RESUMEN
Introduction: Leishmaniasis continues to pose a substantial health burden in 97 countries worldwide. The progression and outcome of Leishmania infection are influenced by various factors, including the cytokine milieu, the skin microbiota at the infection site, the specific Leishmania species involved, the genetic background of the host, and the parasite load. In endemic regions to leishmaniasis, only a fraction of individuals infected actually develops the disease. Overexpression of IL-13 in naturally resistant C57BL/6 mice renders them susceptible to L. major infection. Haplotypes constructed from several single nucleotide variant (SNV) along a chromosome fragment may provide insight into any SNV near the fragment that may be genuinely associated with a phenotype in genetic association studies. Methods: We investigated nine SNVs (SNV1rs1881457A>C, SNV2rs1295687C>G, SNV3rs2069744C>T, SNV4rs2069747C>T, SNV5rs20541A>G, SNV6rs1295685A>G, SNV7rs848A>C, SNV8rs2069750G >C, and SNV9rs847T>C) spanning the entire IL13 gene in patients with L. guyanensis cutaneous leishmaniasis (Lg-CL). Results: Our analysis did not reveal any significant association between the SNVs and susceptibility/protection against Lg-CL development. However, haplotype analysis, excluding SNV4rs2069747 and SNV8rs2069750 due to low minor allele frequency, revealed that carriers of the haplotype CCCTAAC had a 93% reduced likelihood developing Lg-CL. Similarly, the haplotypes ACCCGCT (ORadj=0.02 [95% CI 0.00-0.07]; p-value, 6.0×10-19) and AGCTAAC (ORadj=0.00[95% CI 0.00-0.00]; p-value 2.7×10-12) appeared to provide protection against the development of Lg-CL. Conversely, carriers of haplotype ACCTGCC have 190% increased likelihood of developing Lg-CL (ORadj=2.9 [95%CI 1.68-5.2]; p-value, 2.5×10-6). Similarly, haplotype ACCCAAT (ORadj=2.7 [95%CI 1.5-4.7]; p-value, 3.2×10-5) and haplotype AGCCGCC are associated with susceptibility to the development of Lg-CL (ORadj=1.7[95%CI 1.04-2.8]; p-value, 0.01). In our investigation, we also found a correlation between the genotypes of rs2069744, rs20541, rs1295685, rs847, and rs848 and plasma IL-5 levels among Lg-Cl patients. Furthermore, rs20541 showed a correlation with plasma IL-13 levels among Lg-Cl patients, while rs2069744 and rs848 showed a correlation with plasma IL-4 levels among the same group. Conclusions: Overall, our study identifies three haplotypes of IL13 associated with resistance to disease development and three haplotypes linked to susceptibility. These findings suggest the possibility of a variant outside the gene region that may contribute, in conjunction with other genes, to differences in susceptibility and partially to the pathology.
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Leishmania guyanensis , Leishmaniasis Cutánea , Animales , Humanos , Ratones , Citocinas/genética , Predisposición Genética a la Enfermedad , Haplotipos , Interleucina-13/genética , Interleucina-4/genética , Interleucina-5/genética , Leishmania guyanensis/genética , Leishmaniasis Cutánea/parasitología , Ratones Endogámicos C57BL , Nucleótidos , Polimorfismo de Nucleótido SimpleRESUMEN
Asthma is an inflammatory lung disease that affects more women than men in adulthood. Clinical evidence shows that hormonal fluctuation during the menstrual cycle and menopause are related to increased asthma severity in women. Considering that life expectancy has increased and that most women now undergo menopause, strategies to prevent the worsening of asthma symptoms are particularly important. A recent study from our group showed that re-exposure of ovariectomised allergic mice to antigen (ovalbumin) leads to an exacerbation of lung inflammation that is similar to clinical conditions. However, little is known about the role of probiotics in the prevention of asthma exacerbations during the menstrual cycle or menopause. Thus, our objective was to evaluate the effects of supplementation with kefir, a popular fermented dairy beverage, as a preventive strategy for modulating allergic disease. The results show that the preventive kefir administration decreases the influx of inflammatory cells in the airways and exacerbates the production of mucus and the interleukin 13 cytokine. Additionally, kefir changes macrophage polarisation by decreasing the number of M2 macrophages, as shown by RT-PCR assay. Thus, kefir is a functional food that potentially prevents allergic airway inflammation exacerbations in ovariectomised mice.
