bims-simsho 2025-07-13 papers

Issue of 2025–07–13
seven papers selected by
Chun-Chi Chang, Lunds universitet

Front Immunol. 2025 ;16 1570565

Toward understanding sexual immune dimorphism in humans.

Sexual immune dimorphism refers to the distinct differences in immune responses between males and females, influenced by genetic, hormonal, developmental, social, and behavioral factors. These differences, shaped by evolutionary pressures, manifest in varied susceptibilities to infectious and autoimmune diseases, as well as differences in vaccine responses and disease outcomes. Females generally exhibit stronger immune responses than males, which confer protection against infections but also lead to a higher prevalence of autoimmune diseases. Hormones such as estrogen, progesterone, and testosterone play pivotal roles in modulating these responses. Estrogen enhances immune activation, promoting inflammation and increasing autoimmune susceptibility, while testosterone exerts primarily immunosuppressive effects, reducing autoimmune risks but heightening infection susceptibility. Genetic factors, including X-linked immune-related genes and cellular mosaicism, further contribute to the observed dimorphism, as do epigenetic mechanisms that modulate immune gene expression. From an evolutionary perspective, life history theory explains these differences as the result of trade-offs between reproductive strategies and immune function, with females prioritizing robust immunity for offspring survival and males balancing immune investment with reproductive fitness. Behavioral factors, such as pathogen avoidance and risk-taking, add complexity to the dimorphism. This review adopts a narrative format intentionally designed to provide a cohesive conceptual synthesis of major mechanisms underlying sexual immune dimorphism. While acknowledging the complexity and breadth of this topic, we explicitly focus on integrating hormonal, genetic/epigenetic, behavioral, and evolutionary contexts. By examining the interplay of these factors, the review provides a foundation for understanding the biological underpinnings and evolutionary context of immune differences between sexes.

Keywords: X-chromosome inactivation; estrogen; immune-endocrine interactions; life history theory; pathogen avoidance; regulation of immunity; sexual immune dimorphism; testosterone

DOI: https://doi.org/10.3389/fimmu.2025.1570565

Adv Exp Med Biol. 2025 ;1476 339-379

Innate Immune Mechanisms in Normal and Adverse Pregnancy.

Shanmuga Priyaa Madhukaran, Hadida Yasmin, Uday Kishore.

The innate immune system's recognition of microorganisms through pattern recognition receptors (PRRs) is a fundamental aspect of host defense and microbial symbiosis. During pregnancy, this system is finely tuned to accommodate the fetal allograft while still protecting against infections. Dysregulation in the recognition and response to commensal microorganisms can lead to pathological conditions, which may have implications for both maternal and fetal health. PRRs play a critical role in maintaining a balanced immune response, which is essential during pregnancy to prevent excessive inflammation that could affect pregnancy outcomes. They are involved in the regulation of immune cell proliferation and the integrity of mucosal barriers, which are vital for the protection of the maternal-fetal interface. The signaling pathways of PRRs are also key in the initiation and modulation of inflammation in response to microbial invasion. Changes in PRR function, as observed in certain animal models, indicate that the outcome of immune responses can be significantly altered by the specific signaling pathways activated in immune cells, and by the nature of the microbial environment. This is particularly relevant in pregnancy, where an altered PRR response may influence the risk of developing inflammatory conditions that could impact gestation and labor. In light of these considerations, understanding the role of PRR signaling in pregnancy is crucial for elucidating the mechanisms of maternal immune tolerance and the maintenance of a healthy pregnancy, as well as for identifying potential therapeutic targets for pregnancy-related complications arising from immune system dysregulation.

Keywords: Female reproductive tract; Immune cells; Infertility; Macrophages; Natural killer cells; Neutrophils; Pattern recognition receptors; Pregnancy; Pregnancy loss; Preterm birth; T cells

DOI: https://doi.org/10.1007/978-3-031-85340-1_14

Sci Rep. 2025 Jul 10. 15(1): 24901

Interplay of polymorphisms in sex hormone receptors and facial sexual differentiation in shaping prosocial behavior.

