Adult Immune Function Research Articles

Tissue-specific sex differences in pediatric and adult immune cell composition and function.

Sex-based differences in immune cell composition and function can contribute to distinct adaptive immune responses. Prior work has quantified these differences in peripheral blood, but little is known about sex differences within human lymphoid tissues. Here, we characterized the composition and phenotypes of adaptive immune cells from male and female ex vivo tonsils and evaluated their responses to influenza antigens using an immune organoid approach. In a pediatric cohort, female tonsils had more memory B cells compared to male tonsils direct ex vivo and after stimulation with live-attenuated but not inactivated vaccine, produced higher influenza-specific antibody responses. Sex biases were also observed in adult tonsils but were different from those measured in children. Analysis of peripheral blood immune cells from in vivo vaccinated adults also showed higher frequencies of tissue homing CD4 T cells in female participants. Together, our data demonstrate that distinct memory B and T cell profiles are present in male vs. female lymphoid tissues and peripheral blood respectively and suggest that these differences may in part explain sex biases in response to vaccines and viruses.

Increased pupal temperature has reversible effects on thermal performance and irreversible effects on immune system and fecundity in adult ladybirds

The environmental conditions an organism encounters during development vary in their lasting impact on adult phenotypes. In the context of ongoing climate change, it is particularly relevant to understand how high developmental temperatures can impact adult traits, and whether these effects persist or diminish during adulthood. Here, we assessed the effects of pupal temperature (17 °C – normal temperature, 26 °C – increased temperature, or 35 °C – heat wave) on adult Harmonia axyridis thermal stress tolerance, immune function, starvation resistance, and fecundity. The temperature during pupation significantly affected all investigated traits in fresh adults. Heat acclimation decreased adult haemocyte concentration, cold tolerance, and total egg production, and had a positive effect on heat tolerance and starvation resistance. The negative effects of heat acclimation on cold tolerance diminished after seven days. In contrast, heat acclimation had a lasting positive effect on adult heat tolerance. Our results provide a broad assessment of the effects of developmental thermal acclimation on H. axyridis adult phenotypes. The relative plasticity of several adult traits after thermal acclimation may be consequential for the future geographic distribution and local performance of various insect species.

Correlated responses in basal immune function in response to selection for fast development in Drosophila melanogaster.

Often, immunity is invoked in the context of infection, disease and injury. However, an ever alert and robust immune system is essential for maintaining good health, but resource investment into immunity needs to be traded off against allocation to other functions. In this study, we study the consequences of such a trade-off with growth by ascertaining various components of baseline innate immunity in two types of Drosophila melanogaster populations selected for fast development, in combination with either a long effective lifespan (FLJs) or a short effective lifespan (FEJs). We found that distinct immunological parameters were constitutively elevated in both, FLJs and FEJs compared to their ancestral control (JB) populations, and these constitutive elevated immunological parameters were associated with reduced insulin signalling and comparable total gut microbiota. Our results bring into focus the inter-relationship between egg to adult development time, ecdysone levels, larval gut microbiota, insulin signalling, adult reproductive longevity and immune function. We discuss how changes in selection pressures operating on life-history traits can modulate different components of immune system.

The Thymus Is Critical for Adult Immune Function

The Thymus Is Critical for Adult Immune Function

Sex differences in the impact of childhood socioeconomic status on immune function

Early life stress increases one’s risk for health problems later in life, and many studies find that these effects are sex-differentiated. Here, we examined relationships between multiple sources of early life stress and adult immune function in humans across several functional assays. Adult participants provided retrospective information about their childhood (a) socioeconomic status, (b) household unpredictability, and (c) exposure to adverse experiences. Participants’ peripheral blood mononuclear cells (PBMCs) were then isolated for use in functional assays of immune performance: (a) tumor cell lysis by natural killer cells, (b) phagocytosis of Escherichia coli bioparticles, and (c) mitogen-induced leukocyte proliferation and cytokine release. In men, lower childhood socioeconomic status predicted decrements in immunological performance across functional assays, along with greater spontaneous cytokine release from PBMCs. These changes co-occurred with elevations in plasma testosterone levels. Similar effects were not observed for other sources of stress, nor were they found in women (with the exception of spontaneous cytokine release). These findings provide evidence that low childhood socioeconomic status has a lasting negative impact on multiple aspects of immune function, particularly in men.

