TBX21 and HLX1 Polymorphisms Influence Cytokine Secretion at Birth

Background TBX21 (T cell specific T-box transcription factor) and HLX1 (H.20-like homeobox 1) are crucial transcription factors of TH1-cells, inducing their differentiation and suppressing TH2 commitment, particularly important for early life immune development. This study investigated the influence of TBX21 and HLX1 single nucleotide polymorphisms (SNPs), which have previously been shown to be associated with asthma, on TH1/TH2 lineage cytokines at birth. Methods and Findings Cord blood mononuclear cells (CBMCs) of 200 neonates were genotyped for two TBX21 and three HLX1 SNPs. CBMCs were stimulated with innate (Lipid A, LpA; Peptidoglycan, Ppg), adaptive stimuli (house dust mite Dermatophagoides pteronyssinus 1, Derp1) or mitogen (phytohemagglutinin, PHA). Cytokines, T-cells and mRNA expression of TH1/TH2-related genes were assessed. Atopic diseases during the first 3 years of life were assessed by questionnaire answered by the parents. Carriers of TBX21 promoter SNP rs17250932 and HLX1 promoter SNP rs2738751 showed reduced or trendwise reduced (p≤0.07) IL-5, IL-13 and TNF-α secretion after LpA-stimulation. Carriers of HLX1 SNP rs2738751 had lower IL-13 levels following Ppg-stimulation (p = 0.08). Carriers of HLX1 exon 1 SNP rs12141189 showed increased IL-5 (LpA, p = 0.007; Ppg, p = 0.10), trendwise increased IL-13 (LpA), higher GM-CSF (LpA/Ppg, p≤0.05) and trendwise decreased IFN-γ secretion (Derp1+LpA-stimulation, p = 0.1). Homozygous carriers of HLX1 promoter SNP rs3806325 showed increased IL-13 and IL-6 (unstimulated, p≤0.03). In carriers of TBX21 intron 3 SNP rs11079788 no differences in cytokine secretion were observed. mRNA expression of TH1/TH2-related genes partly correlated with cytokines at protein level. TBX21 SNP rs11079788 carriers developed less symptoms of atopic dermatitis at 3 years of age (p = 0.03). Conclusions Polymorphisms in TBX21 and HLX1 influenced primarily IL-5 and IL-13 secretion after LpA-stimulation in cord blood suggesting that genetic variations in the transcription factors essential for the TH1-pathway may contribute to modified TH2-immune responses already early in life. Further follow-up of the cohort is required to study the polymorphisms' relevance for immune-mediated diseases such as childhood asthma.

[1]  E. von Mutius,et al.  TLR2 polymorphisms influence neonatal regulatory T cells depending on maternal atopy , 2011, Allergy.

[2]  Barmak Modrek,et al.  T-helper type 2-driven inflammation defines major subphenotypes of asthma. , 2009, American journal of respiratory and critical care medicine.

[3]  J. Ernerudh,et al.  Cord blood cytokines and chemokines and development of allergic disease , 2009, Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology.

[4]  J. Adamski,et al.  An IgE-associated polymorphism in STAT6 alters NF-kappaB binding, STAT6 promoter activity, and mRNA expression. , 2009, The Journal of allergy and clinical immunology.

[5]  M. Sato,et al.  Balance between early life tolerance and sensitization in allergy: dependence on the timing and intensity of prenatal and postnatal allergen exposure of the mother , 2009, Immunology.

[6]  P. Rosenstiel,et al.  TBX21 gene variants increase childhood asthma risk in combination with HLX1 variants. , 2009, The Journal of allergy and clinical immunology.

[7]  K. Tokuyama,et al.  Association of cord blood cytokine levels with wheezy infants in the first year of life , 2009, Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology.

[8]  N. Klopp,et al.  Rare TLR2 mutations reduce TLR2 receptor function and can increase atopy risk , 2009, Allergy.

