The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
University of Groningen, University Medical Center Groningen, 9713 EX Groningen, Netherlands; Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboudumc, 6525 GA Nijmegen, Netherlands.
Curr Opin Immunol. 2018 Oct;54:50-58. doi: 10.1016/j.coi.2018.05.012. Epub 2018 Jun 15.
Cytokines are important cell-signaling molecules that activate and modulate immune responses. Major factors influencing cytokine variation in healthy individuals are host genetics, non-heritable factors and the microbiome. Genetic variation accounts for a significant part of heterogeneity in cytokine production by peripheral blood mononuclear cells. Variation in cytokines such as IL-6 and IL-6Ra is strongly influenced by heritability, suggesting an evolutionarily pressure for their genetic regulation that potentially contributes to differences in immune responsiveness between human populations. Non-heritable factors, including age, body weight and environmental variables such as seasonality, drive variation in baseline cytokine levels. Age further affects pathogen-induced lymphocyte-derived cytokine responses, whereas seasonality affects monocyte-derived cytokine production in response to influenza virus, Coxiella burnetti or Cryptococcus neoformans. Another influential factor that shapes the immune system is the human microbiome. Microbes and microbial products (e.g. short-chain fatty acids and tryptophan metabolites) possess strong immunomodulatory effects, induce regulatory T cells and lead to the diversification of B cells and the production of specific antibodies. In particular, differential TNFα and IFNγ production is associated with the gut microbiome. Understanding causes of variation in the healthy human immune system can reveal factors that lead to aberrant cytokine production in immune-related disorders.
细胞因子是重要的细胞信号分子，能激活和调节免疫反应。影响健康个体细胞因子变化的主要因素包括宿主遗传学、非遗传性因素和微生物组。遗传变异解释了外周血单个核细胞产生细胞因子异质性的很大一部分原因。细胞因子（如 IL-6 和 IL-6Ra）的变化强烈受遗传因素影响，这表明它们的遗传调控受到进化压力的影响，可能导致不同人群之间免疫反应的差异。非遗传性因素，包括年龄、体重和季节性等环境变量，会导致细胞因子基线水平的变化。年龄进一步影响病原体诱导的淋巴细胞衍生细胞因子反应，而季节性会影响流感病毒、柯克斯体或新型隐球菌感染时单核细胞衍生细胞因子的产生。影响免疫系统的另一个重要因素是人类微生物组。微生物及其产物（如短链脂肪酸和色氨酸代谢物）具有很强的免疫调节作用，能诱导调节性 T 细胞，并导致 B 细胞的多样化和特定抗体的产生。特别是，不同的 TNFα 和 IFNγ 的产生与肠道微生物组有关。了解健康人体免疫系统变化的原因可以揭示导致免疫相关疾病中细胞因子异常产生的因素。