Serum vaccine antibody concentrations in adults exposed to per- and polyfluoroalkyl substances: A birth cohort in the Faroe Islands

Per- and polyfluoroalkyl substances (PFASs) are highly persistent in the environment and may cause depressed immune function. Previous studies have linked PFAS exposure to lower vaccine responses in children, but research in adults is limited. Therefore, the present study evaluated the associations between exposure to PFASs and serum antibody concentrations in adults vaccinated at age 28 years in the Faroe Islands. PFAS concentrations were determined from cord-blood collected at birth and serum samples collected at ages 7, 14, 22, and 28 years. Serum antibody concentrations against hepatitis type A and B, diphtheria, and tetanus were analyzed from blood samples collected about 6 mo after the first vaccine inoculation at age 28 years. Linear regression models were used to estimate changes in antibody concentration for each doubling of PFAS concentration. Potential effect modification by sex was assessed by including an interaction term between PFAS and sex. Although the 95% confidence intervals contain the null value, inverse trends were observed between serum perfluorooctanoate (PFOA) at ages 14 and 28 years and hepatitis type A antibody (anti-HAV) concentrations, as revealed by an estimated decrease of 0.71 (95% CI: −1.52, 0.09) and 0.24 (95% CI: −0.59, 0.10) signal-to-cutoff ratio for each doubling of exposure, respectively. Inverse trends were also observed between serum PFOA at ages 22 and 28 years and hepatitis type B antibody (anti-HBs) concentration, with an estimated decrease of 21% (95% CI: −42.20%, 7.34%) and of 17% (95% CI: −35.47%, 7.35%) in anti-HBs for each doubling of exposure, respectively. Sex-specific associations with anti-HAV were observed for cord-blood PFASs and serum PFAS concentrations at ages 7 and 14 years. No inverse associations of PFAS exposure were found with diphtheria and tetanus antibody concentrations. Future studies are needed to confirm these findings and further investigate the effects of PFASs on adult immune function.

The impacts of maternal stress on worker phenotypes in the honey bee

Maternal stress is a common source of heritable health and behavioral variation. This type of maternal effect could be particularly important for honey bees (Apis mellifera), as a single queen is responsible for many generations of workers who perform all colony functions including raising subsequent worker generations. Multiple factors work synergistically to cause colony loss, but a role for maternal stress effects is unstudied. We used an artificial cold temperature treatment as a proof-of-concept approach to investigate whether acute queen stress causes changes in worker phenotypes, including egg hatching rate, development time, and adult behavior and immune function. We found that queen stress impacts early-life phenotypes (egg hatching and development time), with more limited impacts on adult phenotypes (behavior and immune function). Thus, if maternal stress impacts colony health, it is likely through cumulative impacts on worker population numbers, not through phenotypic effects that impact individual adult worker behavior or health resilience. This study addresses an important and overlooked question, and provides a baseline understanding of the likely impacts of queen stress on worker phenotypes.

Population history with invasive predators predicts innate immune function response to early-life glucocorticoid exposure in lizards.

Early-life stress can suppress immune function, but it is unclear whether transgenerational stress exposure modulates the immune consequences of early stress. In populations where, historically, the immune system is frequently activated, e.g. persistent stressors that cause injury, it may be maladaptive to suppress immune function after early-life stress. Thus, the relationship between early-life stress and immune function may vary with population-level historical stressor exposure. We collected gravid fence lizards (Sceloporus undulatus) from populations that naturally differ in long-term exposure to invasive fire ants (Solenopsis invicta). We manipulated early-life stress in the resulting offspring via weekly exposure to fire ants, application of the stress-relevant hormone corticosterone or control treatment from 2 to 43 weeks of age. We quantified adult immune function in these offspring with baseline and antigen-induced hemagglutination and plasma bacterial killing ability. Early-life corticosterone exposure suppressed baseline hemagglutination in offspring of lizards from populations not exposed to fire ants but enhanced hemagglutination in those from populations that were exposed to fire ants. This enhancement may prepare lizards for high rates of wounding, toxin exposure and infection associated with fire ant attack. Adult bacterial killing ability and hemagglutination were not affected by early-life exposure to fire ants, but the latter was higher in offspring of lizards from invaded sites. A population's history of persistent stress may thus alter individual long-term immunological responses to early-life stressors. Further consideration of historical stressor exposure (type and duration) may be important to better understand how early-life stressors affect adult physiology.