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Asma/prevención & control , Kéfir/microbiología , Probióticos/administración & dosificación , Animales , Asma/genética , Asma/inmunología , Femenino , Fermentación , Humanos , Interleucina-13/genética , Interleucina-13/inmunología , Kéfir/análisis , Lactobacillales/metabolismo , Pulmón/efectos de los fármacos , Pulmón/inmunología , Activación de Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Ratones , Ratones Endogámicos BALB C , Ovalbúmina/efectos adversos , Ovalbúmina/inmunologíaRESUMEN
The COVID-19 fatality rate is high when compared to the H1N1pdm09 (pandemic Influenza A virus H1N1 subtype) rate, and although both cause an aggravated inflammatory response, the differences in the mechanisms of both pandemic pneumonias need clarification. Thus, our goal was to analyze tissue expression of interleukins 4, 13, (IL-4, IL-13), transforming growth factor-beta (TGF-ß), and the number of M2 macrophages (Sphingosine-1) in patients who died by COVID-19, comparing with cases of severe pneumopathy caused by H1N1pdm09, and a control group without lung injury. Six lung biopsy samples of patients who died of SARS-CoV-2 (COVID-19 group) were used and compared with ten lung samples of adults who died from a severe infection of H1N1pdm09 (H1N1 group) and eleven samples of patients who died from different causes without lung injury (CONTROL group). The expression of IL-4, IL-13, TGF-ß, and M2 macrophages score (Sphingosine-1) were identified through immunohistochemistry (IHC). Significantly higher IL-4 tissue expression and Sphingosine-1 in M2 macrophages were observed in the COVID-19 group compared to both the H1N1 and the CONTROL groups. A different mechanism of diffuse alveolar damage (DAD) in SARS-CoV-2 compared to H1N1pdm09 infections were observed. IL-4 expression and lung remodeling are phenomena observed in both SARS-CoV-2 and H1N1pdm09. However, SARS-CoV-2 seems to promote lung damage through different mechanisms, such as the scarce participation Th1/Th17 response and the higher participation of the Th2. Understanding and managing the aggravated and ineffective immune response elicited by SARS-CoV-2 merits further clarification to improve treatments propose.
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Infecciones por Coronavirus/metabolismo , Interleucina-13/metabolismo , Interleucina-4/metabolismo , Pulmón/metabolismo , Neumonía Viral/metabolismo , Anciano , Anciano de 80 o más Años , Biomarcadores/metabolismo , COVID-19 , Infecciones por Coronavirus/patología , Femenino , Humanos , Interleucina-13/genética , Interleucina-4/genética , Pulmón/patología , Macrófagos/metabolismo , Masculino , Persona de Mediana Edad , Pandemias , Neumonía Viral/patología , Esfingosina/metabolismo , Factor de Crecimiento Transformador beta/genética , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
The etiology of multiple sclerosis (MS) is still not known, but the interaction of genetic, immunological, and environmental factors seem to be involved. This study aimed to investigate genetic alterations and the vitamin D status in patients with relapsing-remitting MS (RRMS) and secondary progressive MS (SPMS). A total of 53 patients (29 RRMS; 24 SPMS) and 25 healthy subjects were recruited to evaluate the micronucleated cell (MNC) frequency and nuclear abnormalities in the buccal mucosa, gene expression profiling in mononuclear cells, and plasmatic vitamin D concentration in the blood. Results showed a higher frequency of cells with karyorrhexis (SPMS) and lower frequencies of nuclear pyknosis (RRMS and SPMS) and karyolysis (SPMS) in patients with MS. Significant increase in the frequency of MNC was detected in the buccal mucosa of RRMS and SPMS patients. HIF1A, IL13, IL18, MYC, and TNF were differentially expressed in MS patients, and APP was overexpressed in cells of RRMS compared to SPMS patients. No relationship was observed between vitamin D level and the differentially expressed genes. In conclusion, the cytogenetic alterations in the buccal mucosa can be important indicators of genetic instability and degenerative processes in patients with MS. Furthermore, our data introduced novel biomarkers associated with the molecular pathogenesis of MS.
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Micronúcleos con Defecto Cromosómico , Esclerosis Múltiple Recurrente-Remitente/genética , Fenotipo , Adulto , Células Cultivadas , Femenino , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Interleucina-13/genética , Interleucina-13/metabolismo , Interleucina-18/genética , Interleucina-18/metabolismo , Masculino , Persona de Mediana Edad , Mucosa Bucal/metabolismo , Mucosa Bucal/patología , Esclerosis Múltiple Recurrente-Remitente/metabolismo , Esclerosis Múltiple Recurrente-Remitente/patología , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Although several cytokines and chemokines have been investigated as possible mediators of fibrosis in systemic sclerosis (SSc), specific correlation between cytokines and organ involvement have not been found yet, and a cytokine profile characteristic of SSc is far to be identified. We studied the profile of antifibrotic and profibrotic transcripts involved in skin of SSc patients. The mRNA expression was detected by fluorescence-based quantitative real-time PCR (qPCR) in skin's biopsies from 14 patients with SSc and 5 healthy controls. PDGF-A, CTGF, CCL3, IL-6, IL-13, IL-7, IFNγ, IL-17, IL-22 and RORc were analysed in these samples. CCL3, IL-7, IL-13 and IFN-γ were more expressed in skin's biopsy of patients with SSc (P = 0.0002, P = 0.0082, P = 0.0243, P = 0.0335, respectively) when compared with healthy controls. We also found a positive correlation between CCL3 and IL-7 transcripts (P = 0.0050 r = 0.7187). Furthermore, we observed that patients with lung involvement had lower expression of PDGF-A (P = 0.0385). We found an increase in IL-7, IFN-γ, CCL3 and IL-13 relative mRNA expressions on the skin's biopsy of patients with SSc, and a positive correlation between IL-7 and CCL3. These molecules are involved in the pathogenesis of SSc, and how their interactions occur should be the subject of further studies.
