RESUMEN
This study evaluated the impact of the TLR7 Gln11Leu (rs179008) and TLR9 -1237 T/C (rs5743836) single nucleotide polymorphisms (SNPs) on susceptibility to placental infections and pregnancy complications in 455 Brazilian women. Demographic, socioeconomic, gynecological, and clinical characteristics of the women were collected. Placental tissues were sampled from pregnant women and human and viral DNA was extracted. Human alphaherpesvirus 1 (Herpes simplex virus type 1, HSV-1), Human alphaherpesvirus 2 (Herpes simplex virus type 2, HSV-2) and Human betaherpesvirus 5 (Human cytomegalovirus, HCMV) were detected by nested PCR. TLR9 and TLR7 SNPs were genotyped by PCR amplification of bi-directional specific alleles (Bi-PASA) and restriction fragment length polymorphism (RFLP), respectively. Infections at the time of birth were detected in 45.71 % of women. The presence of the TT genotype (recessive model) of the TLR7 SNP was associated with increased susceptibility to HSV-1 infection (O.R. = 2.23, p = 0.05). The presence of the C allele of the TLR9 SNP, in heterozygosis or homozygosis (dominant model), decreased the infection risk by HCMV (O.R. = 0.31, p-mod<0.05). The TT genotype (recessive model) of the TLR7 SNP was significantly associated (p < 0.05) with increased occurrence of pre-treated hypertension. The codominant model of the TLR9 SNP was significantly associated (p < 0.05) with reduced risk of hospitalization during pregnancy. In combination, the AA/CT (TLR7-TLR9) genotypes significantly decreased the risk of placental infection by HSV-1 and/or HSV-2 (O.R. = 0.47, p = 0.02), the susceptibility to all infectious agents considered in combination (O.R. = 0.4, p = 0.00), and the need of hospitalization (O.R. = 0.48, p = 0.02). In conclusion, TLR7 and TLR9 SNPs are potential modulating factors for the risk of placental infections and pregnancy complications.
Asunto(s)
Infecciones por Citomegalovirus/genética , Herpes Simple/genética , Complicaciones Infecciosas del Embarazo/genética , Receptor Toll-Like 7/genética , Receptor Toll-Like 9/genética , Adolescente , Adulto , Alelos , Brasil , Estudios de Casos y Controles , Citomegalovirus/inmunología , Citomegalovirus/aislamiento & purificación , Infecciones por Citomegalovirus/inmunología , Infecciones por Citomegalovirus/virología , Epistasis Genética/inmunología , Femenino , Predisposición Genética a la Enfermedad , Herpes Simple/inmunología , Herpes Simple/virología , Herpesvirus Humano 1/inmunología , Herpesvirus Humano 1/aislamiento & purificación , Herpesvirus Humano 2/inmunología , Herpesvirus Humano 2/aislamiento & purificación , Humanos , Placenta/inmunología , Placenta/virología , Polimorfismo de Longitud del Fragmento de Restricción , Polimorfismo de Nucleótido Simple , Embarazo , Complicaciones Infecciosas del Embarazo/inmunología , Complicaciones Infecciosas del Embarazo/virología , Estudios Retrospectivos , Adulto JovenRESUMEN
Preterm birth or PTB (<37 weeks) is a heterogeneous phenotype with numerous biological pathways. The lack of explanation due to complex pathways, inconsistent observations indicates the need for employing the role of genetic determinants to anticipate the danger of PTB. In this present study, we investigated the possible gene-gene interaction of five SNPs with PTB and its association with total MMP-9 levels. A total of 510 recruitments (250 terms and preterm each) were made and were genotyped by Restriction Fragment length polymorphism (RFLP). Generalized Multifactor Dimensionality Reduction (GMDR) method was carried out for determining gene-gene interaction. ANOVA and t-test were used to identify the association of IL-6 polymorphism with PTB alone and correspondingly with PTB and low birth weight infants (i.e. < 2500 kg). The combination of IL-6 and MMP-9 and MMP-1, MMP-8 and MMP-9 polymorphism was selected through GMDR analysis concerning mothers with preterm and term birth (accuracy 0.5921 and 0.8030 with Cross-Validation Consistency (CVC) 10/10 respectively). Increased expression of MMP-9 was reported in cases in those mothers carrying IL-6 G allele, which was profoundly associated with PTB independently. IL-6 polymorphisms showed synergistic effects in terms of increased total MMP-9 levels in the present study.
