Leukocytes: Likely not the immune system’s white knights in the wake of early life adversity

Early Life Adversity (ELA) is a category of negative life events occurring early in development that significantly impacts the trajectory of health. ELA is associated with increased chances of cardiac, liver, skeletal, and psychiatric disease, pointing toward the need for a whole-body approach to studying the effects of childhood stress on physical and mental health (Felitti et al., 1998). In parity with how the discovery of glucocorticoid receptors in the hippocampus opened the door more widely to understanding the broad and long-term health impacts of stress/stress hormones (McEwen, 2013), immune system dysregulation has recently emerged as another key player in the effects of ELA on lifespan health across multiple body systems. In a recent Brain Behavior and Immunity publication (Etzel et al., 2024), Etzel and colleagues sought to elucidate the mechanism by which ELA may set the stage for later dysfunction by examining changes in peripheral immune cell gene expression clusters in young adults with or without ELA history in response to a controlled laboratory stressor. The strength and novelty of this design was the use of both within- and between-subjects measurements to examine resting and challenged gene expression against the backdrop of ELA history, as well as the use of two complementary yet independent gene clustering methods.

Male and female young adults (18–27yo) were screened for ELA events and separated into either control (0 ELA events up to 18 years of age) or ELA (3 + exposures) conditions. Participants then partook in two counterbalanced sessions (no-stress vs. stress conditions) during which blood was collected (four times per session, eight total). In the stress condition, subjects participated in the Trier Social Stress Test (TSST), with a blood sample collected at baseline and at three intervals post-test (− 60, 30, 90, and 240 min). In the control condition, a similar timeline of blood collection was followed. From each blood draw, peripheral blood mononuclear cells were isolated and RNA was sequenced. Gene expression clusters were constructed using latent profile analysis (LPA) and weighted gene co-expression analysis (WGCNA). The use of both LPA and WGCNA analysis richly strengthened the approach, presenting overlapping gene clusters governing distinct categories of biological processes. The findings were largely convergent across the two approaches and also across the time points after being identified based on time point 1. This presents a good strategy for analyzing clusters of genes for future studies of this type, though without a larger sample size it is not possible to single out individual genes to target in future more mechanistic studies, just general functional clusters.

The factors that were taken into account included the subjects’ socioeconomic status, sex, minority status, and BMI; of these, the only significant difference was the ELA group having lower BMI than controls, which was somewhat surprising given the positive association between early life stress and the comorbidity of later depression and obesity (Defina et al., 2024). The TSST was effective for the induction of acute stress, as evinced by an increase in salivary cortisol and mean arterial pressure (MAP). ELA subjects showed greater and more prolonged increases in MAP during the acute stress exposure, possibly a harbinger of future health concerns expected based on their ELA status. Cortisol levels did not differ, somewhat surprisingly as childhood adversity has been shown to influence adult cortisol dynamic range (Karlamangla et al., 2019).

The most impactful part of this study was the combination of within- and between-subjects testing. Peripheral immune cells are poised to act quickly in the face of immune and stress challenge, and as such the related measures obtained are typically labile and become a much more interesting biomarker when probed both at resting state as well as across a challenge. There is however also a downside to repeated sampling – venipuncture can also act as a stressor (McLenon & Rogers, 2019). The authors found a history and time interaction wherein expression went down at 90 min in ELA subjects, and yet went up in control participants. As this happened regardless of stress condition, it is possibly related to the start of the blood collection procedure itself. This adds an interesting though perhaps unintended dimension to the study; given that the underlying premise of the study is that ELA leads to a higher rate of adverse health events, it may be important to assess whether these individuals have a unique response to the stress of receiving treatment/testing in the medical setting.

While there was no response to the stressor that was unique to ELA subjects, there was a baseline difference in clusters of genes related to leukocyte proliferation, innate immune response, chromatin organization, ribosomal and mitochondrial activity, and chromosome condensation/segregation. This is intriguing and corroborates the accumulation of data that suggests long-term increased pro-inflammatory tone and altered white blood cell counts in patients with childhood aversity (Danese et al., 2007). Furthermore, these data suggest an increase in peripheral leukocyte activity that affects innate and adaptive immune system function without changing cortisol dynamics, which agrees with the current theory that early life stress repeatedly activates the sympathetic nervous system, leading to an increase in the proliferation of hematopoietic stem cells and increased production and mobilization of leukocytes (Mondelli & Vernon, 2019).

In contrast to these findings, other work has shown that exposure to a higher level of ELA was associated with a significantly higher expression of pro-inflammatory transcripts in the blood of adolescents following the TSST (Kuhlman et al., 2023). It remains to be seen whether this discrepancy depends on the time of testing (childhood vs later in adulthood), intensity and type of early life adverse events, or other factors altogether. Though this set of work included both male and female subjects, there was insufficient power to draw a conclusion about sex differences. Together, this further underscores the need to focus further studies on expanding findings to more diverse populations and fully powering for sex analysis, as rodent and human studies have indicated that sexual dimorphism in brain and immune system development yields different outcomes of early life adversity (Ganguly & Brenhouse, 2015).

Data availability

No data was used for the research described in the article.