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Quimiocina CCL3/biosíntesis , Interferón gamma/biosíntesis , Interleucina-13/biosíntesis , Interleucina-7/biosíntesis , Adulto , Anciano , Biopsia , Quimiocina CCL3/genética , Femenino , Fibrosis , Regulación de la Expresión Génica , Humanos , Inmunosupresores/uso terapéutico , Interferón gamma/genética , Interleucina-13/genética , Interleucina-7/genética , Pulmón/patología , Masculino , Persona de Mediana Edad , Factor de Crecimiento Derivado de Plaquetas/biosíntesis , Factor de Crecimiento Derivado de Plaquetas/genética , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Esclerodermia Sistémica/tratamiento farmacológico , Esclerodermia Sistémica/genética , Esclerodermia Sistémica/metabolismo , Esclerodermia Sistémica/patología , Transcripción Genética , Regulación hacia ArribaRESUMEN
Asthma and allergy affect hundreds of millions of people from childhood to old age. In most of them, the inflammatory process of respiratory allergies involves the participation of type 2 cytokines, derived from T helper-2 (Th2)-cell, and Group 2 Innate Lymphoid (ILC2) Cells. An efficient memory Th2 cell response is dependent on IL-13 produced by ILC2s, causing allergic lung inflammation and elevated serum levels of immunoglobulin E. ILC2 cells are derived from common lymphoid progenitors and their growing depends on the transcription factor RORA. The aim of this work was to identify genetic variants in RORA associated with asthma phenotypes and allergy markers. Genomic DNA samples of 1246 individuals participating from Social Changes Asthma and Allergy in Latin America Program (SCAALA) have been genotyped using Illumina Human 2.5 Omni Beadchip. Logistics regressions have been performed to analyze the association among RORA variants and asthma, skin prick tests (SPT), specific IgE and type 2 cytokine production. Twelve single nucleotide variants (SNVs) were significantly associated with atopy (Pâ¯<â¯0.01), in which four of them, rs10162630, rs17191519, rs17270243, and rs55796775 and their haplotypes were strongly and positively associated (Pâ¯<â¯0.001). Furthermore, these variants increased the RORA gene expression in silico analysis. Other SNVs in RORA were associated with allergy markers, atopic and non-atopic asthma. Therefore, it is believed that variants in RORA gene may influence immunologic features of asthma and allergies and could be possible targets for future treatment of allergic diseases.
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Asma/genética , Predisposición Genética a la Enfermedad/genética , Hipersensibilidad/genética , Miembro 1 del Grupo F de la Subfamilia 1 de Receptores Nucleares/genética , Polimorfismo de Nucleótido Simple/genética , Biomarcadores/metabolismo , Niño , Preescolar , Estudios de Cohortes , Citocinas/genética , Femenino , Genotipo , Humanos , Inmunidad Innata/genética , Inmunoglobulina E/sangre , Inmunoglobulina E/genética , Inflamación/genética , Interleucina-13/genética , Pulmón/metabolismo , Masculino , Células Th2/metabolismoRESUMEN
In superior vertebrates, Interleukin 4 (IL-4) and Interleukin 13 (IL-13) play key and diverse roles to support immune responses acting on cell surface receptors. When stimulated, receptors activate intracellular signalling cascades switching cell phenotypes according to stimuli. In teleost fish, Interleukin 4/13 (IL-4/13) is the ancestral family cytokine related to both IL-4 and IL-13. Every private and common receptor subunit for IL-4/13 have in fish at least two paralogues and, as in mammals, soluble forms are also part of the receptor system. Reports for findings of fish IL-4/13 receptors have covered comparative analysis, transcriptomic profiles and to a lesser extent, functional analysis regarding ligand-receptor interactions and their biological effects. This review addresses available information from fish IL-4/13 receptors and discusses overall implications on teleost immunity, summarized gene induction strategies and pathogen-induced gene modulation, which may be useful tools to enhance immune response. Additionally, we present novel coding sequences for Atlantic salmon (Salmo salar) common gamma chain receptor (γC), Interleukin 13 receptor alpha 1A chain (IL-13Rα1A) and Interleukin 13 receptor alpha 1B chain (IL-13Rα1B).
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Proteínas de Peces , Receptores Tipo II de Interleucina-4 , Animales , Proteínas de Peces/genética , Proteínas de Peces/metabolismo , Peces , Interleucina-13/genética , Interleucina-13/metabolismo , Interleucina-4/genética , Interleucina-4/metabolismo , Receptores Tipo II de Interleucina-4/genética , Receptores Tipo II de Interleucina-4/metabolismoRESUMEN
Atopic dermatitis (AD) is one of the most common skin diseases, whose incidence is increasing in industrialized countries. The epicutaneous application of a hapten, such as 2,4-dinitrochlorobenzene (DNCB), evokes an experimental murine AD-like reaction. Glycomacropeptide (GMP) is a dairy bioactive peptide derived from hydrolysis of κ-casein by chymosin action. It has anti-inflammatory, prebiotic, and immunomodulatory effects. The present study was aimed to investigate the effect of GMP administration on DNCB-induced AD in rats. The severity of inflammatory process, pruritus, production of cytokines, and total immunoglobulin E (IgE) content were measured, and the histopathological features were analyzed. GMP reduced the intensity of inflammatory process and edema of DNCB-induced dermatitis, with a significant decrease in eosinophils recruitment and mast cells hyperplasia. In addition GMP suppressed the serum levels of total IgE and IL-4, IL-5, and IL-13 expression in AD-lesions. Besides, the levels of IL-10 were significantly increased. Remarkably, GMP administration before AD-induction abolished pruritus in dermatitis-like reactions in the rats. Taken together, these results indicate that GMP has an inhibitory effect on AD by downregulating Th2 dominant immune response, suggesting GMP as a potential effective alternative therapy for the prevention and management of AD.