Asunto(s)
Epistasis Genética/inmunología , Interleucina-6/genética , Metaloproteinasa 9 de la Matriz/genética , Nacimiento Prematuro/genética , Adulto , Alelos , Estudios de Casos y Controles , Femenino , Predisposición Genética a la Enfermedad , Humanos , Recién Nacido de Bajo Peso , Recién Nacido , Interleucina-6/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Polimorfismo de Longitud del Fragmento de Restricción , Embarazo , Nacimiento Prematuro/inmunología , Adulto JovenRESUMEN
Complex tissue communication networks function throughout an organism's lifespan to maintain tissue homeostasis. Using the genetic model Drosophila melanogaster, we have defined a network of immune responses that are activated following the induction of muscle stresses, including hypercontraction, detachment and oxidative stress. Of these stressors, loss of the genes that cause muscle detachment produced the strongest levels of JAK-STAT activation. In one of these mutants, fondue (fon), we also observe hemocyte recruitment and the accumulation of melanin at muscle attachment sites (MASs), indicating a broad involvement of innate immune responses upon muscle detachment. Loss of fon results in pathogen-independent Toll signaling in the fat body and increased expression of the Toll-dependent antimicrobial peptide Drosomycin. Interestingly, genetic interactions between fon and various Toll pathway components enhance muscle detachment. Finally, we show that JAK-STAT and Toll signaling are capable of reciprocal activation in larval tissues. We propose a model of tissue communication for the integration of immune responses at the local and systemic level in response to altered muscle physiology.
Asunto(s)
Drosophila melanogaster/inmunología , Hemocitos/inmunología , Homeostasis/inmunología , Inmunidad Innata/inmunología , Receptores Toll-Like/inmunología , Animales , Proteínas Sanguíneas/inmunología , Proteínas Sanguíneas/metabolismo , Proteínas de Drosophila/inmunología , Proteínas de Drosophila/metabolismo , Epistasis Genética/inmunología , Músculos/inmunología , Músculos/metabolismoRESUMEN
OBJECTIVE: In anti-citrullinated protein antibody positive rheumatoid arthritis (ACPA-positive RA), a particular subset of HLA-DRB1 alleles, called shared epitope (SE) alleles, is a highly influential genetic risk factor. Here, we investigated whether non-HLA single nucleotide polymorphisms (SNP), conferring low disease risk on their own, interact with SE alleles more frequently than expected by chance and if such genetic interactions influence the HLA-DRB1 SE effect concerning risk to ACPA-positive RA. METHODS: We computed the attributable proportion (AP) due to additive interaction at genome-wide level for two independent ACPA-positive RA cohorts: the Swedish epidemiological investigation of rheumatoid arthritis (EIRA) and the North American rheumatoid arthritis consortium (NARAC). Then, we tested for differences in the AP p value distributions observed for two groups of SNPs, non-associated and associated with disease. We also evaluated whether the SNPs in interaction with HLA-DRB1 were cis-eQTLs in the SE alleles context in peripheral blood mononuclear cells from patients with ACPA-positive RA (SE-eQTLs). RESULTS: We found a strong enrichment of significant interactions (AP p<0.05) between the HLA-DRB1 SE alleles and the group of SNPs associated with ACPA-positive RA in both cohorts (Kolmogorov-Smirnov test D=0.35 for EIRA and D=0.25 for NARAC, p<2.2e-16 for both). Interestingly, 564 out of 1492 SNPs in consistent interaction for both cohorts were significant SE-eQTLs. Finally, we observed that the effect size of HLA-DRB1 SE alleles for disease decreases from 5.2 to 2.5 after removal of the risk alleles of the two top interacting SNPs (rs2476601 and rs10739581). CONCLUSION: Our data demonstrate that there are massive genetic interactions between the HLA-DRB1 SE alleles and non-HLA genetic variants in ACPA-positive RA.
Asunto(s)
Alelos , Artritis Reumatoide/genética , Epistasis Genética/genética , Predisposición Genética a la Enfermedad/genética , Cadenas HLA-DRB1/genética , Anticuerpos Antiproteína Citrulinada/genética , Anticuerpos Antiproteína Citrulinada/inmunología , Artritis Reumatoide/inmunología , Estudios de Cohortes , Epistasis Genética/inmunología , Epítopos/genética , Epítopos/inmunología , Femenino , Cadenas HLA-DRB1/inmunología , Humanos , Masculino , América del Norte , Polimorfismo de Nucleótido Simple , Factores de Riesgo , SueciaRESUMEN
The human leukocyte antigen class I gene HLA-B27 is the strongest risk factor for ankylosing spondylitis (AS), a chronic inflammatory arthritic disorder. More recently, the Endoplasmic Reticulum Aminopeptidase (ERAP) 1 and 2 genes have been identified by genome wide association studies (GWAS) as additional susceptibility factors. In the ER, these aminopeptidases trim the peptides to a length suitable to fit into the groove of the major histocompatibility complex (MHC) class I molecules. It is noteworthy that an epistatic interaction between HLA-B27 and ERAP1, but not between HLA-B27 and ERAP2, has been highlighted. However, these observations suggest a paramount centrality for the HLA-B27 peptide repertoire that determines the natural B27 immunological function, i.e. the T cell antigen presentation and, as a by-product, elicits HLA-B27 aberrant behaviours: (i) the misfolding leading to ER stress responses and autophagy and (ii) the surface expression of homodimers acting as ligands for innate immune receptors. In this context, it has been observed that the HLA-B27 carriers, besides being prone to autoimmunity, display a far better surveillance to some viral infections. This review focuses on the ambivalent role of HLA-B27 in autoimmunity and viral protection correlating its functions to the quantitative and qualitative effects of ERAP1 and ERAP2 polymorphisms on their enzymatic activity.
