Sexual dimorphism refers to differences between biological sexes that extend beyond sexual characteristics. In humans, sexual dimorphism in the immune response has been well demonstrated, with ...females exhibiting lower infection rates than males for a variety of bacterial, viral, and parasitic pathogens. There is also a substantially increased incidence of autoimmune disease in females compared to males. Together, these trends indicate that females have a heightened immune reactogenicity to both self and non-self-molecular patterns. However, the molecular mechanisms driving the sexually dimorphic immune response are not fully understood. The female sex hormones estrogen and progesterone, as well as the male androgens, such as testosterone, elicit direct effects on the function and inflammatory capacity of immune cells. Several studies have identified a sex-specific transcriptome and methylome, independent of the well-described phenomenon of X-chromosome inactivation, suggesting that sexual dimorphism also occurs at the epigenetic level. Moreover, distinct alterations to the transcriptome and epigenetic landscape occur in synchrony with periods of hormonal change, such as puberty, pregnancy, menopause, and exogenous hormone therapy. These changes are also mirrored by changes in immune cell function. This review will outline the evidence for sex hormones and pregnancy-associated hormones as drivers of epigenetic change, and how this may contribute to the sexual dimorphism. Determining the effects of sex hormones on innate immune function is important for understanding sexually dimorphic autoimmune diseases, sex-specific responses to pathogens and vaccines, and how innate immunity is altered during periods of hormonal change (endogenous or exogenous).
The placenta is the interface between maternal and fetal circulations, integrating maternal and fetal signals to selectively regulate nutrient, gas, and waste exchange, as well as secrete hormones. ...In turn, the placenta helps create the in utero environment and control fetal growth and development. The unique epigenetic profile of the human placenta likely reflects its early developmental separation from the fetus proper and its role in mediating maternal-fetal exchange that leaves it open to a range of exogenous exposures in the maternal circulation. In this review, we cover recent advances in DNA methylation in the context of placental function and development, as well as the interaction between the pregnancy and the environment.
The Developmental Origins of Health and Disease hypothesis describes how early life environmental factors influence development in a way that impacts later health and disease risk. The hypothesis is ...supported by a large number of animal studies and a smaller number of observational studies in humans. Epigenetic variation induced in early life has emerged as a prime candidate to be the mediator of such effects, but little direct evidence of this relation exists in humans, primarily due to the inherent problems associated with unraveling the relative contributions of genetic and environmental variables to phenotypic diversity. There are several prerequisites for establishing a causal link that include demonstrating interindividual epigenetic variability in early life in response to specific environmental exposures. Further, compelling evidence linking epigenetic change to disease, prior to onset is required. Finally, the functional relevance of specific epigenetic change must be demonstrated. Evidence is emerging in all of these areas but, ultimately, only large longitudinal life‐course studies, commencing prior to birth, can provide direct evidence in support of a role of epigenetic processes as a driver of Developmental Origins of Health and Disease in humans.
β-glucan is a potent inducer of epigenetic and functional reprogramming of innate immune cells, a process called “trained immunity,” resulting in an enhanced host response against secondary ...infections. We investigate whether β-glucan exposure confers protection against pulmonary Mycobacterium tuberculosis (Mtb) infection. β-glucan induces trained immunity via histone modifications at gene promoters in human monocytes, which is accompanied by the enhanced production of proinflammatory cytokines upon secondary Mtb challenge and inhibition of Mtb growth. Mice treated with β-glucan are significantly protected against pulmonary Mtb infection, which is associated with the expansion of hematopoietic stem and progenitor cells in the bone marrow and increased myelopoiesis. The protective signature of β-glucan is mediated via IL-1 signaling, as β-glucan shows no protection in mice lacking a functional IL-1 receptor (IL1R−/−). The administration of β-glucan may be used as a novel strategy in the treatment of mycobacterial infections and possibly as an adjuvant to improve anti-tuberculosis vaccines.
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•β-glucan induces protective trained immunity in human monocytes infected with Mtb•β-glucan induces protective trained immunity in mice infected with Mtb•β-glucan-mediated protection against Mtb is dependent on IL-1 signaling•β-glucan increases expansion of hematopoietic progenitors and myelopoiesis via IL-1
Moorlag et al. show that β-glucan induces protective trained immunity in human monocytes and in mice infected with virulent Mtb. β-glucan-mediated protection against Mtb is dependent on IL-1 signaling and is associated with the expansion of hematopoietic stem and progenitor cells in the bone marrow and increased myelopoiesis.
