This comprehensive review establishes a foundational framework for understanding neuropsychiatric and systemic diseases by examining the intricate bidirectional communication between the central nervous system, peripheral organs, and immune system. It begins with a detailed exposition of how the brain exerts top‑down regulatory control over peripheral physiology and immunity through multiple organ–brain axes such as the brain–gut, brain–liver, and brain–spleen axes. These pathways employ a diverse repertoire of signaling modalities—including neural, endocrine, and immune messengers—to preserve systemic homeostasis, and when dysregulated, they contribute to a wide spectrum of conditions ranging from metabolic disorders and impaired liver regeneration to cancer progression. This review then shifts to a bottom‑up perspective, exploring how the immune system profoundly influences neural function and overall homeostasis, with regulatory T cells (Tregs) positioned at the center as essential guardians of neuroimmune equilibrium. It elaborates on their multifaceted roles, which extend beyond classic immunosuppression to modulate microglial activity, promote oligodendrocyte remyelination and tissue repair, and directly influence neuronal circuits via neuropeptide signaling, thereby highlighting Treg dysfunction as a convergent pathological mechanism underlying disorders such as multiple sclerosis, autoimmune encephalitis, major depressive disorder, and schizophrenia. This review further illustrates immune‑to‑neural impact by dissecting the pathogenic mechanisms of autoantibodies in autoimmune encephalitis—showing how these antibodies can induce reversible synaptic dysfunction or irreversible neuronal loss—and ultimately advocates a holistic, systems‑level approach that integrates peripheral immune modulation with targeted neural interventions to pave the way for innovative therapeutic strategies aimed at recalibrating this complex regulatory network for treating multifactorial diseases, thereby offering new avenues for precision medicine.
Feng et al. (Tue,) studied this question.