Claudia Rodriguez-Ruiz, Denisa Cristina Lupu, Ana Belen Fernandez-Martinez, Miguel Pita, Enrique Turiegano.

Numerous studies have examined how morphological features showing sex differences relate to prosocial behaviors, often yielding contradictory results. However, these studies have never simultaneously considered the affinity of sex hormone receptors alongside variables such as sex-related facial morphology. In this study, we analyze their combined effect on behavior in three economic games: the prisoner's dilemma, the dictator game, and the ultimatum game, as well as participants' considerations regarding these games. Our results indicate that facial morphology and genetic polymorphisms in sex hormone receptors associated with hormone-binding affinity have an effect on prosocial behavior. These effects are often significant in women but not in men. When polymorphisms are included in the models, facial shape difference emerges as a relevant variable. Regarding hormone receptors, polymorphisms in the androgen receptor and β estrogen receptor genes, but not in the α estrogen receptor, show behavioral effects. Short androgen receptor alleles are associated with making larger offers and expecting less generosity. In women, greater facial differentiation shows similar effects, while larger β estrogen receptor alleles are linked to requiring higher offers. Overall, our findings point to the value of jointly considering receptor affinity and proxies for hormone exposure when exploring their relationship with prosocial behavior.

Keywords: Androgen receptor; Economic games; Estrogen receptors; Face shape; Prosocial behavior

DOI: https://doi.org/10.1038/s41598-025-10817-1

Front Immunol. 2025 ;16 1606115

Sex-based immunological differences in multisystem inflammatory syndrome in children: potential role of TR3-56 cells for pathogenesis, diagnosis, and therapy.

Flavia Carriero, Monica Gelzo, Valentina Rubino, Giulia Scalia, Alice Castaldo, Vincenzo Tipo, Antonietta Giannattasio, Carolina D'Anna, Giuseppina Ruggiero, Giuseppe Castaldo, Giuseppe Terrazzano.

Multisystem Inflammatory Syndrome in Children (MIS-C) is characterized by immune dysregulation, exhibiting clinical and immunological features reminiscent of autoimmune processes, although its underlying mechanisms remain incompletely understood. This study examines immune system alterations in MIS-C patients, focusing on TR3-56 lymphocytes, a novel population of regulatory T cells. Our findings reveal a positive correlation between circulating TR3-56 cells and regulatory T cells, suggesting a potential immunoregulatory role in MIS-C pathogenesis. Furthermore, we identified significant sex-based differences in immune responses. Male patients exhibit higher percentages of TR3-56 lymphocytes and increased expression of T cell activation markers, which correlate with greater disease severity. Conversely, female patients display immune profiles characterized by stronger immune T cell memory and regulatory responses, potentially helping to modulate inflammation. These findings highlight the relevance of considering sex-based differences in immune responses to MIS-C and suggest that TR3-56 lymphocytes may serve as novel biomarkers and potentially as therapeutic targets. Our study enhances the understanding of immune dysregulation in MIS-C and underscores the need for sex-specific therapeutic strategies to improve patient outcomes.

Keywords: MIS-C; TR3-56 cells; Treg; biomarkers; immune regulation; sex-based differences

DOI: https://doi.org/10.3389/fimmu.2025.1606115

Front Microbiol. 2025 ;16 1565360

The composition and predictive function of the fecal microbiota in female donkeys across different reproductive cycles.

Jingya Xing, Mingquan Jia, Guoliang Zhang, Lanjie Li, Shuai Liu, Guangyu Li, Guiqin Liu.

