背景:男性与男性的差异女性免疫反应有据可查,具有重要的临床意义.虽然性激素的免疫调节作用已经确立,性染色体补体的贡献(XXvs.XY)和肠道微生物组多样性对免疫性二态的影响最近才被人们所重视。在这里,我们研究了性染色体补体和肠道微生物群对体液免疫激活的个体和协作影响。
方法:用热灭活的肺炎链球菌(HKSP)免疫雄性和雌性四种核心基因型(FCG)小鼠。评估了体液免疫反应,和X连锁免疫相关基因的表达进行评估,以解释鉴定的XX依赖性表型。Kdm6a的功能作用,感兴趣的X连锁表观遗传调控基因,使用促分裂原刺激B细胞进行离体评估。还通过在HKSP免疫之前抗生素消耗肠道微生物群来评估肠道微生物群对性染色体依赖性B细胞活化的其他影响。用产生短链脂肪酸(SCFA)的细菌重建耗尽的微生物组测试了SCFA对XX依赖性免疫激活的影响。
结果:XX小鼠表现出比XY小鼠更高的分泌HKSP特异性IgM的B细胞和浆细胞频率,不管性腺性。尽管Kdm6a在XXB细胞中被鉴定为过表达的X连锁基因,抑制其酶活性不会以性染色体依赖性方式影响促分裂原诱导的浆细胞分化或抗体产生。XX的增强体液反应与XY免疫的FCG小鼠在微生物组耗尽后被消除,表明微生物组有助于确定的XX依赖性免疫增强。用选择产生SCFA的细菌重建微生物群耗尽的小鼠可增强XX中的粪便SCFA浓度并增加体液反应,但不是XY,FCG小鼠。然而,在离体研究中,单独暴露于SCFA丙酸盐并不能增强促有丝分裂的B细胞刺激.
结论:FCG小鼠已用于评估性激素和性染色体补体对各种性二态性状的影响。目前的研究表明,肠道微生物组以XX依赖的方式影响体液反应,这表明,在解释旨在描述促进性二态性机制的数据时,应考虑肠道细菌和其他性别特异性因素的协同影响。
男性和女性的免疫系统对感染的反应能力不同。虽然男性往往更容易受到感染,并产生较少量的抗体来响应疫苗接种,女性更容易发生自身免疫性疾病和炎症性疾病。这些差异的主要原因包括性激素,性染色体补体(女性XX与XY为男性),和不同的肠道微生物群落能够调节免疫激活。虽然每个因素都是单独研究的,这项研究强调了这些因素协同影响免疫激活的潜力.这里,拥有XXvs.已证明XY性染色体补体可增强对热杀死的肺炎链球菌疫苗接种的抗体反应。在试图确定这种免疫增强的根本原因时,肠道微生物组被确定发挥关键作用。在没有完整的肠道微生物组的情况下,XX免疫激活降低至与具有XY性染色体补体的小鼠相似的水平。用选择的产生SCFA的细菌物种替换耗尽的肠道微生物组可提高抗生素治疗小鼠的SCFA水平,并挽救XX依赖性免疫增强,提示SCFA介导的贡献。需要进一步的研究来确定这些选择的细菌如何以性染色体补体依赖性方式影响免疫激活。我们的发现强调,在试图了解免疫性偏见时,需要考虑个体性别特异性因素的协同作用。因为更好地了解这些相互作用将可能为改进针对两性的疗法和疫苗铺平道路。
BACKGROUND: Differences in male vs. female immune responses are well-documented and have significant clinical implications. While the immunomodulatory effects of sex hormones are well established, the contributions of sex chromosome complement (XX vs. XY) and gut microbiome diversity on immune sexual dimorphisms have only recently become appreciated. Here we investigate the individual and collaborative influences of sex chromosome complements and gut microbiota on humoral immune activation.
METHODS: Male and female Four Core Genotype (FCG) mice were immunized with heat-killed Streptococcus pneumoniae (HKSP). Humoral immune responses were assessed, and X-linked immune-related gene expression was evaluated to explain the identified XX-dependent phenotype. The functional role of Kdm6a, an X-linked epigenetic regulatory gene of interest, was evaluated ex vivo using mitogen stimulation of B cells. Additional influences of the gut microbiome on sex chromosome-dependent B cell activation was also evaluated by antibiotically depleting gut microbiota prior to HKSP immunization. Reconstitution of the depleted microbiome with short-chain fatty acid (SCFA)-producing bacteria tested the impact of SCFAs on XX-dependent immune activation.
RESULTS: XX mice exhibited higher HKSP-specific IgM-secreting B cells and plasma cell frequencies than XY mice, regardless of gonadal sex. Although Kdm6a was identified as an X-linked gene overexpressed in XX B cells, inhibition of its enzymatic activity did not affect mitogen-induced plasma cell differentiation or antibody production in a sex chromosome-dependent manner ex vivo. Enhanced humoral responses in XX vs. XY immunized FCG mice were eliminated after microbiome depletion, indicating that the microbiome contributes to the identified XX-dependent immune enhancement. Reconstituting microbiota-depleted mice with select SCFA-producing bacteria enhanced fecal SCFA concentrations and increased humoral responses in XX, but not XY, FCG mice. However, exposure to the SCFA propionate alone did not enhance mitogenic B cell stimulation in ex vivo studies.
CONCLUSIONS: FCG mice have been used to assess sex hormone and sex chromosome complement influences on various sexually dimorphic traits. The current study indicates that the gut microbiome impacts humoral responses in an XX-dependent manner, suggesting that the collaborative influence of gut bacteria and other sex-specific factors should be considered when interpreting data aimed at delineating the mechanisms that promote sexual dimorphism.
Male and female immune systems differ in their ability to respond to infectious challenge. While males tend to be more susceptible to infection and produce lower amounts of antibodies in response to vaccination, females are more prone to develop autoimmune and inflammatory diseases. Key contributors to these differences include sex hormones, sex chromosome complement (XX in females vs. XY in males), and distinct gut microbial communities capable of regulating immune activation. While each factor has been studied individually, this research underscores the potential for these factors to collaboratively impact immune activation. Here, possession of an XX vs. XY sex chromosome complement was demonstrated to enhance antibody responses to heat-killed Streptococcus pneumoniae vaccination. While attempting to determine the underlying cause of this immune enhancement, the gut microbiome was identified to play a critical role. In the absence of an intact gut microbiome, XX immune activation was reduced to levels similar to those seen in XY sex chromosome complement-possessing mice. Replacement of the depleted gut microbiomes with select SCFA-producing bacterial species enhanced SCFA levels in antibiotic-treated mice and rescued the XX-dependent immune enhancement, suggesting a SCFA-mediated contribution. Further studies are needed to determine exactly how these select bacteria impact immune activation in a sex chromosome complement-dependent manner. Our findings highlight the need to consider the collaborative effects of individual sex-specific factors when attempting to understand immune sex biases, as a better understanding of these interactions will likely pave the way for improving therapeutics and vaccines tailored to both sexes.