The immune-brain-gut-endocrine axis

This is the third installment of my short review of immune function. For part one (basics) see here and part two (vitamin D) see here. A discussion of CPPS and immunity and some other related topics will follow within the next days.

While the existence of communication between the immune system and other bodily organs may seem an obvious proposition it was not so not long ago. It is only during the last 30 years that it has been appreciated that the immune system and especially the brain (or rather certain parts of the brain) and the immune system “talk” with each other. The exchange of information modulates behavioral and physiological responses to immune insults and immune responses to conscious and semi-conscious behavioral responses to environmental stressors.

Two pathways link the brain and the immune system: signaling through nerves (e.g. neocortical-sympathetic axis and brainstem-vagus pathway) of the autonomic nervous system (ANS), and “neuroendocrine humoral outflow via the pituitary” (that is: substances transported by/in blood, lymph, saliva etc) or rather under HPA axis control. The major ANS component involved in this is the sympathetic nervous system (SNS). This connection has also been evidenced by the alteration of immune function through behavioral conditioning (e.g. that stress both can drive a pro- and anti-inflammatory response) and specific brain lesions.

The ANS is further divided in three sub-systems: the sympathetic (or noradrenergic) nervous system, the parasympathetic (or cholinergic) nervous system and the (semi-autonomous) enteric nervous system that lies entirely within the wall of the gastrointestinal tract (a sort of second brain in the belly) and that connects to both the SNS and PSNS (via e.g. the vagus nerve).(1)

During immune challenge (or cellular damage for any reason) or stress (work, social etc) the immune system is similarly activated. Levels of norepinephrine (noradrenalin), CRH, vasopressin and other substances change inducing immune activation. The the individual differences in activation are dependant both on early-life events and genes.(2)

Pro-inflammatory cytokines activate the HPA axis which induces increased plasma concentrations of CRH, vasopressin, ACTH and cathecolamines (e.g. epinephrine and noreepinephrine). Activation of the immune system does also induce fever (not always) and sickness behaviour. That immune cytokines cause sickness behaviour has been amply demonstrated due to cytokine therapy of cancer patients, as the symptoms almost immediately disappear upon discontinuation of treatment. It may be interesting to note that “full blown” sickness behaviour is caused by IL-2 and/or IFN-alpha(3). Of special interest is that the fatigue and irritability, commonly seen in CPPS is “caused” by IFN-alpha (which btw, in conjunction with IFN-beta, is central to anti-viral immune response).

An overactive HPA-axis with concomitant hypercortisolemia, is commonly seen in (cytokine-induced) depression. Some anti-depressants have been shown to induce cytokine suppression (and thus immune suppression and regulation), which is interesting in view of the use of anti-depressants against over-active bladder and other micturition disorders. The exact mechanisms are not fully known.

Other cytokine-“antagonists” used in micturition disorders are etanercept and infliximab (both are TNF-alpha-antagonist). (4)

Human visceral obesity is associated with HPA alterations. Cause and effect are still unclear though, but low testosterone and high glucocorticoids result in increased fat. As visceral fat increases it will suppress testosterone and enhance cortisol. (5)

Other substances affecting the immune system are e.g. prolactin, TSH, GH, GNRH and IGF-1. Hyperprolactinemia has e.g. been observed in 20% of SLE sufferers. Low IGF-1 is associated with cognitive decline and sickness behaviour, and low GH with anxiety and depression. IGF-1 is interesting as excercise increases its ratio visavi pro-inflammatory cytokines. Maybe a reason (in addition to the ussal endorphins) why CPPS sufferers (and others) feel better after excercise?(6)

CPPS, prostatit, kroniskt bäckenbottensmärtsyndrom, immune brain gut endocrine axis, enteric immune system, vagus nerve, immunity, cytokines.
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(1) Elenkov IJ, Wilder RL, Chrousos GP, Vizi S. The sympathetic nerve-an integrative interface between two supersystems: the brain and the immune system. Pharmacol Rev 52(4):595-638, 2000.
(2) Anisman H. Cascading effects of stressors and inflammatory immune system activation: implications for major depressive disorder. [2008 CCNP Heinz Lehman Award Paper]. J Psychiatry Neursci 34(1):4-20, 2009.
(3) IFN-beta causes fatigue, depression and “mental fog”. TNF-alpha fatigue and anorexia. IL-2 fatigue, anhedonia (listlessness), dysphoria (depression, anxiety, irritability, restlessness) and “mental fog”. IFN-alpha fatigue, depression, psychomotor slowing, anxiety, social withdrawal, irritability, anorexia and “mental fog”.
(4) Schiepers OJG, Wichers MC, Maes M. Cytokines and major depression. Prog Neuropsychopharmacol Biol Psychiatry. 29(2):201-217, 2005.
(5) Nieuwenhuizen AG, Rutters F. The HPA axis in the regulation of energy balance.
(6) Kelley KW, Weigent DA, Kooijman R. Protein hormones and immunity. Brain Behav Immun 21:384-292, 2007.