Epigenetic mechanisms, often defined as regulating gene activity independently of underlying DNA sequence, are crucial for healthy development. The sum total of epigenetic marks within a cell or ...tissue (the epigenome) is sensitive to environmental influence, and disruption of the epigenome in utero has been associated with adverse pregnancy outcomes. Not surprisingly, given its multifaceted functions and important role in regulating pregnancy outcome, the placenta shows unique epigenetic features. Interestingly however, many of these are only otherwise seen in human malignancy (the pseudomalignant placental epigenome). Epigenetic variation in the placenta is now emerging as a candidate mediator of environmental influence on placental functioning and a key regulator of pregnancy outcome. However, replication of findings is generally lacking, most likely due to small sample sizes and a lack of standardization of analytical approaches. Defining DNA methylation “signatures” in the placenta associated with maternal and fetal outcomes offers tremendous potential to improve pregnancy outcomes, but care must be taken in interpretation of findings. Future placental epigenetic research would do well to address the issues present in epigenetic epidemiology more generally, including careful consideration of sample size, potentially confounding factors, issues of tissue heterogeneity, reverse causation, and the role of genetics in modulating epigenetic profile. The importance of animal or in vitro models in establishing a functional role of epigenetic variation identified in human beings, which is key to establishing causation, should not be underestimated.
Innate immune cells can develop long-term memory after stimulation by microbial products during infections or vaccinations. Here, we report that metabolic signals can induce trained immunity. ...Pharmacological and genetic experiments reveal that activation of the cholesterol synthesis pathway, but not the synthesis of cholesterol itself, is essential for training of myeloid cells. Rather, the metabolite mevalonate is the mediator of training via activation of IGF1-R and mTOR and subsequent histone modifications in inflammatory pathways. Statins, which block mevalonate generation, prevent trained immunity induction. Furthermore, monocytes of patients with hyper immunoglobulin D syndrome (HIDS), who are mevalonate kinase deficient and accumulate mevalonate, have a constitutive trained immunity phenotype at both immunological and epigenetic levels, which could explain the attacks of sterile inflammation that these patients experience. Unraveling the role of mevalonate in trained immunity contributes to our understanding of the pathophysiology of HIDS and identifies novel therapeutic targets for clinical conditions with excessive activation of trained immunity.
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•Induction of trained immunity by β-glucan depends on intracellular mevalonate•Mevalonate induces trained immunity in human monocytes•Mevalonate-induced training is mediated through increased function of IGF1 receptor•Monocytes of HIDS patients (that accumulate mevalonate) have a trained phenotype
A metabolite is critical to train innate immune cells to develop long-term memory.
Induction of trained immunity (innate immune memory) is mediated by activation of immune and metabolic pathways that result in epigenetic rewiring of cellular functional programs. Through ...network-level integration of transcriptomics and metabolomics data, we identify glycolysis, glutaminolysis, and the cholesterol synthesis pathway as indispensable for the induction of trained immunity by β-glucan in monocytes. Accumulation of fumarate, due to glutamine replenishment of the TCA cycle, integrates immune and metabolic circuits to induce monocyte epigenetic reprogramming by inhibiting KDM5 histone demethylases. Furthermore, fumarate itself induced an epigenetic program similar to β-glucan-induced trained immunity. In line with this, inhibition of glutaminolysis and cholesterol synthesis in mice reduced the induction of trained immunity by β-glucan. Identification of the metabolic pathways leading to induction of trained immunity contributes to our understanding of innate immune memory and opens new therapeutic avenues.
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•Cellular metabolism undergoes major shifts in β-glucan-trained monocytes•Glucose, glutamine, and cholesterol metabolism are crucial in trained immunity•Accumulation of fumarate is essential for epigenetic changes in trained immunity
As part of the IHEC consortium, Arts et al. dissect how metabolic pathways regulate epigenetic rewiring in trained immunity (innate immune memory). They show that glycolysis, glutaminolysis, and cholesterol metabolism are indispensable in trained monocytes and link fumarate accumulation to epigenetic changes. Explore the Cell Press IHEC webportal at http://www.cell.com/consortium/IHEC.
