RESUMEN
Host factors that influence Congenital Zika Syndrome (CZS) outcome remain elusive. Interferons have been reported as the main antiviral factor in Zika and other flavivirus infections. Here, we accessed samples from 153 pregnant women (77 without and 76 with CZS) and 143 newborns (77 without and 66 with CZS) exposed to ZIKV conducted a case-control study to verify whether interferon alfa receptor 1 (IFNAR1) and interferon lambda 2 and 4 (IFNL2/4) single nucleotide polymorphisms (SNPs) contribute to CZS outcome, and characterized placenta gene expression profile at term. Newborns carrying CG/CC genotypes of rs2257167 in IFNAR1 presented higher risk of developing CZS (OR=3.41; IC=1.35-8.60; Pcorrected=0.032). No association between IFNL SNPs and CZS was observed. Placenta from CZS cases displayed lower levels of IFNL2 and ISG15 along with higher IFIT5. The rs2257167 CG/CC placentas also demonstrated high levels of IFIT5 and inflammation-related genes. We found CZS to be related with exacerbated type I IFN and insufficient type III IFN in placenta at term, forming an unbalanced response modulated by the IFNAR1 rs2257167 genotype. Despite of the low sample size se findings shed light on the host-pathogen interaction focusing on the genetically regulated type I/type III IFN axis that could lead to better management of Zika and other TORCH (Toxoplasma, Others, Rubella, Cytomegalovirus, Herpes) congenital infections.
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Interleucinas/inmunología , Complicaciones Infecciosas del Embarazo/inmunología , Receptor de Interferón alfa y beta/inmunología , Infección por el Virus Zika/inmunología , Femenino , Genotipo , Humanos , Recién Nacido , Interleucinas/genética , Polimorfismo de Nucleótido Simple/genética , Polimorfismo de Nucleótido Simple/inmunología , Embarazo , Complicaciones Infecciosas del Embarazo/genética , Receptor de Interferón alfa y beta/genética , Infección por el Virus Zika/genéticaRESUMEN
Autoimmune uveitis is characterized by immune disorders of the eyes and the whole body and is often recurrent in young adults, but its pathogenesis is still unclear. IL-35 is an essential regulatory factor in many autoimmune diseases, which is produced by Breg cells and can induce Breg cells to regulate the immune response. The relationship between the expression and gene polymorphism of IL-35 and the immune status of patients with autoimmune uveitis has not been reported. The peripheral blood of the subjects was collected from patients with Behçet's Disease (BD) and those with Vogt-Koyanagi-Harada (VKH) syndrome. The percentage of immune cell subsets including B cells, DC, and T cells, and the expression of IL-35 in serum of these two kinds of disease were analyzed. And then, the associations between seven IL-35 single nucleotide polymorphism (SNP) sites and disease susceptibility, the immune status, the clinical characteristics, and the serum IL-35 levels were analyzed. Our results showed that the percentage of Breg cells was significantly decreased in the blood of patients with VKH syndrome compared to that of healthy controls. The levels of IL-35 in the serum of patients with VKH syndrome or BD patients were not changed significantly, compared to that of healthy controls. Furthermore, the associations between two subunits of IL-35 (IL-12p35 and EBI3) and BD or VKH patients were analyzed. We found that there was an association between the EBI3 rs428253 and the occurrence of BD. There was an association between the IL-12p35 rs2243131 and the low level of Breg cell of VKH patients. In addition, there were associations between the polymorphisms of EBI3 rs4740 and the occurrence of headache and tinnitus of VKH patients, respectively. And the genotype frequency of IL-12p35 rs2243115 was related to the concentration of serum IL-35 in patients with VKH syndrome. Thus, the specific SNP sites change of IL-35 were correlated to the immune disorders in uveitis. And they may also play a guiding role in the occurrence of clinical symptoms in patients with uveitis, especially for VKH syndrome.
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Síndrome de Behçet/inmunología , Interleucinas/inmunología , Polimorfismo de Nucleótido Simple/inmunología , Uveítis/inmunología , Pueblo Asiatico , Síndrome de Behçet/genética , Humanos , Interleucinas/genética , Polimorfismo de Nucleótido Simple/genética , Uveítis/genéticaRESUMEN
Genetic polymorphisms at the IFNL4 loci are known to influence the clinical outcome of several different infectious diseases. Best described is the association between the IFNL4 genotype and hepatitis C virus clearance. However, an influence of the IFNL4 genotype on the adaptive immune system was suggested by several studies but never investigated in humans. In this cross-sectional study, we have genotyped 201 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-positive participants for 3 IFNL4 polymorphisms (rs368234815, rs12979860, and rs117648444) and stratified them according to the IFNλ4 activity. Based on this stratification, we investigated the association between the IFNL4 genotype and the antibody as well as the CD8+ T cell response in the acute phase of the SARS-CoV-2 infection. We observed no differences in the genotype distribution compared with a Danish reference cohort or the 1,000 Genome Project, and we were not able to link the IFNL4 genotype to changes in either the antibody or CD8+ T cell responses of these patients.
