RESUMO
Underexpression of p53 is considered the leading cause of the decreased miR-1246 expression in B cells of systemic lupus erythematosus (SLE) patients, yet the exact mechanism of action still remains unclear. To further explore the molecular mechanism of p53 upregulating miR-1246 expression, we targeted the methylation and acetylation of histone H3 in the miR-1246 promoter region of SLE B cells. We found that increased histone H3 trimethylation at Lys27 (H3K27me3) and decreased histone H3 acetylation at Lys9 and Lys14 (H3K9/K14ac) in the miR-1246 promoter region are essential for the low expression of miR-1246 in SLE B cells. p53 can promote miR-1246 transcription by recruiting Jumonji domain-containing protein 3 (JMJD3), E1A-binding protein p300 (EP300), and CREB-binding protein (CBP) to bind to the miR-1246 promoter, downregulating H3K27me3 and upregulating H3K9/K14ac. Furthermore, early B cell factor 1 (EBF1), CD40, CD38, and X box binding protein-1 (XBP-1) expression levels in SLE B cells transfected with p53 expression plasmid were significantly decreased, whereas autoantibody IgG production in autologous CD4+ T cells cocultured with overexpressed p53 SLE B cells was reduced. Collectively, our data suggest that the reduction of p53 decreases miR-1246 expression via upregulation of H3K27me3 and downregulation of H3K9/14ac, which in turn results in SLE B cell hyperactivity.
Assuntos
Linfócitos B , Lúpus Eritematoso Sistêmico , MicroRNAs , Proteína Supressora de Tumor p53 , Proteína de Ligação a CREB/metabolismo , Histonas/metabolismo , Humanos , Imunoglobulina G/metabolismo , Lúpus Eritematoso Sistêmico/genética , MicroRNAs/genética , Proteína Supressora de Tumor p53/genéticaRESUMO
OBJECTIVE: The potential effects of quercetin and gentamicin combination on the bacteriostatic activity and biofilm formation of Pseudomonas aeruginosa (PA) were examined, and the findings provided a theoretical basis for the development of quercetin as a new biofilm inhibitor. METHODS: The minimum inhibitory concentration (MIC) of eight PAs was determined by microdilution method and the partial inhibitory concentration index (FICI) of the combined drug was analyzed by micro-dilution method. Thereafter, the lowest film inhibitory concentration (MBIC) of quercetin and gentamicin alone and in combination was evaluated by crystal violet staining. Finally, scanning electron microscopy (SEM) and laser confocal microscopy (CLSM) were used to decipher the inhibitory effect of the combination on biofilm formation. OUTCOME: The antibacterial activity of quercetin alone was relatively weak, but after combination with gentamicin, the antibacterial activity was significantly enhanced, as evident by FICI of 0.28 and 0.53 and manifested as synergistic or additive effect, which indicated that quercetin can enhance gentamicin antibacterial activity. The results of crystal violet staining revealed that quercetin and gentamicin alone exhibited a similar biofilm formation inhibitory effect, but the inhibitory effect was substantially weaker, and the antibiofilm activity was stronger and exhibited a dose-dependent response after the combination of the two with 1/2FICI. The results of scanning electron microscopy and laser confocal microscopy also showed that the treatment of PA biofilm after combining quercetin and gentamicin with 1/2FICI could completely destroy the spatial structure of the complete biofilm, significantly reduce the thickness of bacteria, and markedly reduce the proportion of viable bacteria in the membrane. CONCLUSION: The combination of quercetin and gentamicin can effectively inhibit the formation of PA as well as its biofilm, and exhibit synergistic and additive effects.
RESUMO
Mastitis in dairy cows affects milk quality and thereby constrains the development of the dairy industry. A clear understanding of the pathogenesis of mastitis can help its treatment. Mastitis is caused by the invasion of pathogenic bacteria into the mammary gland through the mammary ducts. However, recent studies suggested that an endogenous entero-mammary pathway in dairy cattle might also be playing an important role in regulating mastitis. Also, probiotic intervention regulating host gut microbes has become an interesting tool to control mastitis. This review discusses the association of gastrointestinal microbes with mastitis and the mechanism of action of probiotics in dairy cows to provide new ideas for the management of mastitis in large-scale dairy farms.