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Antiinflamatorios no Esteroideos/uso terapéutico , Caseínas/uso terapéutico , Dermatitis Atópica/tratamiento farmacológico , Dermatitis Atópica/inmunología , Inflamación/tratamiento farmacológico , Fragmentos de Péptidos/uso terapéutico , Prurito/tratamiento farmacológico , Células Th2/inmunología , Animales , Antiinflamatorios no Esteroideos/farmacología , Dermatitis Atópica/inducido químicamente , Dermatitis Atópica/fisiopatología , Dinitroclorobenceno , Modelos Animales de Enfermedad , Eosinófilos , Inmunoglobulina E/sangre , Interleucina-10/sangre , Interleucina-10/genética , Interleucina-13/sangre , Interleucina-13/genética , Interleucina-4/sangre , Interleucina-4/genética , Interleucina-5/sangre , Interleucina-5/genética , Mastocitos , Ratas , Piel/inmunología , Piel/patología , Células Th2/efectos de los fármacosRESUMEN
Several genome-wide association studies have been conducted to investigate the influence of genetic polymorphisms in the development of allergic diseases, but few of them have included the X chromosome. The aim of present study was to perform an X chromosome-wide association study (X-WAS) for asthma symptoms. The study included 1307 children of which 294 were asthma cases. DNA was genotyped using 2.5 HumanOmni Beadchip from Illumina. Statistical analyses were performed in PLINK 1.9, MACH 1.0 and Minimac2. The variant rs12007907 (g.29483892C>A) in IL1RAPL gene was suggestively associated with asthma symptoms in discovery set (odds ratio (OR)=0.49, 95% confidence interval (CI): 0.37-0.67; P=3.33 × 10-6). This result was replicated in the ProAr cohort in men only (OR=0.45, 95% CI: 0.21-0.95; P=0.038). Furthermore, investigating the functional role of the rs12007907 on the production a Th2-type cytokine, IL-13, we found a negative association between the minor allele A with IL-13 production in the discovery set (P=0.044). Gene-based analysis revealed that NUDT10 was the most consistently associated with asthma symptoms in discovery sample. In conclusion, the rs12007907 variant in IL1RAPL gene was negatively associated with asthma and IL-13 production in our study and a sex-specific association was observed in one of the validation samples. It suggests an effect on asthma susceptibility and may explain differences in severe asthma frequency between women and men.
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Asma/genética , Proteína Accesoria del Receptor de Interleucina-1/genética , Polimorfismo de Nucleótido Simple , Estudios de Casos y Controles , Niño , Femenino , Humanos , Interleucina-13/genética , Interleucina-13/metabolismo , América Latina , Masculino , Pirofosfatasas/genética , Factores SexualesRESUMEN
The pathology of schistosomiasis is associated with the formation of granulomas, and this process is associated with liver fibrosis. Studies indicate that Th1 cytokines reduce fibrosis in schistosomiasis, while Th2 cytokines play a part in the progression of fibrosis, and IL-13 has a critical role in this process. The IL-13Rα2 receptor, known as a 'receptor antagonist' binds with high affinity to IL-13, and studies have identified that this plays a part in reducing fibrosis and the size of granulomas. The objective of this study was to evaluate the function of IL-13Rα2 and cellular immune response in hepatic fibrosis. A negative correlation between IL-13Rα2 and IL-13 was found, suggesting an increase in cytokine in early fibrosis. Initially, a negative correlation between IFN-γ and IL-13 was found in patients without fibrosis, and subsequently, this correlation was found to be positive in patients with severe fibrosis, thereby highlighting a new mechanism for regulating the progress of periportal fibrosis. There was a positive correlation between the profiles of Th1 and Th2 cytokines, suggesting the presence of both responses, thus regulating the disease. The results contribute to a better understanding of the immune mechanisms that control the process of hepatic fibrogenesis in schistosomiasis in humans.