Asunto(s)
Aminopeptidasas , Antígeno HLA-B27 , Antígenos de Histocompatibilidad Menor , Espondilitis Anquilosante , Virosis , Aminopeptidasas/genética , Aminopeptidasas/inmunología , Autofagia/genética , Autofagia/inmunología , Estrés del Retículo Endoplásmico/genética , Estrés del Retículo Endoplásmico/inmunología , Epistasis Genética/genética , Epistasis Genética/inmunología , Estudio de Asociación del Genoma Completo , Antígeno HLA-B27/genética , Antígeno HLA-B27/inmunología , Humanos , Antígenos de Histocompatibilidad Menor/genética , Antígenos de Histocompatibilidad Menor/inmunología , Espondilitis Anquilosante/genética , Espondilitis Anquilosante/inmunología , Virosis/genética , Virosis/inmunologíaRESUMEN
Schistosomiasis is a neglected parasitic disease of major public health concern as it affects over 250 million people in developing countries. Currently there is no licensed vaccine available against schistosomiasis. The Schistosoma mansoni calpain protein, Sm-p80, is a leading vaccine candidate now ready to move to clinical trials. In order to better assess Sm-p80 vaccine immunogenicity; here we used a systems biology approach employing RNA-sequencing to identify gene signatures and epistatic interactions following Sm-p80 vaccination in mouse and baboon models that may predict vaccine efficacy. Recombinant Sm-p80 + CpG-oligodeoxynucleotide (ODN) vaccine formulation induced both cellular and humoral immunity genes with a predominant TH1 response as well as TH2 and TH17 gene signatures. Early gene responses and gene-network interactions in mice immunized with rSm-p80 + ODN appear to be initiated through TLR4 signaling. CSF genes, S100A alarmin genes and TNFRSF genes appear to be a signature of vaccine immunogenicity/efficacy as identified by their participation in gene network interactions in both mice and baboons. These gene families may provide a basis for predicting desirable outcomes for vaccines against schistosomiasis leading to a better understanding of the immune system response to vaccination.
Asunto(s)
Antígenos Helmínticos/inmunología , Schistosoma mansoni/inmunología , Esquistosomiasis mansoni/inmunología , Vacunas/inmunología , Animales , Anticuerpos Antihelmínticos/inmunología , Epistasis Genética/genética , Epistasis Genética/inmunología , Femenino , Redes Reguladoras de Genes/genética , Redes Reguladoras de Genes/inmunología , Inmunidad Celular/genética , Inmunidad Celular/inmunología , Inmunidad Humoral/genética , Inmunidad Humoral/inmunología , Masculino , Ratones Endogámicos C57BL , Oligodesoxirribonucleótidos/administración & dosificación , Oligodesoxirribonucleótidos/inmunología , Papio , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Schistosoma mansoni/metabolismo , Schistosoma mansoni/fisiología , Esquistosomiasis mansoni/parasitología , Esquistosomiasis mansoni/prevención & control , Transducción de Señal/genética , Transducción de Señal/inmunología , Transcriptoma/genética , Transcriptoma/inmunología , Vacunación/métodos , Vacunas/administración & dosificaciónRESUMEN
RATIONALE: How host genetic factors affect Mycobacterium tuberculosis (Mtb) infection outcomes remains largely unknown. SP110b, an IFN-induced nuclear protein, is the nearest human homologue to the mouse Ipr1 protein that has been shown to control host innate immunity to Mtb infection. However, the function(s) of SP110b remains unclear. OBJECTIVES: To elucidate the role of SP110b in controlling host immunity and susceptibility to tuberculosis (TB), as well as to identify the fundamental immunological and molecular mechanisms affected by SP110b. METHODS: Using cell-based approaches and mouse models of Mtb infection, we characterized the function(s) of SP110b/Ipr1. We also performed genetic characterization of patients with TB to investigate the role of SP110 in controlling host susceptibility to TB. MEASUREMENTS AND MAIN RESULTS: SP110b modulates nuclear factor-κB (NF-κB) activity, resulting in downregulation of tumor necrosis factor-α (TNF-α) production and concomitant upregulation of NF-κB-induced antiapoptotic gene expression, thereby suppressing IFN-γ-mediated monocyte and/or macrophage cell death. After Mtb infection, TNF-α is also downregulated in Ipr1-expressing mice that have alleviated cell death, less severe necrotic lung lesions, more efficient Mtb growth control in the lungs, and longer survival. Moreover, genetic studies in patients suggest that SP110 plays a key role in modulating TB susceptibility in concert with NFκB1 and TNFα genes. CONCLUSIONS: These results indicate that SP110b plays a crucial role in shaping the inflammatory milieu that supports host protection during infection by fine-tuning NF-κB activity, suggesting that SP110b may serve as a potential target for host-directed therapy aimed at manipulating host immunity against TB.
