Stress Induced Immune Dysfunction

1. Stress Induced Immune
Dysfunction

2. 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.

3. 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.

4. 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.

5. 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.

6. 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.

8. 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.

9. 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).

10. 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 in
activation 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.

11. 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.

12. 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.

13. 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.

14. 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.

15. 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.

16. 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.

17. 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.