Summary:
The hypothalamic-pituitary-adrenal (HPA) axis is the body’s primary system for responding to stress and coordinating signals between the brain and hormones to regulate immune function and inflammation. Chronic stress can disrupt this system, which may contribute to the development or worsening of autoimmune diseases, where the immune system mistakenly attacks the body’s own tissues. While genetics, environment, and hormones all play a role, stress-related HPA dysfunction is increasingly recognized as a key factor. This study examines how impaired HPA activity promotes a pro-inflammatory state that can trigger or exacerbate autoimmune diseases such as rheumatoid arthritis, lupus, and multiple sclerosis. It explored how prolonged stress can interfere with cortisol regulation, reducing the body’s anti-inflammatory capacity, disturbing cytokine balance, and weakening protective immune cells. Persistent HPA dysfunction can shift the immune system toward autoimmunity and impact multiple organ systems, including neuroimmune, cardiovascular, gastrointestinal, skin, and musculoskeletal systems. Clinical data show that patients with autoimmune diseases often have elevated cortisol levels, supporting the link between chronic stress and disease. Targeting stress-responsive pathways through lifestyle interventions, stress management, or therapies aimed at restoring HPA function may help prevent or reduce autoimmune disease risk. Future research could clarify whether HPA axis changes are reversible and identify factors that enhance resilience to stress-induced immune dysfunction.
Abstract:
Autoimmune diseases are chronic inflammatory conditions characterized by the breakdown of immune tolerance to self-antigens. While genetic and environmental factors play key roles, growing evidence highlights chronic stress as a significant contributor to immune dysregulation through its impact on the hypothalamic–pituitary–adrenal (HPA) axis. The HPA axis, primarily via cortisol secretion, serves as the major neuroendocrine mediator of stress responses, influencing both immune regulation and systemic homeostasis. This review synthesizes current literature on HPA axis physiology, the mechanisms of cortisol signaling, and the maladaptive effects of chronic stress. Emphasis is placed on clinical and experimental findings linking HPA dysfunction to immune imbalance and autoimmunity, as well as organ-specific consequences across neuroimmune, endocrine, cardiovascular, gastrointestinal, integumentary, and musculoskeletal systems. Chronic stress leads to impaired HPA axis feedback, glucocorticoid receptor resistance, and paradoxical cortisol dysregulation, fostering a pro-inflammatory state. This dysregulation promotes cytokine imbalance, weakens protective immune mechanisms, and shifts the immune response toward autoimmunity. Evidence from both human and animal studies associates persistent HPA dysfunction with diseases such as systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis. HPA axis dysregulation under chronic stress constitutes a critical mechanistic link between psychological stress and autoimmune disease. Understanding these pathways provides opportunities for therapeutic interventions, including stress management, lifestyle modification, and neuroendocrine-targeted treatments. Future research should focus on multi-omics and longitudinal approaches to clarify the reversibility of HPA alterations and identify resilience factors.
Article Publication Date: 14/10/2025
DOI: 10.3390/ijms26209994
