Estradiol Mediates Greater Germinal Center Responses to Influenza Vaccination in Female than Male Mice.
Estradiol Mediates Greater Germinal Center Responses to Influenza Vaccination in Female than Male Mice.
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雌二醇介导雌性小鼠比雄性小鼠生发中心对流感疫苗的更大反应。
DOI：
10.1101/2023.11.27.568847
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Klein,SabraL
中科院分区：
文献类型：
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作者：
Dhakal,Santosh;Park,Han-Sol;Seddu,Kumba;Lee,John;Creisher,PatrickS;Davis,KimberlyM;Hernandez,IsabellaR;Maul,RobertW;Klein,SabraL
育龄成年女性对灭活流感疫苗 (IIV) 的抗体反应比男性更强。分析了性别、年龄和性类固醇浓度如何影响 B 细胞以及 IIV 诱导的免疫和疫苗接种后 4 个月内保护 (mpv) 的持久性。与成年男性相比，接种疫苗的成年女性在淋巴组织中具有更高的生发中心 B 细胞和浆母细胞频率，更高的中和抗体反应 1-4 mpv，并且对活 H1N1 攻击有更好的保护。与成年小鼠相比，老年小鼠，无论性别如何，B 细胞频率降低，抗体反应持久性较差，攻击后的保护能力较差，这与老年雌性雌二醇的减少有关。为了证实更大的 IIV 诱导的免疫力是由性激素引起的，使用了四只核心基因型 (FCG) 小鼠，其中睾丸决定基因 Sry 从 Y 染色体 (ChrY) 中删除，并转移到 Chr3，以将性腺性别 (即卵巢或睾丸) 与性染色体补体 (即 XX 或 XY 补体) 分开。与性腺 FCG 雄性小鼠（XYM 和 XXM）相比，接种疫苗的性腺雌性 FCG 小鼠（XXF 和 XYF）在活 H1N1 攻击后具有更多数量的 B 细胞、更高的抗病毒抗体滴度和降低的肺部病毒滴度。为了确定较低的雌二醇浓度会导致免疫力下降，成年和老年女性在 IIV 之前接受了安慰剂或雌二醇替代治疗。雌二醇替代疗法显着增加了 IIV 诱导的抗体反应，并降低了老年女性 H1N1 流感攻击后的发病率。这些数据强调，雌二醇是一种可靶向机制，可在成年女性接种疫苗后介导更大的体液免疫。 重要性 育龄女性比男性对流感疫苗产生更强的抗体反应。我们假设女性偏好的免疫力和针对流感的保护是由 B 细胞中的雌二醇信号介导的。使用从高龄小鼠到将性类固醇与性染色体补体分离的转基因小鼠等多种小鼠模型，雌二醇浓度较高的小鼠在淋巴组织中始终具有更多数量的产生抗体的 B 细胞，抗病毒抗体滴度更高，并且对活流感病毒的攻击具有更强的保护作用。用雌二醇治疗老年雌性小鼠可增强疫苗诱导的免疫力和预防疾病的能力，这表明 B 细胞中的雌二醇信号传导对于改善雌性小鼠的疫苗效果至关重要。
Adult females of reproductive age develop greater antibody responses to inactivated influenza vaccines (IIV) than males. How sex, age, and sex steroid concentrations impact B cells and durability of IIV-induced immunity and protection over 4 months post-vaccination (mpv) was analyzed. Vaccinated adult females had greater germinal center B cell and plasmablast frequencies in lymphoid tissues, higher neutralizing antibody responses 1–4 mpv, and better protection against live H1N1 challenge than adult males. Aged mice, regardless of sex, had reduced B cell frequencies, less durable antibody responses, and inferior protection after challenge than adult mice, which correlated with diminished estradiol among aged females. To confirm that greater IIV-induced immunity was caused by sex hormones, four core genotype (FCG) mice were used, in which the testes-determining gene,Sry, was deleted from chromosome Y (ChrY) and transferred to Chr3 to separate gonadal sex (i.e., ovaries or testes) from sex chromosome complement (i.e., XX or XY complement). Vaccinated, gonadal female FCG mice (XXF and XYF) had greater numbers of B cells, higher antiviral antibody titers, and reduced pulmonary virus titers following live H1N1 challenge than gonadal FCG males (XYM and XXM). To establish that lower estradiol concentrations cause diminished immunity, adult and aged females received either a placebo or estradiol replacement therapy prior to IIV. Estradiol replacement significantly increased IIV-induced antibody responses and reduced morbidity after the H1N1 challenge among aged females. These data highlight that estradiol is a targetable mechanism mediating greater humoral immunity following vaccination among adult females.IMPORTANCEFemales of reproductive ages develop greater antibody responses to influenza vaccines than males. We hypothesized that female-biased immunity and protection against influenza were mediated by estradiol signaling in B cells. Using diverse mouse models ranging from advanced-age mice to transgenic mice that separate sex steroids from sex chromosome complement, those mice with greater concentrations of estradiol consistently had greater numbers of antibody-producing B cells in lymphoid tissue, higher antiviral antibody titers, and greater protection against live influenza virus challenge. Treatment of aged female mice with estradiol enhanced vaccine-induced immunity and protection against disease, suggesting that estradiol signaling in B cells is critical for improved vaccine outcomes in females.