Asunto(s)
Antígenos Nucleares , Autoantígenos , Epistasis Genética/inmunología , Predisposición Genética a la Enfermedad , Inmunidad Innata/genética , Antígenos de Histocompatibilidad Menor , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/inmunología , Proteínas Nucleares , Tuberculosis/genética , Tuberculosis/inmunología , Animales , Antígenos Nucleares/genética , Antígenos Nucleares/inmunología , Apoptosis/genética , Apoptosis/inmunología , Autoantígenos/genética , Autoantígenos/inmunología , Modelos Animales de Enfermedad , Regulación de la Expresión Génica/inmunología , Humanos , Ratones , Análisis por Micromatrices , Antígenos de Histocompatibilidad Menor/genética , Antígenos de Histocompatibilidad Menor/inmunología , FN-kappa B/genética , FN-kappa B/inmunología , Proteínas Nucleares/genética , Proteínas Nucleares/inmunología , Polimorfismo de Nucleótido Simple , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/inmunologíaRESUMEN
Natural killer (NK) cell function is regulated by a fine balance between numerous activating and inhibitory receptors, of which killer-cell immunoglobulin-like receptors (KIRs) are among the most polymorphic and comprehensively studied. KIRs allow NK cells to recognize downregulation or the absence of HLA class I molecules on target cells (known as missing-self), a phenomenon that is commonly observed in virally infected cells or cancer cells. Because KIR and HLA genes are located on different chromosomes, in an allogeneic environment such as after hematopoietic stem cell transplantation, donor NK cells that express an inhibitory KIR for an HLA class I molecule that is absent on recipient targets (KIR/KIR-ligand mismatch), can recognize and react to this missing self and mediate cytotoxicity. Accumulating data indicate that epistatic interactions between KIR and HLA influence outcomes in several clinical conditions. Herein, we discuss the genetic and functional features of KIR/KIR-ligand interactions in hematopoietic stem cell transplantation and how these data can guide donor selection. We will also review clinical studies of adoptive NK cell therapy in leukemia and emerging data on the use of genetically modified NK cells that could broaden the scope of cancer immunotherapy.
Asunto(s)
Traslado Adoptivo , Selección de Donante/métodos , Técnicas de Genotipaje , Trasplante de Células Madre Hematopoyéticas , Inmunoterapia , Células Asesinas Naturales , Receptores KIR , Epistasis Genética/inmunología , Antígenos HLA/genética , Antígenos HLA/inmunología , Humanos , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/trasplante , Neoplasias/genética , Neoplasias/inmunología , Neoplasias/terapia , Receptores KIR/genética , Receptores KIR/inmunologíaRESUMEN
The genes MyD88 and TIRAP encode the adaptor proteins MyD88 and TIRAP. TIRAP plays the crucial role of activating the MyD88-dependent pathway, which in turn controls the immune response (innate and adaptive) to Helicobacter pylori. We looked for an association of MyD88 and TIRAP with H. pylori infection. Cases and controls were genotyped at the polymorphic sites MyD88 rs6853 and TIRAP rs8177374 by real-time PCR. When the genes were analyzed separately, only TIRAP was associated with infection. When the genes were analyzed concurrently, certain combinations of MyD88 and TIRAP protected the host against H. pylori colonization more efficiently than could be done by TIRAP alone.
Asunto(s)
Epistasis Genética/inmunología , Infecciones por Helicobacter , Helicobacter pylori/inmunología , Glicoproteínas de Membrana , Factor 88 de Diferenciación Mieloide , Polimorfismo Genético/inmunología , Receptores de Interleucina-1 , Adulto , Femenino , Infecciones por Helicobacter/genética , Infecciones por Helicobacter/inmunología , Humanos , Masculino , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/inmunología , Persona de Mediana Edad , Factor 88 de Diferenciación Mieloide/genética , Factor 88 de Diferenciación Mieloide/inmunología , Receptores de Interleucina-1/genética , Receptores de Interleucina-1/inmunologíaRESUMEN
BACKGROUND: Several lines of evidence suggest the involvement of neuroinflammatory changes in Alzheimer's disease (AD) pathophysiology such as amyloidosis and neurodegeneration. In fact, genome-wide association studies (GWAS) have shown a link between genes involved in neuroinflammation and AD. In order to further investigate whether interactions between candidate genetic variances coding for neuroinflammatory molecules are associated with brain amyloid ß (Aß) fibrillary accumulation, we conducted an epistasis analysis on a pool of genes associated with molecular mediators of inflammation. METHODS: [(18)F]Florbetapir positron emission tomography (PET) imaging was employed to assess brain Aß levels in 417 participants from ADNI-GO/2 and posteriorly 174 from ADNI-1. IL-1ß, IL4, IL6, IL6r, IL10, IL12, IL18, C5, and C9 genes were chosen based on previous studies conducted in AD patients. Using the [(18)F]florbetapir standardized uptake value ratio (SUVR) as a quantitative measure of fibrillary Aß, epistasis analyses were performed between two sets of markers of immune-related genes using gender, diagnosis, and apolipoprotein E (APOE) as covariates. Voxel-based analyses were also conducted. The results were corrected for multiple comparison tests. Cerebrospinal fluid (CSF) Aß1-42/phosphorylated tau (p-tau) ratio concentrations were used to confirm such associations. RESULTS: Epistasis analysis unveiled two significant single nucleotide polymorphism (SNP)-SNP interactions (false discovery rate (FDR) threshold 0.1), both interactions between C9 gene (rs261752) and IL6r gene (rs4240872, rs7514452). In a combined sample, the interactions were confirmed (p ≤ 10-5) and associated with amyloid accumulation within cognitively normal and AD spectrum groups. Voxel-based analysis corroborated initial findings. CSF biomarker (Aß1-42/p-tau) confirmed the genetic interaction. Additionally, rs4240872 and rs7514452 SNPs were shown to be associated with CSF and plasma concentrations of IL6r protein. CONCLUSIONS: Certain allele combinations involving IL6r and C9 genes are associated with Aß burden in the brain. Hypothesis-driven search for epistasis is a valuable strategy for investigating imaging endophenotypes in complex neurodegenerative diseases.