The microorganisms residing in the gastrointestinal tract of monogastric herbivores play a vital role in nutrient absorption and maintaining the host's health. However, the quantitative and functional establishment of these microorganisms in female donkeys across different reproductive cycles has not yet been examined. Knowledge regarding the composition and function of gut microbiota in female donkeys during different reproductive cycles remains limited. By applying high-throughput sequencing technology and functional prediction applied to fecal samples from female donkeys across different reproductive cycles, we characterized their gut microbial composition and predicted their functional profiles. The fecal microbiota diversity in female donkeys showed no significant differences across different reproductive cycles through alpha diversity. However, the relative abundance of Firmicutes was higher during lactation, whereas Bacteroidetes were significantly higher during pregnancy. Principal coordinate analysis (PCoA) revealed the gut microbiota composition of pregnant female donkeys differed significantly from that in lactating and non-pregnant female donkeys. Bacteroidetes and Alloprevotella dominated during pregnancy in donkeys, while Firmicutes and unidentified Clostridiales were more prevalent during lactation. For functional prediction, there were significant differences in the relative abundance of pathways in the feces of female donkeys across different reproductive cycles, such as immune system processes, metabolism, glycan biosynthesis and metabolism, environmental adaptation and cell motility (p < 0.05 or p < 0.01). By correlating metabolic functions with microbial phyla, we suggest that metabolic and immune functions associated with the gut microbiota in lactating donkeys may be reduced compared to pregnant donkeys. Principal component analysis (PCA) revealed that the functional KEGG Orthologs (KOs) in the fecal microbiota of pregnant donkeys were distinctly separated from the lactation and non-pregnant female donkeys. Microbial community composition and structure exhibit distinct characteristics across different reproductive cycle, which are closely related to the functions of the microbiome. Our findings provide a foundation for understanding the compositional and functional differences in the microbial communities of mares' feces across different reproductive cycles, offering valuable insights for the precise feeding of mares throughout different reproductive cycles.

Keywords: different reproductive cycles; fecal microbiota; female donkey; functional prediction; microbial communities

DOI: https://doi.org/10.3389/fmicb.2025.1565360

Commun Biol. 2025 Jul 05. 8(1): 1008

TLR2 and TLR4 bridge physiological and pathological inflammation in the reproductive system.

Alireza Mansouri, Ihshan Akthar, Akio Miyamoto.

Toll-like receptors (TLRs), particularly TLR2 and TLR4, are critical components of the innate immune system that play significant roles in reproductive biology beyond their well-established functions in immune defense. These receptors recognize distinct pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), triggering signaling cascades that impact diverse reproductive processes. TLR2-induced physiological inflammation, characterized by transient and precisely controlled inflammatory responses, is essential for facilitating sperm-triggered uterine clearance and promoting embryo implantation, thus maintaining reproductive homeostasis. This homeostasis represents a dynamic equilibrium of immune, endocrine, and cellular interactions essential for successful reproduction. Conversely, pathological inflammation, often driven by TLR4, can result in severe tissue damage, impairing fertility and pregnancy outcomes. This review highlights the shared and distinct signaling pathways of TLR2 and TLR4, their interplay mediated by co-receptors (TLR1 and TLR6) and regulatory molecules such as SOCS-1 and A20, and the implications of their dimerization. Understanding how physiological and pathological inflammation overlap and influence reproductive processes is critical for advancing fertility treatments. Targeting these pathways presents a promising therapeutic approach to address inflammation-related infertility and improve reproductive health.

DOI: https://doi.org/10.1038/s42003-025-08424-x

Cell Host Microbe. 2025 Jul 09. pii: S1931-3128(25)00233-1. [Epub ahead of print]33(7): 1036-1038

Bugged before birth?: How maternal microbes reprogram offspring immunity.

Madison S Strine, Liza Konnikova.

Early-life microbial exposures can have long-lasting health impacts. In a recent Cell paper, Stevens et al. show that maternal antibiotic treatment induces dysbiosis and impairs offspring immunity to influenza. CD8+ T cell dysfunction could be reversed with a Bifidobacterium metabolite, supporting a gut-lung immune axis that begins in utero.

DOI: https://doi.org/10.1016/j.chom.2025.06.003