RESUMO
OBJECTIVES: Few studies have been conducted on gene-environment interactions in the Chinese population with Crohn's disease (CD). We aimed to investigate the association between single nucleotide polymorphisms (SNPs) on the T helper 17 (Th17) cell and CD susceptibility/performance in Chinese individuals. METHODS: We conducted a case-control and case-only study at the Peking Union Medical College Hospital. Four SNPs related to the Th17 cell pathway genes were prioritized, including rs2284553 (interferon gamma receptor 2), rs7517847 (interleukin 23 receptor), rs7773324 (interferon regulatory factor 4), and rs4263839 (tumor necrosis factor superfamily 15). SNP frequency was calculated, and gene-environment interaction was assessed by multifactor dimensionality reduction analysis. RESULTS: Altogether 159 CD patients and 316 healthy controls were included. All analyzed SNPs were found in Hardy-Weinberg equilibrium (P > 0.05). The frequency of rs2284553-A allele and rs4263839-A allele were lower in CD patients compared with controls (P < 0.05). While the rs4263839-A allele was more prevalent in ileocolonic CD patients than in those with isolated small intestinal or colonic disease (P = 0.035). Gene-environment interactions revealed associations between rs2284553 and breastfeeding, sunshine exposure, and fridge-stored food, affecting age at diagnosis, intestinal involvement, and intestinal stricture. Interaction of rs4263839 and breastfeeding influenced small intestinal lesions and intestinal stricture in CD. CONCLUSIONS: This study provided information on the genetic background in Chinese CD patients. Incorporating these SNPs into predictive models may improve risk assessment and outcome prediction. Gene-environment interaction contributes to the understanding of CD pathogenesis.
Assuntos
Povo Asiático , Doença de Crohn , Interação Gene-Ambiente , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Células Th17 , Humanos , Doença de Crohn/genética , Masculino , Feminino , Adulto , Estudos de Casos e Controles , Povo Asiático/genética , China , Pessoa de Meia-Idade , Adulto Jovem , Receptores de Interleucina/genética , Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/genética , Adolescente , Fatores de Risco , População do Leste AsiáticoRESUMO
Previous studies reveal that psoriatic arthritis (PsA) and ankylosing spondylitis (AS) share susceptibility genes, such as HLA-B27, demonstrating a degree of genetic overlap between these diseases. Recent studies have identified a number of novel AS and PsA genetic susceptibility loci, but data on these loci in Chinese PsA patients are limited. To identify candidate genes that confer susceptibility to PsA in Chinese patients with PsA, psoriasis vulgaris (PsV), and healthy controls. Sixteen susceptibility loci, reported in a genome-wide association study of AS, and nine susceptibility loci, reported in candidate gene studies of PsA, were examined. Single-nucleotide polymorphisms (SNPs) were genotyped in 503 patients with PsA, 496 patients with PsV, and 979 healthy controls using the SNPscanTM multiplex SNP genotyping platform. PLINK software and logistic regression analysis were used to estimate the statistical significance of associations. PPP2R3C (rs8006884) was shown to significantly associate with PsA+PsV (p = 1.92×10-3, OR = 1.28) and was suggested to associate with PsV (p = 0.03, OR = 1.19). A suggestive association was also observed between IL-23R (rs12141575) and PsA as well as with axial PsA based on subtype analysis, KIF3A (rs2897442) and PsV, and ERN1 (rs196941) or IFIH1 (rs984971) and axial PsA. Our results suggest that PPP2R3C confers susceptibility to PsA and PsV, and that this gene may be related to the pathogenesis of psoriatic lesions and arthritis. Moreover, our results indicate a possible association between IL-23R, ERN1, or IFIH1 and subtypes of PsA, and between KIF3A and PsV.
Assuntos
Artrite Psoriásica , Povo Asiático , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Espondilite Anquilosante , Humanos , Artrite Psoriásica/genética , Espondilite Anquilosante/genética , Masculino , Feminino , Povo Asiático/genética , Adulto , Pessoa de Meia-Idade , Estudos de Casos e Controles , China , Receptores de Interleucina/genética , Proteína Fosfatase 2/genética , Genótipo , Estudo de Associação Genômica Ampla , Psoríase/genética , População do Leste AsiáticoRESUMO
Some benign and malignant breast tumours are similar in pathological morphology, which are difficult to be distinguished in clinical diagnosis. In this study, we intended to explore novel biomarkers for differential diagnosis of benign and malignant breast tumours. Methylation EPIC 850K beadchip and RNA-sequencing were used to analyse 29 tissue samples from patients with early-stage breast cancer (BC) and benign breast tumours for differently methylated and expressed genes. The altered methylation of IL21R was semi-quantitatively validated in an independent study with 566 tissue samples (279 BC vs. 287 benign breast tumours) using mass spectrometry. Binary logistic regression analysis was performed to evaluate the association between IL21R methylation and BC. BC-associated IL21R hypomethylation and overexpression were identified in the discovery round. In the validation round, BC patients presented significant IL21R hypomethylation compared to women with benign breast tumours (ORs ≥1.29 per-10% methylation, p-values ≤ 5.69E-14), and this hypomethylation was even enhanced in BC patients with ER-negative and PR-negative tumours as well as with triple-negative tumours. The methylation of IL21R showed efficient discriminatory power to distinguish benign breast tumours from BC (area under curve (AUC) = 0.88), and especially from ER-negative BC (AUC = 0.95), PR-negative BC (AUC = 0.93) and triple-negative BC (AUC = 0.96). We disclosed significant IL21R hypomethylation in patients with BC compared to women with benign breast tumours, and revealed the somatic change of DNA methylation could be a potential biomarker for molecular pathology of BC.
