Stress Induced Immune Dysfunction

Introduction

A relatively new branch of interdisciplinar science called “psychoneuroimmunology” looks into the interactions among psychological states, neurological system and immune functions. The studies indicate that psychological stress suppresses various parameters of immune functions and consequently can cause diseases. They suggest that depending on the nature of stressor (acute or chronic) the impact upon the immune function may be different. Brief acute stress enhancing some parameters of immunity whereas chronic stress adversely affecting almost all parameters of immune functions.

Stress and immune functions are mediated by the hypothalamic-pituitary-adrenal (HPA) axis and the autonomic (sympathetic and parasympathetic) nervous system. In addition, there is a possibility of behavioral pathways (such as alcohol intake, sleep disturbances) through which stress affects immune functions.

It is now well established with the help of psychoneuroimmunology, that there are very complex bi-directional interactions between the CNS and the immune system mediated by the endocrine system. Two important aspects of these interactions include the production of stress hormones by the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic-adrenal-medullary (SAM) axis.

Stress-induced immune dysregulation has been shown to be significant enough to result in health consequences: • Including reducing the immune response to vaccines• Slowing wound healing• Reactivating latent herpes viruses, such as Epstein–Barr virus (EBV)• Enhancing the risk for more severe infectious disease.

Chronic stress/depression can increase the peripheral production of proinflammatory cytokines, such as interleukin (IL)-6. High serum levels of IL-6 have been linked to risks for several conditions, such as:

• Cardiovascular disease• Type 2 diabetes• Mental health complications • Some cancers.

Stress and stressors

Stress can be defined as a psychophysiological process, usually experienced as a negative emotional state.It is a product of the appraisal of a situation and the resulting coping ability available to the individual.Stressors, defined as events posing threat, are judged in the context of dispositional and environmental factors.

Stressors may be: • Physical (i.e. infection, chemical exposure)• Cognitive (death of a loved one, perception of

imminent danger)• Combination of both physical and cognitive

(firefighter on a 24-h shift).Stressors are further classified into:

• Acute (minutes to hours)• Subchronic (less than 1 month)• Chronic (months to years).

Some investigators have used the terms `eustress' and `distress' to describe situations in which stressors do not cause harm or alter homeostasis, respectively.

As mentioned before stress response results inactivation of both the hypothalamic-pituitary-adrenal axis (H-P-A) and the sympathetic nervous system (SNS). By activating these they provoke the release of pituitary and adrenal hormones.

For example, the catecholamines (adrenaline and noradrenaline), adrenocorticotropic hormone (ACTH), cortisol, growth hormone and prolactin are all influenced by negative events and negative emotions, and each of these hormones can induce quantitative and qualitative changes in immune function. Furthermore, depression can substantially boost cortisol levels, and increases in cortisol levels can provoke multiple adverse immunological changes.

The body's primary stress management system is the HPA axis. The HPA axis responds to physical and mental challenge to maintain homeostasis in part by controlling the body's cortisol level. Dysregulation of the HPA axis is implicated in numerous stress-related diseases.

HPA axis activity and cytokines are intrinsically intertwined: inflammatory cytokines stimulate adrenocorticotropic hormone (ACTH) and cortisol secretion, while, in turn, glucocorticoids suppress the synthesis of proinflammatory cytokines.

Almost all immune cells have receptors for one or more of the hormones that are associated with the HPA and SAM axes; these are called ‘stress’ hormones. Immune modulation by these hormones might proceed through two pathways:

Directly, through binding of the hormone to its cognate receptor at the surface of a cell

Indirectly — for example, by inducing dysregulation of the production of cytokines, such as IFN-γ, IL-1, IL-2, IL-6 and TNF. Cytokines such as IFN-γ have many functions and affect different target cells. Therefore, there are secondary effects of many stress hormones on the immune response.

Mechanism

The paraventricular nucleus (PVN) of the hypothalamus receives excitatory stimuli from the catacholaminergic pathways of the brainstem and limbic forebrain circuits. The central, medial and cortical amygdaloid nuclei connect with the PVN via GABA-containing neurones in the bed of the nucleus of the stria terminalis.

The PVN may also be activated by aminergic input from the locus coeruleus. Activation of glutamatergic neurones in the PVN results in the secretion of corticotropinreleasing hormone (CRH) from nerve terminals in the median eminence. CRH reaches the anterior pituitary gland via the hypophysial portal circulation and stimulates corticotrophs to release adrenocorticotropic hormone (ACTH) into the peripheral circulation.

ACTH subsequently stimulates the production of glucocorticoids by the cells of the zona fasciculata and the zona reticularis of the adrenal cortex. Activation of the SNS causes an increased secretion of catecholamines in nerve termini as well as the adrenal medulla. Psychological stress also has effects on other neuroendocrine pathways such as the hypothalamicpituitary-gonadal axis, which may result in alterations in menstrual cycle regulation.

The neuroendocrine mediators reach the cells of the immune system either through the peripheral circulation or through direct innervation of lymphoid organs. Primary and secondary lymphoid organs are innervated by sympathetic nerve fibers. Lymphocytes and monocytes express receptors for several stress hormones, including CRH, ACTH, cortisol, norepinephrine and epinephrine.