype at position -4 was also identified as a possible risk factor for lupus nephritis (odds ratio: 3.12 (95% confidence interval: 1.25-7.84); p = 0.024). CONCLUSION: The FCN2 promoter polymorphisms may contribute to susceptibility to pSLE in Egyptian children and adolescents. Moreover, the FCN2 GG genotype at position -986 and AA genotype at position -4 were associated with low serum ficolin-2 levels and may constitute risk factors for lupus nephritis in pSLE.


Assuntos
Predisposição Genética para Doença , Lectinas/genética , Lúpus Eritematoso Sistêmico/genética , Nefrite Lúpica/genética , Adolescente , Alelos , Estudos de Casos e Controles , Criança , Egito , Feminino , Humanos , Modelos Logísticos , Masculino , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Fatores de Risco
6.
Nat Immunol ; 20(7): 902-914, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31209404

RESUMO

Lupus nephritis is a potentially fatal autoimmune disease for which the current treatment is ineffective and often toxic. To develop mechanistic hypotheses of disease, we analyzed kidney samples from patients with lupus nephritis and from healthy control subjects using single-cell RNA sequencing. Our analysis revealed 21 subsets of leukocytes active in disease, including multiple populations of myeloid cells, T cells, natural killer cells and B cells that demonstrated both pro-inflammatory responses and inflammation-resolving responses. We found evidence of local activation of B cells correlated with an age-associated B-cell signature and evidence of progressive stages of monocyte differentiation within the kidney. A clear interferon response was observed in most cells. Two chemokine receptors, CXCR4 and CX3CR1, were broadly expressed, implying a potentially central role in cell trafficking. Gene expression of immune cells in urine and kidney was highly correlated, which would suggest that urine might serve as a surrogate for kidney biopsies.


Assuntos
Rim/imunologia , Nefrite Lúpica/imunologia , Biomarcadores , Biópsia , Análise por Conglomerados , Biologia Computacional/métodos , Células Epiteliais/metabolismo , Citometria de Fluxo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Humanos , Imunofenotipagem , Interferons/metabolismo , Rim/metabolismo , Rim/patologia , Leucócitos/imunologia , Leucócitos/metabolismo , Nefrite Lúpica/genética , Nefrite Lúpica/metabolismo , Nefrite Lúpica/patologia , Linfócitos/imunologia , Linfócitos/metabolismo , Anotação de Sequência Molecular , Células Mieloides/imunologia , Células Mieloides/metabolismo , Análise de Célula Única , Transcriptoma
7.
Nat Immunol ; 20(7): 915-927, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31110316

RESUMO

The molecular and cellular processes that lead to renal damage and to the heterogeneity of lupus nephritis (LN) are not well understood. We applied single-cell RNA sequencing (scRNA-seq) to renal biopsies from patients with LN and evaluated skin biopsies as a potential source of diagnostic and prognostic markers of renal disease. Type I interferon (IFN)-response signatures in tubular cells and keratinocytes distinguished patients with LN from healthy control subjects. Moreover, a high IFN-response signature and fibrotic signature in tubular cells were each associated with failure to respond to treatment. Analysis of tubular cells from patients with proliferative, membranous and mixed LN indicated pathways relevant to inflammation and fibrosis, which offer insight into their histologic differences. In summary, we applied scRNA-seq to LN to deconstruct its heterogeneity and identify novel targets for personalized approaches to therapy.


Assuntos
Perfilação da Expressão Gênica , Interferon Tipo I/metabolismo , Queratinócitos/metabolismo , Túbulos Renais/citologia , Túbulos Renais/metabolismo , Nefrite Lúpica/genética , Nefrite Lúpica/metabolismo , Transcriptoma , Biópsia , Linhagem da Célula/genética , Biologia Computacional/métodos , Proteínas da Matriz Extracelular/genética , Proteínas da Matriz Extracelular/metabolismo , Fibrose , Perfilação da Expressão Gênica/métodos , Humanos , Nefrite Lúpica/patologia , Ligação Proteica , Transdução de Sinais , Análise de Célula Única , Pele/imunologia , Pele/metabolismo , Pele/patologia
8.
Mol Med Rep ; 20(1): 245-251, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31115581