Asunto(s)
Enfermedad de Alzheimer/inmunología , Amiloidosis/inmunología , Disfunción Cognitiva/inmunología , Epistasis Genética/inmunología , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/genética , Amiloidosis/diagnóstico , Amiloidosis/genética , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/genética , Epistasis Genética/genética , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Diversity within the innate and adaptive immune response to hepatitis C is important in determining spontaneous resolution (SR) and treatment response. The aim of this study was to analyze how these variables interact in combination; furthering our understanding of the mechanisms that drive successful immunological clearance. Multivariate analysis was performed on retrospectively collected data for 357 patients previously genotyped for interferon (IFN)-λ3/4, killer cell immunoglobulin (KIR), human leukocyte antigen (HLA) class I and II and tapasin. High resolution KIR genotyping was performed for individuals with chronic infection and haplotypes determined. Outcomes for SR, IFN response and cirrhosis were examined. Statistical analysis included univariate methods, χ(2) test for trend, multivariate logistic regression, synergy and principal component analysis (PCA). Although KIR2DL3:HLA-C1C1 (P = 0.027), IFN-λ3/4 rs12979860 CC (P = 0.027), tapasin G in individuals with aspartate at residue 114 of HLA-B (TapG:HLA-B(114D) ) (P = 0.007) and HLA-DRB1*04:01 (P = 0.014) were associated with SR with a strong additive influence (χ(2) test for trend P < 0.0001); favorable polymorphisms did not interact synergistically, nor did patients cluster by outcome. In the treatment cohort, IFN-λ3/4 rs12979860 CC was protective in hepatitis C virus (HCV) G1 infection and KIR2DL3:HLA-C1 in HCV G2/3. In common with SR, variables did not interact synergistically. Polymorphisms predictive of viral clearance did not predict disease progression. In summary, different individuals resolve HCV infection using discrete and non-interacting immunological pathways. These pathways are influenced by viral genotype. This work provides novel insights into the complexity of the interaction between host and viral factors in determining the outcome of HCV infection.
Asunto(s)
Epistasis Genética/inmunología , Hepacivirus/inmunología , Hepatitis C Crónica/genética , Interacciones Huésped-Patógeno/genética , Cirrosis Hepática/genética , Progresión de la Enfermedad , Expresión Génica , Heterogeneidad Genética , Genotipo , Hepacivirus/patogenicidad , Hepatitis C Crónica/diagnóstico , Hepatitis C Crónica/inmunología , Hepatitis C Crónica/virología , Antígenos de Histocompatibilidad Clase I/genética , Antígenos de Histocompatibilidad Clase I/inmunología , Antígenos de Histocompatibilidad Clase II/genética , Antígenos de Histocompatibilidad Clase II/inmunología , Interacciones Huésped-Patógeno/inmunología , Humanos , Interferones , Interleucinas/genética , Interleucinas/inmunología , Cirrosis Hepática/diagnóstico , Cirrosis Hepática/inmunología , Cirrosis Hepática/virología , Modelos Logísticos , Proteínas de Transporte de Membrana/genética , Proteínas de Transporte de Membrana/inmunología , Análisis Multivariante , Pronóstico , Receptores KIR/genética , Receptores KIR/inmunología , Remisión Espontánea , Estudios RetrospectivosRESUMEN
Most current gene coexpression databases support the analysis for linear correlation of gene pairs, but not nonlinear correlation of them, which hinders precisely evaluating the gene-gene coexpression strengths. Here, we report a new database, MIrExpress, which takes advantage of the information theory, as well as the Pearson linear correlation method, to measure the linear correlation, nonlinear correlation, and their hybrid of cell-specific gene coexpressions in immune cells. For a given gene pair or probe set pair input by web users, both mutual information (MI) and Pearson correlation coefficient (r) are calculated, and several corresponding values are reported to reflect their coexpression correlation nature, including MI and r values, their respective rank orderings, their rank comparison, and their hybrid correlation value. Furthermore, for a given gene, the top 10 most relevant genes to it are displayed with the MI, r, or their hybrid perspective, respectively. Currently, the database totally includes 16 human cell groups, involving 20,283 human genes. The expression data and the calculated correlation results from the database are interactively accessible on the web page and can be implemented for other related applications and researches.
