与雄性相比,雌性通常对疫苗和病原体如流感病毒和SARS-CoV-2表现出优异的免疫应答。为了解释这些差异,我们首先研究了C57BL/6雄性和雌性小鼠的血清免疫球蛋白同种型模式。我们专注于IgG2b,一种有助于病毒控制的同种型,以前已经证明在小鼠雌性中比雄性中升高。IgG2b血清水平的改善,和/或IgG2b与其他非IgM同种型的比率,在以下情况下观察到:(i)将野生型(WT)雌性小鼠与雌激素受体敲除小鼠(IgG2b,在WT小鼠中IgG2b/IgG3、IgG2b/IgG1和IgG2b/IgA均较高),(ii)将未操作的雌性小鼠与卵巢切除的小鼠进行比较(未操作的动物中IgG2b/IgA较高),(iii)雌性小鼠在炎症损伤的背景下补充雌激素(IgG2b和IgG2b/IgG3通过补充雌激素得到改善),和(iv)雄性小鼠补充睾酮,一种可以在体内转化为雌激素的激素(IgG2b,IgG2b/IgG3、IgG2b/IgG1和IgG2b/IgA均通过补充得到改善)。我们接下来检查来自三组先前描述的男性和女性人类血液样品的数据。在每种情况下,有更高的IgG2水平,和/或IgG2与非IgM同种型的比率,与男性相比,女性。性别和性激素在小鼠和人类研究中的影响是微妙的,但频繁,这表明性激素只代表影响同种型模式的一小部分因素。对基因座的检查表明,鼠IgG2b或人IgG2的上调可能是由雌激素受体与雌激素反应元件的结合以及各个Cγ基因上游的胞嘧啶腺嘌呤(CA)重复序列介导的。鉴于鼠IgG2b和人IgG2有助于病毒控制,女性的同种型偏差可能足以改善疫苗接种或感染后的结局.未来关注性激素水平,以及随之而来的免疫球蛋白同种型模式,在临床试验中,鼓励为男性和女性宿主优化疫苗和药物产品。
Females often exhibit superior immune responses compared to males toward vaccines and pathogens such as influenza viruses and SARS-CoV-2. To help explain these differences, we first studied serum immunoglobulin isotype patterns in C57BL/6 male and female mice. We focused on IgG2b, an isotype that lends to virus control and that has been previously shown to be elevated in murine females compared to males. Improvements in
IgG2b serum levels, and/or
IgG2b ratios with other non-IgM isotypes, were observed when: (i) wildtype (WT) female mice were compared to estrogen receptor knockout mice (
IgG2b,
IgG2b/IgG3,
IgG2b/IgG1, and
IgG2b/IgA were all higher in WT mice), (ii) unmanipulated female mice were compared to ovariectomized mice (IgG2b/IgA was higher in unmanipulated animals), (iii) female mice were supplemented with estrogen in the context of an inflammatory insult (
IgG2b and
IgG2b/IgG3 were improved by estrogen supplementation), and (iv) male mice were supplemented with testosterone, a hormone that can convert to estrogen in vivo (IgG2b,
IgG2b/IgG3,
IgG2b/IgG1, and
IgG2b/IgA were all improved by supplementation). We next examined data from three sets of previously described male and female human blood samples. In each case, there were higher IgG2 levels, and/or ratios of IgG2 with non-IgM isotypes, in human females compared to males. The effects of sex and sex hormones in the mouse and human studies were subtle, but frequent, suggesting that sex hormones represent only a fraction of the factors that influence isotype patterns. Examination of the gene loci suggested that upregulation of murine IgG2b or human IgG2 could be mediated by estrogen receptor binding to estrogen response elements and cytosine-adenine (CA) repeats upstream of respective Cγ genes. Given that murine IgG2b and human IgG2 lend to virus control, the isotype biases in females may be sufficient to improve outcomes following vaccination or infection. Future attention to sex hormone levels, and consequent immunoglobulin isotype patterns, in clinical trials are encouraged to support the optimization of vaccine and drug products for male and female hosts.