[9]  E. von Mutius,et al.  Maternal farm exposure modulates neonatal immune mechanisms through regulatory T cells. , 2009, The Journal of allergy and clinical immunology.

[10]  M. Ege,et al.  Cord blood cytokines are modulated by maternal farming activities and consumption of farm dairy products during pregnancy: the PASTURE Study. , 2009, The Journal of allergy and clinical immunology.

[11]  Christopher B Wilson,et al.  Epigenetic control of T-helper-cell differentiation , 2009, Nature Reviews Immunology.

[12]  L. Pinto,et al.  Impact of genetics in childhood asthma. , 2008, Jornal de pediatria.

[13]  O. Kaminuma,et al.  Downregulation of IL-13 Gene Transcription by T-bet in Human T Cells , 2008, International Archives of Allergy and Immunology.

[14]  S. Weiland,et al.  IRF-1 gene variations influence IgE regulation and atopy. , 2008, American journal of respiratory and critical care medicine.

[15]  F. Finkelman,et al.  Advances in asthma, allergy mechanisms, and genetics in 2006. , 2007, The Journal of allergy and clinical immunology.

[16]  Minghua Wu,et al.  Increased Bleomycin-Induced Skin Fibrosis in Mice Lacking the Th1-Specific Transcription Factor T-bet , 2007, Pathobiology.

[17]  Yusuke Nakamura,et al.  Functional promoter polymorphism in the TBX21 gene associated with aspirin-induced asthma , 2005, Human Genetics.

[18]  S. Weiland,et al.  A signal transducer and activator of transcription 6 haplotype influences the regulation of serum IgE levels. , 2004, The Journal of allergy and clinical immunology.

[19]  Martin J Firth,et al.  Association between antenatal cytokine production and the development of atopy and asthma at age 6 years , 2003, The Lancet.

[20]  H. Shin,et al.  Association analysis of novel TBX21 variants with asthma phenotypes , 2003, Human mutation.

[21]  L. Chodosh,et al.  Hlx is induced by and genetically interacts with T-bet to promote heritable TH1 gene induction , 2002, Nature Immunology.

[22]  S. Szabo,et al.  Distinct Effects of T-bet in TH1 Lineage Commitment and IFN-γ Production in CD4 and CD8 T Cells , 2002, Science.

[23]  J. Warner,et al.  Fetal and neonatal IL-13 production during pregnancy and at birth and subsequent development of atopic symptoms. , 2000, The Journal of allergy and clinical immunology.

[24]  Laurie H Glimcher,et al.  A Novel Transcription Factor, T-bet, Directs Th1 Lineage Commitment , 2000, Cell.

[25]  R. Prentice.  Linear rank tests with right censored data , 1978 .

[26]  E. Kaplan,et al.  Nonparametric Estimation from Incomplete Observations , 1958 .

[27]  P. Rosenstiel,et al.  HLX1 gene variants influence the development of childhood asthma. , 2009, The Journal of allergy and clinical immunology.

[28]  E. Mutius.  Gene-environment interactions in asthma , 2009 .

[29]  E. von Mutius,et al.  Impairment of T-regulatory cells in cord blood of atopic mothers. , 2008, The Journal of allergy and clinical immunology.

[30]  K. Carlsen,et al.  T cell-specific T-box transcription factor haplotype is associated with allergic asthma in children. , 2008, The Journal of allergy and clinical immunology.

[31]  J. Rioux,et al.  T-bet polymorphisms are associated with asthma and airway hyperresponsiveness. , 2006, American journal of respiratory and critical care medicine.

[32]  S. Szabo,et al.  Distinct effects of T-bet in TH1 lineage commitment and IFN-gamma production in CD4 and CD8 T cells. , 2002, Science.

[33]  Lorian,et al.  ENVIRONMENTAL EXPOSURE TO ENDOTOXIN AND ITS RELATION TO ASTHMA IN SCHOOL-AGE CHILDREN , 2022 .