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<p>Adverse childhood experiences (ACEs) represent a critical environmental trigger for the adult comorbidity of depression and autoimmune diseases. This review synthesizes evidence showing that ACEs induce persistent dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis and the sympathetic nervous system, thereby promoting a chronic low-grade inflammatory state. This state is characterized by elevated pro-inflammatory cytokines (e.g., IL-6, TNF-α), immune cell dysfunction, and epigenetic modifications. Facilitated by microglial activation and monocyte-mediated disruption of the blood–brain barrier, this pro-inflammatory milieu disrupts central nervous system homeostasis, contributing to the pathogenesis of both depressive symptoms and autoimmune disorders. Aberrant neuroimmune crosstalk emerges as a core mechanism underlying this comorbidity. Future research must delineate developmental windows of vulnerability and the differential effects of adversity types to translate these insights into novel therapeutic strategies targeting the neuroimmune axis—such as anti-cytokine therapies or vagus nerve stimulation—for high-risk populations.</p> Graphical Abstract <p>Schematic of neuroimmune pathways underlying ACEs-induced comorbidity of depression and autoimmune diseases<b>.</b> This figure summarizes the core pathological cascade through which adverse childhood experiences (ACEs) drive the co-occurrence of depression and autoimmune diseases. ACEs initiate persistent dysregulation of the hypothalamic‑pituitary‑adrenal (HPA) axis and the sympathetic nervous system (SNS), characterized by disturbed release of CRH, ACTH, and cortisol. This neuroendocrine dysfunction promotes systemic immune alterations, including chronic low‑grade inflammation, T‑cell overactivation, reduced regulatory T-cell (Treg) number and function, and epigenetic modifications of immune‑related genes. These immune changes disrupt neuroimmune homeostasis via two major pathways: (1) Peripheral immune activation damages the blood-brain barrier (BBB), allowing inflammatory mediators to enter the central nervous system (CNS), where they activate microglia and amplify neuroinflammation; (2) Sustained neuroinflammation, together with HPA‑axis dysregulation, leads to structural and functional alterations in emotion‑related brain regions (e.g., prefrontal cortex（PFC）, hippocampus), reduced synaptic plasticity, and neurotransmitter imbalance——key neural substrates of depression. Concurrently, the persistent systemic immune dysregulation (chronic inflammation and loss of immune tolerance) directly elevates the risk for various autoimmune disorders. Abbreviations: ACEs, adverse childhood experiences; ACTH, Adrenocorticotropic Hormone; CRH, corticotropin-releasing hormone; DNAm, DNA methylation; HM, histone modification; NIDS, neuro‑immune dysfunction syndrome; PFC prefrontal cortex SPIHR, sustained peripheral immune hyper‑reactivity.</p> <p></p>

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Neuroimmune programming of childhood trauma: comorbid mechanisms and developmental origins of depression and autoimmune diseases

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月18日

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  • Jiajia Wang,
  • Qinglu Xu,
  • Xinge Tang,
  • Aimi Hu,
  • Dengke Zhang,
  • Zheng Liu

摘要

Adverse childhood experiences (ACEs) represent a critical environmental trigger for the adult comorbidity of depression and autoimmune diseases. This review synthesizes evidence showing that ACEs induce persistent dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis and the sympathetic nervous system, thereby promoting a chronic low-grade inflammatory state. This state is characterized by elevated pro-inflammatory cytokines (e.g., IL-6, TNF-α), immune cell dysfunction, and epigenetic modifications. Facilitated by microglial activation and monocyte-mediated disruption of the blood–brain barrier, this pro-inflammatory milieu disrupts central nervous system homeostasis, contributing to the pathogenesis of both depressive symptoms and autoimmune disorders. Aberrant neuroimmune crosstalk emerges as a core mechanism underlying this comorbidity. Future research must delineate developmental windows of vulnerability and the differential effects of adversity types to translate these insights into novel therapeutic strategies targeting the neuroimmune axis—such as anti-cytokine therapies or vagus nerve stimulation—for high-risk populations.

Graphical Abstract

Schematic of neuroimmune pathways underlying ACEs-induced comorbidity of depression and autoimmune diseases. This figure summarizes the core pathological cascade through which adverse childhood experiences (ACEs) drive the co-occurrence of depression and autoimmune diseases. ACEs initiate persistent dysregulation of the hypothalamic‑pituitary‑adrenal (HPA) axis and the sympathetic nervous system (SNS), characterized by disturbed release of CRH, ACTH, and cortisol. This neuroendocrine dysfunction promotes systemic immune alterations, including chronic low‑grade inflammation, T‑cell overactivation, reduced regulatory T-cell (Treg) number and function, and epigenetic modifications of immune‑related genes. These immune changes disrupt neuroimmune homeostasis via two major pathways: (1) Peripheral immune activation damages the blood-brain barrier (BBB), allowing inflammatory mediators to enter the central nervous system (CNS), where they activate microglia and amplify neuroinflammation; (2) Sustained neuroinflammation, together with HPA‑axis dysregulation, leads to structural and functional alterations in emotion‑related brain regions (e.g., prefrontal cortex（PFC）, hippocampus), reduced synaptic plasticity, and neurotransmitter imbalance——key neural substrates of depression. Concurrently, the persistent systemic immune dysregulation (chronic inflammation and loss of immune tolerance) directly elevates the risk for various autoimmune disorders. Abbreviations: ACEs, adverse childhood experiences; ACTH, Adrenocorticotropic Hormone; CRH, corticotropin-releasing hormone; DNAm, DNA methylation; HM, histone modification; NIDS, neuro‑immune dysfunction syndrome; PFC prefrontal cortex SPIHR, sustained peripheral immune hyper‑reactivity.