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Inmunidad Adaptativa/inmunología , COVID-19/inmunología , Interleucinas/inmunología , SARS-CoV-2/inmunología , Inmunidad Adaptativa/genética , Adulto , Anciano , Linfocitos T CD8-positivos/inmunología , Estudios de Cohortes , Estudios Transversales , Femenino , Genotipo , Humanos , Interleucinas/genética , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/genética , Polimorfismo de Nucleótido Simple/inmunología , SARS-CoV-2/genética , Adulto JovenRESUMEN
Complement Factor H-Related 3 (FHR-3) is a major regulator of the complement system, which is associated with different diseases, such as age-related macular degeneration (AMD). However, the non-canonical local, cellular functions of FHR-3 remained poorly understood. Here, we report that FHR-3 bound to oxidative stress epitopes and competed with FH for interaction. Furthermore, FHR-3 was internalized by viable RPE cells and modulated time-dependently complement component (C3, FB) and receptor (C3aR, CR3) expression of human RPE cells. Independently of any external blood-derived proteins, complement activation products were detected. Anaphylatoxin C3a was visualized in treated cells and showed a translocation from the cytoplasm to the cell membrane after FHR-3 exposure. Subsequently, FHR-3 induced a RPE cell dependent pro-inflammatory microenvironment. Inflammasome NLRP3 activation and pro-inflammatory cytokine secretion of IL-1ß, IL-18, IL-6 and TNF-α were induced after FHR-3-RPE interaction. Our previously published monoclonal anti-FHR-3 antibody, which was chimerized to reduce immunogenicity, RETC-2-ximab, ameliorated the effect of FHR-3 on ARPE-19 cells. Our studies suggest FHR-3 as an exogenous trigger molecule for the RPE cell "complosome" and as a putative target for a therapeutic approach for associated degenerative diseases.
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Proteínas Sanguíneas/inmunología , Activación de Complemento/inmunología , Factor H de Complemento/inmunología , Células Epiteliales/inmunología , Epitelio Pigmentado de la Retina/citología , Proteínas Sanguíneas/genética , Proteínas Sanguíneas/metabolismo , Línea Celular , Activación de Complemento/genética , Complemento C3/genética , Complemento C3/inmunología , Complemento C3/metabolismo , Factor H de Complemento/genética , Factor H de Complemento/metabolismo , Células Epiteliales/citología , Células Epiteliales/metabolismo , Transición Epitelial-Mesenquimal/genética , Transición Epitelial-Mesenquimal/inmunología , Expresión Génica/genética , Expresión Génica/inmunología , Células HEK293 , Humanos , Inflamasomas/genética , Inflamasomas/inmunología , Inflamasomas/metabolismo , Antígeno de Macrófago-1/genética , Antígeno de Macrófago-1/inmunología , Antígeno de Macrófago-1/metabolismo , Degeneración Macular/genética , Degeneración Macular/inmunología , Degeneración Macular/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Proteína con Dominio Pirina 3 de la Familia NLR/inmunología , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Polimorfismo de Nucleótido Simple/genética , Polimorfismo de Nucleótido Simple/inmunologíaRESUMEN
Takotsubo syndrome (TTS), recognized as stress's cardiomyopathy, or as left ventricular apical balloon syndrome in recent years, is a rare pathology, described for the first time by Japanese researchers in 1990. TTS is characterized by an interindividual heterogeneity in onset and progression, and by strong predominance in postmenopausal women. The clear causes of these TTS features are uncertain, given the limited understanding of this intriguing syndrome until now. However, the increasing frequency of TTS cases in recent years, and particularly correlated to the SARS-CoV-2 pandemic, leads us to the imperative necessity both of a complete knowledge of TTS pathophysiology for identifying biomarkers facilitating its management, and of targets for specific and effective treatments. The suspect of a genetic basis in TTS pathogenesis has been evidenced. Accordingly, familial forms of TTS have been described. However, a systematic and comprehensive characterization of the genetic or epigenetic factors significantly associated with TTS is lacking. Thus, we here conducted a systematic review of the literature before June 2021, to contribute to the identification of potential genetic and epigenetic factors associated with TTS. Interesting data were evidenced, but few in number and with diverse limitations. Consequently, we concluded that further work is needed to address the gaps discussed, and clear evidence may arrive by using multi-omics investigations.