Assuntos
Mastite Bovina , Probióticos , Feminino , Animais , Bovinos , Humanos , Mastite Bovina/microbiologia , Indústria de Laticínios , Leite/microbiologia , Probióticos/uso terapêutico , Glândulas Mamárias AnimaisRESUMO
This study aimed to investigate the presence of eight virulence genes (ace, asa1, esp, efaA, gelE, cylA, agg, fsr) in Enterococcus from a variety of animals and to explore the drug resistance and pathogenicity. This could provide a theoretical basis for clinical treatment of Enterococcus infections. Anal swabs from pigs, chickens, cattle, and dogs in farms and pet hospitals were collected for Enterococcus isolation and identification. Eight virulence genes were detected (PCR method), and drug resistance was assessed (drug-sensitive paper method). The strains containing different virulence genes were then divided into EV1, EV2, and EV3 groups. The LD50 and pathogenicity was examined by intra-peritoneal injection to infect mice. Differences were found in the detection rates of virulence genes in Enterococcus from the different animals. The highest overall detection rate was for the esp gene (78.0%), and the lowest for the cylA gene (15.5%). Eight genes were detected most frequently in Enterococcus from dogs and least frequently from cattle. Among the Enterococcus strains from four variety of animals, drug resistance was highest against sulfamethoxazole (100%), cefotaxime (>97%), and cefotaxitin (>93%). Drug resistance was lowest against vancomycin (0%), levofloxacin (<12%) and ciprofloxacin (<13%). The LD50 for each of the three groups was EV1LD50=8.71×109CFUï¼ EV2LD50=2.34×1010CFUï¼and EV3LD50=9.33×1010CFU. The Enterococcus12LD50 dose group caused significant clinical symptoms in mice, with pathological effects on the heart, liver, lungs, and kidneys, and particularly on the urinary system. The abundance of Enterococcus virulence genes, drug resistance, and pathogenicity vary among different animal origins, and the pathology caused by Enterococcus requires effective treatment protocols based on species and regional characteristics.
Assuntos
Enterococcus faecium , Infecções por Bactérias Gram-Positivas , Animais , Animais Domésticos , Antibacterianos/farmacologia , Bovinos , Cefotaxima/farmacologia , Galinhas , Ciprofloxacina/farmacologia , Cães , Resistência a Medicamentos , Farmacorresistência Bacteriana/genética , Enterococcus , Enterococcus faecalis , Infecções por Bactérias Gram-Positivas/veterinária , Levofloxacino/farmacologia , Camundongos , Testes de Sensibilidade Microbiana , Sulfametoxazol/farmacologia , Suínos , Vancomicina/farmacologia , Virulência/genética , Fatores de Virulência/genéticaRESUMO
The peripheral blood of systemic lupus erythematosus patients showed an increased expression of CXCR5 positive T cells. However, the molecular mechanism of the abnormal expression of CXCR5 in SLE CD4+ T cells remains unclear. The present study demonstrated that the levels of H3K4me3 and H3K36me3 in CXCR5 promoter were significantly higher in SLE patients than those in healthy controls. Furthermore, the expression of SETD3 was upregulated in SLE CD4+ T cells as compared to the healthy controls. Excessive SETD3 increased the level of H3K4me3 and H3K36me3 and promoted the expression of CXCR5. These data strongly suggested that SETD3 plays a major role in the regulation of CXCR5 expression and the progression of SLE.
Assuntos
Linfócitos T CD4-Positivos/metabolismo , Histona Metiltransferases/metabolismo , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/metabolismo , Receptores CXCR5/metabolismo , Adolescente , Adulto , Feminino , Humanos , Pessoa de Meia-Idade , Regulação para Cima , Adulto JovemRESUMO
Autoimmune diseases are common diseases of the immune system that are characterized by the loss of self-tolerance and the production of autoantibodies; the breakdown of immune tolerance and the prolonged inflammatory reaction are undisputedly core steps in the initiation and maintenance of autoimmunity. Peroxisome proliferator-activated receptors (PPARs) are ligand-dependent transcription factors that belong to the nuclear hormone receptor family and act as ligand-activated transcription factors. There are three different isotypes of PPARs: PPARα, PPARγ, and PPARß/δ. PPARγ is an established regulator of glucose homeostasis and lipid metabolism. Recent studies have demonstrated that PPARγ exhibits anti-inflammatory and anti-fibrotic effects in multiple disease models. PPARγ can also modulate the activation and polarization of macrophages, regulate the function of dendritic cells and mediate T cell survival, activation, and differentiation. In this review, we summarize the signaling pathways and biological functions of PPARγ and focus on how PPARγ and its agonists play protective roles in autoimmune diseases, including autoimmune thyroid diseases, multiple sclerosis, rheumatoid arthritis, systemic sclerosis, systemic lupus erythematosus, primary Sjogren syndrome and primary biliary cirrhosis.