RESUMO

Lupus nephritis (LN) is one of the principal causes of mortality and disability in patients with systemic lupus erythematosus. Sirolimus has been used to treat patients with LN; however, the effects and mechanism of sirolimus in these patients remains unclear. The present study aimed to elucidate the therapeutic effects and mechanisms of sirolimus in LN mice using low, medium and high doses of sirolimus (0.1, 0.3 and 1 mg/kg, respectively). The survival probability and kidney index were calculated, and renal fibrosis was determined using Masson's Trichrome staining. The expression levels of E­cadherin, α­smooth muscle actin (α­SMA) and vimentin were assessed via immunofluorescence analysis. Transcriptome analysis of control and sirolimus­treated LN mice was performed using RNA­sequencing, differentially expressed gene (DEG) identification and annotation, and Gene Ontology (GO) functional and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment. The results suggested that a medium dose of sirolimus alleviated renal fibrosis and increased the survival rates of mice with LN (P<0.05). Furthermore, transcriptome analysis revealed 334 DEGs associated with LN, 176 of which were upregulated and 158 were downregulated. Following GO functional enrichment, 'biological process', 'molecular function' and 'cellular component' terms were identified. A total of 10 KEGG pathways were enriched, with 'cytokine­cytokine receptor interaction' and 'interleukin­17 signaling pathway' being significantly enriched (P<0.05). To the best of our knowledge, the present study is the first to conduct transcriptome analysis of LN mice treated with sirolimus, and demonstrated that a dose of 0.3 mg/kg exerted the greatest therapeutic effects.


Assuntos
Biologia Computacional , Redes Reguladoras de Genes/efeitos dos fármacos , Nefrite Lúpica/tratamento farmacológico , Sirolimo/farmacologia , Animais , Modelos Animais de Doenças , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Ontologia Genética , Humanos , Nefrite Lúpica/genética , Nefrite Lúpica/patologia , Camundongos , Mapeamento de Interação de Proteínas , Mapas de Interação de Proteínas/genética , Transcriptoma/efeitos dos fármacos
9.
DNA Cell Biol ; 38(7): 639-650, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31090450

RESUMO

In this study, we explored the genes genetically associated with lupus nephritis (LN), and their function by bioinformatics analysis. We collected genes potentially associated with LN from National Center for Biotechnology Information Center (NCBI-Gene) and Online Mendelian Inheritance in Man (OMIM) databases. The major bioinformatics analysis linked with genes was then revealed by weighted gene co-expression network analysis (WGCNA), crosstalk analysis, functional analysis, and Pivot algorithm. Two hundred twenty-three LN-related genes were obtained by intersecting NCBI-Gene and OMIM databases. Two thousand five hundred sixty-eight LN-related proteins and 23 modules were excavated by String protein interaction network and WGCNA co-expression analysis, respectively. Pivot algorithm included no coding RNA, transcription factor and drug indicated the high-count correlation-associated modules related to cancer, kidney pathophysiological changes, and kidney injury, respectively. Gene ontology and Kyoto Encyclopedia of Genes and Genomes analysis based on 23 modules revealed LN-related genes mainly involved in immune response. Moreover, 19 genes that came from intersection of LN, arthritis, pleurisy, and myocarditis have close relationship with immune diseases and immune processes. Our results from this research may have important implications for understanding the genes underlying LN. Also, the framework proposed in this work can be used to research pathological molecular network and genes related to LN.


Assuntos
Redes Reguladoras de Genes , Nefrite Lúpica/genética , Metaboloma/genética , Biologia Computacional/métodos , Bases de Dados Genéticas , Predisposição Genética para Doença , Humanos
10.
Crit Rev Eukaryot Gene Expr ; 29(1): 85-94, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31002598