Assuntos
Biomarcadores Tumorais , Neoplasias da Mama , Metilação de DNA , Feminino , Humanos , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Neoplasias da Mama/diagnóstico , Diagnóstico Diferencial , Subunidade alfa de Receptor de Interleucina-21 , Receptores de Interleucina/genética , Receptores de Interleucina/metabolismoRESUMO
INTRODUCTION: Optimizing treatment with biological agents is an ideal goal for patients with ulcerative colitis (UC). Recent data suggest that mucosal inflammation patterns and serum cytokine profiles differ between patients who respond and those who do not. Ustekinumab, a monoclonal antibody targeting the p40 subunit of interleukin (IL)-12 and IL-23, has shown promise, but predicting treatment response remains a challenge. We aimed to identify prognostic markers of response to ustekinumab in patients with active UC, utilizing information from their mucosal transcriptome. METHODS: We performed a prospective observational study of 36 UC patients initiating treatment with ustekinumab. Colonic mucosal biopsies were obtained before treatment initiation for a gene expression analysis using a microarray panel of 84 inflammatory genes. A differential gene expression analysis (DGEA), correlation analysis, and network centrality analysis on co-expression networks were performed to identify potential biomarkers. Additionally, machine learning (ML) models were employed to predict treatment response based on gene expression data. RESULTS: Seven genes, including BCL6, CXCL5, and FASLG, were significantly upregulated, while IL23A and IL23R were downregulated in non-responders compared to responders. The co-expression analysis revealed distinct patterns between responders and non-responders, with key genes like BCL6 and CRP highlighted in responders and CCL11 and CCL22 in non-responders. The ML algorithms demonstrated a high predictive power, emphasizing the significance of the IL23R, IL23A, and BCL6 genes. CONCLUSIONS: Our study identifies potential biomarkers associated with ustekinumab response in UC patients, shedding light on its underlying mechanisms and variability in treatment outcomes. Integrating transcriptomic approaches, including gene expression analyses and ML, offers valuable insights for personalized treatment strategies and highlights avenues for further research to enhance therapeutic outcomes for patients with UC.
Assuntos
Colite Ulcerativa , Biologia Computacional , Ustekinumab , Humanos , Ustekinumab/uso terapêutico , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/genética , Masculino , Feminino , Biologia Computacional/métodos , Adulto , Pessoa de Meia-Idade , Resultado do Tratamento , Receptores de Interleucina/genética , Receptores de Interleucina/metabolismo , Estudos Prospectivos , Transcriptoma , Perfilação da Expressão Gênica/métodos , Subunidade p19 da Interleucina-23/genética , Subunidade p19 da Interleucina-23/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Mucosa Intestinal/efeitos dos fármacos , Aprendizado de Máquina , PrognósticoRESUMO
The IL-22RA1 receptor is highly expressed in the pancreas, and exogenous IL-22 has been shown to reduce endoplasmic reticulum and oxidative stress in human pancreatic islets and promote secretion of high-quality insulin from beta-cells. However, the endogenous role of IL-22RA1 signaling on these cells remains unclear. Here, we show that antibody neutralisation of IL-22RA1 in cultured human islets leads to impaired insulin quality and increased cellular stress. Through the generation of mice lacking IL-22ra1 specifically on pancreatic alpha- or beta-cells, we demonstrate that ablation of murine beta-cell IL-22ra1 leads to similar decreases in insulin secretion, quality and islet regeneration, whilst increasing islet cellular stress, inflammation and MHC II expression. These changes in insulin secretion led to impaired glucose tolerance, a finding more pronounced in female animals compared to males. Our findings attribute a regulatory role for endogenous pancreatic beta-cell IL-22ra1 in insulin secretion, islet regeneration, inflammation/cellular stress and appropriate systemic metabolic regulation.