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Subunidad alfa2 del Receptor de Interleucina-13/inmunología , Interleucina-13/inmunología , Cirrosis Hepática/inmunología , Hígado/inmunología , Esquistosomiasis mansoni/inmunología , Anciano , Animales , Brasil , Diagnóstico Precoz , Femenino , Regulación de la Expresión Génica , Humanos , Interferón gamma/genética , Interferón gamma/inmunología , Interleucina-13/genética , Subunidad alfa2 del Receptor de Interleucina-13/genética , Interleucina-2/genética , Interleucina-2/inmunología , Interleucina-4/genética , Interleucina-4/inmunología , Interleucina-6/genética , Interleucina-6/inmunología , Hígado/parasitología , Hígado/patología , Cirrosis Hepática/complicaciones , Cirrosis Hepática/diagnóstico , Cirrosis Hepática/parasitología , Masculino , Persona de Mediana Edad , Schistosoma mansoni/patogenicidad , Schistosoma mansoni/fisiología , Esquistosomiasis mansoni/complicaciones , Esquistosomiasis mansoni/diagnóstico , Esquistosomiasis mansoni/parasitología , Transducción de Señal , Clase Social , Células TH1/inmunología , Células TH1/parasitología , Células TH1/patología , Balance Th1 - Th2 , Células Th2/inmunología , Células Th2/parasitología , Células Th2/patología , Factores de TiempoRESUMEN
The aim of this study was to examine the association between polymorphisms in the interleukin-3 and -13 (IL-3 and IL-13) genes and rheumatoid arthritis (RA). In this hospital-based case-control study, we analyzed the IL-3 rs2073506 G/A, IL-3 rs40401 C/T, and IL-13 rs1800925 C/T polymorphisms in 615 RA patients and 839 controls from a Chinese Han population. Genotyping was performed using a custom-by-design 48-Plex single nucleotide polymorphism scanTM kit. Our results indicated that the IL-3 rs2073506 G/A, IL-3 rs40401 C/T, and IL-13 rs1800925 C/T polymorphisms were not associated with RA. However, stratification analyses suggested that the IL-13 rs1800925 CT and CT/CC genotypes increased the risk of RA in patients with erythrocyte sedimentation rate (ESR) <25.00. To sum up, these findings suggest that the IL-13 rs1800925 C/T polymorphism may be associated with increased risk of RA in ESR <25.00 patients. Future studies with larger sample sizes and inclusion of other ethnic populations must be conducted to confirm the findings of this study.
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Artritis Reumatoide/genética , Predisposición Genética a la Enfermedad , Interleucina-13/genética , Interleucina-3/genética , Anciano , Alelos , Artritis Reumatoide/sangre , Artritis Reumatoide/patología , Sedimentación Sanguínea , Femenino , Estudios de Asociación Genética , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido SimpleRESUMEN
Pediatric autoimmune hepatitis (AIH) patients present hypergammaglobulinemia, periportal CD8(+) cytotoxic T cell infiltration, and cirrhosis. Autoantibody profile defines AIH types 1 and 2 in addition to strong association with HLA-DRB1. We previously detected increased IgE serum levels and sought to compare clinical and histological features according to IgE levels in AIH (n = 74, ages 1-14 years) patients. Additionally, we typed 117 patients and 227 controls for functional polymorphisms of IL4, IL13, IL5, and IL4RA genes involved in IgE switching and eosinophil maturation that might contribute to overall genetic susceptibility to AIH. Serum IgE levels were high in 55% of AIH-1, but only in 12% of AIH-2 (P = 0.003) patients. Liver IgE was present in 91.3% of AIH-1 patients. The A alleles at both IL13 rs20541 and IL4RA rs1805011 were associated with AIH-1 (P = 0.024, OR = 1.55 and P < 0.0001, OR = 2.15, resp.). Furthermore, individuals presenting homozygosis for the A allele at IL4RA rs1805011 and HLA-DRB1(∗)03 and/or (∗)13 allele had sixfold greater risk to develop the disease (OR = 14.00, P < 0.001). The novel association suggests an additional role for IgE-linked immune response genes in the pathogenesis of AIH.
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Eosinófilos/fisiología , Cadenas HLA-DRB1/genética , Hepatitis Autoinmune/inmunología , Inmunoglobulina E/metabolismo , Interleucina-13/genética , Adolescente , Autoanticuerpos/sangre , Brasil , Niño , Preescolar , Predisposición Genética a la Enfermedad , Hepatitis Autoinmune/diagnóstico , Hepatitis Autoinmune/genética , Humanos , Lactante , Polimorfismo de Nucleótido Simple , RiesgoRESUMEN
BACKGROUND: Dynamic interactions between the host and gastrointestinal microbiota play an important role for local and systemic immune homeostasis. Helminthic parasites modulate the host immune response, resulting in protection against autoimmune disease but also increased susceptibility to pathogen infection. The underlying mechanisms remain largely unknown. RESULTS: We showed that the type 2 immune response to enteric Nippostrongylus brasiliensis infection in mice was associated with altered intestinal mucin and AMP expression and shifts in microbiota composition. Most strikingly, infection reduced concentrations of intestinal segmented filamentous bacteria (SFB), known inducers of T helper 17 cells, and IL-17-associated gene expression. Infected mice deficient in IL-13 or STAT6 did not reduce SFB or IL-17, and exogenous IL-25 replicated the effects of parasite infection in wild type mice. CONCLUSIONS: Our data show that parasite infection acts through host type 2 immunity to reduce intestinal SFB and expression of IL-17, providing an example of a microbiota-dependent immune modulation by parasites.