Asunto(s)
Bases de Datos Genéticas , Epistasis Genética/inmunología , Programas Informáticos , Linfocitos T/metabolismo , Perfilación de la Expresión Génica , Humanos , Teoría de la Información , Internet , Modelos Lineales , Dinámicas no Lineales , Linfocitos T/inmunologíaRESUMEN
Several molecules (LYST, AP3, RAB27A, STX11, STXBP2, MUNC13-4, and PRF1) have been associated with the function of cytotoxic lymphocytes. Biallelic defects in all of these molecules have been associated with familial hemophagocytic lymphohistiocytosis (FHL). We retrospectively reviewed the genetic and immunology test results from 2701 patients with a clinically suspected diagnosis of hemophagocytic lymphohistiocytosis and found 28 patients with single heterozygous mutations in 2 FHL-associated genes. Of these patients, 21 had mutations within PRF1 and a degranulation gene, and 7 were found to have mutations within 2 genes involved in the degranulation pathway. In patients with combination defects involving 2 genes in the degranulation pathway, CD107a degranulation was decreased, comparable to patients with biallelic mutations in one of the genes in the degranulation pathway. This suggests a potential digenic mode of inheritance of FHL as a result of a synergistic function effect within genes involved in cytotoxic lymphocyte degranulation.
Asunto(s)
Degranulación de la Célula , Epistasis Genética , Linfocitos/inmunología , Linfohistiocitosis Hemofagocítica , Proteína 1 de la Membrana Asociada a los Lisosomas , Modelos Genéticos , Mutación , Proteínas Citotóxicas Formadoras de Poros , Adolescente , Adulto , Degranulación de la Célula/genética , Degranulación de la Célula/inmunología , Niño , Preescolar , Epistasis Genética/genética , Epistasis Genética/inmunología , Femenino , Humanos , Lactante , Linfohistiocitosis Hemofagocítica/genética , Linfohistiocitosis Hemofagocítica/inmunología , Proteína 1 de la Membrana Asociada a los Lisosomas/genética , Proteína 1 de la Membrana Asociada a los Lisosomas/inmunología , Masculino , Perforina , Proteínas Citotóxicas Formadoras de Poros/genética , Proteínas Citotóxicas Formadoras de Poros/inmunología , Estudios RetrospectivosRESUMEN
The host defense of the model organism Drosophila is under the control of two major signaling cascades controlling transcription factors of the NF-B family, the Toll and the immune deficiency (IMD) pathways. The latter shares extensive similarities with the mammalian TNF-R pathway and was initially discovered for its role in anti-Gram-negative bacterial reactions. A previous interactome study from this laboratory reported that an unexpectedly large number of proteins are binding to the canonical components of the IMD pathway. Here, we focus on DNA methyltransferase-associated protein 1 (DMAP1), which this study identified as an interactant of Relish, a Drosophila transcription factor reminiscent of the mammalian p105 NF-B protein. We show that silencing of DMAP1 expression both in S2 cells and in flies results in a significant reduction of Escherichia coli-induced expression of antimicrobial peptides. Epistatic analysis indicates that DMAP1 acts in parallel or downstream of Relish. Co-immunoprecipitation experiments further reveal that, in addition to Relish, DMAP1 also interacts with Akirin and the Brahma-associated protein 55 kDa (BAP55). Taken together, these results reveal that DMAP1 is a novel nuclear modulator of the IMD pathway, possibly acting at the level of chromatin remodeling.
Asunto(s)
Proteínas de Drosophila/inmunología , Infecciones por Escherichia coli/inmunología , Escherichia coli/inmunología , Inmunidad Innata/fisiología , FN-kappa B/inmunología , Proteínas Represoras/inmunología , Factores de Transcripción/inmunología , Animales , Línea Celular , Ensamble y Desensamble de Cromatina/genética , Ensamble y Desensamble de Cromatina/inmunología , Proteínas de Drosophila/genética , Drosophila melanogaster , Epistasis Genética/genética , Epistasis Genética/inmunología , Infecciones por Escherichia coli/genética , FN-kappa B/genética , Proteínas Nucleares , Proteínas Represoras/genética , Transducción de Señal/genética , Transducción de Señal/inmunología , Factores de Transcripción/genéticaRESUMEN
The nonobese diabetic (NOD) mouse strain serves as a genomic standard for assessing how allelic variation for insulin-dependent diabetes (Idd) loci affects the development of autoimmune diabetes. We previously demonstrated that C57BL/6 (B6) mice harbor a more diabetogenic allele than NOD mice for the Idd14 locus when introduced onto the NOD genetic background. New congenic NOD mouse strains, harboring smaller B6-derived intervals on chromosome 13, now localize Idd14 to an ~18-Mb interval and reveal a new locus, Idd31. Notably, the B6 allele for Idd31 confers protection against diabetes, but only in the absence of the diabetogenic B6 allele for Idd14, indicating genetic epistasis between these two loci. Moreover, congenic mice that are more susceptible to diabetes are more resistant to Listeria monocytogenes infection. This result co-localizes Idd14 and Listr2, a resistance locus for listeriosis, to the same genomic interval and indicates that congenic NOD mice may also be useful for localizing resistance loci for infectious disease.