Assuntos
Glucose , Homeostase , Células Secretoras de Insulina , Insulina , Camundongos Knockout , Receptores de Interleucina , Animais , Células Secretoras de Insulina/metabolismo , Receptores de Interleucina/metabolismo , Receptores de Interleucina/genética , Feminino , Humanos , Masculino , Insulina/metabolismo , Camundongos , Glucose/metabolismo , Secreção de Insulina , Camundongos Endogâmicos C57BL , Interleucina 22 , Intolerância à Glucose/metabolismo , Interleucinas/metabolismo , Interleucinas/genética , Envelhecimento/metabolismoRESUMO
Interleukin 22 (IL-22) promotes intestinal barrier integrity, stimulating epithelial cells to enact defense mechanisms against enteric infections, including the production of antimicrobial peptides. IL-22 binding protein (IL-22BP) is a soluble decoy encoded by the Il22ra2 gene that decreases IL-22 bioavailability, attenuating IL-22 signaling. The impact of IL-22BP on gut microbiota composition and functioning is poorly understood. We found that Il22ra2-/- mice are better protected against Clostridioides difficile and Citrobacter rodentium infections. This protection relied on IL-22-induced antimicrobial mechanisms before the infection occurred, rather than during the infection itself. Indeed, the gut microbiota of Il22ra2-/- mice mitigated infection of wild-type (WT) mice when transferred via cohousing or by cecal microbiota transplantation. Indicator species analysis of WT and Il22ra2-/- mice with and without cohousing disclosed that IL22BP deficiency yields a gut bacterial composition distinct from that of WT mice. Manipulation of dietary fiber content, measurements of intestinal short-chain fatty acids and oral treatment with acetate disclosed that resistance to C. difficile infection is related to increased production of acetate by Il22ra2-/--associated microbiota. Together, these findings suggest that IL-22BP represents a potential therapeutic target for those at risk for or with already manifest infection with this and perhaps other enteropathogens.
Assuntos
Citrobacter rodentium , Clostridioides difficile , Infecções por Enterobacteriaceae , Microbioma Gastrointestinal , Interleucina 22 , Camundongos Knockout , Animais , Camundongos , Infecções por Enterobacteriaceae/imunologia , Infecções por Enterobacteriaceae/microbiologia , Infecções por Enterobacteriaceae/prevenção & controle , Receptores de Interleucina/metabolismo , Receptores de Interleucina/genética , Interleucinas/metabolismo , Camundongos Endogâmicos C57BL , Infecções por Clostridium/imunologia , Infecções por Clostridium/microbiologia , Infecções por Clostridium/prevenção & controleRESUMO
Background: This study aimed to characterize the clinical phenotype and genetic variations in patients with Kallmann syndrome (KS). Methods: This study involved the collection and analysis of clinical data from an individual with sporadic KS. Following this, peripheral blood samples were obtained from the patient and his parents. Genomic deoxyribonucleic acid was extracted and subjected to whole-exome sequencing and genomic copy number variation (CNV) detection. Finally, Sanger sequencing was performed to validate the suspected pathogenic variants. Results: Whole-exome sequencing confirmed that the child carried both the IL17RD variant (c.2101G>A, p.Gly701Ser) inherited from the mother and the new CPEB4 variant (c.1414C>T, p.Arg472*). No pathogenic CNVs were identified in CNV testing. Conclusion: Bioinformatics analysis shows that the IL17RD protein undergoing Gly701Ser mutation and is speculated to be phosphorylated and modified, thereby disrupting fibroblast growth factor signaling. This study also suggested that the CPEB4 might play a crucial role in the key signaling process affecting olfactory bulb morphogenesis. Overall, the findings of this study broaden the gene expression profile of KS-related pathogenic genes. This offers a new avenue for exploring the pathogenic mechanism of KS and provides valuable insights for precise clinical diagnosis and treatment strategies for this condition.
Assuntos
Síndrome de Kallmann , Feminino , Criança , Humanos , Síndrome de Kallmann/genética , Variações do Número de Cópias de DNA , Mutação , Fenótipo , Mães , Receptores de Interleucina/genética , Proteínas de Ligação a RNA/genéticaRESUMO
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a poor survival rate, largely due to the lack of early diagnosis. Although myeloid cells are crucial in the tumour microenvironment, whether their specific subset can be a biomarker of PDAC progression is unclear. METHODS: We analysed IL-22 receptor expression in PDAC and peripheral blood. Additionally, we analysed gene expression profiles of IL-10R2+/IL-22R1+ myeloid cells and the presence of these cells using single-cell RNA sequencing and murine orthotropic PDAC models, respectively, followed by examining the immunosuppressive function of IL-10R2+/IL-22R1+ myeloid cells. Finally, the correlation between IL-10R2 expression and PDAC progression was evaluated. RESULTS: IL-10R2+/IL-22R1+ myeloid cells were present in PDAC and peripheral blood. Blood IL-10R2+ myeloid cells displayed a gene expression signature associated with tumour-educated circulating monocytes. IL-10R2+/IL-22R1+ myeloid cells from human myeloid cell culture inhibited T cell proliferation. By mouse models for PDAC, we found a positive correlation between pancreatic tumour growth and increased blood IL-10R2+/IL-22R1+ myeloid cells. IL-10R2+/IL-22R1+ myeloid cells from an early phase of the PDAC model suppressed T cell proliferation and cytotoxicity. IL-10R2+ myeloid cells indicated tumour recurrence 130 days sooner than CA19-9 in post-pancreatectomy patients. CONCLUSIONS: IL-10R2+/IL-22R1+ myeloid cells in the peripheral blood might be an early marker of PDAC prognosis.
