Adverse childhood experiences, posttraumatic stress, and FKBP5 methylation patterns in postpartum women and their newborn infants.

BACKGROUND: Genetic variation and epigenetic mechanisms involving the stress-related gene FKBP5 have been implicated in the intergenerational transmission of trauma-related effects in adult offspring of trauma-exposed caregivers, but these processes have not been fully explored in postpartum women and their newborn infants. METHODS: Women recruited from a prenatal care clinic during their third trimester of pregnancy (N = 114) completed a battery of instruments assessing adverse childhood experiences (ACEs), adversity in adulthood, posttraumatic stress disorder (PTSD) symptoms, negative emotional state, and emotion dysregulation. FKBP5 rs1360780 genotype and intron 7 methylation were derived from saliva collected from postpartum mothers and their newborn infants within 24 h of delivery. RESULTS: Allele-specific associations of methylation with maternal ACEs and prenatal trauma-related symptoms were evident; however, relations differed between mothers and newborns. In mothers carrying the stress sensitive T-allele (CT and TT genotypes), maternal FKBP5 methylation negatively correlated with threat-based ACEs and maternal PTSD symptoms during pregnancy, but not deprivation-based ACEs. In infants homozygous for the C allele (CC genotype), infant FKBP5 methylation positively correlated with maternal threat-based ACEs and prenatal PTSD symptom severity, but not deprivation-based ACEs or adversity in adulthood. CONCLUSIONS: Our results provide evidence that links maternal threat-based ACEs and trauma-related symptoms during pregnancy with allele-specific epigenetic patterns in postpartum women and their newborn infants. These findings provide mechanistic insight into the potential intergenerational impact of ACEs and the effect of maternal PTSD symptoms during pregnancy.

Immune evasion and recognition of the syphilis spirochete in blood and skin of secondary syphilis patients: two immunologically distinct compartments.

BACKGROUND: The clinical syndrome associated with secondary syphilis (SS) reflects the propensity of Treponema pallidum (Tp) to escape immune recognition while simultaneously inducing inflammation. METHODS: To better understand the duality of immune evasion and immune recognition in human syphilis, herein we used a combination of flow cytometry, immunohistochemistry (IHC), and transcriptional profiling to study the immune response in the blood and skin of 27 HIV(-) SS patients in relation to spirochetal burdens. Ex vivo opsonophagocytosis assays using human syphilitic sera (HSS) were performed to model spirochete-monocyte/macrophage interactions in vivo. RESULTS: Despite the presence of low-level spirochetemia, as well as immunophenotypic changes suggestive of monocyte activation, we did not detect systemic cytokine production. SS subjects had substantial decreases in circulating DCs and in IFNγ-producing and cytotoxic NK-cells, along with an emergent CD56-/CD16+ NK-cell subset in blood. Skin lesions, which had visible Tp by IHC and substantial amounts of Tp-DNA, had large numbers of macrophages (CD68+), a relative increase in CD8+ T-cells over CD4+ T-cells and were enriched for CD56+ NK-cells. Skin lesions contained transcripts for cytokines (IFN-γ, TNF-α), chemokines (CCL2, CXCL10), macrophage and DC activation markers (CD40, CD86), Fc-mediated phagocytosis receptors (FcγRI, FcγR3), IFN-ß and effector molecules associated with CD8 and NK-cell cytotoxic responses. While HSS promoted uptake of Tp in conjunction with monocyte activation, most spirochetes were not internalized. CONCLUSIONS: Our findings support the importance of macrophage driven opsonophagocytosis and cell mediated immunity in treponemal clearance, while suggesting that the balance between phagocytic uptake and evasion is influenced by the relative burdens of bacteria in blood and skin and the presence of Tp subpopulations with differential capacities for binding opsonic antibodies. They also bring to light the extent of the systemic innate and adaptive immunologic abnormalities that define the secondary stage of the disease, which in the skin of patients trends towards a T-cell cytolytic response.

Pilot study of iPS-derived neural cells to examine biologic effects of alcohol on human neurons in vitro.

BACKGROUND: Studies of the effects of alcohol on N-methyl-d-aspartate (NMDA) receptor function and gene expression have depended on rodent or postmortem human brain models. Ideally, the effects of alcohol might better be examined in living neural tissue derived from human subjects. In this study, we used new technologies to reprogram human subject-specific tissue into pluripotent cell colonies and generate human neural cultures as a model system to examine the molecular actions of alcohol. METHODS: Induced pluripotent stem (iPS) cells were generated from skin biopsies taken from 7 individuals, 4 alcohol-dependent subjects, and 3 social drinkers. We differentiated the iPS cells into neural cultures and characterized them by immunocytochemistry using antibodies for the neuronal marker beta-III tubulin, glial marker s100ß, and synaptic marker synpasin-1. Electrophysiology was performed to characterize the iPS-derived neurons and to measure the effects of acute alcohol exposure on the NMDA receptor response in chronically alcohol exposed and nonexposed neural cultures from 1 nonalcoholic. Finally, we examined changes in mRNA expression of the NMDA receptor subunit genes GRIN1, GRIN2A, GRIN2B, and GRIN2D after 7 days of alcohol exposure and after 24-hour withdrawal from chronic alcohol exposure. RESULTS: Immunocytochemistry revealed positive staining for neuronal, glial, and synaptic markers. iPS-derived neurons displayed spontaneous electrical properties and functional ionotropic receptors. Acute alcohol exposure significantly attenuated the NMDA response, an effect that was not observed after 7 days of chronic alcohol exposure. After 7 days of chronic alcohol exposure, there were significant increases in mRNA expression of GRIN1, GRIN2A, and GRIN2D in cultures derived from alcoholic subjects but not in cultures derived from nonalcoholics. CONCLUSIONS: These findings support the potential utility of human iPS-derived neural cultures as in vitro models to examine the molecular actions of alcohol on human neural cells.

A functional serotonin transporter gene polymorphism and depressive effects associated with interferon-alpha treatment.

BACKGROUND: Interferon-alpha (IFN-alpha) treatment frequently induces depression, potentially leading to early dose reductions or a shorter duration of treatment, which can adversely affect outcomes, including quality of life. OBJECTIVE: Defining relevant risk factors for IFN-alpha-induced depression is essential in order to identify prophylactic treatment strategies. METHOD: The authors examined whether a functional polymorphism (5-HTTLPR) in the gene encoding the serotonin transporter moderates IFN-alpha-induced depressive symptoms in 1,015 patients with chronic hepatitis C (CHC) receiving pegylated IFN-alpha and ribavirin. Depressive symptoms were assessed at baseline, 12 weeks, and 20 weeks of treatment. RESULTS: Depression symptoms increased during antiviral treatment; 5-HTTLPR genotype moderated IFN-alpha-induced depression symptoms in both non-Hispanic Caucasians and Hispanic patients, although the opposite risk allele was associated with depression in the two populations. CONCLUSION: 5-HTTLPR may moderate risk for the development of depressive symptoms during IFN-alpha therapy for CHC in a population-specific manner.