Hellberg Sandra, Raffetseder Johanna, Rundquist Olof, Magnusson Rasmus, Papapavlou Georgia, Jenmalm Maria C, Ernerudh Jan, Gustafsson Mika
Bioinformatics, Department of Physics, Chemistry and Biology, Linköping University, Linköping, Sweden.
Division of Inflammation and Infection, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
Front Immunol. 2021 May 12;12:672168. doi: 10.3389/fimmu.2021.672168. eCollection 2021.
The changes in progesterone (P4) levels during and after pregnancy coincide with the temporary improvement and worsening of several autoimmune diseases like multiple sclerosis (MS) and rheumatoid arthritis (RA). Most likely immune-endocrine interactions play a major role in these pregnancy-induced effects. In this study, we used next generation sequencing to investigate the direct effects of P4 on CD4 T cell activation, key event in pregnancy and disease. We report profound dampening effects of P4 on T cell activation, altering the gene and protein expression profile and reversing many of the changes induced during the activation. The transcriptomic changes induced by P4 were significantly enriched for genes associated with diseases known to be modulated during pregnancy such as MS, RA and psoriasis. STAT1 and STAT3 were significantly downregulated by P4 and their downstream targets were significantly enriched among the disease-associated genes. Several of these genes included well-known and disease-relevant cytokines, such as IL-12β, CXCL10 and OSM, which were further validated also at the protein level using proximity extension assay. Our results extend the previous knowledge of P4 as an immune regulatory hormone and support its importance during pregnancy for regulating potentially detrimental immune responses towards the semi-allogenic fetus. Further, our results also point toward a potential role for P4 in the pregnancy-induced disease immunomodulation and highlight the need for further studies evaluating P4 as a future treatment option.
孕期及产后孕酮（P4）水平的变化与多种自身免疫性疾病（如多发性硬化症（MS）和类风湿性关节炎（RA））的暂时改善和恶化相吻合。免疫 - 内分泌相互作用很可能在这些妊娠诱导的效应中起主要作用。在本研究中，我们使用下一代测序技术来研究P4对CD4 T细胞活化的直接影响，这是妊娠和疾病中的关键事件。我们报告了P4对T细胞活化有显著的抑制作用，改变了基因和蛋白质表达谱，并逆转了活化过程中诱导的许多变化。P4诱导的转录组变化在与已知在孕期受调节的疾病（如MS、RA和银屑病）相关的基因中显著富集。STAT1和STAT3被P4显著下调，并且它们的下游靶点在疾病相关基因中显著富集。其中一些基因包括众所周知且与疾病相关的细胞因子，如IL - 12β、CXCL10和OSM，使用邻位延伸分析在蛋白质水平上进一步验证了这些细胞因子。我们的结果扩展了之前关于P4作为免疫调节激素的认识，并支持其在孕期调节针对半同种异体胎儿潜在有害免疫反应的重要性。此外，我们的结果还指出了P4在妊娠诱导的疾病免疫调节中的潜在作用，并强调需要进一步研究评估P4作为未来治疗选择的可能性。