Assuntos
Biomarcadores Tumorais , Carcinoma Ductal Pancreático , Subunidade beta de Receptor de Interleucina-10 , Células Mieloides , Recidiva Local de Neoplasia , Neoplasias Pancreáticas , Receptores de Interleucina , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/diagnóstico , Carcinoma Ductal Pancreático/sangue , Humanos , Animais , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/sangue , Camundongos , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/sangue , Receptores de Interleucina/genética , Células Mieloides/metabolismo , Células Mieloides/patologia , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Subunidade beta de Receptor de Interleucina-10/genética , Feminino , Masculino , Microambiente Tumoral/genética , Linhagem Celular TumoralRESUMO
Epstein-Barr virus (EBV) infection can engender severe B cell lymphoproliferative diseases1,2. The primary infection is often asymptomatic or causes infectious mononucleosis (IM), a self-limiting lymphoproliferative disorder3. Selective vulnerability to EBV has been reported in association with inherited mutations impairing T cell immunity to EBV4. Here we report biallelic loss-of-function variants in IL27RA that underlie an acute and severe primary EBV infection with a nevertheless favourable outcome requiring a minimal treatment. One mutant allele (rs201107107) was enriched in the Finnish population (minor allele frequency = 0.0068) and carried a high risk of severe infectious mononucleosis when homozygous. IL27RA encodes the IL-27 receptor alpha subunit5,6. In the absence of IL-27RA, phosphorylation of STAT1 and STAT3 by IL-27 is abolished in T cells. In in vitro studies, IL-27 exerts a synergistic effect on T-cell-receptor-dependent T cell proliferation7 that is deficient in cells from the patients, leading to impaired expansion of potent anti-EBV effector cytotoxic CD8+ T cells. IL-27 is produced by EBV-infected B lymphocytes and an IL-27RA-IL-27 autocrine loop is required for the maintenance of EBV-transformed B cells. This potentially explains the eventual favourable outcome of the EBV-induced viral disease in patients with IL-27RA deficiency. Furthermore, we identified neutralizing anti-IL-27 autoantibodies in most individuals who developed sporadic infectious mononucleosis and chronic EBV infection. These results demonstrate the critical role of IL-27RA-IL-27 in immunity to EBV, but also the hijacking of this defence by EBV to promote the expansion of infected transformed B cells.
Assuntos
Infecções por Vírus Epstein-Barr , Interleucina-27 , Receptores de Interleucina , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Adulto Jovem , Alelos , Linfócitos B/patologia , Linfócitos B/virologia , Linfócitos T CD8-Positivos/patologia , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/genética , Infecções por Vírus Epstein-Barr/terapia , Finlândia , Frequência do Gene , Herpesvirus Humano 4 , Homozigoto , Mononucleose Infecciosa/complicações , Mononucleose Infecciosa/genética , Mononucleose Infecciosa/terapia , Interleucina-27/imunologia , Interleucina-27/metabolismo , Mutação com Perda de Função , Receptores de Interleucina/deficiência , Receptores de Interleucina/genética , Receptores de Interleucina/metabolismo , Resultado do TratamentoRESUMO
The importance of IL-23 and its specific receptor, IL-23R, in the pathogenesis of several chronic inflammatory diseases has been established, but the underlying pathological mechanisms are not fully understood. This review focuses on IL-23R expression and regulation in immune cells.
Assuntos
Receptores de Interleucina , Transdução de Sinais , Receptores de Interleucina/genética , Interleucina-23/metabolismoRESUMO
Systemic autoimmune diseases frequently induce lupus nephritis, causing altered balance and expression of interleukin 36 receptor (IL-36R) ligands, including agonists (IL-36α, ß, γ) and antagonists (IL-36Ra, IL-38), in kidneys. Here, we established and analyzed a mouse model of lupus nephritis, MRL/MpJ-Faslpr/lpr with IL-36R-knockout (KO), compared to wild-type (WT) mice. In both genotypes, indices for immune abnormalities and renal functions were comparable, although female WT mice showed higher serum autoantibody levels than males. IL-36R ligand expression did not differ significantly between genotypes at the mRNA level or in IL-36α and IL-38 scores. However, glomerular lesions, especially mesangial matrix expansion, were significantly ameliorated in both sexes of IL-36R-KO mice compared to WT mice. Cell infiltration into the tubulointerstitium with the development of tertiary lymphoid structures was comparable between genotypes. However, the positive correlation with the IL-36α score in WT mice was not evident in IL-36R-KO mice. Fibrosis was less in female IL-36R-KO mice than in WT mice. Importantly, some IL-36α+ nuclei co-localized with acetylated lysine and GCN5 histone acetyltransferase, in both genotypes. Therefore, IL-36R ligands, especially IL-36α, contribute to the progression of renal pathology in lupus nephritis via IL-36R-dependent and IL-36R-independent pathways.
