Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
Viruses. 2023 Feb 9;15(2):482. doi: 10.3390/v15020482.
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.
女性对疫苗和病原体（如流感病毒和 SARS-CoV-2）的免疫反应通常优于男性。为了帮助解释这些差异，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，这是一种有助于控制病毒的同种型，并且已经表明在雌性小鼠中比雄性小鼠中升高。当：(i) 与雌激素受体敲除小鼠（IgG2b、IgG2b/IgG3、IgG2b/IgG1 和 IgG2b/IgA 在 WT 小鼠中均较高）相比，野生型（WT）雌性小鼠；(ii) 未经处理的雌性小鼠与卵巢切除小鼠相比（未经处理的动物 IgG2b/IgA 较高）；(iii) 在炎症损伤的情况下用雌激素补充雌性小鼠（IgG2b 和 IgG2b/IgG3 因雌激素补充而改善）；(iv) 用可以在体内转化为雌激素的激素睾酮补充雄性小鼠（IgG2b、IgG2b/IgG3、IgG2b/IgG1 和 IgG2b/IgA 均因补充而改善）时，观察到 IgG2b 血清水平提高，和/或 IgG2b 与非 IgM 同种型的比值提高。接下来，我们检查了以前描述的三组男性和女性人类血液样本的数据。在每种情况下，与男性相比，女性的 IgG2 水平更高，和/或 IgG2 与非 IgM 同种型的比值更高。在小鼠和人类研究中，性别的影响和性激素是微妙但频繁的，这表明性激素仅代表影响同种型模式的部分因素。对基因座的检查表明，小鼠 IgG2b 或人类 IgG2 的上调可能由雌激素受体与各自 Cγ 基因上游的雌激素反应元件和胞嘧啶-腺嘌呤（CA）重复结合介导。鉴于小鼠 IgG2b 和人类 IgG2 有助于控制病毒，女性的同种型偏向可能足以改善接种或感染后的结果。鼓励在临床试验中关注性激素水平和随之而来的免疫球蛋白同种型模式，以支持为男性和女性宿主优化疫苗和药物产品。