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Bacterias/inmunología , Inmunidad , Nippostrongylus , Infecciones por Strongylida/inmunología , Infecciones por Strongylida/microbiología , Animales , Péptidos Catiónicos Antimicrobianos/metabolismo , Bacterias/clasificación , Biomarcadores , Expresión Génica , Inmunomodulación , Interleucina-13/genética , Interleucina-13/metabolismo , Interleucina-17/genética , Interleucina-17/metabolismo , Mucosa Intestinal/metabolismo , Intestinos/inmunología , Intestinos/microbiología , Ratones , Mucinas/metabolismo , Factor de Transcripción STAT6/genética , Factor de Transcripción STAT6/metabolismo , Infecciones por Strongylida/parasitología , Células Th17/inmunología , Células Th17/metabolismoRESUMEN
BACKGROUND: Single nucleotide polymorphisms in the human gene for the receptor for advanced glycation end-products (RAGE) are associated with an increased incidence of asthma. RAGE is highly expressed in the lung and has been reported to play a vital role in the pathogenesis of murine models of asthma/allergic airway inflammation (AAI) by promoting expression of the type 2 cytokines IL-5 and IL-13. IL-5 and IL-13 are prominently secreted by group 2 innate lymphoid cells (ILC2s), which are stimulated by the proallergic cytokine IL-33. OBJECTIVE: We sought to test the hypothesis that pulmonary RAGE is necessary for allergen-induced ILC2 accumulation in the lung. METHODS: AAI was induced in wild-type and RAGE knockout mice by using IL-33, house dust mite extract, or Alternaria alternata extract. RAGE's lung-specific role in type 2 responses was explored with bone marrow chimeras and induction of gastrointestinal type 2 immune responses. RESULTS: RAGE was found to drive AAI by promoting IL-33 expression in response to allergen and by coordinating the inflammatory response downstream of IL-33. Absence of RAGE impedes pulmonary accumulation of ILC2s in models of AAI. Bone marrow chimera studies suggest that pulmonary parenchymal, but not hematopoietic, RAGE has a central role in promoting AAI. In contrast to the lung, the absence of RAGE does not affect IL-33-induced ILC2 influx in the spleen, type 2 cytokine production in the peritoneum, or mucus hypersecretion in the gastrointestinal tract. CONCLUSIONS: For the first time, this study demonstrates that a parenchymal factor, RAGE, mediates lung-specific accumulation of ILC2s.
Asunto(s)
Asma/inmunología , Inmunidad Innata , Interleucina-33/inmunología , Pulmón/inmunología , Linfocitos/inmunología , Receptor para Productos Finales de Glicación Avanzada/inmunología , Alérgenos/administración & dosificación , Alérgenos/inmunología , Alternaria/química , Animales , Antígenos Dermatofagoides/administración & dosificación , Antígenos Dermatofagoides/inmunología , Asma/inducido químicamente , Asma/genética , Asma/patología , Médula Ósea/inmunología , Médula Ósea/patología , Proliferación Celular , Tracto Gastrointestinal/inmunología , Tracto Gastrointestinal/patología , Regulación de la Expresión Génica , Interleucina-13/genética , Interleucina-13/inmunología , Interleucina-33/genética , Interleucina-5/genética , Interleucina-5/inmunología , Pulmón/patología , Linfocitos/patología , Ratones , Especificidad de Órganos , Peritoneo/inmunología , Peritoneo/patología , Pyroglyphidae/química , Receptor para Productos Finales de Glicación Avanzada/genética , Transducción de Señal , Bazo/inmunología , Bazo/patología , Quimera por TrasplanteRESUMEN
BACKGROUND: Asthma is one of the most common respiratory diseases worldwide, and the complexity of its etiology has been widely documented. Chromosome 5q31-33 is one of the main loci implicated in asthma and asthma-related traits. IL13, CD14 and ADRB2, which are located in this risk locus, are among the genes most strongly associated with asthma susceptibility. OBJECTIVES: This study evaluated whether single-nucleotide polymorphisms or haplotypes at 5q31-33 conferred risk for asthma in Mexican-Mestizo pediatric patients. METHODS: We performed a case-controlled study including 851 individuals, 421 of them affected with childhood-onset asthma and 430 ethnically matched unaffected subjects. We used the TaqMan Allelic Discrimination Assay to genotype 20 single-nucleotide polymorphisms within IL5, RAD50, IL13, IL4, CD14, SPINK5, HTR4, ADRB2 and IL12B. RESULTS: Although no association was detected for any risk allele, three SPINK5 haplotypes (GGCT: p = 6 × 10(-6); AATC: p = 0.0001; AGTT: p = 0.0001) and five ADRB2 haplotypes (AGGACC: p = 0.0014; AGGAAG: p = 0.0002; TGAGAG: p = 0.0001; AGGAAC: p = 0.0002; AAGGAG: p = 0.003) were associated with asthma. Notably, the AGTT SPINK5 haplotype exhibited a male gender-dependent association (p = 7.6 × 10(-5)). CONCLUSION: Our results suggest that SPINK5 and ADRB2 haplotypes might play a role in the susceptibility to childhood-onset asthma.