Assuntos
Nefrite Lúpica , Receptores de Interleucina , Animais , Feminino , Masculino , Camundongos , Núcleo Celular , Interleucinas , Rim , Glomérulos Renais , Receptores de Interleucina/genéticaRESUMO
BACKGROUND: Severe tuberculosis constitutes a significant menace to human safety and well-being, with a considerable mortality rate. The severity of tuberculosis can be impacted by genetic variations in host genes, particularly single nucleotide polymorphisms (SNPs). METHODS: A caseâcontrol study was undertaken, encompassing a cohort of 1137 tuberculosis patients (558 with severe tuberculosis and 579 with mild tuberculosis), alongside 581 healthy controls within the age range of fifteen to forty-five years. Whole blood DNA was extracted from all participants, and three tag polymorphisms (rs1884444, rs7518660, rs7539625) of the IL23R gene were selectively identified and genotyped. RESULTS: No significant correlation was observed between the IL23R gene polymorphisms (rs1884444, rs7518660, and rs7539625) and tuberculosis. Upon comparing the tuberculosis group with the healthy control group, the mild tuberculosis group with the healthy control group, and the severe tuberculosis group with the healthy control group, the obtained P-values were> 0.05. However, in the comparison between severe tuberculosis and mild tuberculosis, the presence of rs1884444 G alleles exhibited a significantly increased risk of severe tuberculosis after adjusting for age and sex (ORa: 1.199, 95% CI: 1.009-1.424; Pa=0.039, respectively). In subgroup analysis, after accounting for confounding factors, including age and sex, rs1884444 G alleles continued to demonstrate a significantly heightened risk of severe tuberculosis. Nonetheless, the comparison between the multisystemic tuberculosis group and the mild tuberculosis group was no significant difference. Notably, rs1884444 of the IL23R gene exhibited a noteworthy association with the risk of severe tuberculosis in the comparison between severe tuberculosis and mild tuberculosis before and after adjusting for age and sex (ORa: 1.301, 95% CI: 1.030-1.643; Pa=0.027, respectively). Furthermore, the presence of the rs1884444 G allele exhibited a significantly increased risk of severe tuberculosis after adjusting for age and sex in the comparison between tuberculous meningitis and mild tuberculosis (ORa: 1.646, 95% CI: 1.100-2.461; Pa=0.015, respectively). CONCLUSIONS: The present study suggests that there is no significant association between IL23R gene polymorphism and tuberculosis susceptibility in the Chinese Han population. However, it does indicate a potential link between IL23R polymorphism and an increased risk of developing severe tuberculosis.
Assuntos
Polimorfismo de Nucleotídeo Único , Tuberculose , Humanos , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Predisposição Genética para Doença , Estudos de Casos e Controles , População do Leste Asiático , Genótipo , Tuberculose/genética , Frequência do Gene , Receptores de Interleucina/genéticaRESUMO
Association of single nucleotide polymorphisms in the IL-23 receptor with several auto-inflammatory diseases, led to the heterodimeric receptor and its cytokine-ligand IL-23, becoming important drug targets. Successful antibody-based therapies directed against the cytokine have been licenced and a class of small peptide antagonists of the receptor have entered clinical trials. These peptide antagonists may offer therapeutic advantages over existing anti-IL-23 therapies, but little is known about their molecular pharmacology. In this study, we use a fluorescent version of IL-23 to characterise antagonists of the full-length receptor expressed by living cells using a NanoBRET competition assay. We then develop a cyclic peptide fluorescent probe, specific to the IL23p19:IL23R interface and use this molecule to characterise further receptor antagonists. Finally, we use the assays to study the immunocompromising C115Y IL23R mutation, demonstrating that the mechanism of action is a disruption of the binding epitope for IL23p19.