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Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/inmunología , Epistasis Genética/inmunología , Listeriosis/genética , Listeriosis/inmunología , Alelos , Animales , Femenino , Predisposición Genética a la Enfermedad , Fenómenos Inmunogenéticos , Ratones , Ratones Congénicos , Ratones Endogámicos C57BL , Ratones Endogámicos NODRESUMEN
Interferon (IFN) activation signaling and T helper 17 (Th17)-cell/B-cell regulation play a critical role in the pathogenesis of systemic lupus erythematosus (SLE). Several studies have provided convincing evidence that polymorphisms in IRF5, STAT4, IKZF1 and ETS1 from these pathways may be involved in SLE by affecting gene expression or epistasis. We analyzed the genetic interaction in known SLE susceptibility loci from the four genes in northern Han Chinese. A total of 946 northern Han Chinese participated in this study (370 unrelated SLE patients and 576 healthy controls). Subjects underwent genotyping for the single-nucleotide polymorphisms (SNPs) rs2004640 in IRF5, rs7574865 in STAT4, rs4917014 in IKZF1 and rs1128334 in ETS1 by use of a TaqMan SNP genotyping assay and direct sequencing. Gene-gene interaction analysis involved direct counting, multifactor dimensionality reduction (MDR) and linear regression analysis. SLE patients and controls differed in allele frequencies of rs7574865, rs1128334 (P < 0.001) and rs4917014 (P < 0.01). Direct counting revealed that the frequency of risk homozygote combinations was higher for SLE patients than controls (P < 0.01). Furthermore, 2-, 3- and 4-way gene-gene epistasis in SLE was confirmed by parametric methods and MDR analysis. Gene expression analysis partially supported the findings. Our study confirmed the association of the IFN pathway or Th17/B-cells and the pathogenesis of SLE, and gene-gene interaction in this pathway may increase the risk of SLE.
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Pueblo Asiatico/genética , Epistasis Genética , Factor de Transcripción Ikaros/genética , Factores Reguladores del Interferón/genética , Lupus Eritematoso Sistémico/genética , Proteína Proto-Oncogénica c-ets-1/genética , Factor de Transcripción STAT4/genética , Adulto , Alelos , Estudios de Casos y Controles , Epistasis Genética/genética , Epistasis Genética/inmunología , Femenino , Regulación de la Expresión Génica , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Interferones/fisiología , Lupus Eritematoso Sistémico/etnología , Lupus Eritematoso Sistémico/inmunología , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , ARN Mensajero/biosíntesis , Reacción en Cadena en Tiempo Real de la Polimerasa , Células Th17/inmunología , Adulto JovenRESUMEN
In a recent study on multiple sclerosis (MS), we observed additive effects and epistatic interactions between variants of four genes that converge to induce T-cell hyperactivity by altering Asn-(N)-linked protein glycosylation: namely, the Golgi enzyme MGAT1, cytotoxic T-lymphocyte antigen 4 (CTLA-4), interleukin-2 receptor-α (IL2RA) and interleukin-7 receptor-α (IL7RA). As the CTLA-4, IL2RA and IL7RA variants are associated with type 1 diabetes (T1D), we examined for joint effects in T1D. Employing a novel conditional logistic regression for family-based data sets, epistatic and additive effects were observed using 1423 multiplex families from the Type 1 Diabetes Genetic Consortium data set. The IL2RA and IL7RA variants had univariate association in MS and T1D, whereas the MGAT1 and CTLA-4 variants associated with only MS or T1D, respectively. However, similar to MS, the MGAT1 variant haplotype interacted with CTLA4 (P=0.03), and a combination of IL2RA and IL7RA (P=0.01). The joint effects of MGAT1, CTLA4, IL2RA, IL7RA and the two interactions using a multiple conditional logistic regression were statistically highly significant (P<5 × 10(-10)). The MGAT1-CTLA-4 interaction was replicated (P=0.01) in 179 trio families from the Genetics of Kidneys in Diabetes study. These data are consistent with defective N-glycosylation of T cells contributing to T1D pathogenesis.