Assuntos
Anti-Inflamatórios/farmacologia , Doenças Autoimunes/imunologia , PPAR gama/metabolismo , Animais , Anti-Inflamatórios/uso terapêutico , Doenças Autoimunes/tratamento farmacológico , Modelos Animais de Doenças , Glucose/metabolismo , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolismo dos Lipídeos/imunologia , PPAR gama/agonistas , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologiaRESUMO
Although the original purpose of the systemic lupus erythematosus (SLE) classification criteria was to distinguish SLE from other mimic diseases, and to facilitate sample selection in scientific research, they have become widely used as diagnostic criteria in clinical situations. It is not known yet if regarding classification criteria as diagnostic criteria, what problems might be encountered? This is the first study comparing the three sets of classification criteria for SLE, the 1997 American College of Rheumatology (ACR'97), 2012 Systemic Lupus International Collaborating Clinics (SLICC'12) and 2019 European League Against Rheumatism/American College of Rheumatology (EULAR/ACR'19), for their ability to distinguish patients with SLE from patients with pure mucocutaneous manifestations (isolated cutaneous lupus erythematosus without internal disease, i-CLE) in the lupus disease spectrum. 1,865 patients with SLE and 232 patients with i-CLE were recruited from a multicenter study. We found that, due to low specificity, none of the three criteria are adept at distinguishing patients with SLE from patients with i-CLE. SLICC'12 performed best among the original three criteria, but if a positive ANA was removed as an entry criterion, EULAR/ACR'19 would performed better. A review of previous studies that compared the three sets of criteria was presented in this work.
Assuntos
Lúpus Eritematoso Cutâneo/diagnóstico , Lúpus Eritematoso Sistêmico/diagnóstico , Adulto , Anticorpos Antinucleares/sangue , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reumatologia/métodos , Sensibilidade e Especificidade , Sociedades MédicasRESUMO
OBJECTIVE: To investigate the value of platelet count in evaluating the degree of liver fibrosis in patients with chronic hepatitis B (CHB). METHODS: A total of 158 CHB patients who underwent liver biopsy in our hospital were included, and the clinical characteristics of these patients were retrospectively analyzed. The diagnostic values of platelet count, aspartate aminotransferase-to-platelet ratio index (APRI), and the fibrosis index based on four factors (FIB-4) for significant fibrosis (F ≥ 2) and early cirrhosis (F = 4) stages in CHB patients were assessed by the use of receiver operating characteristic (ROC) analysis. RESULTS: The median (F0: 221.0; F1: 210.0; F2: 188.0; F3: 171.0; and F4: 155.5) and mean rank (F0: 120.4; F1: 100.1; F2: 82.2; F3: 67.9; and F4: 49.5) of platelet count decreased along the aggravation of fibrosis (F0-F4). The areas under the ROC curve for the platelet count in diagnosis of significant fibrosis stage was 0.70, which had no significant difference with FIB-4 (0.73) and APRI (0.68) in diagnostic efficacy (P = .428). The areas under the ROC curve of platelet count in diagnosis of early cirrhosis were 0.72, which had no significant difference with FIB-4 (0.76) and APRI (0.68) (P = .094). CONCLUSION: The platelet count, as a simple and non-invasive index, could evaluate the degree of liver fibrosis in CHB individuals. At the same time, the diagnostic efficiency of platelet count to evaluate the significant liver fibrosis and early cirrhosis is comparable to FIB-4 and APRI.