Assuntos
Corantes Fluorescentes , Receptores de Interleucina , Células HEK293 , Humanos , Receptores de Interleucina/antagonistas & inibidores , Receptores de Interleucina/genética , Corantes Fluorescentes/metabolismo , Mutação , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/genética , Bibliotecas de Moléculas Pequenas/farmacologia , Polimorfismo de Nucleotídeo Único , Peptídeos CíclicosRESUMO
Red blood cells (RBCs) are the most abundant cell types in the circulatory system of vertebrates. In fish, RBCs retain their nuclei throughout their lifetime and remain transcriptionally and translationally active. While their primary function is typically associated with gas exchange, recent reports indicate that nucleated red blood cells can play a significant role in regulating the body's innate immune response. The current article describes the innate immune role of red blood cells in rohu (Labeo rohita), a freshwater fish species that holds significant commercial importance in India and South-East Asian nations. From the whole blood and mucosal surface RBCs have been isolated through density gradient centrifugation with HiSep™LSM 1077 (density 1.007 ± 0.0010) and their purity has been confirmed by the Giemsa staining followed by microscopical observations. Toll-like receptors (TLR2, 3, 4, 5) and nucleotide oligomerization domain (NOD)-like receptors (NOD1 and NOD2) in RBCs of rohu fingerlings were observed to be significantly activated (P < 0.05) on infection with Aeromonas hydrophila and Edwardsiella tarda. This activation resulted in increased expression of interleukins (IL-8, IL-1ß) and interferon (IFN)-I genes. The activation of TLR4, NOD1 and NOD2, as well as the expression of interleukins and IFN-I genes have been observed in both in vivo and in vitro stimulation of rohu RBCs with lipopolysaccharides. These findings highlight the importance of fish RBCs in enhancing innate immunity against various pathogenic invasions in rohu.
Assuntos
Cyprinidae , Doenças dos Peixes , Infecções por Bactérias Gram-Negativas , Animais , Lipopolissacarídeos/farmacologia , Interferons/genética , Nucleotídeos , Regulação da Expressão Gênica , Receptores Toll-Like/genética , Cyprinidae/genética , Infecções por Bactérias Gram-Negativas/veterinária , Interleucinas/genética , Imunidade Inata/genética , Eritrócitos , Receptores de Interleucina/genética , Aeromonas hydrophilaRESUMO
AIMS: Studies have confirmed that the IL-23R/IL-17A axis plays an important role in the development of autoimmune and inflammatory diseases. However, its role in coronary artery disease (CAD) remains unclear. Here, we conducted a large sample case-control study to investigate the association between the IL23R/IL17A axis and CAD in the Chinese Han population. METHODS: Two SNPs, rs2275913: G>A (IL17A) and rs6682925: T>C (IL23R), were genotyped in 3042 CAD cases and 3216 controls using the high-resolution melt technology (HRM). Logistic regression analyses were used to adjust the traditional risk factors for CAD and perform the gene interaction analyses. Multiple linear regression analyses were used to study the relationships between the selected SNPs and the levels of serum lipids. In addition, meta-analysis also was performed for the association between rs6682925 and rs2275913 with CAD in different popolations. RESULTS: Our case-control and meta-analysis for single SNPs demonstrated that the frequencies of the alleles and the distribution of the genotypes had no significant differences in CAD cases compared with controls. In the stratified analysis, we observed that the frequency of the IL17A rs2275913-A allele was more epidemic in early-onset CAD than in the controls (Padjâ¯=â¯0.005, ORâ¯=â¯1.209, 95% CI: 1.059-1.382), and the minor allele C of rs6682925 was associated with a decreased level of serum total cholesterol under a recessive model (Padjâ¯=â¯0.011). We demonstrated a significant interaction between rs6682925 and rs2275913 and CAD in the Chinese Han population. Four genotypes (CTGG, CCAA, CCAG, CCGG) were significantly associated with CAD (Padjâ¯=â¯2.94â¯×â¯10-4, ORâ¯=â¯0.619, 95% CI: 0.478-0.803; Padjâ¯=â¯0.01, ORâ¯=â¯1.808, 95% CI: 1.152-1.869; Padjâ¯=â¯6â¯×â¯10-6, ORâ¯=â¯2.179, 95% CI: 1.558-3.049; Padjâ¯=â¯0.001, ORâ¯=â¯1.883, 95% CI: 1.282-2.762, respectively). CONCLUSION: Our study found no single SNP of rs2275913 in IL17A and rs6682925 in IL23R was associated with CAD in the Chinese population, but the interaction of them were significantly associated with CAD susceptibility, highlighting the key role of the IL-23R/IL-17A axis in the development of CAD. In addition, we also found rs2275913 was associated with early-onset CAD and rs6682925 was associated with total cholesterol levels, which will contribute to the clinical stratified management of this common disease.