RESUMO

Plasminogen activator inhibitor type 1 (PAI-1) correlates with the risk and progression of systemic lupus erythematosus (SLE). We aimed to assess the relationship between the PAI-1 4G/5G gene polymorphism and SLE/lupus nephritis risk. We identified the eligible studies regarding the association between the PAI-1 4G/5G gene polymorphism and the risk of SLE/lupus nephritis. The odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using a fixed-effects model or, in the presence of heterogeneity, a random-effects model. A total of six studies were enrolled in our pooled analysis. The PAI-1 4G/5G gene polymorphism had no significant association with the risk of SLE among overall populations, Asians and Caucasians. Nor was it associated with susceptibility to lupus nephritis among overall populations, Asians and Caucasians. Sensitivity analysis yielded similar results. No marked publication bias was noted. In conclusion, the PAI-1 4G/5G gene polymorphism is not associated with susceptibility to SLE/lupus nephritis among overall populations, Asians and Caucasians. However, more studies should be conducted in the future.


Assuntos
Predisposição Genética para Doença , Lúpus Eritematoso Sistêmico/genética , Nefrite Lúpica/genética , Inibidor 1 de Ativador de Plasminogênio/genética , Polimorfismo de Nucleotídeo Único , Grupo com Ancestrais do Continente Asiático/genética , Grupo com Ancestrais do Continente Europeu/genética , Humanos , Lúpus Eritematoso Sistêmico/metabolismo , Nefrite Lúpica/metabolismo
11.
BMC Med Genet ; 20(1): 46, 2019 03 22.
Artigo em Inglês | MEDLINE | ID: mdl-30902069

RESUMO

BACKGROUND: The purpose of this study was to detect the effects of vascular endothelial growth factor (VEGF) on systemic lupus erythematosus (SLE) risk. METHODS: Associated studies were extracted from the China Biological Medicine Database (CBM), and PubMed on June 10, 2018, and applicable investigations were pooled and analyzed by meta-analysis using RevMan 5.3. RESULTS: VEGF levels was associated with SLE risk (mean differences (MD) =196.02, 95% CI: 135.29-256.75, P < 0.00001), and VEGF levels was associated with active SLE risk (MD =77.51, 95% CI: 10.98-144.05, P = 0.02). We also found that VEGF levels was associated with SLE developing into lupus nephritis (LN) risk (MD =223.16, 95% CI: 144.38-301.93, P < 0.00001). However, VEGF -634G/C gene polymorphism (rs2010963) was not associated with SLE risk. CONCLUSIONS: VEGF levels was associated with SLE risk, active SLE risk and SLE developing into LN risk. However, there was no an association between VEGF -634G/C gene polymorphism and SLE risk.


Assuntos
Estudos de Associação Genética/métodos , Lúpus Eritematoso Sistêmico/genética , Polimorfismo de Nucleotídeo Único , Fator A de Crescimento do Endotélio Vascular/genética , Adulto , Estudos de Casos e Controles , Progressão da Doença , Feminino , Predisposição Genética para Doença , Humanos , Nefrite Lúpica/genética , Masculino , Pessoa de Meia-Idade , Adulto Jovem
12.
Lupus ; 28(4): 545-554, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30857465

RESUMO

Several studies have demonstrated associations between interleukin-18 polymorphisms and risk of systemic lupus erythematosus in different populations except one of Indian origin. We therefore investigated for the influence of interleukin-18 (-1297T/C, -607A/C, -137G/C; + 105A/C) polymorphisms on genetic susceptibility and clinical expression of the disease in Indian systemic lupus erythematosus patients. A total of 200 systemic lupus erythematosus patients and 201 controls were recruited. Genotyping of interleukin-18 polymorphisms were performed by polymerase chain reaction-restriction fragment length polymorphism. Serum interleukin-18 levels were measured by enzyme-linked immunosorbent assay. Interleukin-18 (-1297T/C; -137G/C) polymorphisms showed significant association with genetic susceptibility to the disease in our systemic lupus erythematosus cohort. Stratification analysis revealed -1297CC and -1297C associated with renal involvement (odds ratio = 3.4, correcting p value = 0.0207), (odds ratio = 2.0, correcting p value = 0.0054) respectively. Additionally, -1297C allele frequency was significantly increased in patients with anti-nucleosome antibody (odds ratio = 2.1, correcting p value = 0.0301). Haplotype analysis showed CC haplotype strongly associated with serositis (odds ratio = 9.1, correcting p values = 0.0009) and neurologic involvement (odds ratio = 9.3, correcting p value = 0.0018). We reported a 2.7-fold increase in serum interleukin-18 levels in patients (511.5 ± 242.3 pg/ml) compared to controls (189.4 ± 80.8 pg/ml) ( p < 0.0001). Furthermore, interleukin-18 levels were positively correlated with disease activity ( r = 0.548, p = 0.0001) and renal involvement in the patients with lupus nephritis ( r = 0.569, p < 0.0001). In summary, interleukin-18 polymorphisms elucidated in this study appear to confer genetic susceptibility to the disease and are associated with renal, serositis and neurologic involvement in Indian systemic lupus erythematosus patients.