Assuntos
Hepatite B Crônica/sangue , Hepatite B Crônica/patologia , Cirrose Hepática/patologia , Contagem de Plaquetas , Adulto , Aspartato Aminotransferases/sangue , Feminino , Humanos , Cirrose Hepática/sangue , Cirrose Hepática/virologia , Masculino , Pessoa de Meia-Idade , Curva ROC , Estudos RetrospectivosRESUMO
OBJECTIVE: T cell receptor (TCR) diversity determines the autoimmune responses in systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) and is closely associated with autoimmune diseases prognosis and prevention. However, the characteristics of variations in TCR diversity and their clinical significance is still unknown. Large series of patients must be studied in order to elucidate the effects of these variations. METHODS: Peripheral blood from 877 SLE patients, 206 RA patients and 439 healthy controls (HC) were amplified for the TCR repertoire and sequenced using a high-throughput sequencer. We have developed a statistical model to identify disease-associated TCR clones and diagnose autoimmune diseases. RESULTS: Significant differences were identified in variable (V), joining (J) and V-J pairing between the SLE or RA and HC groups. These differences can be utilised to discriminate the three groups with perfect accuracy (V: area under receiver operating curve > 0.99). One hundred ninety-eight SLE-associated and 53 RA-associated TCRs were identified and used for diseases classification by cross validation with high specificity and sensitivity. Disease-associated clones showed common features and high similarity between both autoimmune diseases. SLE displayed higher TCR heterogeneity than RA with several organ specific properties. Furthermore, the association between clonal expansion and the concentration of disease-associated clones with disease severity were identified, and pathogen-related TCRs were enriched in both diseases. CONCLUSIONS: These characteristics of the TCR repertoire, particularly the disease-associated clones, can potentially serve as biomarkers and provide novel insights for disease status and therapeutical targets in autoimmune diseases.
Assuntos
Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Adulto , Análise de Variância , Artrite Reumatoide/sangue , Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , Autoimunidade , Biomarcadores/sangue , Estudos de Casos e Controles , Feminino , Seguimentos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lúpus Eritematoso Sistêmico/sangue , Masculino , Pessoa de Meia-Idade , Receptores de Antígenos de Linfócitos T/metabolismo , Valores de Referência , Medição de Risco , Estatísticas não ParamétricasAssuntos
Anticorpos Monoclonais Humanizados , Dermatomiosite , Humanos , Dermatomiosite/tratamento farmacológico , Dermatomiosite/complicações , Estudos Retrospectivos , Anticorpos Monoclonais Humanizados/uso terapêutico , Feminino , Masculino , Criança , Adolescente , Imunossupressores/uso terapêutico , Índice de Gravidade de Doença , Adulto , Resultado do Tratamento , Pessoa de Meia-IdadeRESUMO
The aim of this work was to study the effect of high pressure processing (HPP) and post-HPP cold storage on the distribution of polyglutamyl and monoglutamyl folate and the absolute concentration of total folate in green beans, yardlong beans and winged beans using a validated ultra-high performance liquid chromatography-tandem mass spectrometry method. The results showed that HPP led to the deglutamylation of polyglutamyl folate to monoglutamyl folate in all of the investigated beans. The degree of deglutamylation was increased with enhancing processing pressure and extending holding time. During HPP, significant loss of total folate was observed under 600 MPa/10 min treatment. Uniquely 300 MPa/5 min and 450 MPa/5 min could significantly release more folate from yardlong beans and green beans matrix. During the following cold-storage, the deglutamylation keep progressing. For those untreated beans, no significant deglutamylation and total folate loss was observed during cold storage for yardlong beans and green beans while there is slight change for the total folate in winged beans. For those HPP treated beans, total folate loss followed the first order kinetics over the storage. The rate constant of degradation was positively proportional to the applied pressure, holding time and the proportion of monoglutamyl folate. This research provided a reference for understanding the deglutamylation of polyglutamyl folate and folate loss during HPP treatment and further shelf life.
RESUMO
A 29-year-old male patient with extranodal NK/T-cell lymphoma, a nasal type lymphoma with involvement of skin as the first symptom, was reported. The patient presented with swelling in the left side of the nose and suffered intermittent fever for 1 month. The fester in the oral mucosa and skin under the left nostril and redness, and the swelling on the orbit of the left eye lasted for 1 week. Physical examination showed that the left side of nose was swelling, and the skin below the left nostril was anabrotic and crusted. There were different ulcers in his jaws and buccal mucosa. Bilateral eyelid was redness and swelling, especially in the left side. Binocular conjunctival was congestive. The diagnosis of extranodal NK/T-cell lymphoma (nasal type) was confirmed by biopsy and immunohistochemistry.
