Psycho-Neuro-Immunology (PNI) is the study of the interactions between the central nervous system (brain and spinal cord), the endocrine system, and the immune system and how psychological stressors modulate these interactions. Ongoing research suggests that the mind and body share bidirectional influences and the science of Psycho-Neuro-Immunology identifies specific mechanisms by which these mind-body changes are mediated. The mind and body share continuous bidirectional communication through chemical messengers (neurotransmitters, neuroendocrine hormones and cytokines). Positive and negative mental states - create different neuroendocrine and immune responses in the body and thus influence health and disease.  


PNI Communication:  


Both the CNS and the immune system, produce certain chemical messengers, which they use to interact and communicate with one another.  


The CNS: uses neurotransmitters and neuroendocrine hormones to communicate with the immune system.  

The immune system: uses cytokines (small proteins) to communicate with the CNS. 


How does the CNS and Immune System use Chemical Messages to Communicate? 


The CNS communicates with the immune system via the autonomic nervous system (ANS), specifically the sympathetic nervous system (fight and flight) and with neuroendocrine hormones, specifically adrenaline.  


Both of these pathways use chemical messengers to interact with the immune system via neuropeptide receptors located on the surface of lymphocytes (WBC) and other immune cells.  

In turn, an activated immune system, produce chemical messengers – cytokines - that interact with the CNS.  


Thus, these bidirectional pathways connect the brain, the endocrine system and the immune system. 


Stress and Cytokines: 


Stress (both psychological and physical) has a significant impact on both the CNS and immune system, due to its ability to stimulate the production of cytokines.  


Cytokines are chemical messengers that get released by stimulated immune cells. There are many different types of cytokines, but the ones that get released by stress are called pro-inflammatory cytokines, which mediate both systemic and neuro-inflammation.  


Under normal circumstances, your immune system will release pro-inflammatory cytokines in response to an infection (to destroy pathogens) or in response to an injury (to repair the damaged tissue).  


Stress, also causes your body to release certain neuroendocrine hormones (adrenaline and noradrenaline), which have been shown to modulate the immune system. Adrenaline can bind to adrenergic receptors on immune cells that signal for the production of pro-inflammatory cytokines.  


Stress impacts immune function through emotional and behavioural manifestations such as; anxiety, fear, tension, anger and sadness.  


Physiological changes due to stress include; increased heart rate, blood pressure, and sweating. These changes are beneficial – acutely - but when stress is chronic, the body is unable to maintain equilibrium (homeostasis) - the body remains in a state of hyperarousal, causing digestion to become slower and sluggish (indigestion) and blood pressure to remain at higher levels.


The Immune-Brain Loop  

HPA axis and SNS 


The immune system and the brain communicate through signalling pathways. The brain and the immune system are the two major adaptive systems of the body, which work to maintain balance within the body (homeostasis).  

The brain and immune systems use two major pathways to communicate: 


1) The Hypothalamic-pituitary-adrenal axis (HPA axis) - stress response   

2) The sympathetic nervous system (SNS) - fight and flight  

*This communication is known as the sympathetic-adrenal-medullary axis (SAM axis).  


The activation of SNS (fight or flight) during an immune response may be a way for the body to localize the inflammatory response. 


The HPA axis is the body's primary stress management system. The HPA axis responds to physical and psychological stressors by controlling cortisol levels, to maintain homeostasis.  


Dysregulation of the HPA axis is at the root of any stress-related diseases. The different types of stressors as well as the duration of stressors, combined with our unique personal variables - defines our individual HPA activity and response to perceived stress. 


Stress (HPA axis) and Cytokines: 


There is a close relationship between stress (HPA axis) and pro-inflammatory cytokines:  

Pro-inflammatory cytokines: stimulate ACTH and cortisol secretion = stress. 

*Anti-inflammatory glucocorticoids: suppresses the synthesis of pro-inflammatory cytokines.  



Immune System Involvement 


Pro-inflammatory cytokines, include: interleukin-1 (IL-1), Interleukin-2 (IL-2), interleukin-6 (IL-6), Interleukin-12 (IL-12), Interferon-gamma (IFN-Gamma) and tumor necrosis factor alpha (TNF-alpha).  


Immune cells: macrophages and glial cells (microglia and astrocytes) secrete cytokines.  


Cytokines mediate and control immune and inflammatory responses. 


Pro-inflammatory cytokines can induce neuro-inflammation which in turn impacts brain growth and neuronal function. 

Complex interactions exist between: cytokines, inflammation and the adaptive responses (immune and nervous systems) in maintaining homeostasis.  


Acute inflammation as well as acute stress is crucial for survival. Which is mediated by the SNS and HPA axis. However, chronic inflammation and chronic stress, leads to the dysregulation of PNI.  


Cytokines and Disease: 


Common human diseases such as allergies, autoimmunity, chronic infections and sepsis are all characterized by an imbalance between pro-inflammatory and anti-inflammatory cytokines as well as dysregulation between T helper 1 (Th1) versus T helper 2 (Th2) cytokine balance.  


Pro-inflammatory cytokines mediate neuro-inflammation, which is associated with depression, mania, bipolar disease and generalised anxiety disorders.


Chronic Inflammation and Pathology: 


The failure of the adaptive systems (brain and immune system) to resolve inflammation = impacts the well-being of an individual, including: their behaviour, sleep, metabolic and cardiovascular health, due to hyperactivity of the SNS and HPA axis, mediating chronic stress and inflammation, which may contribute to the pathogenesis of disease. 


Chronic neuroimmune activation has been shown to play a role in the pathogenesis of neurodegenerative disorders such as Parkinson's and Alzheimer's disease, multiple sclerosis, pain, and AIDS-associated dementia. 


Stress Hormones

 Neuroendocrine Involvement 


Chronic secretion of stress hormones: glucocorticoids and adrenaline (as a result of disease) may reduce the effect of neurotransmitters (serotonin, noradrenaline and dopamine) and other receptors located in the brain - leading to the dysregulation of neuroendocrine hormones.  


Catecholamines: noradrenaline and adrenaline – have been shown to modulate the immune system by influencing the activity of lymphocytes and can modulate cytokine production.  


Glucocorticoids (anti-inflammatory) - inhibits the secretion of corticotropin-releasing hormone (CRH) from the hypothalamus and ACTH from the pituitary = reduces stress (HPA axis activation).  


Communication between Glucocorticoids (GCs) and the Immune System:  


1) GCs are anti-inflammatory hormones, which improves an organism's response to stress.  

2) GCs prevent the overreaction of the body's own defence system. 

3) GCs regulate the immune system = immunosuppressive.  


Corticotropin-Releasing Hormone (CRH)


CRH is released from the hypothalamus in response to physical and psychological stress. The hypothalamus links the nervous system to the endocrine system via the pituitary gland (neuroendocrinology) and functions to maintain homeostasis within the body.  


1) CRH is a major regulator of the HPA axis (stress response). 

2) CRH regulates secretion of ACTH (type of stress hormone).  

3) CRH regulates the actions of the immune system (pertaining to both pro and anti-inflammatory action).   

4) CRH regulates the SNS (fight and flight response).  


*Stressors that enhance the release of CRH = suppresses immunity.   

*Stressors that depress the release of CRH = potentiates immunity.