Assuntos
Predisposição Genética para Doença , Interleucina-18/genética , Lúpus Eritematoso Sistêmico/epidemiologia , Lúpus Eritematoso Sistêmico/genética , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Frequência do Gene , Genótipo , Haplótipos , Humanos , Índia/epidemiologia , Lúpus Eritematoso Sistêmico/sangue , Nefrite Lúpica/genética , Masculino , Pessoa de Meia-Idade , Polimorfismo de Fragmento de Restrição , Estatísticas não Paramétricas , Adulto Jovem
13.
Front Immunol ; 10: 158, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30787934

RESUMO

Background: The role of miR-152 in lupus nephritis has not been elucidated. The aim of this study was to investigate the role of miR-152 in the pathogenesis of lupus nephritis (LN). Methods: miR-152 expression was detected using RT-PCR in LN tissue and normal controls. The miR-152 expression was compared with clinical parameters such as 24 h urine protein excretion level, serum creatinine, and serum complement level and SLEDAI score. The function of miR-152 was examined using human renal proximal tubular epithelial cells (HRPTE). miR-152 mimics and inhibitors were transfected to HRPTEs to ascertain the effects of miR-152. Results: miR-152 expression was downregulated in LN tissue. There was an inverse correlation between miR-152 expression in LN tissue and clinical parameters like 24 h urine protein excretion levels and serum creatinine, but not serum complement levels or SLEDAI. Further analysis showed that macrophage migration inhibitory factor (MIF) was a direct target of miR-152. Downregulation of MIF through complementary binding of miR-152 inhibited the renal expression of COL1A1. Conclusion: miR-152 expression was tapered in LN tissue and miR-152 expression was inversely correlated with chronicity index (CI), serum creatinine and severity of proteinuria. miR-152 may attenuate the severity of LN through the downregulation of MIF-induced expression of COL1A1. These findings suggest that miR-152 may be a potential target for the treatment of LN.


Assuntos
Colágeno Tipo I/genética , Regulação da Expressão Gênica , Oxirredutases Intramoleculares/metabolismo , Nefrite Lúpica/genética , Nefrite Lúpica/metabolismo , Fatores Inibidores da Migração de Macrófagos/metabolismo , MicroRNAs/genética , Interferência de RNA , Regiões 3' não Traduzidas , Biópsia , Humanos , Nefrite Lúpica/diagnóstico , RNA Mensageiro/genética , Índice de Gravidade de Doença
14.
Clin Rheumatol ; 38(5): 1361-1366, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30767092

RESUMO

Elevated IL-17 levels with higher Th17 numbers are identified in systemic lupus erythematosus (SLE). STAT3 signaling plays a crucial role in the Th17 generation, and SOCS3 negatively regulates their formation. We investigated IL-17, STAT3, and SOCS3 expression, and analyzed their correlations to elucidate the regulatory mechanisms of IL-17 production in SLE. This study enrolled 32 patients, and venous mononuclear cells (MNCs) were isolated with further purification of CD4-positive T cells. IL-17 and SOCS3 levels were measured by real-time quantitative PCR, and pSTAT3/STAT3 expression was analyzed by immunoblot. Elevated IL-17 and SOCS3 levels were identified in lupus patients. There were higher IL-17 levels in lupus nephritis (class IV) than in SLE without renal involvement. Positive correlations were found between IL-17 levels and SOCS3 expression, lupus activity (SLEDAI-2K), or daily proteinuria. There were higher intensities of pSTAT3/ß-actin and STAT3/ß-actin in SLE, and a positive correlation between IL-17 expression and pSTAT3/ß-actin or STAT3/ß-actin intensity. Lupus nephritis (class IV) had higher STAT3/ß-actin intensity than SLE without renal involvement. These results suggest upregulated STAT3/IL-17 expression in lupus patients. Such findings might facilitate the development of novel compounds and the application of existing therapeutics targeting the STAT3/IL-17 signal in SLE.