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Antígeno CTLA-4/genética , Diabetes Mellitus Tipo 1/genética , Epistasis Genética , Familia , Variación Genética/inmunología , Subunidad alfa del Receptor de Interleucina-2/genética , N-Acetilglucosaminiltransferasas/genética , Receptores de Interleucina-7/genética , Antígeno CTLA-4/inmunología , Conjuntos de Datos como Asunto , Diabetes Mellitus Tipo 1/inmunología , Epistasis Genética/inmunología , Femenino , Humanos , Subunidad alfa del Receptor de Interleucina-2/inmunología , Masculino , N-Acetilglucosaminiltransferasas/inmunología , Receptores de Interleucina-7/inmunologíaRESUMEN
Elevation of serum IgE levels has long been associated with allergic diseases. Many genes have been linked to IgE production, but few have been linked to the developmental aspects of genetic association with IgE production. To clarify developmental genetic association, we investigated what genes and gene-gene interactions affect IgE levels among fetus, infancy and childhood in Taiwan individuals. A birth cohort of 571 children with completion of IgE measurements from newborn to 1.5, 3, and 6 years of age was subject to genetic association analysis on the 384-customized SNPs of 159 allergy candidate genes. Fifty-three SNPs in 37 genes on innate and adaptive immunity, and stress and response were associated with IgE production. Polymorphisms of the IL13, and the HLA-DPA1 and HLA-DQA1 were, respectively, the most significantly associated with the IgE production at newborn and 6 years of age. Analyses of gene-gene interactions indentified that the combination of NPSR1, rs324981 TT with FGF1, rs2282797 CC had the highest risk (85.7%) of IgE elevation at 1.5 years of age (P=1.46 × 10(-4)). The combination of IL13, CYFIP2 and PDE2A was significantly associated with IgE elevation at 3 years of age (P=5.98 × 10(-7)), and the combination of CLEC2D, COLEC11 and CCL2 was significantly associated with IgE elevation at 6 years of age (P=6.65 × 10(-7)). Our study showed that the genetic association profiles of the IgE production among fetus, infancy and childhood are different. Genetic markers for early prediction and prevention of allergic sensitization may rely on age-based genetic association profiles.
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Epistasis Genética/inmunología , Feto/metabolismo , Inmunoglobulina E/biosíntesis , Polimorfismo de Nucleótido Simple/inmunología , Niño , Preescolar , Estudios de Cohortes , Femenino , Feto/inmunología , Humanos , Hipersensibilidad/genética , Inmunoglobulina E/sangre , Inmunoglobulina E/inmunología , Lactante , Recién Nacido , Masculino , Reducción de Dimensionalidad MultifactorialRESUMEN
An increased understanding of antitumor immunity is necessary for improving cell-based immunotherapies against human cancers. Here, we investigated the roles of two immune system-expressed microRNAs (miRNAs), miR-155 and miR-146a, in the regulation of antitumor immune responses. Our results indicate that miR-155 promotes and miR-146a inhibits interferon γ (IFNγ) responses by T cells and reduces solid tumor growth in vivo. Using a double-knockout (DKO) mouse strain deficient in both miR-155 and miR-146a, we have also identified an epistatic relationship between these two miRNAs. DKO mice had defective T cell responses and tumor growth phenotypes similar to miR-155(-/-) mice. Further analysis of the T cell compartment revealed that miR-155 modulates IFNγ expression through a mechanism involving repression of Ship1. Our work reveals critical roles for miRNAs in the reciprocal regulation of CD4(+) and CD8(+) T cell-mediated antitumor immunity and demonstrates the dominant nature of miR-155 during its promotion of immune responses.
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Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Epistasis Genética/inmunología , Regulación Neoplásica de la Expresión Génica/inmunología , Inmunidad Celular , MicroARNs/inmunología , Neoplasias Experimentales/inmunología , Animales , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD4-Positivos/patología , Linfocitos T CD8-positivos/metabolismo , Linfocitos T CD8-positivos/patología , Línea Celular Tumoral , Epistasis Genética/genética , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Inositol Polifosfato 5-Fosfatasas , Interferón gamma/biosíntesis , Interferón gamma/genética , Interferón gamma/inmunología , Ratones , Ratones Noqueados , MicroARNs/biosíntesis , MicroARNs/genética , Neoplasias Experimentales/genética , Neoplasias Experimentales/metabolismo , Neoplasias Experimentales/patología , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatasas , Monoéster Fosfórico Hidrolasas/genética , Monoéster Fosfórico Hidrolasas/inmunología , Monoéster Fosfórico Hidrolasas/metabolismoRESUMEN
Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease characterized by the production of antinuclear autoantibodies. Antinuclear autoantibody development is recognized as one of the initial stages of disease that often results in systemic inflammation, kidney disease, and death. The etiology is complex, but it is clear that innate pathways may play an important role in disease progression. Recent data have highlighted an important role for the TLR family, particularly TLR7, in both human disease and murine models. In this study, we have presented a low copy conditional TLR7 transgenic (Tg7) mouse strain that does not develop spontaneous autoimmunity. When we combine Tg7 with the Sle1 lupus susceptibility locus, the mice develop severe disease. Using the CD19(Cre) recombinase system, we normalized expression of TLR7 solely within the B cells. Using this method we demonstrated that overexpression of TLR7 within the B cell compartment reduces the marginal zone B cell compartment and increases B and T cell activation but not T follicular helper cell development. Moreover, this enhanced B cell TLR7 expression permits the specific development of Abs to RNA/protein complexes and exacerbates SLE disease.