Asunto(s)
Asma/genética , Haplotipos , Proteínas Inhibidoras de Proteinasas Secretoras/genética , Receptores Adrenérgicos beta 2/genética , Adolescente , Alelos , Asma/etnología , Niño , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Indígenas Norteamericanos , Interleucina-13/genética , Masculino , México , Pruebas del Parche , Polimorfismo de Nucleótido Simple , Factores de Riesgo , Inhibidor de Serinpeptidasas Tipo Kazal-5 , Índice de Severidad de la Enfermedad , Factores SexualesRESUMEN
BACKGROUND: Asthma is a complex disease influenced by multiple genetic and environmental factors. While Madeira has the highest prevalence of asthma in Portugal (14.6%), the effect of both genetic and environmental factors in this population has never been assessed. We categorized 98 asthma patients according to the Global Initiative for Asthma (GINA) guidelines, established their sensitization profile, and measured their forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) indexes. Selected single nucleotide polymorphisms (SNPs) were analysed as potential markers for asthma susceptibility and severity in the interleukin 4 (IL4), interleukin 13 (IL13), beta-2-adrenergic receptor (ADRB2), a disintegrin and metalloprotease 33 (ADAM33), gasdermin-like (GSDML) and the signal transducer and activator of transcription 6 (STAT6) genes comparatively to a population reference set. RESULTS: Although mites are the major source of allergic sensitization, no significant difference was found amongst asthma severity categories. IL4-590*CT/TT and IL4-RP2*253183/183183 were found to predict the risk (2-fold) and severity (3 to 4-fold) of asthma and were associated with a lower FEV1 index. ADRB2-c.16*AG is a risk factor (3.5-fold), while genotype GSDML-236*TT was protective (4-fold) for moderate-severe asthma. ADAM33-V4*C was associated to asthma and mild asthma by the transmission disequilibrium test (TDT). Finally, ADAM33-V4*CC and STAT6-21*TT were associated with higher sensitization (mean wheal size ≥10 mm) to house dust (1.4-fold) and storage mite (7.8-fold). CONCLUSION: In Madeira, IL4-590C/T, IL4-RP2 253/183, GSDML-236C/T and ADAM33-V4C/G SNPs are important risk factors for asthma susceptibility and severity, with implications for asthma healthcare management.
Asunto(s)
Asma/genética , Polimorfismo Genético/genética , Proteínas ADAM/análisis , Proteínas ADAM/genética , Adolescente , Biomarcadores , Estudios de Casos y Controles , Niño , Desintegrinas/análisis , Desintegrinas/genética , Femenino , Volumen Espiratorio Forzado/genética , Genotipo , Humanos , Interleucina-13/análisis , Interleucina-13/genética , Interleucina-4/análisis , Interleucina-4/genética , Masculino , Proteínas de Neoplasias/análisis , Proteínas de Neoplasias/genética , Polimorfismo de Nucleótido Simple/genética , Portugal , Receptores Adrenérgicos beta 2/análisis , Receptores Adrenérgicos beta 2/genética , Factores de Riesgo , Factor de Transcripción STAT6/análisis , Factor de Transcripción STAT6/genética , Índice de Severidad de la Enfermedad , Estadísticas no Paramétricas , Capacidad Vital/genéticaRESUMEN
Our objective was to investigate the distributions of six single nucleotide polymorphisms (SNPs) MS4A2 E237G, MS4A2 C-109T, ADRB2 R16G, IL4RA I75V, IL4 C-590T, and IL13 C1923T in Mauritian Indian and Chinese Han children with asthma. This case-control association study enrolled 382 unrelated Mauritian Indian children, 193 with asthma and 189 healthy controls, and 384 unrelated Chinese Han children, 192 with asthma and 192 healthy controls. The SNP loci were genotyped using polymerase chain reaction (PCR)-restriction fragment length polymorphism for the Chinese Han samples and TaqMan real-time quantitative PCR for the Mauritian Indian samples. In the Mauritian Indian children, there was a significant difference in the distribution of IL13 C1923T between the asthma and control groups (P=0.033). The frequency of IL13 C1923T T/T in the Mauritian Indian asthma group was significantly higher than in the control group [odds ratio (OR)=2.119, 95% confidence interval=1.048-4.285]. The Chinese Han children with asthma had significantly higher frequencies of MS4A2 C-109T T/T (OR=1.961, P=0.001) and ADRB2 R16G A/A (OR=2.575, P=0.000) than the control group. The IL13 C1923T locus predisposed to asthma in Mauritian Indian children, which represents an ethnic difference from the Chinese Han population. The MS4A2 C-109T T/T and ADRB2 R16G A/A genotypes were associated with asthma in the Chinese Han children.