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COVID-19/complicaciones , Epigénesis Genética/inmunología , Heterogeneidad Genética , Predisposición Genética a la Enfermedad , Cardiomiopatía de Takotsubo/genética , Biomarcadores/análisis , COVID-19/inmunología , COVID-19/virología , Variaciones en el Número de Copia de ADN/inmunología , Sitios Genéticos/inmunología , Ventrículos Cardíacos/inmunología , Ventrículos Cardíacos/patología , Humanos , Anamnesis , Polimorfismo de Nucleótido Simple/inmunología , SARS-CoV-2/inmunología , Cardiomiopatía de Takotsubo/diagnóstico , Cardiomiopatía de Takotsubo/inmunología , Cardiomiopatía de Takotsubo/patologíaRESUMEN
Objectives: Systemic sclerosis (SSc) is an uncommon autoimmune disease that varies with ethnicity. Single nucleotide polymorphisms (SNPs) in the GTFSI, NFKB1, and TYK2 genes have been reported to be associated with SSc in other populations and in individuals with various autoimmune diseases. This study aimed to investigate the association between these SNPs and susceptibility to SSc in a Chinese Han population. Method: A case-control study was performed in 343 patients with SSc and 694 ethnically matched healthy controls. SNPs in GTF2I, NFKB1, and TYK2 were genotyped using a Sequenom MassArray iPLEX system. Association analyses were performed using PLINK v1.90 software. Result: Our study demonstrated that the GTF2I rs117026326 T allele and the GTF2I rs73366469 C allele were strongly associated with patients with SSc (P = 6.97E-10 and P = 1.33E-08, respectively). Patients carrying the GTF2I rs117026326 TT genotype and the GTF2I rs73366469 CC genotype had a strongly increased risk of SSc (P = 6.25E-09 and P = 1.67E-08, respectively), and those carrying the NFKB1 rs1599961 AA genotype had a suggestively significantly increased risk of SSc (P = 0.014). Moreover, rs117026326 and rs73366469 were associated with SSc in different genetic models (additive model, dominant model, and recessive model) (P < 0.05) whereas rs1599961 was associated with SSc in the dominant genetic model but not in the addictive and recessive models (P = 0.0026). TYK2 rs2304256 was not significantly associated with SSc in this study. Conclusion: GTF2I rs117026326 and rs73366469 SNPs were strongly associated with SSc in this Chinese Han population. NFKB1 rs1599961 showed a suggestive association with SSc, and no significant association was found between TYK2 rs2304256 and SSc in this Chinese Han population.
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Pueblo Asiatico/genética , Predisposición Genética a la Enfermedad/genética , Subunidad p50 de NF-kappa B/genética , Polimorfismo de Nucleótido Simple/inmunología , Esclerodermia Sistémica/genética , TYK2 Quinasa/genética , Factores de Transcripción TFII/genética , Enfermedades Autoinmunes/genética , Estudios de Casos y Controles , Femenino , Frecuencia de los Genes/genética , Genotipo , Humanos , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Epidemiological evidence suggests that synchronous or metachronous presentation of breast and thyroid cancers exceeds that predicted by chance alone. The following potential explanations have been hypothesized: common environmental or hormonal factors, oncogenic effect of the treatment for the first cancer, closer follow-up of cancer survivors, shared underlying genetic risk factors. While some cases were found to be related to monogenic disorders with autosomal inheritance, the genetic background of most cases of co-occurring breast and thyroid cancer is thought to be polygenic. METHODS: In this retrospective case-control study we compared the genetic profile of patients with a history of breast cancer (n = 15) to patients with co-occurring breast and thyroid cancer (n = 19) using next generation sequencing of 112 hereditary cancer risk genes. Identified variants were categorized based on their known association with breast cancer and oncogenesis in general. RESULTS: No difference between patients with breast and double cancers was observed in clinical and pathological characteristics or the number of neutral SNPs. The unweighted and weighted number of SNPs with an established or potential association with breast cancer was significantly lower in the group with breast cancer only (mean difference - 0.58, BCa 95% CI [- 1.09, - 0.06], p = 0.029, and mean difference - 0.36, BCa 95% CI [- 0.70, - 0.02], p = 0.039, respectively). The difference was also significant when we compared the number of SNPs with potential or known association with any malignancy (mean difference - 1.19, BCa 95% CI [- 2.27, - 0.11], p = 0.032 for unweighted, and mean difference - 0.73, BCa 95% CI [- 1.32, - 0.14], p = 0.017 for weighted scores). CONCLUSION: Our findings are compatible with the hypothesis of genetic predisposition in the co-occurrence of breast and thyroid cancer. Further exploration of the underlying genetic mechanisms may help in the identification of patients with an elevated risk for a second cancer at the diagnosis of the first cancer.