Assuntos
Interleucina-17/metabolismo , Lúpus Eritematoso Sistêmico/metabolismo , Fator de Transcrição STAT3/metabolismo , Proteína 3 Supressora da Sinalização de Citocinas/metabolismo , Adulto , Linfócitos T CD4-Positivos/imunologia , Feminino , Citometria de Fluxo , Humanos , Interleucina-17/genética , Leucócitos Mononucleares/metabolismo , Modelos Lineares , Lúpus Eritematoso Sistêmico/genética , Nefrite Lúpica/genética , Nefrite Lúpica/metabolismo , Masculino , Fator de Transcrição STAT3/genética , Transdução de Sinais , Proteína 3 Supressora da Sinalização de Citocinas/genética , Taiwan , Células Th17/imunologia , Regulação para Cima
15.
Immunity ; 50(2): 334-347.e9, 2019 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-30709743

RESUMO

Elevated endogenous retrovirus (ERV) transcription and anti-ERV antibody reactivity are implicated in lupus pathogenesis. Overproduction of non-ecotropic ERV (NEERV) envelope glycoprotein gp70 and resultant nephritis occur in lupus-prone mice, but whether NEERV mis-expression contributes to lupus etiology is unclear. Here we identified suppressor of NEERV (Snerv) 1 and 2, Krüppel-associated box zinc-finger proteins (KRAB-ZFPs) that repressed NEERV by binding the NEERV long terminal repeat to recruit the transcriptional regulator KAP1. Germline Snerv1/Snerv2 deletion increased activating chromatin modifications, transcription, and gp70 expression from NEERV loci. F1 crosses of lupus-prone New Zealand Black (NZB) and 129 mice to Snerv1/Snerv2-/- mice failed to restore NEERV repression, demonstrating that loss of SNERV underlies the lupus autoantigen gp70 overproduction that promotes nephritis in susceptible mice and that SNERV encodes for Sgp3 (in NZB mice) and Gv-1 loci (in 129 mice). Increased ERV expression in lupus patients inversely correlated with three putative ERV-suppressing KRAB-ZFPs, suggesting that loss of KRAB-ZFP-mediated ERV control may contribute to human lupus pathogenesis.


Assuntos
Proteínas de Transporte/imunologia , Retrovirus Endógenos/imunologia , Glicoproteínas/imunologia , Nefrite Lúpica/imunologia , Chaperonas Moleculares/imunologia , Proteínas Nucleares/imunologia , Proteínas Repressoras/imunologia , Animais , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Retrovirus Endógenos/genética , Retrovirus Endógenos/metabolismo , Regulação da Expressão Gênica/imunologia , Predisposição Genética para Doença/genética , Glicoproteínas/genética , Glicoproteínas/metabolismo , Células HEK293 , Humanos , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/metabolismo , Nefrite Lúpica/genética , Nefrite Lúpica/metabolismo , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NZB , Camundongos Knockout , Chaperonas Moleculares/genética , Chaperonas Moleculares/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo
16.
Lupus ; 28(3): 290-294, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30691345

