Spolarics Zoltan, Peña Geber, Qin Yong, Donnelly Robert J, Livingston David H
Department of Surgery, Rutgers-New Jersey Medical School, Newark, NJ, United States.
Department of Pathology and Laboratory Medicine, Rutgers-New Jersey Medical School, Newark, NJ, United States.
Front Immunol. 2017 Nov 13;8:1455. doi: 10.3389/fimmu.2017.01455. eCollection 2017.
Females have a longer lifespan and better general health than males. Considerable number of studies also demonstrated that, after trauma and sepsis, females present better outcomes as compared to males indicating sex-related differences in the innate immune response. The current notion is that differences in the immuno-modulatory effects of sex hormones are the underlying causative mechanism. However, the field remains controversial and the exclusive role of sex hormones has been challenged. Here, we propose that polymorphic X-linked immune competent genes, which are abundant in the population are important players in sex-based immuno-modulation and play a key role in causing sex-related outcome differences following trauma or sepsis. We describe the differences in X chromosome (ChrX) regulation between males and females and its consequences in the context of common X-linked polymorphisms at the individual as well as population level. We also discuss the potential pathophysiological and immune-modulatory aspects of ChrX cellular mosaicism, which is unique to females and how this may contribute to sex-biased immune-modulation. The potential confounding effects of ChrX skewing of cell progenitors at the bone marrow is also presented together with aspects of acute trauma-induced ChrX skewing at the periphery. In support of the hypothesis, novel observations indicating ChrX skewing in a female trauma cohort as well as case studies depicting the temporal relationship between trauma-induced cellular skewing and the clinical course are also described. Finally, we list and discuss a selected set of polymorphic X-linked genes, which are frequent in the population and have key regulatory or metabolic functions in the innate immune response and, therefore, are primary candidates for mediating sex-biased immune responses. We conclude that sex-related differences in a variety of disease processes including the innate inflammatory response to injury and infection may be related to the abundance of X-linked polymorphic immune-competent genes, differences in ChrX regulation, and inheritance patterns between the sexes and the presence of X-linked cellular mosaicism, which is unique to females.
女性比男性寿命更长，总体健康状况更好。大量研究还表明，在创伤和脓毒症后，与男性相比，女性的预后更好，这表明先天免疫反应存在性别差异。目前的观点认为，性激素免疫调节作用的差异是潜在的致病机制。然而，该领域仍存在争议，性激素的唯一作用受到了挑战。在此，我们提出，人群中丰富的多态性X连锁免疫相关基因是基于性别的免疫调节的重要参与者，并且在创伤或脓毒症后导致性别相关的预后差异中起关键作用。我们描述了男性和女性之间X染色体（ChrX）调控的差异及其在个体和群体水平上常见X连锁多态性背景下的后果。我们还讨论了ChrX细胞镶嵌现象（这是女性特有的）的潜在病理生理和免疫调节方面，以及这如何可能导致性别偏向的免疫调节。还介绍了骨髓中细胞祖细胞的ChrX偏斜的潜在混杂效应以及外周急性创伤诱导的ChrX偏斜的情况。为支持这一假设，还描述了表明女性创伤队列中ChrX偏斜的新观察结果以及描述创伤诱导的细胞偏斜与临床病程之间时间关系的病例研究。最后，我们列出并讨论了一组选定的多态性X连锁基因，这些基因在人群中很常见，并且在先天免疫反应中具有关键的调节或代谢功能，因此是介导性别偏向免疫反应的主要候选基因。我们得出结论，包括对损伤和感染的先天炎症反应在内的各种疾病过程中的性别相关差异可能与X连锁多态性免疫相关基因的丰富性、ChrX调控的差异、两性之间的遗传模式以及女性特有的X连锁细胞镶嵌现象的存在有关。