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Neoplasias de la Mama/genética , Oncogenes/genética , Polimorfismo de Nucleótido Simple/inmunología , Neoplasias de la Tiroides/genética , Neoplasias de la Mama/patología , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo Genético , Estudios Retrospectivos , Neoplasias de la Tiroides/patologíaRESUMEN
TNFRSF13B encodes the transmembrane activator and CAML interactor (TACI) receptor, which drives plasma cell differentiation. Although TNFRSF13B supports host defense, dominant-negative TNFRSF13B alleles are common in humans and other species and only rarely associate with disease. We reasoned that the high frequency of disruptive TNFRSF13B alleles reflects balancing selection, the loss of function conferring advantage in some settings. Testing that concept, we investigated how a common human dominant-negative variant, TNFRSF13B A181E, imparts resistance to enteric pathogens. Mice engineered to express mono- or biallelic A144E variants of tnrsf13B, corresponding to A181E, exhibited a striking resistance to pathogenicity and transmission of Citrobacter rodentium, a murine pathogen that models enterohemorrhagic Escherichia coli, and resistance was principally owed to natural IgA deficiency in the intestine. In WT mice with gut IgA and in mutant mice reconstituted with enteric IgA obtained from WT mice, IgA induces LEE expression of encoded virulence genes, which confer pathogenicity and transmission. Taken together, our results show that C. rodentium and most likely other enteric organisms appropriated binding of otherwise protective antibodies to signal induction of the virulence program. Additionally, the high prevalence of TNFRSF13B dominant-negative variants reflects balancing selection.
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Citrobacter rodentium/inmunología , Colitis/inmunología , Infecciones por Enterobacteriaceae/inmunología , Inmunoglobulina A/inmunología , Proteína Activadora Transmembrana y Interactiva del CAML/genética , Alelos , Animales , Linfocitos B , Colitis/microbiología , Modelos Animales de Enfermedad , Resistencia a la Enfermedad/genética , Infecciones por Enterobacteriaceae/microbiología , Femenino , Humanos , Inmunoglobulina A/metabolismo , Mutación con Pérdida de Función , Activación de Linfocitos/genética , Masculino , Polimorfismo de Nucleótido Simple/inmunología , Proteína Activadora Transmembrana y Interactiva del CAML/metabolismoRESUMEN
In fish, interleukin-6 (IL-6) is a very important immune-regulatory cytokine that plays a polyfunctional role in inflammation, metabolism, regeneration, and neural processes. IL-6 signal transducer (IL-6ST) is a specific receptor for IL-6 and expressed mainly in immune cells and hepatocytes. In this study, the complete cDNA and genomic DNA sequences of mandarin fish (Siniperca chuatsi) IL-6 and IL-6ST genes were identified and analyzed. Quantitative real-time PCR showed that IL-6 and IL-6ST were chiefly expressed in the immune organs. After challenge with infectious spleen and kidney necrosis virus (ISKNV), the expression levels of IL-6 were significantly up-regulated after 6 h and 24 h in the head kidney and spleen, respectively (p < 0.01), the peak value for both reached at 72 h, IL-6ST increased significantly after 120 h with a peak at 168 h in the head kidney (p < 0.01) and improved markedly at 168 h in the spleen (p < 0.01). Besides, IL-6 and IL-6ST have been identified 3 and 8 single nucleotide polymorphisms (SNPs), respectively. Statistical analysis showed that one SNP locus (1625C/T) in the coding region of IL-6 was significantly related to the resistance of mandarin fish against ISKNV. The 1625CâT locus in the coding region of IL-6 is a synonymous mutation; compared with the susceptible group, the frequency of allele T in the disease resistance group was significantly higher, which may be due to the rare codon produced by the mutation affecting translation. The involvement of IL-6 and IL-6ST in response to ISKNV infection in mandarin fish clearly indicate that the role of SNP markers in IL-6 was associated with the ISKNV resistance, which was demonstrated for the first time in our results. Thus, the current study may provide fundamental information for further breeding of mandarin fish with resistance to ISKNV infection.
