Immunological Factors in Major Depressive Disorder

Major depressive disorder (MDD) has long been viewed through the lens of neurotransmitter imbalance, but accumulating evidence highlights a critical role for immune system dysregulation. Both peripheral and central compartments display heightened inflammatory signatures in a subset of patients, characterised by elevated pro-inflammatory cytokines such as interleukin-1β, interleukin-6 and tumour necrosis factor-α. Peripheral immune cell profiles are altered, with shifts in monocyte subsets and changes in T lymphocyte phenotypes, including regulatory T cell deficits and skewing of CD4+ T helper populations. In the central nervous system, activated microglia and astrocytes release inflammatory mediators that disrupt synaptic plasticity, impair neurogenesis—particularly within the hippocampal dentate gyrus—and compromise blood–brain barrier integrity. Stress-induced hypothalamic–pituitary–adrenal (HPA) axis dysregulation further amplifies immune reactivity through glucocorticoid resistance in immune cells. These intersecting pathways contribute to neural circuit dysfunction underlying mood and cognitive symptoms. An improved understanding of these mechanisms has spurred interest in immunomodulatory biomarkers and therapies, opening avenues for precision medicine in depression.

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Immunological Factors in Major Depressive Disorder publication trend

The graph below shows the total number of articles in immunological factors in major depressive disorder across all publications each year (not limited to Nature Index journals).

Technical terms

Cytokine: A small protein released by immune cells that modulates inflammation and cell signalling.

Microglia: Resident immune cells of the central nervous system that mediate neuroinflammatory responses.

T regulatory cell (Treg): A subset of CD4+ T cells that suppress excessive immune activation and maintain immune tolerance.

Neuroinflammation: Inflammatory processes within the brain involving glial activation and cytokine release.

Mass cytometry (CyTOF): A high-throughput technique for quantifying multiple cell-surface and intracellular markers at the single-cell level.

References

1. Development of machine-learning-driven signatures for diagnosing and monitoring therapeutic response in major depressive disorder using integrated immune cell profiles and plasma cytokines. Theranostics (2024).
2. Integrated Single‐Cell RNA‐seq and ATAC‐seq Reveals Heterogeneous Differentiation of CD4+ Naive T Cell Subsets is Associated with Response to Antidepressant Treatment in Major Depressive Disorder. Advanced Science (2024).
3. Low-dose interleukin 2 antidepressant potentiation in unipolar and bipolar depression: Safety, efficacy, and immunological biomarkers. Brain Behavior and Immunity (2024).