性别肯定睾酮治疗期间的免疫系统适应

Immune system adaptation during gender-affirming testosterone treatment

——原载《自然》2024年第633卷第8028期——

<Nature> Volume 633, issue 8028, 2024

【摘要】男性和女性的感染性、炎症性和自身免疫性疾病表现不同。未感染 SARS-CoV-2的男性死亡风险增加，而女性患长期COVID的风险增加，这与其他感染的观察结果相似。与大多数自身免疫性疾病一样，女性对疫苗的反应更强烈，不良反应也更频繁。免疫性别差异源于遗传、激素和行为因素，但它们的相对重要性仅被部分理解。在出生时被指定为女性并接受性别肯定睾酮治疗（跨性别男性）的个体中，激素浓度发生显著变化，但免疫学后果尚不清楚。在这里，我们对23名跨性别男性进行了纵向系统级分析，发现睾酮调节I型干扰素和肿瘤坏死因子之间的交叉调节轴。这是由浆细胞样树突状细胞和单核细胞中I型干扰素反应的功能性衰减介导的。相反，睾酮增强单核细胞反应，导致肿瘤坏死因子、白细胞介素6和白细胞介素15产生增加，下游激活核因子κB调节基因，增强干扰素γ反应，主要在自然杀伤细胞中。跨性别男性的这些发现得到了公共数据集中性别差异反应的证实，并说明了性激素对人体免疫的动态调节，这对接受激素治疗的个体的健康和我们对顺性别个体性别差异免疫反应的理解具有重要意义。

[Abstract] Infectious, inflammatory and autoimmune conditions present differently in males and females. SARS-CoV-2 infection in naive males is associated with increased risk of death, whereas females are at increased risk of long COVID, similar to observations in other infections. Females respond more strongly to vaccines, and adverse reactions are more frequent, like most autoimmune diseases. Immunological sex differences stem from genetic, hormonal and behavioural factors but their relative importance is only partially understood. In individuals assigned female sex at birth and undergoing gender-affirming testosterone therapy (trans men), hormone concentrations change markedly but the immunological consequences are poorly understood. Here we performed longitudinal systems-level analyses in 23 trans men and found that testosterone modulates a cross-regulated axis between type-I interferon and tumour necrosis factor. This is mediated by functional attenuation of type-I interferon responses in both plasmacytoid dendritic cells and monocytes. Conversely, testosterone potentiates monocyte responses leading to increased tumour necrosis factor, interleukin-6 and interleukin-15 production and downstream activation of nuclear factor kappa B-regulated genes and potentiation of interferon-γ responses, primarily in natural killer cells. These findings in trans men are corroborated by sex-divergent responses in public datasets and illustrate the dynamic regulation of human immunity by sex hormones, with implications for the health of individuals undergoing hormone therapy and our understanding of sex-divergent immune responses in cisgender individuals.

论文原文：Tadepally Lakshmikanth, Camila Consiglio, Fabian Sardh, et al. (2024). Immune system adaptation during gender-affirming testosterone treatment. Nature, volume 633, issue 8028, pages155–164. Published: 04 September 2024

https://doi.org/10.1038/s41586-024-07789-z

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