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Receptor gp130 de Citocinas/inmunología , Resistencia a la Enfermedad/genética , Enfermedades de los Peces/inmunología , Inmunidad Innata/genética , Interleucina-6/inmunología , Iridoviridae/fisiología , Perciformes/inmunología , Animales , Receptor gp130 de Citocinas/genética , Infecciones por Virus ADN/inmunología , Infecciones por Virus ADN/veterinaria , ADN Complementario , Proteínas de Peces/genética , Proteínas de Peces/inmunología , Interleucina-6/genética , Perciformes/genética , Polimorfismo de Nucleótido Simple/inmunología , Distribución Aleatoria , TranscriptomaRESUMEN
The red-spotted grouper, Epinephelus akaara, has been cultured widely in China, and in several countries of Southeast Asia, due to its important economic value. However, in recent years the outbreak of disease caused by red-spotted grouper nervous necrosis virus (RGNNV) has caused mass mortality in the stage of the grouper lifecycle from fry to juvenile, resulting in considerable economic loss in commercial aquaculture. However, the molecular mechanism underlying anti-RGNNV infection in red-spotted grouper has never been fully understood. To identify the anti-RGNNV related markers and candidate genes, we performed a genome-wide association study (GWAS) on a natural population of 100 individuals for a full-genome screen of the red-spotted grouper. In this research, 36,311 single, high quality nucleotide polymorphisms (SNPs) were developed. Two significantly associated SNPs and three suggestively associated SNPs were identified at the genome level. From these identified SNPs, five candidate genes were annotated: EPHA7, Osbpl2, GPC5, CDH4 and Pou3f1. These genes are involved in nervous system development, retinal formation, and lipid metabolism regulation. In combination with studies on the characteristics of NNV infection, it was speculated that in the fry stage of the grouper lifecycle, the immune system is not fully developed. Therefore, improved resistance to RGNNV may come through regulating nervous system development or lipid metabolism related pathways. In addition, the genotypes of SNPs associated with disease-resistant traits were analyzed. The markers and genes obtained in this study may facilitate a marker-assisted selection for red-spotted grouper aiming at disease resistance to RGNNV.
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Lubina/genética , Lubina/inmunología , Enfermedades de los Peces/inmunología , Proteínas de Peces/genética , Estudio de Asociación del Genoma Completo/veterinaria , Animales , Enfermedades de los Peces/genética , Enfermedades de los Peces/virología , Proteínas de Peces/inmunología , Nodaviridae/fisiología , Polimorfismo de Nucleótido Simple/inmunología , Infecciones por Virus ARN/genética , Infecciones por Virus ARN/inmunología , Infecciones por Virus ARN/veterinaria , Infecciones por Virus ARN/virologíaRESUMEN
Prophylactic human papillomavirus (HPV) vaccines are commercially available for prevention of infection with cancerogenic HPV genotypes but are not able to combat pre-existing HPV-associated disease. In this study, we designed a nanomaterial-based therapeutic HPV vaccine, comprising manganese (Mn4+)-doped silica nanoparticles (Mn4+-SNPs) and the viral neoantigen peptide GF001 derived from the HPV16 E7 oncoprotein. We show in mice that Mn4+-SNPs act as self-adjuvants by activating the inflammatory signaling pathway via generation of reactive oxygen species, resulting in immune cell recruitment to the immunization site and dendritic cell maturation. Mn4+-SNPs further serve as Ag carriers by facilitating endo/lysosomal escape via depletion of protons in acidic endocytic compartments and subsequent Ag delivery to the cytosol for cross-presentation. The Mn4+-SNPs+GF001 nanovaccine induced strong E7-specific CD8+ T cell responses, leading to remission of established murine HPV16 E7-expressing solid TC-1 tumors and E7-expressing transgenic skin grafts. This vaccine construct offers a simple and general strategy for therapeutic HPV and potentially other cancer vaccines.
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Antígenos de Neoplasias/inmunología , Manganeso/inmunología , Nanopartículas/administración & dosificación , Neoplasias/inmunología , Neoplasias/terapia , Dióxido de Silicio/inmunología , Adyuvantes Inmunológicos/farmacología , Animales , Linfocitos T CD8-positivos/inmunología , Vacunas contra el Cáncer/inmunología , Células Cultivadas , Femenino , Humanos , Inmunización/métodos , Inmunoterapia/métodos , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Papillomaviridae/inmunología , Proteínas E7 de Papillomavirus/inmunología , Infecciones por Papillomavirus/inmunología , Vacunas contra Papillomavirus/inmunología , Polimorfismo de Nucleótido Simple/inmunología , Especies Reactivas de Oxígeno/inmunología , Transducción de Señal/inmunologíaRESUMEN
Pemphigus foliaceus (PF) is an autoimmune blistering disease of the skin, clinically characterized by erosions and, histopathologically, by acantholysis. PF is endemic in the Brazilian Central-Western region. Numerous single nucleotide polymorphisms (SNPs) have been shown to affect the susceptibility for PF, including SNPs at long non-coding RNA (lncRNA) genes, which are known to participate in many physiological and pathogenic processes, such as autoimmunity. Here, we investigated whether the genetic variation of immune-related lncRNA genes affects the risk for endemic and sporadic forms of PF. We analysed 692 novel SNPs for PF from 135 immune-related lncRNA genes in 227 endemic PF patients and 194 controls. The SNPs were genotyped by Illumina microarray and analysed by applying logistic regression at additive model, with correction for sex and population structure. Six associated SNPs were also evaluated in an independent German cohort of 76 sporadic PF patients and 150 controls. Further, we measured the expression levels of two associated lncRNA genes (LINC-PINT and LY86-AS1) by quantitative PCR, stratified by genotypes, in peripheral blood mononuclear cells of healthy subjects. We found 27 SNPs in 11 lncRNA genes associated with endemic PF (p < .05 without overlapping with protein-coding genes). Among them, the LINC-PINT SNP rs10228040*A (OR = 1.47, p = .012) was also associated with increased susceptibility for sporadic PF (OR = 2.28, p = .002). Moreover, the A+ carriers of LY86-AS1*rs12192707 mark lowest LY86-AS1 RNA levels, which might be associated with a decreasing autoimmune response. Our results suggest a critical role of lncRNA variants in immunopathogenesis of both PF endemic and sporadic forms.
