The immune system plays a vital role in defending the body against disease by fighting off invading pathogens and monitoring personal cellular health. The human body remains within a homeostatic equilibrium, allowing bodily functions to be conducted at an optimum level. When this balance is disturbed, the health of the individual is at risk.
Psychological stress is defined as the neurological response to experiencing environmental demands or events that surpass their ability to cope. Stress is a familiar sensation to all people, usually heightening during periods of urgency and reaching a peak that provides optimum performance. However, beyond this peak, stress can induce symptoms of anxiety or irritability and impede successful results. Prolonged periods of stress can result in mental fatigue and exhaustion and can prompt physical symptoms of distress as the endocrine system responds.
These physical symptoms can manifest as disruptions to the immune system and pose a statistically significant health risk. The Central Nervous System (CNS) has a reciprocal relationship with the immune and endocrine systems, making them vulnerable to fluctuations in stress levels. This field of study is known as psychoneuroimmunology.
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How Stress Acts on the Immune System: The Endocrine Route
Stress triggers the sympathetic nervous system to release hormones as a survival instinct. These hormones are produced by the sympathetic-adrenal-medullary (SAM) axis and the hypothalamic-pituitary-adrenal (HPA) axis. The HPA axis is modulated by cytokines and feedback to the brain.
The SAM axis stimulates the release of Epinephrine (Adrenaline) and Norepinephrine (Noradrenaline) as an immediate response to stress. These hormones are catecholamines that work in tandem to produce the symptoms colloquially known as the ‘fight or flight’ response. Norepinephrine is the main neurotransmitter for the sympathetic nervous system while Epinephrine is released from the adrenal glands situated above the kidneys.
Epinephrine produces metabolic changes such as raised heart rate, blood pressure, and raised blood sugar levels. Norepinephrine is typically responsible for cardiac tone and is active even during sleep. However, when levels of Norepinephrine increase due to stress, it activates a response from the HPA axis.
The hypothalamus releases corticotrophin-releasing hormone (CRH), which induces the pituitary gland to release adrenocorticotropic hormone (ACTH). This hormone binds to the adrenal glands, causing the secretion of Cortisol and other glucocorticoids. Cortisol increases blood sugar levels and diverts the glucose to the muscles by suppressing systems deemed less important in the present situation; this includes the immune system.
Immune System Suppression and Health Consequences
Hormones alter the function of the immune system by directly binding to immune cell receptors or affecting brain chemistry through the negative feedback of cytokines. This can affect appetite and sleep, producing more serious health effects such as a reduced immune response to disease. These immune consequences have been chronicled through multiple studies.
Restraint stress on mouse models infected with influenza virus shows a marked difference between stressed animals and controls. Proinflammatory and anti-inflammatory cytokines were increased, while levels of antibodies produced in response to the virus were reduced over time. Stress was highlighted as a key cause as suppression of the glucocorticoid receptor resulted in stressed mice resembling the controls in the aforementioned immune responses.
Vaccine studies have been thoroughly investigating the effect of stress on the immune response. Medical students with differing levels of stress or anxiety took part in a study with the Hepatitis B vaccine. Stressed groups demonstrated a reduction in antibody and virus-specific T-cell responses. Social support was also identified to have an ameliorating effect on immune alterations.
Caregivers as a study group are often utilized within this sphere of vaccine literature due to the marked chronic stress of their daily lives. An influenza vaccine trial between caregivers and non-caregivers identified a weaker antibody and virus-specific T-cell response in the caregiver group. The same response was replicated with the rubella vaccine. Production of proinflammatory cytokines has also been found to increase with chronic stress.
Upon investigation with bacterial vaccines, caregivers produced lower levels of IgG antibodies to the pneumococcal vaccine in comparison to controls. This response was supported through replication in another study using the meningitis conjugate vaccine. These data are important to highlight that individuals under stress are not only at a higher risk of poor immune responses to infection but also to vaccinations.
Wound healing is another casualty of stress and the endocrine modulation of the immune system. A study using restraint-stressed mice demonstrated a 27% inhibition of wound healing in comparison to unstressed controls. This response was alleviated by blocking the glucocorticoid receptor.
A standardized dermal wound was used for further investigations with the student and caregiver groups. The same cohort of students were investigated during holiday and exam periods, resulting in a 40% slower response to wound healing during the latter. Caregivers showed a 24% lag in wound healing in comparison to control subjects. Both studies found that stimulated peripheral blood leukocytes had a decrease in IL-1β mRNA levels in stressed individuals.
Chronic stress has a ripple effect on the health of an individual. Stress diverts the metabolic resources of the body towards facing the source and repressing less immediate bodily functions. The immune system is directly disrupted by the endocrine response to stress.
During these periods, individuals are at risk of poor immune responses to infections, wound recovery, and reduced immunity conferred from vaccinations. In addition to this, the production of pro-inflammatory cytokines is increased, posing a tissue damage threat resulting from prolonged inflammation.
Several severe diseases such as some cancers and cardiovascular diseases have an association with high serum levels of cytokines like IL-6. With the current shift towards vaccinations as a means of mitigating the most extreme diseases – such as coronavirus and the development of some cancers – stress will be a key factor to assess in association with vaccine success. Dissemination of knowledge of the relationship between stress and the immune system is important to improve collective public health.
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References:
- Godbout, J.P., Glaser, R. Stress-Induced Immune Dysregulation: Implications for Wound Healing, Infectious Disease, and Cancer. Jrnl Neuroimmune Pharm 1, 421–427 (2006). <https://doi.org/10.1007/s11481-006-9036-0>
- Chrousos GP. Stress and disorders of the stress system. Nat Rev Endocrinol. 2009 Jul;5(7):374-81. doi: 10.1038/nrendo.2009.106. Epub 2009 Jun 2. PMID: 19488073. <https://pubmed.ncbi.nlm.nih.gov/19488073/>
- Glaser, R. and Kiecolt-glaser, J., 2009. Stress Damages Immune System and Health. [online] Discoverymedicine.com. Available at: <https://www.discoverymedicine.com/Ronald-Glaser/2009/07/18/stress-damages-immune-system-and-health/>.
- @neurochallenged. 2014. Know your brain: HPA axis. [online] Available at: <https://neuroscientificallychallenged.com/posts/what-is-the-hpa-axis>.
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