Exposure to adversity during sensitive periods of immune development (early life and pregnancy) is linked to increased health risks. These periods are characterized by heightened immune plasticity, making them particularly vulnerable to environmental stressors. The study aimed to determine if adversity during these sensitive periods has unique immunological effects compared to lifetime adversity. The researchers hypothesized that greater adversity during early life and pregnancy would be associated with alterations in macrophage-associated M1/M2 gene expression, reflecting a pro-inflammatory imbalance. Inflammation is a key pathway by which adversity increases disease risk, and macrophages play a crucial role in inflammatory responses. Early childhood is a sensitive period for immune development, with adversity potentially influencing the balance between innate and adaptive immunity. Pregnancy is another sensitive period, characterized by both inflammation and immunosuppression, crucial for maternal and fetal survival. Stress during pregnancy can skew macrophage phenotypes towards a pro-inflammatory state, potentially impacting fetal development and health outcomes. The study aimed to investigate these associations using a cohort of low-income, ethnically diverse women with significant interpersonal trauma exposure. The researchers also sought to analyze alternative immune biomarkers alongside M1/M2 to evaluate specificity, by comparing it with an endotoxin tolerance (ET) phenotype and standard pro and anti-inflammatory cytokine levels. This approach aimed to provide a comprehensive picture of immune alterations associated with adversity during various life stages.

The introduction extensively reviews existing literature on the impact of adversity on health outcomes, emphasizing the role of sensitive periods in immune development. It cites studies linking adverse childhood experiences to cardiovascular, metabolic, psychiatric, and neurodevelopmental disorders, as well as premature mortality. The concept of "biological embedding" of stress through epigenetic changes is discussed, highlighting the long-term consequences of adversity exposure. The literature review also details the role of inflammation in mediating the effects of adversity and discusses the immune system's plasticity during early life and pregnancy. The challenges in using single biomarkers to assess inflammatory responses and the need for composite biomarkers are highlighted. The plasticity and vulnerability of the immune system during sensitive periods, specifically early life and pregnancy, are explained in detail, citing various studies in this field. The interplay between chronic stressors like low socioeconomic status and interpersonal violence, and their impact on health outcomes, are also reviewed. The importance of macrophages in immune regulation and the complex interplay of M1 and M2 phenotypes are explained.

This cross-sectional study utilized data from the Child Parent Psychotherapy Health Study (CPP-HEALTH). 53 low-income women seeking family-based trauma treatment following exposure to interpersonal violence were enrolled. Structured interviews assessed early life adversity (ELA, trauma exposure before age 5), pregnancy adversity (PA), and total lifetime adversity (TLA). Blood samples were collected for cytokine assays (TNF-α, IL-1β, IL-6, CRP, IL-1RA, IL-4, and IL-10). A subset of 42 participants underwent RNA sequencing to analyze CD14⁺ monocyte gene expression, focusing on the M1/M2 phenotype. Multivariable regression models examined the association between each adversity factor and the M1/M2 phenotype, adjusting for demographic, socioeconomic, and psychopathology factors. The M1/M2 phenotype was further compared with a second, clinically validated macrophage-associated immunosuppressive phenotype (endotoxin tolerance, ET). The study utilized several statistical methods: Variables were checked for normality, with transformations applied as needed. Multivariable regression models were employed, with Model 1 including demographics and medical covariates, and Model 2 incorporating sociodemographic factors. Specificity analyses compared M1/M2 with other biomarkers (ET, pro-inflammatory, anti-inflammatory cytokines). The study also included exploratory post-hoc analyses.

Early life adversity (ELA) and pregnancy adversity (PA) were significantly associated with a higher M1/M2 RNA score (pro-inflammatory imbalance), while total lifetime adversity (TLA) was associated with a lower M1/M2 score. This suggests distinct immune responses to adversity based on timing. Neither ELA nor PA were significantly associated with serum pro-inflammatory cytokines. However, TLA was significantly associated with lower pro-inflammatory cytokine levels after adjusting for socioeconomic factors. Higher PA (but not ELA or TLA) was significantly associated with lower anti-inflammatory cytokine levels in unadjusted analyses but became non-significant after adjusting for other factors. In multivariate analyses, ELA remained significantly associated with the M1/M2 RNA score independent of PA and mental health symptoms. The association between PA and M1/M2 showed a non-significant trend in the presence of ELA. The TLA-ET association (lower TLA related to higher ET) remained significant after adjustment for confounding factors. Post-hoc analyses identified toll-like receptor 2 (TLR2) as a gene significantly associated with the M1/M2 phenotype and ELA. The findings support the hypothesis that adversity during sensitive periods uniquely impacts immune function. The study provides evidence for the M1/M2 phenotype as a specific biomarker of ELA and PA, independent of lifetime adversity.

The study's findings highlight the unique immunological effects of adversity exposure during sensitive developmental periods. The association of ELA and PA with a pro-inflammatory M1/M2 phenotype, contrasted with the association of TLA with reduced inflammation, suggests distinct biological mechanisms. The results are discussed in relation to the concept of "trained immunity," where initial exposures to stress might lead to long-lasting alterations in immune responsiveness. The differential effects of ELA and TLA on immune responses were discussed in relation to the contrasting roles of pro-inflammatory and anti-inflammatory responses. The association between TLA and endotoxin tolerance is viewed as evidence that chronic adversity might impair the body's ability to regulate inflammatory responses. The findings raise several questions for future research, specifically regarding the mechanisms underlying the effects of adversity on immune function during these sensitive periods. The study reinforces the importance of considering both timing and cumulative exposure when studying the impact of adversity on health. It suggests the importance of exploring the implications of trained immunity and the possibility of a "weathering effect" from chronic adversity.

This study identifies the macrophage-associated M1/M2 RNA phenotype as a novel biomarker for adversity during early life and pregnancy. The distinct immunological responses to adversity during these sensitive periods highlight the need for a developmental perspective in understanding the long-term health consequences of adversity. Future research should focus on validating the functional significance of the M1/M2 phenotype and exploring the underlying biological mechanisms involved.

The cross-sectional design limits causal inferences. The sample of low-income, ethnically diverse women with a history of interpersonal violence may limit generalizability. The assessment of adversity during only one pregnancy is a limitation. The study's reliance on self-reported adversity may introduce recall bias. The in vitro nature of the M1/M2 assessment simplifies the dynamic in vivo reality, and future research should investigate this.