Independent and interactive effects of immune activation and larval diet on adult immune function, growth and development in the greater wax moth (Galleria mellonella).

Organisms in the wild are likely to face multiple immune challenges as well as additional ecological stressors, yet their interactive effects on immune function are poorly understood. Insects are found to respond to cues of increased infection risk by enhancing their immune capacity. However, such adaptive plasticity in immune function may be limited by physiological and environmental constraints. Here, we investigated the effects of two environmental stressors - poor larval diet and an artificial parasite-like immune challenge at the pupal stage - on adult immune function, growth and development in the greater wax moth (Galleria mellonella). Males whose immune system was activated with an artificial parasite-like immune challenge had weaker immune response - measured as strength of encapsulation response - as adults compared to the control groups, but only when reared on high-nutrition larval diet. Immune activation did not negatively affect adult immune response in males reared on low-nutrition larval diet, indicating that poor larval diet improved the capacity of the insects to respond to repeated immune challenges. Low-nutrition larval dietalso had a positive independent effect on immune capacity in females, yet it negatively affected development time and adult body mass in both sexes. As in the nature immune challenges are rarely isolated, and adverse nutritional environment may indicate an elevated risk of infection, resilience to repeated immune challenges as a response to poor nutritional conditions could provide a significant fitness advantage. This study highlights the importance of considering environmental context when investigating the effects of immune activation in insects.

Neonatal Inflammation Impairs Multiple Pathways to Adult Respiratory Plasticity

Bacterial‐induced inflammation is a common clinical problem in neonates and acutely impairs respiratory control, but we know little about the long‐term effects of neonatal inflammation on adult respiratory control. Since neonatal inflammation blunts adult immune function, reduces adult hippocampal plasticity, and increases the vulnerability to neuropsychiatric disorders, we hypothesized that neonatal systemic inflammation would inhibit adult phrenic long‐term facilitation (pLTF), a form of respiratory neuroplasticity induced by acute intermittent hypoxia (AIH). pLTF can be induced by distinct cellular mechanisms including the Q‐pathway, induced by moderate AIH (PaO2 35–45 mmHg), and the S‐pathway, induced by severe AIH (PaO2 25–35 mmHg). Therefore, we tested the hypothesis that neonatal inflammation would undermine both the Q‐ and S‐pathway to pLTF. Postnatal day 4 (P4) pups of both sexes were injected with either lipopolysaccharide (LPS; 1 mg/kg) or sterile saline and allowed to mature to adulthood. In order to control the known effects of estrus cycle hormones on pLTF, adult females were ovariectomized 7–8 days prior and given 17‐β estradiol (40 μg/ml/kg, 3 hours) before AIH. Neonatal LPS undermined adult mAIH‐induced (Q‐pathway) pLTF in both females (−15 ± 17%, n=6, p < 0.0001) and males (14 ± 14%, n=12, p = 0.01) relative to neonatal Saline controls (females; 97 ± 24%, n=7, males; 55 ± 13%, n=7). Acute, adult treatment with a systemic anti‐inflammatory (ketoprofen, 12.5 mg/ml/kg, i.p., 3 hours) restored Q‐pathway pLTF after neonatal LPS in both females (118 ± 24%, n=4) and males (58 ± 9%, n=4) to saline controls treated with ketoprofen (P4 Saline females; 67 ± 11%, n=4, males; 54 ± 9%, n=4). Additionally, sAIH‐induced (S‐pathway) pLTF was undermined in adults after neonatal LPS in females (0 ± 17%, n=4, p < 0.001) and males (7 ± 9%, n=4, p < 0.01) compared to neonatal saline control females (86 ± 23%, n=4) and males (47 ± 17%, n=4). However, systemic ketoprofen in adults did not restore S‐pathway pLTF after neonatal inflammation in females (P4 Saline; 136 ± 11%, n=4, P4 LPS; 23 ± 15%, n=5, p < 0.0001) or males (P4 Saline; 67 ± 11%, n=4, P4 LPS; −5 ± 37%, n=4, p < 0.01). Thus, neonatal systemic inflammation has a lasting effect of respiratory plasticity by abolishing multiple pathways to adult respiratory plasticity. Furthermore, the restoration of Q‐pathway, but not S‐pathway, mediated plasticity by acute ketoprofen demonstrates different mechanisms impair adult respiratory plasticity after neonatal inflammation. Understanding how neonatal inflammation impairs the adult respiratory system will elucidate links between neonatal conditions and adult respiratory insufficiency, leading to better therapies to enhance breathing in all age groups.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Blue light-induced immunosuppression in Bactrocera dorsalis adults, as a carryover effect of larval exposure.