Assuntos
Linfoma Extranodal de Células T-NK/diagnóstico , Linfoma Extranodal de Células T-NK/patologia , Nariz/patologia , Adulto , Biópsia , Humanos , Imuno-Histoquímica , Linfoma Extranodal de Células T-NK/cirurgia , Masculino , Órbita/patologiaRESUMO
Systemic lupus erythematosus (SLE) is an autoimmune disease well known for its clinical heterogeneity, and its etiology secondary to a cross-talk involving genetic predisposition and environmental stimuli. Although genome-wide analysis has contributed greatly to our understanding of the genetic basis of SLE, there is increasing evidence for a role of epigenetics. Indeed, recent data have demonstrated that in patients with SLE, there are striking alterations of DNA methylation, histone modifications, and deregulated microRNA expression, the sum of which contribute to over-expression of select autoimmune-related genes and loss of tolerance. To address this issue at the level of clinical phenotype, we performed DNA methylation, mRNA and microRNA expression screening using high-throughput sequencing of purified CD4+ T cells from patients with SLE, compared to age and sex matched controls. In particular, we studied 42 patients with SLE and divided this group into three clinical phenotypes: a) the presence of skin lesions without signs of systemic pathology; b) skin lesions but also chronic renal pathology; and c) skin lesions, chronic renal pathology and polyarticular disease. Interestingly, and as expected, sequencing data revealed changes in DNA methylation in SLE compared to controls. However, and more importantly, although there were common methylation changes found in all groups of SLE compared to controls, there was specific DNA methylation changes that correlated with clinical phenotype. These included changes in the novel key target genes NLRP2, CD300LB and S1PR3, as well as changes in the critical pathways, including the adherens junction and leukocyte transendothelial migration. We also noted that a significant proportion of genes undergoing DNA methylation changes were inversely correlated with gene expression and that miRNA screening revealed the existence of subsets with changes in expression. Integrated analysis of this data highlights specific sets of miRNAs controlled by DNA methylation, and genes that are altered by methylation and targeted by miRNAs. In conclusion, our findings suggest select epigenetic mechanisms that contribute to clinical phenotypes and further shed light on a new venue for basic SLE research.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Metilação de DNA/imunologia , Regulação da Expressão Gênica/imunologia , Lúpus Eritematoso Sistêmico/imunologia , MicroRNAs/imunologia , RNA Mensageiro/imunologia , Proteínas Adaptadoras de Transdução de Sinal/imunologia , Adulto , Proteínas Reguladoras de Apoptose , Linfócitos T CD4-Positivos/patologia , Feminino , Humanos , Lúpus Eritematoso Sistêmico/patologia , Masculino , Receptores Imunológicos/imunologia , Receptores de Lisoesfingolipídeo/imunologia , Receptores de Esfingosina-1-FosfatoRESUMO
Escherichia coli (E. coli) is closely associated with the occurrence of puerperal metritis in dairy cows. E. coli carries some the virulence and multi-drug resistant genes, which pose a serious threat to the health of postpartum cows. In this study, E. coli was isolated and identified from the uterine contents of postpartum cows with puerperal metritis in the Ningxia region of China, and its phylogenetic subgroups were determined. Meanwhile, virulence and drug resistance genes carried by E. coli and drug sensitivity were detected, and the characteristics of virulence and drug resistance genes distribution in E. coli phylogroups were further analyzed. The results showed that the isolation rate of E. coli in puerperal metritis samples was 95.2%. E. coli was mainly divided into phylogroups B2 and D, followed by groups A and B1, and was more connected to O157:H7, O169:H4, and ECC-1470 type strains. The virulence genes were mainly dominated by ompF (100%), traT (100%), fimH (97%), papC (96%), csgA (95%), Ang43 (93.9%), and ompC (93%), and the resistance genes were dominated by TEM (99%), tetA (71.7%), aac(3)II (66.7%), and cmlA (53.5%). Additionally, it was observed that the virulence and resistance gene phenotypes could be divided into two subgroups, with subgroup B2 and D having the highest distributions. Drug sensitivity tests also revealed that the E. coli was most sensitive to the fluoroquinolones enrofloxacin, followed by macrolides, aminoglycosides, tetracyclines, ß-lactams, peptides and sulfonamides, and least sensitive to lincosamides. These results imply that pathogenic E. coli, which induces puerperal metritis of dairy cows in the Ningxia region of China, primarily belongs to the group B2 and D, contains multiple virulence and drug resistance genes, Moreover, E. coli has evolved resistance to several drugs including penicillin, lincomycin, cotrimoxazole, and streptomycin. It will offer specific guidelines reference for the prevention and treatment of puerperal metritis in dairy cows with E. coli infections in the Ningxia region of China.