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Antígenos de Superficie/genética , Pénfigo/genética , Polimorfismo de Nucleótido Simple/genética , ARN Largo no Codificante/genética , Antígenos de Superficie/inmunología , Predisposición Genética a la Enfermedad , Humanos , Pénfigo/inmunología , Polimorfismo de Nucleótido Simple/inmunología , ARN Largo no Codificante/inmunologíaRESUMEN
Cytolytic T cell responses are predicted to be biased towards membrane proteins. The peptide-binding grooves of most alleles of histocompatibility complex class I (MHC-I) are relatively hydrophobic, therefore peptide fragments derived from human transmembrane helices (TMHs) are predicted to be presented more often as would be expected based on their abundance in the proteome. However, the physiological reason of why membrane proteins might be over-presented is unclear. In this study, we show that the predicted over-presentation of TMH-derived peptides is general, as it is predicted for bacteria and viruses and for both MHC-I and MHC-II, and confirmed by re-analysis of epitope databases. Moreover, we show that TMHs are evolutionarily more conserved, because single nucleotide polymorphisms (SNPs) are present relatively less frequently in TMH-coding chromosomal regions compared to regions coding for extracellular and cytoplasmic protein regions. Thus, our findings suggest that both cytolytic and helper T cells are more tuned to respond to membrane proteins, because these are evolutionary more conserved. We speculate that TMHs are less prone to mutations that enable pathogens to evade T cell responses.
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Presentación de Antígeno/genética , Epítopos de Linfocito T/genética , Antígenos de Histocompatibilidad Clase II/genética , Antígenos de Histocompatibilidad Clase I/genética , Proteínas de la Membrana/genética , Estructura Secundaria de Proteína/genética , Alelos , Presentación de Antígeno/inmunología , Cromosomas/genética , Cromosomas/inmunología , Citoplasma/genética , Citoplasma/inmunología , Epítopos de Linfocito T/inmunología , Antígenos de Histocompatibilidad Clase I/inmunología , Antígenos de Histocompatibilidad Clase II/inmunología , Humanos , Proteínas de la Membrana/inmunología , Péptidos/genética , Péptidos/inmunología , Polimorfismo de Nucleótido Simple/genética , Polimorfismo de Nucleótido Simple/inmunología , Linfocitos T Colaboradores-Inductores/inmunologíaRESUMEN
Recent evidence suggests that several cattle breeds may be more resistant to infection with the zoonotic pathogen Mycobacterium bovis. Our data presented here suggests that the response to mycobacterial antigens varies in macrophages generated from Brown Swiss (BS) and Holstein Friesian (HF) cattle, two breeds belonging to the Bos taurus family. Whole genome sequencing of the Brown Swiss genome identified several potential candidate genes, in particular Toll-like Receptor-2 (TLR2), a pattern recognition receptor (PRR) that has previously been described to be involved in mycobacterial recognition. Further investigation revealed single nucleotide polymorphisms (SNP) in TLR2 that were identified between DNA isolated from cells of BS and HF cows. Interestingly, one specific SNP, H326Q, showed a different genotype frequency in two cattle subspecies, Bos (B.) taurus and Bos indicus. Cloning of the TLR2 gene and subsequent gene-reporter and chemokine assays revealed that this SNP, present in BS and Bos indicus breeds, resulted in a significantly higher response to mycobacterial antigens as well as tri-acylated lipopeptide ligands in general. Comparing wild-type and H326Q containing TLR2 responses, wild-type bovine TLR2 response showed clear, diminished mycobacterial antigen responses compared to human TLR2, however bovine TLR2 responses containing H326Q were found to be partially recovered compared to human TLR2. The creation of human:bovine TLR2 chimeras increased the response to mycobacterial antigens compared to the full-length bovine TLR2, but significantly reduced the response compared to the full-length human TLR2. Thus, our data, not only present evidence that TLR2 is a major PRR in the mammalian species-specific response to mycobacterial antigens, but furthermore, that there are clear differences between the response seen in different cattle breeds, which may contribute to their enhanced or reduced susceptibility to mycobacterial infection.