Detrimental effects of ultraviolet (UV) light on living organisms are well understood, little is known about the effects of blue light irradiation. Although a recent study revealed that blue light caused more harmful effects on insects than UV light and blue light irradiation killed insect pests of various orders including Diptera, the effects of blue light on physiology of insects are still largely unknown. Here we studied the effects of blue light irradiation on cuticular melanin in larval and the immune response in adult stage of Bactrocera dorsalis. We also evaluated the effects of blue light exposure in larval stage on various age and mass at metamorphosis and the mediatory role of cuticular melanin in carryover effects of larval stressors across metamorphosis. We found that larvae exposed to blue light decreased melanin contents in their exoskeleton with smaller mass and delayed metamorphosis than insects reared without blue light exposure. Across metamorphosis, lower melanotic encapsulation response and higher susceptibility to Beauveria bassiana was detected in adults that had been exposed to blue light at their larval stage, thereby constituting the first evidence that blue light impaired adult immune function in B. dorsalis as a carryover effect of larval exposure.

Thermal imprinting modifies adult stress and innate immune responsiveness in the teleost sea bream.

The impact of thermal imprinting on the plasticity of the hypothalamic-pituitary-interrenal (HPI) axis and stress response in an adult ectotherm, the gilthead sea bream (Sparusaurata, L.), during its development was assessed. Fish were reared under 4 thermal regimes, and the resulting adults exposed to acute confinement stress and plasma cortisol levels and genes of the HPI axis were monitored. Changes in immune function, a common result of stress, were also evaluated using histomorphometric measurements of melanomacrophages centers (MMCs) in the head kidney and by monitoring macrophage-related transcripts. Thermal history significantly modified the HPI responsiveness in adult sea bream when eggs and larvae were reared at a higher than optimal temperature (HT, 22°C), and they had a reduced amplitude in their cortisol response and significantly upregulated pituitary pomc and head kidney star transcripts. Additionally, after an acute stress challenge, immune function was modified and the head kidney of adult fish reared during development at high temperatures (HT and LHT, 18-22°C) had a decreased number of MMCs and a significant downregulation of dopachrome tautomerase. Thermal imprinting during development influenced adult sea bream physiology and increased plasma levels of glucose and sodium even in the absence of an acute stress in fish reared under a high-low thermal regime (HLT, 22-18°C). Overall, the results demonstrate that temperature during early development influences the adult HPI axis and immune function in a teleost fish.

Characterization of the direct targets of FOXO transcription factors throughout evolution.

Summary FOXO transcription factors (FOXOs) are central regulators of lifespan across species, yet they also have cell‐specific functions, including adult stem cell homeostasis and immune function. Direct targets of FOXOs have been identified genome‐wide in several species and cell types. However, whether FOXO targets are specific to cell types and species or conserved across cell types and throughout evolution remains uncharacterized. Here, we perform a meta‐analysis of direct FOXO targets across tissues and organisms, using data from mammals as well as Caenorhabditis elegans and Drosophila. We show that FOXOs bind cell type‐specific targets, which have functions related to that particular cell. Interestingly, FOXOs also share targets across different tissues in mammals, and the function and even the identity of these shared mammalian targets are conserved in invertebrates. Evolutionarily conserved targets show enrichment for growth factor signaling, metabolism, stress resistance, and proteostasis, suggesting an ancestral, conserved role in the regulation of these processes. We also identify candidate cofactors at conserved FOXO targets that change in expression with age, including CREB and ETS family factors. This meta‐analysis provides insight into the evolution of the FOXO network and highlights downstream genes and cofactors that may be particularly important for FOXO's conserved function in adult homeostasis and longevity.