RESUMO
Henoch-Schönlein purpura (HSP), the most common type of leukocytoclastic vasculitis, is caused by T cell-mediated autoimmune reactions. In this study, we analyze histone modification patterns in peripheral blood mononuclear cells (PBMCs) of HSP patients, and investigate the expression levels of inflammatory cytokines (IFN-γ, IL-2, IL-4, IL-6 and IL-13), transcription factors (T-bet, GATA-3 and TIM-1) and chemokines (CXCL4 and CXCL10) in HSP patients. Our results show that histone H3 acetylation and methylation are significantly enhanced in PBMCs from HSP patients. We also demonstrate specifically that marked increases in histone H3 acetylation and H3 lysine 4 trimethylation occur at the IL-4 loci in these patients. In addition, the expression levels of IL-4, IL-6, IL-13, GATA-3, TIM-1 and CXCL4 are also increased. These findings suggest that abnormal histone modifications are present in the PBMCs of patients with HSP, possibly contributing to the activation of pathological immune responses associated with HSP.
Assuntos
Histonas/metabolismo , Vasculite por IgA/metabolismo , Leucócitos Mononucleares/metabolismo , Acetilação , Adolescente , Adulto , Citocinas/sangue , Citocinas/genética , Feminino , Fator de Transcrição GATA3 , Receptor Celular 1 do Vírus da Hepatite A , Humanos , Vasculite por IgA/imunologia , Leucócitos Mononucleares/citologia , Masculino , Glicoproteínas de Membrana , Metilação , Pessoa de Meia-Idade , RNA Mensageiro/metabolismo , Receptores Virais , Subpopulações de Linfócitos T/imunologia , Adulto JovemRESUMO
Systemic lupus erythematosus (SLE) is a prototype autoimmune disease characterized by various immunological abnormalities, including dysregulated activation of T and B lymphocytes, which trigger autoantibody production and immune-complex deposition. E4BP4, also known as NFIL3, has emerged as a major transcription factor that regulates the development and function of immune cells in a number of lineages. E4BP4 has been shown to regulate cytokines expression, and its synthesis is in turn controlled by various cytokines. To date, the roles of E4BP4 in immune dysregulation and autoimmune disorders are unclear. In this study, we demonstrated that E4BP4 expression is increased in CD4(+) T cells isolated from patients with active systemic lupus erythematosus (SLE), especially in patients treated with glucocorticoid (GC). Increased expression of E4BP4 inhibited the activation and self-reactivity of T cells stimulated by anti-CD3/CD28 antibodies. In contrast, the self-reactivity was enhanced in CD4(+) T cells from SLE patients following E4BP4 gene silencing and the production of autoantibody was increased in autologous B cells. We further demonstrated that E4BP4 directly regulated CD40L expression by binding to the promoter region and altering histone acetylation and methylation of the CD40L loci. Taken together, our data provide evidence that E4BP4 can inhibit CD40L expression through epigenetic modifications in the promoter region of CD40L, thus negatively regulating self-reactivity of SLE CD4(+) T cells. Furthermore, our data demonstrate that overexpression of E4BP4 initiates a protective mechanism in SLE CD4(+) T cells, which may be a promising target in the therapy for SLE.
Assuntos
Fatores de Transcrição de Zíper de Leucina Básica/imunologia , Linfócitos T CD4-Positivos/imunologia , Expressão Gênica/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Adolescente , Adulto , Anticorpos/imunologia , Anticorpos/farmacologia , Fatores de Transcrição de Zíper de Leucina Básica/genética , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Western Blotting , Antígenos CD28/imunologia , Complexo CD3/imunologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/metabolismo , Ligante de CD40/genética , Ligante de CD40/imunologia , Ligante de CD40/metabolismo , Células Cultivadas , Feminino , Citometria de Fluxo , Glucocorticoides/uso terapêutico , Histonas/metabolismo , Humanos , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Masculino , Pessoa de Meia-Idade , Regiões Promotoras Genéticas/genética , Ligação Proteica , Interferência de RNA , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Adulto JovemRESUMO
OBJECTIVE: Lupus erythematosus (LE) is a complicated disease with highly heterogeneous clinical manifestations. Previous studies have rarely included all subgroups of patients with lupus and have overlooked the importance of the cutaneous manifestations thereof. We aimed to compare the demographic and clinical differences among patients with different subtypes of lupus. METHODS: This is the first real-world study with a relatively large sample size that simultaneously includes patients with isolated cutaneous lupus erythematosus (iCLE) and SLE. All samples were obtained from the Lupus Erythematosus Multicenter Case-control Study in Chinese populations (LEMCSC) (registration number: ChiCTR2100048939). Comparative analyses between different LE subgroups were performed. RESULTS: A total of 2097 patients with lupus were included, with 1865 patients with SLE, 1648 with cutaneous lupus erythematosus (CLE), and 232 with iCLE. Among the patients with CLE, 1330 had acute cutaneous lupus erythematosus (ACLE); 160 had subacute cutaneous lupus erythematosus (SCLE); and 546 had chronic cutaneous lupus erythematosus (CCLE). The study included a relatively large number of patients with CCLE subtypes, including 