More than 7 million individuals have been conceived by Assisted Reproductive Technologies (ART) and there is clear evidence that ART is associated with a range of adverse early life outcomes, ...including rare imprinting disorders. The periconception period and early embryogenesis are associated with widespread epigenetic remodeling, which can be influenced by ART, with effects on the developmental trajectory in utero, and potentially on health throughout life. Here we profile genome-wide DNA methylation in blood collected in the newborn period and in adulthood (age 22-35 years) from a unique longitudinal cohort of ART-conceived individuals, previously shown to have no differences in health outcomes in early adulthood compared with non-ART-conceived individuals. We show evidence for specific ART-associated variation in methylation around birth, most of which occurred independently of embryo culturing. Importantly, ART-associated epigenetic variation at birth largely resolves by adulthood with no direct evidence that it impacts on development and health.
BACKGROUNDThe antituberculosis vaccine bacillus Calmette-Guérin (BCG) reduces overall infant mortality. Induction of innate immune memory, also termed trained immunity, contributes toward protection ...against heterologous infections. Since immune cells display oscillations in numbers and function throughout the day, we investigated the effect of BCG administration time on the induction of trained immunity.METHODSEighteen volunteers were vaccinated with BCG at 6 pm and compared with 36 age- and sex-matched volunteers vaccinated between 8 am and 9 am. Peripheral blood mononuclear cells were stimulated with Staphylococcus aureus and Mycobacterium tuberculosis before, as well as 2 weeks and 3 months after, BCG vaccination. Cytokine production was measured to assess the induction of trained immunity and adaptive responses, respectively. Additionally, the influence of vaccination time on induction of trained immunity was studied in an independent cohort of 302 individuals vaccinated between 8 am and 12 pm with BCG.RESULTSCompared with evening vaccination, morning vaccination elicited both a stronger trained immunity and adaptive immune phenotype. In a large cohort of 302 volunteers, early morning vaccination resulted in a superior cytokine production capacity compared with later morning. A cellular, rather than soluble, substrate of the circadian effect of BCG vaccination was demonstrated by the enhanced capacity to induce trained immunity in vitro in morning- compared with evening-isolated monocytes.CONCLUSIONSBCG vaccination in the morning induces stronger trained immunity and adaptive responses compared with evening vaccination. Future studies should take vaccine administration time into account when studying specific and nonspecific effects of vaccines; early morning should be the preferred moment of BCG administration.FUNDINGThe Netherlands Organization for Scientific Research, the European Research Council, and the Danish National Research Foundation.
The tuberculosis vaccine bacillus Calmette-Guérin (BCG) protects against some heterologous infections, probably via induction of non-specific innate immune memory in monocytes and natural killer (NK) ...cells, a process known as trained immunity. Recent studies have revealed that the induction of trained immunity is associated with a bias toward granulopoiesis in bone marrow hematopoietic progenitor cells, but it is unknown whether BCG vaccination also leads to functional reprogramming of mature neutrophils. Here, we show that BCG vaccination of healthy humans induces long-lasting changes in neutrophil phenotype, characterized by increased expression of activation markers and antimicrobial function. The enhanced function of human neutrophils persists for at least 3 months after vaccination and is associated with genome-wide epigenetic modifications in trimethylation at histone 3 lysine 4. Functional reprogramming of neutrophils by the induction of trained immunity might offer novel therapeutic strategies in clinical conditions that could benefit from modulation of neutrophil effector function.
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•BCG vaccination of humans induces long-term immunophenotypic changes in neutrophils•BCG increases antimicrobial activity of neutrophils against unrelated pathogens•BCG-induced functional changes associate with modifications in histone methylation•Trained immunity may be a therapeutic target in neutrophil-mediated diseases
Moorlag et al. show that BCG vaccination induces long-lasting functional changes in human neutrophils, characterized by increased expression of activation markers and enhanced antimicrobial function upon secondary stimulation. These findings highlight the potential of trained immunity as a therapeutic target to modulate neutrophil effector function.
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