Non-additive response of larval ringed salamanders to intraspecific density

Conditions experienced in early developmental stages can have long-term consequences for individual fitness. High intraspecific density during the natal period can affect juvenile and eventually adult growth rates, metabolism, immune function, survival, and fecundity. Despite the important ecological and evolutionary effects of early developmental density, the form of the relationship between natal density and resulting juvenile phenotype is poorly understood. To test competing hypotheses explaining responses to intraspecific density, we experimentally manipulated the initial larval density of ringed salamanders (Ambystoma annulatum), a pond-breeding amphibian, over 11 densities. We modeled the functional form of the relationship between natal density and juvenile traits, and compared the relative support for the various hypotheses based on their goodness of fit. These functional form models were then used to parameterize a simple simulation model of population growth. Our data support non-additive density dependence and presents an alternate hypothesis to additive density dependence, self-thinning and Allee effects in larval amphibians. We posit that ringed salamander larvae may be under selective pressure for tolerance to high density and increased efficiency in resource utilization. Additionally, we demonstrate that models of population dynamics are sensitive to assumptions of the functional form of density dependence.

Larval UV exposure impairs adult immune function through a trade‐off with larval investment in cuticular melanin

Summary Despite the strong impact of ultraviolet (UV) radiation on invertebrates, it is unknown whether it affects immune function across metamorphosis. More generally, the mechanisms on how larval stressors bridge metamorphosis and shape adult fitness in animals with a complex life cycle remain poorly understood. We studied whether cuticular melanin content is upregulated under UV exposure in the larval stage of the damselfly Coenagrion puella and whether this is traded off across metamorphosis against a key component of the invertebrate immune response, the melanotic encapsulation response, in the adult stage. Larvae exposed to UV increased the melanin content in their exoskeleton and metamorphosed later and at a smaller mass than animals reared without UV. Across metamorphosis, this was associated with a reduced melanotic encapsulation response, thereby constituting the first proof for a UV‐driven impaired immune response in an invertebrate. The demonstrated costs of UV exposure in terms of age and mass at metamorphosis and reduced adult immune response likely translate into reduced adult fitness. Path analysis indicated that the immunosuppressive property of larval UV exposure was not mediated by age and mass at metamorphosis, but instead that the adult immune response was traded off against larval cuticular melanin investment. Melanin‐based trade‐off across metamorphosis provides a new pathway by which effects of larval stressors are carried over to the adult stage and thereby advances our understanding of the still largely enigmatic mechanisms of carryover effects of larval stressors across metamorphosis. Given the mechanistic basis, this carryover effect of larval UV exposure on adult immune function is expected to be general and may constitute a widespread and important cost of UV exposure in invertebrates.

Strong negative effects of simulated heat waves in a tropical butterfly.

Climate change poses a significant challenge to all natural systems on Earth. Especially increases in extreme weather events such as heat waves have the potential to strongly affect biodiversity, though their effects are poorly understood because of a lack of empirical data. Therefore, we here explore the sensitivity of a tropical ectotherm, which are in general believed to have a low warming tolerance, to experimentally simulated climate change using ecologically realistic diurnal temperature cycles. Increasing the mean temperature permanently by 3°C had mostly minor effects on developmental traits in the butterfly Bicyclus anynana. Simulated heat waves (strongly elevated temperatures for some time though retaining the same overall temperature mean), in contrast, caused strong negative effects by prolonging development time (by up to 10%) and reducing body mass (-21%), especially when combined with reduced relative humidity. Detrimental effects were carried over into the adult stage, diminishing subsequent performance. Most strikingly, higher temperatures suppressed adult immune function (haemocytes: -54%, lysozyme activity: -32%), which may potentially change the way species interact with antagonists. Heat waves thus reduced fitness parameters by 10-25% for development time and body mass and by up to 54% for immune parameters even in this plastic and widespread butterfly, exemplifying the potentially dramatic impact of extreme weather events on biodiversity.