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Cruzamiento , Inmunidad Innata/inmunología , Infecciones por Mycobacterium/inmunología , Polimorfismo de Nucleótido Simple/inmunología , Receptor Toll-Like 2/inmunología , Animales , Bovinos , Inmunidad Innata/genética , Mycobacterium bovis/inmunología , Mycobacterium tuberculosis/inmunología , Polimorfismo de Nucleótido Simple/genética , Receptor Toll-Like 2/genéticaRESUMEN
Background: Growing evidence has shown that alterations in gut microbiota composition are associated with multiple autoimmune diseases (ADs). However, it is unclear whether these associations reflect a causal relationship. Objective: To reveal the causal association between gut microbiota and AD, we conducted a two-sample Mendelian randomization (MR) analysis. Materials and Methods: We assessed genome-wide association study (GWAS) summary statistics for gut microbiota and six common ADs, namely, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, type 1 diabetes (T1D), and celiac disease (CeD), from published GWASs. Two-sample MR analyses were first performed to identify causal bacterial taxa for ADs in discovery samples. Significant bacterial taxa were further replicated in independent replication outcome samples. A series of sensitivity analyses was performed to validate the robustness of the results. Finally, a reverse MR analysis was performed to evaluate the possibility of reverse causation. Results: Combining the results from the discovery and replication stages, we identified one causal bacterial genus, Bifidobacterium. A higher relative abundance of the Bifidobacterium genus was associated with a higher risk of T1D [odds ratio (OR): 1.605; 95% CI, 1.339-1.922; PFDR = 4.19 × 10-7] and CeD (OR: 1.401; 95% CI, 1.139-1.722; PFDR = 2.03 × 10-3), respectively. Further sensitivity analyses validated the robustness of the above associations. The results of reverse MR analysis showed no evidence of reverse causality from T1D and CeD to the Bifidobacterium genus. Conclusion: This study implied a causal relationship between the Bifidobacterium genus and T1D and CeD, thus providing novel insights into the gut microbiota-mediated development mechanism of ADs.
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Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/microbiología , Microbioma Gastrointestinal/inmunología , Adulto , Anciano , Artritis Reumatoide/inmunología , Causalidad , Enfermedad Celíaca/inmunología , Diabetes Mellitus Tipo 1/inmunología , Estudio de Asociación del Genoma Completo/métodos , Humanos , Enfermedades Inflamatorias del Intestino/inmunología , Lupus Eritematoso Sistémico/inmunología , Análisis de la Aleatorización Mendeliana , Persona de Mediana Edad , Esclerosis Múltiple/inmunología , Polimorfismo de Nucleótido Simple/inmunología , Estudios ProspectivosRESUMEN
To determine the respective contribution of the LAT transmembrane adaptor and CD5 and CD6 transmembrane receptors to early TCR signal propagation, diversification, and termination, we describe a CRISPR/Cas9-based platform that uses primary mouse T cells and permits establishment of the composition of their LAT, CD5, and CD6 signalosomes in only 4 mo using quantitative mass spectrometry. We confirmed that positive and negative functions can be solely assigned to the LAT and CD5 signalosomes, respectively. In contrast, the TCR-inducible CD6 signalosome comprised both positive (SLP-76, ZAP70, VAV1) and negative (UBASH3A/STS-2) regulators of T cell activation. Moreover, CD6 associated independently of TCR engagement to proteins that support its implication in inflammatory pathologies necessitating T cell transendothelial migration. The multifaceted role of CD6 unveiled here accounts for past difficulties in classifying it as a coinhibitor or costimulator. Congruent with our identification of UBASH3A within the CD6 signalosome and the view that CD6 constitutes a promising target for autoimmune disease treatment, single-nucleotide polymorphisms associated with human autoimmune diseases have been found in the Cd6 and Ubash3a genes.