RESUMO

OBJECTIVE: Vitamin D receptor (VDR) has potent anti-inflammatory activities. VDR gene polymorphism has been linked with systemic lupus erythematosus (SLE). However, its expression in the kidney has not been evaluated. This study aimed to investigate the relationship between VDR expression and renal pathology as well as clinical manifestations in lupus nephritis (LN). METHODS: A total of 20 renal biopsy specimens from 35 patients with LN were classified according to the International Society of Nephrology/Renal Pathology Society 2003 LN-type standards pathological type, and the activity index and chronicity index were determined. Five normal renal tissue samples were obtained from surrounding areas distal to nephronophthisis or renal tumors (>2 cm). The expression of VDR was assessed by immunohistochemistry. The relationships between VDR expression and histological injury index, proteinuria and Systemic Lupus International Collaborating Clinics (SLICC) renal activity scores were analyzed. RESULTS: As compared to the control group, the expression of VDR in the LN group was lower ( p < 0.001) and negatively correlated with activity index (r = -0.548, p = 0.012) but not with chronicity index (r = -0.277, p = 0.236). The expression of VDR in renal tissue was also associated with SLICC renal activity scores (r = -0.470, p = 0.037). CONCLUSION: The down-regulation of VDR expression in renal tissues of LN patients was negatively correlated with renal activity and injury severity.


Assuntos
Rim/lesões , Nefrite Lúpica/genética , Receptores de Calcitriol , Adulto , Estudos de Casos e Controles , Regulação para Baixo , Feminino , Humanos , Rim/patologia , Rim/fisiopatologia , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Proteinúria/genética , Índice de Gravidade de Doença
17.
Int J Rheum Dis ; 22(3): 458-467, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30398001

RESUMO

AIM: Lupus nephritis (LN) is a severe complication of systemic lupus erythematosus (SLE). There is a great interest in using microRNAs (miRNAs) as diagnostic and prognostic biomarkers in autoimmune diseases. MATERIALS AND METHODS: This study evaluated miR-16, miR-21, miR-141, miR-146a, and miR-155 expression levels in peripheral blood mononuclear cells (PBMCs) of 55 female SLE patients with absent, inactive, or active nephritis, and 30 healthy controls (HCs) using quantitative polymerase chain reaction. RESULTS: MiR-21 and miR-155 levels were significantly greater in the active nephritis group than in the absent, inactive or HC groups. Moreover, receiver operating characteristic and logistic regression analyses revealed miR-21 and miR-155 were significant risk factors for LN. CONCLUSION: Overexpression of miR-21 and miR-155 in PBMCs may participate in LN pathophysiology and these miRNAs could be used as biomarkers for the condition.


Assuntos
Leucócitos Mononucleares/química , Nefrite Lúpica/genética , MicroRNAs/genética , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Marcadores Genéticos , Humanos , Irã (Geográfico) , Nefrite Lúpica/sangue , Nefrite Lúpica/diagnóstico , MicroRNAs/sangue , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Risco , Regulação para Cima , Adulto Jovem
18.
Scand J Rheumatol ; 48(2): 133-140, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30269634

RESUMO

OBJECTIVE: Peptidylarginine deiminase-4 (PAD4) is highly expressed by neutrophils and essential for citrullination occurring during the formation of neutrophil extracellular traps, which have been implicated in the pathogenesis of systemic lupus erythematosus (SLE) and lupus nephritis (LN). Single-nucleotide polymorphisms (SNPs) in PADI4 influence PAD4 expression and functionality. Here, we investigate whether SNPs in PADI4 influence the risk of SLE or LN. METHOD: Altogether, 234 SLE patients and 484 controls were genotyped for nine PADI4 SNPs known to alter PAD4 functionality and/or expression, or to be associated with other autoimmune diseases, using an in-house multiplex Luminex assay. All analyses were adjusted for age and gender. RESULTS: Heterozygosity for rs1748033, and heterozygosity and homozygosity for rs1635564, were associated with increased occurrence of SLE [odds ratio (OR) 1.55, 95% confidence interval (CI) 1.08-2.23; OR 1.52, 95% CI 1.06-2.19; and OR 2.06, 95% CI 1.08-3.93, respectively]. Homozygosity for rs1635564 was also associated with increased occurrence of LN (OR 3.35, 95% CI 1.2-10.97). Notably, gene dose effects of the rs1635564 variant allele were observed for SLE (p = 0.005) and LN (p = 0.01). Carriage of minor alleles of five other SNPs (rs11203366, rs11203367, rs874881, rs2240340, and rs11203368) was associated with increased occurrence of LN and hypertension. CONCLUSION: The rs1635564 polymorphism of PADI4 is a candidate risk factor for SLE, particularly with renal involvement. Additional PADI4 polymorphisms also conferred increased risk of LN. Overall, these findings support the notion of PAD4 contributing to the pathogenesis of SLE and LN.