311 with discoid lupus erythematosus (DLE), 262 with chilblain lupus erythematosus (CHLE) and 45 with lupus erythematosus profundus (LEP). Demographic characteristics, systemic involvement, mucocutaneous manifestations and autoantibodies were significantly different among the groups. CONCLUSIONS: CLE and iCLE are two distinct disease states, and the selection of broad or narrow CLE definitions should be emphasised in scientific reports. LE-non-specific cutaneous lesions imply more severity, while self-reported photosensitivity and LE-specific cutaneous manifestations imply milder severity. Generalised ACLE appears to be a more severe state than localised ACLE, and CHLE appears to be more severe than DLE. Anti-Sjögren's syndrome-related antigen B (SSB) antibodies have higher specific directivity than anti-Sjögren's syndrome-related antigen A (SSA) antibodies for SCLE lesions. Anti-double-stranded DNA antibodies have a higher co-occurrence with ACLE and a lower co-occurrence with SCLE and CCLE. Compared with DLE, CHLE has significantly higher positive rates of anti-SSA/Ro60 (71%) and anti-SSA/Ro52 (42.4%) antibodies, whereas LEP is associated with a higher positive rate of antinucleosome antibodies (31.1%).
Assuntos
Lúpus Eritematoso Cutâneo , Lúpus Eritematoso Discoide , Lúpus Eritematoso Sistêmico , Síndrome de Sjogren , Humanos , Estudos Transversais , Estudos de Casos e Controles , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/diagnóstico , Lúpus Eritematoso Sistêmico/epidemiologia , Lúpus Eritematoso Cutâneo/complicações , Lúpus Eritematoso Cutâneo/diagnóstico , Lúpus Eritematoso Discoide/complicações , Lúpus Eritematoso Discoide/epidemiologia , Síndrome de Sjogren/complicações , Doença AgudaRESUMO
OBJECTIVES: This study aims to compare the differences among patients of different onset ages in various subtypes of lupus erythematosus (LE) and to draw a panorama of the clinical characteristics of patients with different onset ages. METHOD: Subjects were recruited from the Lupus Erythematosus Multicenter Case-control Study in Chinese populations (LEMCSC), grouped by the age of onset (childhood-onset: onset < 18 years, adult-onset: onset 18-50 years, late-onset: onset > 50 years). The data collected included demographic characteristics, LE-related systemic involvement, LE-related mucocutaneous manifestations, and laboratory results. All included patients were assigned into three groups: systemic LE (SLE) group (with systemic involvement, with or without mucocutaneous lesions), cutaneous LE (CLE) group (patients who were accompanied by any type of LE-specific cutaneous manifestations), and isolated cutaneous LE (iCLE) group (patients who were in CLE group without systemic involvements). Data were analyzed using R version 4.0.3. RESULTS: A total of 2097 patients were involved, including 1865 with SLE and 232 with iCLE. We also identified 1648 patients with CLE among them, as there was some overlap between the SLE population and CLE population (patients with SLE and LE-specific cutaneous manifestations). Later-onset lupus patients seemed to be less female predominance (p < 0.001) and have less systemic involvement (except arthritis), lower positive rates of autoimmune antibodies, less ACLE, and more DLE. Moreover, childhood-onset SLE patients presented a higher risk of LE family history (p = 0.002, vs adult-onset SLE). In contrast to other LE-nonspecific manifestations, the self-reported photosensitivity history decreased with the age of onset in SLE patients (51.8%, 43.4%, and 39.1%, respectively) but increased in iCLE patients (42.4%, 64.9%, and 89.2%, respectively). There was also a gradual increase in self-reported photosensitivity from SLE, CLE, to iCLE in both adult-onset and late-onset lupus patients. CONCLUSIONS: A negative correlation was suggested between the age of onset and the likelihood of systemic involvement, except for arthritis. As the age of onset increases, patients have a greater propensity to exhibit DLE compared to ACLE. Moreover, the presence of rapid response photodermatitis (i.e., self-reported photosensitivity) was associated with a lower rate of systemic involvement. TRIAL REGISTRATION: This study was registered with the Chinese Clinical Trial Registry (registration number: ChiCTR2100048939) on July 19, 2021, retrospectively registered. Key Points ⢠We confirmed some phenomena that have been found in patients with SLE, such as the highest proportion of females of reproductive age, the higher risk of LE family history in childhood-onset SLE patients, and the less self-reported photosensitivity in the late-onset SLE group. We also compared the similarities and differences of these phenomena in patients with CLE or iCLE for the first time. ⢠In patients with SLE, the proportion of females peaked in adult-onset patients, but this phenomenon disappeared in iCLE patients: the female-male ratio tends to decrease from childhood-onset iCLE, adult-onset iCLE, to late-onset iCLE. ⢠Patients with early-onset lupus are more likely to have acute cutaneous lupus erythematosus (ACLE), and patients with late-onset lupus are more likely to have discoid lupus erythematosus (DLE). ⢠In contrast to other LE-nonspecific manifestations, the incidence of rapid response photodermatitis (i.e., self-reported photosensitivity) decreased with the age of onset in SLE patients but increased with the age of onset in iCLE patients.
