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  • Differentiation to either Th or Th cells is significantly

    2022-05-13

    Differentiation to either Th1 or Th2 Sorbitol is significantly influenced by the relative expression of T-bet and GATA-3, respectively (Zhu et al., 2006, Jenner et al., 2009). T-bet acts as a key regulator of Th1 cell fate determination and directly activates IFN-γ and suppresses IL-4 (Szabo et al., 2002, Djuretic et al., 2007), whereas GATA3 acts in the opposite manner to activate IL-4 and suppress IFN-γ (Zheng and Flavell, 1997, Chang and Aune, 2007). Both factors exert their roles at gene loci that encode Th1 and Th2 cytokines, respectively. There was a trend toward down-regulation on T-bet mRNA expression one week post-marathon compared to pre-marathon. The small sample size of this subset may have contributed to failure to detect a statistically significant decrease or it may reflect less effect of the stressor on T-bet expression. However, a significant increase of GATA3 expression was detected after the event. Thus, the T-bet/GATA3 mRNA ratio was significantly decreased post-marathon compared to pre-marathon. These results further contribute to understanding the molecular mechanisms associated with the reported stress-induced Th1/Th2 imbalance (Salicru et al., 2007, Xiang and Marshall, 2011, Xiang et al., 2012). Sixteen participants had been recruited in this study including 5 female and 11 male. It will be important to do future studies to search for effects of gender, race and age. This small sample size (n=16) was predominantly male (69%), all Caucasians and a relatively young age. A larger sample is needed for a meaningful analysis in future investigation. We are only proposing that Th1/Th2 reduction lingers one week post-marathon and a potential mechanism to this is reduced mRNA expression as opposed to post transcriptional modifications. The current study provides intriguing data to suggest that strenuous exercise can cause a prolonged Th1/Th2 imbalance and that transcription factor gene expression associated with Th1 and Th2 cytokine production is affected. This may contribute to an increased susceptibility to post-race infections. Our study suggests that a mechanism for Th1/Th2 imbalance in this physical stress model (Rehm et al., 2013) is an altered cascade including IFN-γ/IL-4 mRNA ratio, T-bet/GATA3 mRNA ratio and the other Th2 related genes which were detected by PCR Array. Psychological stress can increase the production of stress hormones which are potential regulators in immune balance (Salicru et al., 2007). Previous studies by our group have shown the effects of stress level doses of dexamethasone (cortisol analog) on in vitro cultures of PBMC from normal individuals and demonstrated a shift in the secreted supernatant cytokine balance toward a Th2 predominant profile (Agarwal and Marshall, 1998, Agarwal and Marshall, 2001). Using a focused PCR Array that allows screening of relevant genes, we have added additional data to further characterize the physiological basis of this physical stress-induced immune imbalance. Given that the ultimate clinical risks likely involve more pathways than just Th1/Th2 imbalances (such as altered regulatory T cell and other T cell subpopulations) in different individuals, the PCR Array technology may become a useful screening tool for categorizing and characterizing differing immune dysfunction profiles in specific patient populations as well as providing possible monitoring of effects that could help design and predict efficacy of therapeutic interventions. This would allow tailoring of these interventions for prophylaxis and/or early therapeutic interventions. Further definition of these mechanisms will require additional investigations in larger, more diverse populations.
    Introduction Predictive, preventive, personalized medicine (PPPM) is an emerging but quickly expanding concept in the provision of Health care services that aim to provide individualized risk assessment, preventive strategies and therapeutic options that are adapted to the needs of each patient and to the characteristics of the specific patient's disease, taking into account both genetic and environmental factors [1]. Within the context of PPPM, it is essential that we obtain a deeper knowledge of the mechanisms that underlie diseases, so as to be able to discern the subtle differences that render each patient unique and consequently offer him more prompt, cost effective interventions that treat or-ideally-completely interrupt the pathway from predisposition to disease [2]. To attain this target, the identification of reliable, clinically relevant biomarkers is of paramount importance. As defined by NIH, a biomarker is a “characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to therapeutic interventions” [3]. Establishing validated biomarkers for disease risk, early and accurate disease diagnosis, staging and response to treatment (pharmacological or not) is one of the main pillars of a highly precise, personalized medicine. Proteomics is a technology-based science which studies the proteins, their post-translational modifications, their interactions, the changes in their levels, which result on account of specific diseases or from various external factors, and has as a goal the detection of novel therapeutic and diagnostic biomarkers [4]. Over the years, proteomics have been increasingly applied in multiple biological materials and in a wide spectrum of diseases. The techniques involved in proteomic analysis have been greatly refined and are now considered the “gold standard” for the measuring of a number of proteins and other molecules such steroid hormones [5]. The field of Endocrinology & Metabolism has greatly benefited from the outcomes of proteomics research, not only in terms of analytical specificity and sensitivity, but also with regards to poorly studied processes that lead to disease and, later on, disease complications.