Assuntos
Lúpus Eritematoso Sistêmico/genética , Desiminases de Arginina em Proteínas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Creatinina/metabolismo , Feminino , Humanos , Hipertensão/genética , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/metabolismo , Nefrite Lúpica/genética , Masculino , Pessoa de Meia-Idade , Síndrome Nefrótica/genética , Polimorfismo de Nucleotídeo Único , Adulto Jovem
19.
Clin Exp Rheumatol ; 37(1): 67-72, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-29998838

RESUMO

OBJECTIVES: The aim of this study was to explore the value of serum miRNA for evaluating renal tissue activity in patients with class IV lupus nephritis (LN). METHODS: First, we used a microRNA array to identify miRNAs differentially expressed between class IV LN patients and healthy volunteers (n=4/group). Then, we analysed the association between these identified miRNAs and renal tissue activity in class IV LN patients. Finally, to validate the results, 20 class IV LN patients (confirmed by renal biopsy) and 20 healthy control volunteers were further studied. RESULTS: We found 23 miRNAs to be significantly differentially expressed between the 2 groups. We selected 5 of these miRNAs (miR-3165, miR-4762-5p, miR-146a-5p, miR-151a-3p, and miR-21-5p) for further experiments. In validation experiments, expression of miRNA-151a-3p was significantly down-regulated in the class IV LN group compared to that in the control group (p<0.01) and was negatively correlated with the activity index (AI) in the class IV LN group(r=-0.526, p=0.017); the internal correlation was described with a linear fitting equation (p<0.01). CONCLUSIONS: Serum miR-151a-3p expression was decreased in class IV LN patients compared with healthy control volunteers and was negatively correlated with renal tissue activity. Thus, miR-151a-3p may play a employed for diagnosing class IV LN and evaluating renal tissue activity.


Assuntos
Nefrite Lúpica/metabolismo , MicroRNAs , Estudos de Casos e Controles , Regulação para Baixo , Humanos , Nefrite Lúpica/genética , MicroRNAs/metabolismo
20.
Immunol Cell Biol ; 97(1): 17-28, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30052286

RESUMO

Inflammasomes are protein complexes activated by infection and cellular stress that promote caspase-1 activation and subsequent inflammatory cytokine processing and cell death. It has been anticipated that inflammasome activity contributes to autoimmunity. However, we previously showed that macrophages from autoimmune New Zealand Black (NZB) mice lack NLRP3 inflammasome function, and their absent in melanoma 2 (AIM2) inflammasome responses are compromised by high expression of the AIM2 antagonist protein p202. Here we found that the point mutation leading to lack of NLRP3 expression occurred early in the NZB strain establishment, as it is shared with the related obese strain New Zealand Obese, but not with the unrelated New Zealand White (NZW) strain. The first cross progeny of NZB and NZW mice develop more severe lupus nephritis than the NZB strain. We have compared AIM2 and NLRP3 inflammasome function in macrophages from NZB, NZW, and NZB/W F1 mice. The NZW parental strain showed strong inflammasome function, whereas the NZB/W F1 have haploinsufficient expression of NLRP3 and show reduced NLRP3 and AIM2 inflammasome responses, particularly at low stimulus strength. It remains to be established whether the low inflammasome function could contribute to loss of tolerance and the onset of autoimmunity in NZB and NZB/W F1. However, with amplifying inflammatory stimuli through the course of disease, the NLRP3 response in the NZB/W F1 may be sufficient to contribute to kidney damage at later stages of disease.


Assuntos
Autoimunidade , Proteínas de Ligação a DNA/deficiência , Inflamassomos , Macrófagos , Proteína 3 que Contém Domínio de Pirina da Família NLR/deficiência , Animais , Autoimunidade/genética , Proteínas de Ligação a DNA/imunologia , Feminino , Inflamassomos/genética , Nefrite Lúpica/genética , Nefrite Lúpica/imunologia , Nefrite Lúpica/patologia , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos NZB , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Mutação Puntual
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