Assuntos
Artrite , Lúpus Eritematoso Cutâneo , Lúpus Eritematoso Discoide , Lúpus Eritematoso Sistêmico , Transtornos de Fotossensibilidade , Adulto , Humanos , Masculino , Feminino , Adolescente , Idade de Início , Estudos Transversais , Estudos de Casos e Controles , Lúpus Eritematoso Discoide/complicações , Lúpus Eritematoso Discoide/patologia , Transtornos de Fotossensibilidade/complicações , Transtornos de Fotossensibilidade/epidemiologia , Lúpus Eritematoso Sistêmico/epidemiologia , Lúpus Eritematoso Sistêmico/complicações , Artrite/complicações , Doença Aguda , China/epidemiologiaRESUMO
Familial aggregation of hepatocellular carcinoma (HCC), the third leading cause of cancer death worldwide, has shown to be a common phenomenon. We investigated the association between the genetic background and HCC familial aggregation. Serum samples were collected from HCC family members and normal control family members for screening the differentially expressed protein peaks with the approach of surface-enhanced laser desorption ionization time-of-flight mass spectrometry. Potential genetically associated protein peaks were selected and further identified by matrix assisted laser desorption ionization-time of flight mass spectrometry. A panel of six protein peaks (m/z 6432.94, 8478.35, 9381.91, 17284.67, 17418.34, and 18111.04) were speculated to reflect the genetic susceptibility of HCC familial aggregation. Three of them (m/z 6432.94, 8478.35, and 9381.91) were selected to identify as the candidate proteins. Nine identified proteins, including mostly apolipoprotein family (ApoA1, ApoA2, ApoC3, ApoE) and serum amyloid A protein (SAA), were found overexpressed in the multiple HCC cases family members. The comparative proteomic profiles have suggested that genetic factors ought to be taken into account for familial aggregation of HCC.
Assuntos
Carcinoma Hepatocelular/genética , Predisposição Genética para Doença/genética , Neoplasias Hepáticas/genética , Adulto , Carcinoma Hepatocelular/sangue , Feminino , Humanos , Lactente , Neoplasias Hepáticas/sangue , Masculino , Linhagem , Proteômica/métodos , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , TranscriptomaRESUMO
Total glucosides of paeony (TGP), an active compound extracted from Paeony root, has been used in therapy for autoimmune diseases. However the molecular mechanism of TGP in the prevention of autoimmune response remains unclear. In this study, we found that TGP treatment significantly increased the percentage and number of Treg cells in lupus CD4(+) T cells. Further investigation revealed that treatment with TGP increased the expression of Foxp3 in lupus CD4(+) T cells by down-regulating Foxp3 promoter methylation levels. However, we couldn't observe similar results in healthy control CD4(+) T cells treated by TGP. Moreover, our results also showed that IFN-γ and IL-2 expression was enhanced in TGP-treated lupus CD4(+) T cells. These findings indicate that TGP inhibits autoimmunity in SLE patients possibly by inducing Treg cell differentiation, which may in turn be due to its ability to regulate the methylation status of the Foxp3 promoter and activate IFN-γ and IL-2 signaling.