Assuntos
Doença da Artéria Coronariana , Interleucina-17 , Humanos , Interleucina-17/genética , Doença da Artéria Coronariana/genética , Estudos de Casos e Controles , Polimorfismo de Nucleotídeo Único/genética , Colesterol , Predisposição Genética para Doença , Receptores de Interleucina/genéticaRESUMO
BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a worldwide public health problem. Previous genetic association studies have identified several susceptibility loci in the interleukin genes that may participate in the nosogenesis of COPD. This study aimed to evaluate the relationship between IL23R loci and COPD susceptibility in the Chinese population. METHODS: Agena MassARRAY technology was applied to genotype five single nucleotide polymorphisms (SNPs) in the IL23R gene in 498 COPD patients and 498 healthy people. The association between IL23R SNPs and COPD risk was calculated by logistic regression analysis, with odds ratios and 95% confidence intervals. The false-positive report probability analysis was noteworthy for evaluating the significant results. Also, haplotype analysis was performed among IL23R variants, and multifactor dimensionality reduction analysis was performed to assess the SNP-SNP interactions to predict the risk of COPD. RESULTS: Overall analysis showed that rs7517847 had a significant association with an increased risk of COPD. Age-stratified analysis revealed that rs7517847 was significantly related to an increased risk of COPD in people aged over 68 years old. Sex-stratified analysis illustrated a significant association between rs2295359 and rs7517847 and COPD risk in the female population. The significant association of COPD risk with IL23R SNPs was assessed by false-positive report probability values. Additionally, we observed that the haplotypes AAC and GGA formed by rs2201841, rs12743974 and rs10889677 were associated with a reduced risk of COPD (p = 0.009, p = 0.026). Also, the five-loci interaction model formed by rs2295359, rs7517847, rs2201841, rs12743974 and rs10889677 became the best predictor of COPD, with 10/10 cross-validation consistency and 52.4% testing balance accuracy. CONCLUSION: The research indicated a remarkable association between IL23R variants and COPD susceptibility in the Chinese population. Larger samples and functional research are required to ascertain the relationship between IL23R variants and COPD susceptibility.
Assuntos
Predisposição Genética para Doença , Doença Pulmonar Obstrutiva Crônica , Humanos , Feminino , Idoso , População do Leste Asiático , Doença Pulmonar Obstrutiva Crônica/genética , Genótipo , Povo Asiático , Receptores de Interleucina/genéticaRESUMO
Atopic dermatitis (AD) is a common skin disease caused by genetic and environmental factors. However, the mechanisms underlying AD development remain unclear. In this study, we examined the genetic factors contributing to the onset of itch-associated scratching in different strains of mice. Interleukin-31 (IL-31) induces severe scratching and dermatitis in mice. However, the site of action of IL-31 remains unclear. Cutaneous IL-31 and IL-31 receptor A (IL-31RA) mRNAs in the dorsal root ganglion (DRG) are expressed exclusively in the AD model, i.e., NC/Nga mice. Here we evaluated the effects of repeated administration of IL-31 on the scratching behavior in NC/Nga, BALB/c, and C57BL/6 mice. The results showed that repeated administration of IL-31 significantly increased itch-associated scratching (LLS) behavior in the three strains of mice. One hour after an intravenous IL-31 injection, BALB/c mice showed alloknesis-like behavior. Mite infestation and IL-31 administration triggered itchy skin, increased LLS counts and DRG neuronal IL-31RA expression, and eventually caused dermatitis. The dermatitis severity and LLS counts induced by mite infestation and IL-31 administration were in the order NC/Nga > BALB/c > C57BL/6. In conclusion, neuronal IL-31RA expression in the DRG was the most important genetic factor affecting the severity of LLS and dermatitis in mice.
Assuntos
Dermatite Atópica , Receptores de Interleucina , Animais , Camundongos , Dermatite Atópica/induzido quimicamente , Dermatite Atópica/genética , Dermatite Atópica/metabolismo , Modelos Animais de Doenças , Gânglios Espinais/metabolismo , Interleucinas/genética , Interleucinas/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Infestações por Ácaros/metabolismo , Prurido/induzido quimicamente , Prurido/genética , Prurido/metabolismo , Pele/metabolismo , Receptores de Interleucina/genéticaRESUMO
BACKGROUND: To predict primary failure of infliximab (IFX) therapy in Crohn's disease (CD) and to identify patients who maintain long-term effectiveness to IFX is currently not feasible. Some genetic variations are proposed as potential biomarkers. AIM: We assessed a set of single nucleotide polymorphisms (SNPs) in genes related to the IFX mechanism of action and the presence of HLA-DQA1 * 05 allele on the primary response and long-term durability in CD patients. METHODS: A multi-centre cross-sectional study of IFX-exposed adult patients with CD was undertaken. Treatment persistence and time to failure were co-primary endpoints. DNA from the 131 patients was genotyped. Association between SNPs and clinical variables with IFX persistence was assessed. RESULTS: Failure to IFX was documented in 65 (49.6%) out of 131 patients. IFX persistence was associated either with carrying the TT genotype in ADAM17 rs10929587 (ORa=0.2; 95%CI=0.1-0.8; p = 0.021), or the CC genotype in SLCO1C1 rs3794271 (ORa=0.2; 95%CI=0.1-0.7; p = 0.008), according to multivariate logistic regression. In contrast, previous bowel resection increased the risk of IFX failure (ORa=2.8; 95%CI=1.1-7.3; p = 0.025). Cox regression analysis confirmed these findings and also identified IL23R rs10489629-TT (HRa 0.41; 95%CI=0.22-0.75; p = 0.004) and concomitant immunosuppressants (HRa 0.46; 95%CI=0.27-0.77; p = 0.003) as protection from IFX failure. However, no association between HLA-DQA1 * 05 allele and persistence of IFX therapy was found, with similar failure rates among carriers and non-carriers (52.8% vs. 47.4%, respectively; p = 0.544). CONCLUSIONS: SNPs rs10929587-TT in ADAM17, rs10489629-TT in IL23R and rs3794271-CC in SLCO1C1, together with no previous bowel surgery and concomitant immunosuppression, were identified as protection from failure to IFX.
