Background: Accumulating evidence indicates the presence of bidirectional cross-talks between the endocrine and the immune system. However, no data are available on the influence of either the thyroid hormones or TSH within the normal range on the immune cell function in healthy humans.
Aim: To comprehensively investigate the effects of the hypothalamic-pituitary-thyroid axis on the variation of immune responses in a cohort of healthy volunteers.
Methods: The immune phenotype was characterized at the level of immune cell subpopulations counts, circulatory mediators of inflammation, platelet function, and production of six cytokines after stimulation with 19 microbial and non-microbial stimuli. The study was performed in a cohort of 534 well described healthy individuals (the 500 Human Functional Genomics cohort (500FG)). Results were obtained using systems biology-based approaches and were subsequently validated in an independent cohort of 324 healthy volunteers with comparable demographic characteristics.
Results: T4 and TSH did not affect cytokine production, circulatory mediators of inflammation (except for the TSH association with leptin) and innate immune cell population numbers. In contrast, we found significant and distinct effects of TSH and T4 on lymphocyte populations in the 500FG cohort. TSH was positively associated with 36 of the 73 independent cell types, particularly the total circulating lymphocyte counts and T-cell populations. Interestingly, T4 correlated positively with 18 of the 73 independent cell types, mainly circulating B-cell populations. These results were validated in the independent cohort of 324 healthy volunteers. Furthermore, we performed a GWAS on a SNP array covering around 8.8 million SNPs. We identified a high degree of overlap, with 35 SNPs being associated with both the TSH (22 SNPs) or T4 (13 SNPs) concentrations and the cell counts. Some SNPs had strong eQTLs influencing the expression of important genes such as a genetic variant within the PTGER3 gene and a SNP between ZC3H7A and TXNDC11, the latter being involved in folding of DUOX proteins involved in H202 generating system within the thyroid.
Conclusion: T4 and TSH have a minimal impact on innate immune responses in healthy volunteers. However, there is a strong interaction between TSH and T4 and adaptive immune responses, particularly with the lymphocyte numbers. These findings represent the first step in understanding the biology of these newly identified interactions, and pave the way towards assessing their impact in clinical situations. Furthermore, the novel genetic loci have to be tested in future experiments, to decipher their precise role in thyroid-immune biology.
18 - 21 May 2019
European Society of Endocrinology