Abstract
BackgroundTBX21 (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 FindingsCord 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).ConclusionsPolymorphisms 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.
Highlights
Asthma and inflammatory diseases are induced by a complex interplay of genetic and environmental factors influencing early immune responses [1,2,3]
We assessed the effect of 5 genetic variants located in TH1 lineage transcription factors on cord blood immune responses of 200 neonates, namely TBX21 and HLX1 (Table 1) which have previously been related to the development or protection from asthma [10,14]
TH2-related cytokine secretion upon innate stimulation was modulated in carriers of TBX21 and HLX1 polymorphisms
Summary
Asthma and inflammatory diseases are induced by a complex interplay of genetic and environmental factors influencing early immune responses [1,2,3]. The interaction between TBX21 and HLX1 is required to induce maximal IFN-c secretion [11] Both genes have the capacity to revert TH2 cell commitment of T cells already expressing TH2 cytokines [11]. 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, 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
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