Asunto(s)
Pueblo Asiatico/genética , Asma/genética , Predisposición Genética a la Enfermedad/etnología , Polimorfismo de Nucleótido Simple/genética , Adolescente , Asma/epidemiología , Asma/etnología , Estudios de Casos y Controles , Causalidad , Niño , Preescolar , China/epidemiología , China/etnología , Femenino , Estudios de Asociación Genética , Sitios Genéticos , Predisposición Genética a la Enfermedad/epidemiología , Genotipo , Humanos , Interleucina-13/genética , Interleucina-4/genética , Subunidad alfa del Receptor de Interleucina-4/genética , Masculino , Mauricio/epidemiología , Mauricio/etnología , Polimorfismo de Longitud del Fragmento de Restricción , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptores Adrenérgicos beta 2/genética , Receptores de IgE/genética , Adulto JovenRESUMEN
BACKGROUND: Asthma is a complex disease influenced by multiple genetic and environmental factors. While Madeira has the highest prevalence of asthma in Portugal (14.6%), the effect of both genetic and environmental factors in this population has never been assessed. We categorized 98 asthma patients according to the Global Initiative for Asthma (GINA) guidelines, established their sensitization profile, and measured their forced expiratory volume in 1second (FEV1) and forced vital capacity (FVC) indexes. Selected single nucleotide polymorphisms (SNPs) were analysed as potential markers for asthma susceptibility and severity in the interleukin 4 (IL4), interleukin 13 (IL13), beta-2-adrenergic receptor (ADRB2), a disintegrin and metalloprotease 33 (ADAM33), gasdermin-like (GSDML) and the signal transducer and activator of transcription 6 (STAT6) genes comparatively to a population reference set. RESULTS: Although mites are the major source of allergic sensitization, no significant difference was found amongst asthma severity categories. IL4-590*CT/TT and IL4-RP2*253183/183183 were found to predict the risk (2-fold) and severity (3 to 4-fold) of asthma and were associated with a lower FEV1 index. ADRB2-c.16*AG is a risk factor (3.5-fold), while genotype GSDML-236*TT was protective (4-fold) for moderate-severe asthma. ADAM33-V4*C was associated to asthma and mild asthma by the transmission disequilibrium test (TDT). Finally, ADAM33-V4*CC and STAT6-21*TT were associated with higher sensitization (mean wheal size ≥10mm) to house dust (1.4-fold) and storage mite (7.8-fold). CONCLUSION: In Madeira, IL4-590C/T, IL4-RP2 253/183, GSDML-236C/T and ADAM33-V4C/G SNPs are important risk factors for asthma susceptibility and severity, with implications for asthma healthcare management.
Asunto(s)
Humanos , Masculino , Femenino , Niño , Adolescente , Polimorfismo Genético/genética , Asma/genética , Portugal , Índice de Severidad de la Enfermedad , Biomarcadores , Estudios de Casos y Controles , Capacidad Vital/genética , Volumen Espiratorio Forzado/genética , Factores de Riesgo , Interleucina-4/análisis , Interleucina-4/genética , Receptores Adrenérgicos beta 2/análisis , Receptores Adrenérgicos beta 2/genética , Estadísticas no Paramétricas , Interleucina-13/análisis , Interleucina-13/genética , Desintegrinas/análisis , Desintegrinas/genética , Polimorfismo de Nucleótido Simple/genética , Proteínas ADAM/análisis , Proteínas ADAM/genética , Factor de Transcripción STAT6/análisis , Factor de Transcripción STAT6/genética , Genotipo , Proteínas de Neoplasias/análisis , Proteínas de Neoplasias/genéticaRESUMEN
Interleukin (IL)-13 is a central mediator in allergic asthma. Our previous results have indicated that sulfatase-modifying factor 2 (SUMF2) interacts with IL-13 and inhibits its secretion. In this study, we investigated the interactions between SUMF2 subtypes and 2 types of IL-13. Wild type IL-13 (wh-IL-13) and its mutated counterpart (mh-IL-13) were analyzed and cloned into pSos yeast expression vectors. Protein was expressed in host cdc25H yeast strains. A quartet of agar growth plates was prepared for the yeast two-hybrid system, which was used to detect IL-13 and SUMF2 subtype interactions. Both yeast expression vectors, pSos/whIL-13 and pSos/whIL-13, and recombinant expression vectors for the 5 subtypes of SUMF2 (pMyr/SUMF2-Vx) were constructed. Our data showed that all of the SUMF2 subtypes bound to whIL-13 and mhIL-13 in the CytoTrap system. Five SUMF2 subtypes - SUMF2-V2, SUMF2-V3, SUMF2-V4, SUMF2-V5, and SUMF2-V7--interacted with whIL-13 and mhIL-13. These subtypes may contribute to allergic asthma by mediating IL-13 release.
Asunto(s)
Interleucina-13/metabolismo , Sulfatasas/metabolismo , Humanos , Interleucina-13/genética , Mutación , Unión Proteica , Sulfatasas/genética , Técnicas del Sistema de Dos HíbridosRESUMEN
In this study, B cell function in protective T(H)2 immunity against N. brasiliensis infection was investigated. Protection against secondary infection depended on IL-4Rα and IL-13; but not IL-4. Protection did not associate with parasite specific antibody responses. Re-infection of B cell-specific IL-4Rαâ»/â» mice resulted in increased worm burdens compared to control mice, despite their equivalent capacity to control primary infection. Impaired protection correlated with reduced lymphocyte IL-13 production and B cell MHC class II and CD86 surface expression. Adoptive transfer of in vivo N. brasiliensis primed IL-4Rα expressing B cells into naïve BALB/c mice, but not IL-4Rα or IL-13 deficient B cells, conferred protection against primary N. brasiliensis infection. This protection required MHC class II compatibility on B cells suggesting cognate interactions by B cells with CD4⺠T cells were important to co-ordinate immunity. Furthermore, the rapid nature of these protective effects by B cells suggested non-BCR mediated mechanisms, such as via Toll Like Receptors, was involved, and this was supported by transfer experiments using antigen pulsed Myd88â»/â» B cells. These data suggest TLR dependent antigen processing by IL-4Rα-responsive B cells producing IL-13 contribute significantly to CD4⺠T cell-mediated protective immunity against N. brasiliensis infection.