Assuntos
Doença de Crohn , Humanos , Adulto , Infliximab/uso terapêutico , Doença de Crohn/tratamento farmacológico , Doença de Crohn/genética , Polimorfismo de Nucleotídeo Único/genética , Fármacos Gastrointestinais/uso terapêutico , Estudos Transversais , Resultado do Tratamento , Proteína ADAM17/genética , Receptores de Interleucina/genética , Receptores de Interleucina/uso terapêuticoRESUMO
BACKGROUND: Several investigations have disclosed the involvement of the interleukin (IL)-23/IL-17 pathway in rheumatoid arthritis (RA) pathogenesis. Here we investigated the association of single nucleotide polymorphisms (SNPs) in the IL23 receptor (IL23R) gene with RA risk. In addition, the role of these SNPs with the inflammatory state of the patients were determined. METHODS: In this case-control study, 200 RA cases and 200 healthy subjects were recruited. Using allelic discrimination real-time polymerase chain reaction, both IL23R rs10489629 and rs1004819 SNPs were genotyped. The messenger RNA (mRNA) expression levels of IL-23R, IL-23, and IL-17A were determined in peripheral blood mononuclear cells (PBMCs). The serum levels of IL-23 and IL-17A were also determined. RESULTS: The A allele (odds ratio [OR] = 1.52, 95% CI: 1.15-2.01; P = .0030), AA genotype (OR = 2.41, 95% CI: 1.33-4.35; P = .0035), and AG genotype (OR = 2.55, 95% CI: 1.56-4.16, P = .0002) of rs1004819 SNP was significantly associated with increased RA risk. The mRNA expression of IL-17A (fold change = 2.55, P = .00027), IL-23 (fold change = 1.62, P = .0081), and IL-23R (fold change = 1.59, P = .0077) was significantly upregulated in the PBMCs from RA patients compared to that of healthy controls. Serum levels of IL-17A (P = .00019) and IL-23 (P = .00055) was significantly higher in the RA patients compared to the controls. No significant association was detected between patient data and SNPs. CONCLUSIONS: The IL-23/IL-27 pathway plays a role in RA pathogenesis, but IL23R gene rs1004819 SNP might not be regulating this pathway in RA disease.
Assuntos
Artrite Reumatoide , Interleucina-17 , Humanos , Interleucina-17/genética , Irã (Geográfico) , Predisposição Genética para Doença , Estudos de Casos e Controles , Leucócitos Mononucleares , Frequência do Gene , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/genética , Genótipo , Receptores de Interleucina/genética , Polimorfismo de Nucleotídeo Único , Interleucina-23/genéticaRESUMO
A subset of interleukin (IL)-17A-producing γδ T cells called γδT17 cells may contribute to progression of hypertension. γδT17 cell development is in part dependent upon IL-23 receptor (IL-23R) stimulation. We hypothesized that angiotensin (Ang) II-induced blood pressure (BP) elevation and vascular injury would be blunted in Il23r knock-in (Il23rgfp/gfp) mice deficient in functional IL-23R. To test this hypothesis, we infused wild-type (WT) and Il23rgfp/gfp mice with Ang II (490 ng/kg/min, SC) for 7 or 14 days. We recorded BP by telemetry, assessed vascular function and remodeling using pressurized myography, and profiled T cell populations and cytokine production by flow cytometry. An additional set of Il23rgfp/gfp mice was infused with Ang II for 7 days and injected with interferon (IFN)-γ-neutralizing or control antibodies. Il23rgfp/gfp mice had smaller and stiffer mesenteric arteries and were not protected against Ang II-induced BP elevation. BP was higher in Il23rgfp/gfp mice than WT mice from day 3 until day 9 of Ang II infusion. Il23rgfp/gfp mice had less γδT17 cells and more IFN-γ-producing γδ, CD4+, and CD8+ T cells than WT mice. Seven days of Ang II infusion led to increased IFN-γ-producing γδ, CD4+, and CD8+ T cells in Il23rgfp/gfp mice, whereas only IFN-γ-producing γδ T cells were increased in WT mice. Blocking IFN-γ with a neutralizing antibody reduced the pressor response to 7 days of Ang II infusion in Il23rgfp/gfp mice. Functional IL-23R deficiency was associated with increased IFN-γ-producing T cells and exaggerated initial development of Ang II-induced hypertension, which was in part mediated by IFN-γ.