Rapid evolution of larval life history, adult immune function and flight muscles in a poleward‐moving damselfly

Although a growing number of studies have documented the evolution of adult dispersal-related traits at the range edge of poleward-expanding species, we know little about evolutionary changes in immune function or traits expressed by nondispersing larvae. We investigated differentiation in larval (growth and development) and adult traits (immune function and flight-related traits) between replicated core and edge populations of the poleward-moving damselfly Coenagrion scitulum. These traits were measured on individuals reared in a common garden experiment at two different food levels, as allocation trade-offs may be easier to detect under energy shortage. Edge individuals had a faster larval life history (growth and development rates), a higher adult immune function and a nearly significant higher relative flight muscle mass. Most of the differentiation between core and edge populations remained and edge populations had a higher relative flight muscle mass when corrected for latitude-specific thermal regimes, and hence could likely be attributed to the range expansion process per se. We here for the first time document a higher immune function in individuals at the expansion front of a poleward-expanding species and documented the rarely investigated evolution of faster life histories during range expansion. The rapid multivariate evolution in these ecological relevant traits between edge and core populations is expected to translate into changed ecological interactions and therefore has the potential to generate novel eco-evolutionary dynamics at the expansion front.

Juvenile Nutritional Stress Affects Growth Rate, Adult Organ Mass, and Innate Immune Function in Zebra Finches (Taeniopygia guttata)

Developmental conditions may influence many aspects of adult phenotype, including growth and immune function. Whether poor developmental environments impair both growth and immune function or induce a trade-off between the two processes is inconclusive, and the impact of the timing of stress in determining this relationship has so far been overlooked. We tested the hypothesis that the long-term effects of nutritional stress on growth, body composition, and immune function in zebra finches (Taeniopygia guttata) are different depending on whether stress is experienced during an early or a juvenile phase (i.e., before or after nutritional independence, respectively). We raised birds on high (H) or low (L) food conditions until posthatch day (PHD) 35 and switched treatments for half of the birds in each of the H and L groups from PHD 36 to 61. We found that unfavorable juvenile conditions (PHD 36-61) increased somatic growth rates and liver mass, body fat, and some aspects of immune function. We also observed a positive relationship between growth and immune function, as individuals that grew faster as juveniles also had better innate immune responses as adults. There was no effect of treatment on basal metabolic rate. These findings demonstrate the importance of juvenile developmental conditions in shaping multiple aspects of the adult phenotype.

High larval density does not induce a prophylactic immune response in a butterfly

Immune function is greatly affected by biotic and abiotic factors, arguably owing to resource allocation trade‐offs. While starvation typically exerts negative effects on immune function, there are two competing hypotheses regarding the impact of population density: a high population density may decrease or increase immune competence, either as a result of reduced energy stores or of augmented resource allocation to minimise infection risk (density‐dependent prophylaxis). Against this background, the effects of population (= larval rearing) density and transient food stress on adult immune function and life‐history traits in the temperate‐zone butterfly Pieris napi (Linnaeus) have been examined. Both a period of larval starvation and high larval rearing density prolonged the development time and reduced the body mass. All immune parameters measured (pro‐phenoloxidase and phenoloxidase activity, haemocyte number, encapsulation rate) were also negatively affected by high density, whereas starvation had no effect. We thus found no evidence for density‐dependent prophylaxis, but a diminished performance at a high density probably caused by reduced energy stores. The present study reinforces that the maintenance and deployment of an efficient immune system is costly, which may prohibit prophylactic responses to high population densities.

Disproportionate early fetal growth predicts postnatal thymic size in humans.

Prenatal events can affect neonatal thymus size and adult immune function. The causal insults are unknown, although fetal nutrient restriction is suspected. We used ultrasound at three time points during pregnancy (14, 19 and 30 weeks) to measure the growth of six fetal dimensions in rural Bangladeshi women participating in the Maternal and Infant Nutrition Interventions, Matlab study. Postnatal ultrasound was used to calculate thymic index (TI) at birth, 2, 6 and 12 m. Of the 3267 women recruited, 2861 participated by providing data at least at one fetal biometry and one TI time point. Patterns of fetal growth were summarized using principal components calculated from fetal dimension z-scores. Random effects regression, controlling for infant size and season of measurement were used to relate these patterns to TI. We found that smaller leg length relative to head circumference, characteristic of head-sparing growth restriction, was predictive of lower TI. This association was significant at all time points but strongest in earlier pregnancy. Each standard deviation increase in leg-head proportion was associated with an increase in TI of ∼5%. We conclude that growth patterns typical of poor fetal nutrition are associated with poor thymic development. The greater strength of this association in the first trimester is consistent with a period of vulnerability during the early ontogeny of the thymus and suggests that preventative intervention would need to be given in early pregnancy.