RESUMEN
Neonates show an impaired anti-microbial host defence, but the underlying immune mechanisms are not understood fully. Myeloid-derived suppressor cells (MDSCs) represent an innate immune cell subset characterized by their capacity to suppress T cell immunity. In this study we demonstrate that a distinct MDSC subset with a neutrophilic/granulocytic phenotype (Gr-MDSCs) is highly increased in cord blood compared to peripheral blood of children and adults. Functionally, cord blood isolated Gr-MDSCs suppressed T cell proliferation efficiently as well as T helper type 1 (Th1), Th2 and Th17 cytokine secretion. Beyond T cells, cord blood Gr-MDSCs controlled natural killer (NK) cell cytotoxicity in a cell contact-dependent manner. These studies establish neutrophilic Gr-MDSCs as a novel immunosuppressive cell subset that controls innate (NK) and adaptive (T cell) immune responses in neonates. Increased MDSC activity in cord blood might serve as key fetomaternal immunosuppressive mechanism impairing neonatal host defence. Gr-MDSCs in cord blood might therefore represent a therapeutic target in neonatal infections.
Asunto(s)
Inmunidad Adaptativa , Linfocitos T CD8-positivos/inmunología , Sangre Fetal/inmunología , Inmunidad Innata , Células Mieloides/inmunología , Neutrófilos/inmunología , Adulto , Sangre Fetal/citología , Humanos , Tolerancia Inmunológica , Lactante , Recién NacidoRESUMEN
BACKGROUND: Allergic disorders are characterized by an increase in the Th2 cytokines IL-4, IL-5 and IL-13, produced primarily by Th2 cells. These cells are marked by the expression of CRTh2 (chemoattractant receptor-homologous molecule expressed on Th2 cells), a receptor for prostaglandin D(2). As genetic variation plays a significant role in the predisposition for allergic disorders, we investigated the influence of single nucleotide polymorphisms (SNPs) in CRTh2. METHODS: In a large study population of German children (n = 4264) from the International Study of Asthma and Allergy in Children (ISAAC II), six polymorphisms in CRTh2 were genotyped. Statistical analyses were performed using single SNP and haplotype analyses. RESULTS: Uncorrected associations among -6373G>A, +1431G>C and +1538A>G were observed with a number of allergic phenotypes (P < 0.05). After correction, association between +1431C and specific IgE to food allergens remained significant (P = 0.04). Associations of haplotype (H)3 (containing +1538G) with reduced risk for asthma and H2 (containing +1431C) with increased risk for specific IgE to food allergens also remained significant after correction for multiple testing (P = 0.004). CONCLUSIONS: Genetic variation within CRTh2 modifies the development of allergic sensitization and asthma in a population of German children.
Asunto(s)
Variación Genética , Hipersensibilidad Inmediata/genética , Hipersensibilidad Inmediata/fisiopatología , Polimorfismo de Nucleótido Simple , Receptores Inmunológicos/genética , Receptores de Prostaglandina/genética , Asma/genética , Asma/fisiopatología , Niño , Estudios Transversales , Eccema/genética , Eccema/fisiopatología , Hipersensibilidad a los Alimentos/genética , Hipersensibilidad a los Alimentos/fisiopatología , Genotipo , Alemania , Humanos , Fenotipo , Ruidos Respiratorios/genética , Ruidos Respiratorios/fisiopatología , Rinitis Alérgica Estacional/genética , Rinitis Alérgica Estacional/fisiopatologíaRESUMEN
BACKGROUND: Common genetic variations in toll-like receptor 2 (TLR2), an innate pathogen recognition receptor, may influence the development of atopic diseases. So far, very little is known about the role of rare TLR2 mutations in these diseases. OBJECTIVE: We investigated the functional properties of six rare amino acid changes in TLR2 (and one amino acid change in a TLR2 pseudogene) and studied their effect on atopic sensitization and disease. METHODS: We identified rare TLR2 mutations leading to amino acid changes from databases. Functional effects of TLR2 variants were analyzed by NF-kappaB-dependent luciferase reporter assay and interleukin-8 enzyme linked immunosorbent assay in vitro. The frequency of these mutations was determined in a random sample of the general population (n = 368). Association with atopic diseases were studied in a cross sectional German study population (n = 3099). RESULTS: Three out of six mutations in the TLR2 gene altered receptor activity in vitro. Out of these, only the minor allele of R753Q occurred reasonably frequent in the German population (minor allele frequency 3%). The risk to develop atopy increased by 50% in carriers of the 753Q allele (P = 0.021) and total (P = 0.040) as well as allergen specific serum IgE levels (P = 0.011) were significantly elevated. CONCLUSION: The rare but functionally relevant mutation R753Q in TLR2 may significantly affect common conditions such as atopic sensitization in the general population.