Sex hormone signaling and regulation of immune function

Hoffmann, Joseph P.; Liu, Jennifer A.; Seddu, Kumba; Klein, Sabra L.

doi:10.1016/j.immuni.2023.10.008

Cited by 63 publications

(26 citation statements)

References 227 publications

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“…We further found changes in the splenic cytokine environment. Prior studies have demonstrated clear sex-based differences in T cell polarization and cytokine production in several infection, allergic, and autoimmune models that were driven by differences in sex hormone levels (87)(88)(89)(90)(91)(92)(93). Production of regulatory T cells was also shown to be enhanced by estrogen, and during pneumococcal pneumonia, female mice were reported to have higher Treg numbers in the lungs compared to male mice (94,95).…”

Section: Discussionmentioning

confidence: 99%

Sex-based difference in immune responses and efficacy of the pneumococcal conjugate vaccine

Tchalla,

Betadpur,

Khalil

et al. 2024

Preprint

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Vaccine-mediated protection and susceptibility to Streptococcus pneumoniae (pneumococcus) infections are influenced by biological sex. The incidence of invasive pneumococcal disease remains higher in males compared to females even after the introduction of the pneumococcal conjugate vaccine (PCV). However, sex-based differences in the immune response to this conjugate vaccine remain unexplored. To investigate those differences, we vaccinated adult male and female mice with PCV and assessed cellular and humoral immune responses. Compared to females, male mice displayed lower levels of T follicular helper cells, germinal center B cells and plasmablasts, which are all required for antibody production following vaccination. This was linked to lower IgG and IgM levels against pneumococci and lower isotype switching to IgG3 in vaccinated males. Additionally, sera of vaccinated male mice had lower efficacy in several anti-pneumococcal functions including neutralization of bacterial binding to pulmonary epithelial cells as well as direct cytotoxicity against S. pneumoniae. Importantly, while the vaccine was highly protective in females, vaccinated males succumbed to infection more readily and were more susceptible to both lung-localized infection and systemic spread following S. pneumoniae challenge. These findings identify sex-based differences in immune responses to PCV that can inform future vaccine strategies.

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Section: Discussionmentioning

confidence: 99%

Sex-based difference in immune responses and efficacy of the pneumococcal conjugate vaccine

Tchalla,

Betadpur,

Khalil

et al. 2024

Preprint

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“…ER signaling plays a crucial role in regulating various aspects of cellular processes, including cell proliferation, growth factors, cytokines (e.g., interferons, IL-6, IL-1, vascular endothelial growth factor (VEGF), amphiregulin, and transforming growth factor (TGF)-beta), receptors and signaling pathways (e.g., NF-kB, signal transducer and activator of transcription (STAT), TGF-beta, and tumor necrosis factor (TNF)), as well as transcription factors and coregulators (e.g., c-Fos, c-Myc, Myb, and JunB). The transcriptional regulation by ER extends to immune cell functions, and significant fluctuations in estrogen concentrations throughout a woman’s life course can lead to alterations in the activation of ER signaling in immune cells [ 14 ]. E2 can bind to both intracellular (genomic) and membrane-bound (nongenomic) estrogen receptors, leading to transcriptional changes in immune cells.…”

Section: Sex Differences In Immunitymentioning

confidence: 99%

“…The immune system elicits different responses to antigens in men and women [ 14 ]. Consistently, there is a substantial difference in the prevalence of autoimmune diseases, as almost 80% of patients are women [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

Immune Cells, Gut Microbiota, and Vaccines: A Gender Perspective

Rio,

Caldarelli,

Chiantore

et al. 2024

Cells

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The development of preventive and therapeutic vaccines has played a crucial role in preventing infections and treating chronic and non-communicable diseases, respectively. For a long time, the influence of sex differences on modifying health and disease has not been addressed in clinical and preclinical studies. The interaction of genetic, epigenetic, and hormonal factors plays a role in the sex-related differences in the epidemiology of diseases, clinical manifestations, and the response to treatment. Moreover, sex is one of the leading factors influencing the gut microbiota composition, which could further explain the different predisposition to diseases in men and women. In the same way, differences between sexes occur also in the immune response to vaccines. This narrative review aims to highlight these differences, focusing on the immune response to vaccines. Comparative data about immune responses, vaccine effectiveness, and side effects are reviewed. Hence, the intricate interplay between sex, immunity, and the gut microbiota will be discussed for its potential role in the response to vaccination. Embracing a sex-oriented perspective in research may improve the efficacy of the immune response and allow the design of tailored vaccine schedules.

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“…Hyperandrogenism is an important pathogenic factor of PCOS, and is closely related to insulin resistance and obesity, which interact with each other to aggravate PCOS 11 . In addition to their effect in reproduction and metabolism, androgens also play an important role in immunomodulation 12,13 . Androgens mediate their function by binding to the androgen receptor (AR), which is widely expressed in multiple immune organs and immune cells including neutrophils and macrophages 14–16 .…”

Section: Introductionmentioning

confidence: 99%

Hyperandrogenic environment regulates the function of ovarian granulosa cells by modulating macrophage polarization in PCOS

Chen,

Hong,

Diao

et al. 2024

American J Rep Immunol

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BackgroundPolycystic ovary syndrome (PCOS) is a common endocrine‐metabolic disorder characterized by oligo‐anovulation, hyperandrogenism, and polycystic ovaries, with hyperandrogenism being the most prominent feature of PCOS patients. However, whether excessive androgens also exist in the ovarian microenvironment of patients with PCOS, and their modulatory role on ovarian immune homeostasis and ovarian function, is not clear.MethodsFollicular fluid samples from patients participating in their first in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) treatment were collected. Androgen concentration of follicular fluid was assayed by chemiluminescence, and the macrophage M1:M2 ratio was detected by flow cytometry. In an in vitro model, we examined the regulatory effects of different concentrations of androgen on macrophage differentiation and glucose metabolism levels using qRT‐PCR, Simple Western and multi‐factor flow cytometry assay. In a co‐culture model, we assessed the effect of a hyperandrogenic environment in the presence or absence of macrophages on the function of granulosa cells using qRT‐PCR, Simple Western, EdU assay, cell cycle assay, and multi‐factor flow cytometry assay.ResultsThe results showed that a significantly higher androgen level and M1:M2 ratio in the follicular fluid of PCOS patients with hyperandrogenism. The hyperandrogenic environment promoted the expression of pro‐inflammatory and glycolysis‐related molecules and inhibited the expression of anti‐inflammatory and oxidative phosphorylation‐related molecules in macrophages. In the presence of macrophages, a hyperandrogenic environment significantly downregulated the function of granulosa cells.ConclusionThere is a hyperandrogenic microenvironment in the ovary of PCOS patients with hyperandrogenism. Hyperandrogenic microenvironment can promote the activation of ovarian macrophages to M1, which may be associated with the reprogramming of macrophage glucose metabolism. The increased secretion of pro‐inflammatory cytokines by macrophages in the hyperandrogenic microenvironment would impair the normal function of granulosa cells and interfere with normal ovarian follicle growth and development.

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Sex hormone signaling and regulation of immune function

Cited by 63 publications

References 227 publications

Sex-based difference in immune responses and efficacy of the pneumococcal conjugate vaccine

Sex-based difference in immune responses and efficacy of the pneumococcal conjugate vaccine

Immune Cells, Gut Microbiota, and Vaccines: A Gender Perspective

Hyperandrogenic environment regulates the function of ovarian granulosa cells by modulating macrophage polarization in PCOS

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