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Antígenos CD/inmunología , Antígenos de Diferenciación de Linfocitos T/inmunología , Activación de Linfocitos/inmunología , Receptores de Antígenos de Linfocitos T/inmunología , Linfocitos T/inmunología , Proteínas Adaptadoras Transductoras de Señales/inmunología , Animales , Enfermedades Autoinmunes/inmunología , Secuencia de Bases , Femenino , Inflamación/inmunología , Ratones , Ratones Endogámicos C57BL , Polimorfismo de Nucleótido Simple/inmunología , Transducción de Señal/inmunologíaRESUMEN
Pemphigus foliaceus (PF) is an autoimmune blistering skin disease characterized by the presence of pathogenic autoantibodies against desmoglein 1, a component of intercellular desmosome junctions. PF occurs sporadically across the globe and is endemic in some Brazilian regions. Because PF is a B-cell-mediated disease, we aimed to study the impact of variants within genes encoding molecules involved in the different steps of B-cell development and antibody production on the susceptibility of endemic PF. We analysed 3,336 single nucleotide polymorphisms (SNPs) from 167 candidate genes genotyped with Illumina microarray in a cohort of 227 PF patients and 193 controls. After quality control and exclusion of non-informative and redundant SNPs, 607 variants in 149 genes remained in the logistic regression analysis, in which sex and ancestry were included as covariates. Our results revealed 10 SNPs within or nearby 11 genes that were associated with susceptibility to endemic PF (OR >1.56; p < 0.005): rs6657275*G (TGFB2); rs1818545*A (RAG1/RAG2/IFTAP);rs10781530*A (PAXX), rs10870140*G and rs10781522*A (TRAF2); rs535068*A (TNFRSF1B); rs324011*A (STAT6);rs6432018*C (YWHAQ); rs17149161*C (YWHAG); and rs2070729*C (IRF1). Interestingly, these SNPs have been previously associated with differential gene expression, mostly in peripheral blood, in publicly available databases. For the first time, we show that polymorphisms in genes involved in B-cell development and antibody production confer differential susceptibility to endemic PF, and therefore are candidates for possible functional studies to understand immunoglobulin gene rearrangement and its impact on diseases.
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Formación de Anticuerpos/genética , Formación de Anticuerpos/inmunología , Linfocitos B/inmunología , Pénfigo/genética , Pénfigo/inmunología , Polimorfismo de Nucleótido Simple/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Autoanticuerpos/genética , Autoanticuerpos/inmunología , Enfermedades Autoinmunes/genética , Enfermedades Autoinmunes/inmunología , Brasil , Estudios de Casos y Controles , Niño , Estudios de Cohortes , Femenino , Expresión Génica/genética , Expresión Génica/inmunología , Predisposición Genética a la Enfermedad/genética , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/inmunología , Adulto JovenRESUMEN
Endoplasmic reticulum aminopeptidases ERAP1 and ERAP2 trim peptides to a length of 8-10 amino acids optimal for binding by HLA class I molecules. Although these two enzymes may work separately, but they may also form a heterodimer of enhanced trimming efficiency. We have earlier described a role for ERAP1 single nucleotide polymorphism rs26618 and HLA-C*05:01 as risk factors for atopic dermatitis (AD). Here, we examined whether ERAP2 single nucleotide polymorphism rs2248374, determining the presence or absence of the functional form of enzyme, would influence the rs26618 effect. Out of nine rs2248374 - rs26618 genotypic combinations, only one, rs2248374*A/A - rs26618*C/C, was associated with a risk of AD. Interestingly, the odds ratio increased from 1.10 (CI95%: 0.72; 1.69; p = 0.657) for ERAP2 rs2248374*A/A and 1.88 (CI95%: 1.07; 3.28; p = 0.025) for ERAP1 rs26618*C/C to 3.36 (CI95%: 1.41; 8.01; p = 0.004) for their combination, therefore revealing a synergistic effect.
Asunto(s)
Aminopeptidasas/genética , Dermatitis Atópica/epidemiología , Predisposición Genética a la Enfermedad , Antígenos de Histocompatibilidad Menor/genética , Adolescente , Adulto , Aminopeptidasas/metabolismo , Estudios de Casos y Controles , Niño , Preescolar , Dermatitis Atópica/diagnóstico , Dermatitis Atópica/genética , Dermatitis Atópica/inmunología , Femenino , Antígenos de Histocompatibilidad Clase I/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Antígenos de Histocompatibilidad Menor/metabolismo , Oportunidad Relativa , Polimorfismo de Nucleótido Simple/inmunología , Prevalencia , Factores de Riesgo , Índice de Severidad de la Enfermedad , Adulto JovenRESUMEN
The purpose of this research is to identify and characterize deleterious genetic variants in the co-stimulatory ligand B7-1, also known as the human cluster of differentiation CD80 marker. The B7-1 ligand and the major histocompatibility complex class II (MHC II) molecules are the main determinants that provide B-cells the required competency to act as antigen presenting cells. For this, participation of both MHC class II molecules and CD80 is required. The interaction of the CD80 ligand with CD28 on the surface 7 of TH cells plays a key role in the activation of TH cells and progression of B cells through the S phase, hence, leading to their proliferation in mitosis. A set of 2313 genetic variants in the B7-1 ligand have been mapped and retrieved from dbSNP database. Subsequently, 150 non-synonymous single nucleotide polymorphisms (nsSNPs) were mapped and subjected to the sequence and structural homology based predictions, which were further analyzed for protein stability and the disease phenotypes. Finally, we identified 7 potentially damaging nsSNPs in the B7-1 ligand that may affect its interaction with the cognitive receptor CD28, hence, may also interfere with TH cell activation and B cell proliferation. We propose that subsequent experimental analyses (stability, expression and interactions) on these proteins can provide a deep understanding about the effect of these variants on the structure and function of CD80.