Question

Can anyone breakdown the neurological interactions of this diagram from my stress and immune system lecture?

"(b) SNS activation releases noradrenaline (from SNS

nerve fibers) into primary and secondary lymphoid organs, other major organ systems (vasculature, perivascular tissues), and many peripheral tissues in which proinflammatory reactions occur. SNS nerve fibers can also stimulate the adrenal glands to release

stored adrenaline into circulation. Both of these neuromediators can enhance pro-inflammatory cytokine responses and gene expression.

Proinflammatory cytokines enhance inflammation and anti-inflammatory cytokines suppress inflammation. Healthy immune function requires balanced pro- and anti-inflammatory cytokines. Depression and anxiety are associated with excessive pro-inflammatory cytokines."

What i want to know are what the structures are and how they interact with each other going from the top with the SNS system from the brain to IL1B, IL6, and TNF genes made down at the bottom. How does the stress response from the SNS affect the immune system based on this diagram?

SNS SNS nerve fibres Circulation Noradrenaline Adrenaline Beta-adrenergic receptor T Expression of pro-inflammatory immune response genes IL1B, IL6, TNF VIVA

Answer 1

Introduction

Interleukin (IL) 1β, IL6 and tumour necrosis factor α (TNFα) are the major inflammatory cytokines that regulate peripheral and CNS-mediated responses to infection and inflammation. These cytokines are products of both activated microglia and activated astrocytes that powerfully stimulate their activity. They have many common redundant and pleiotropic effects, such as T- and B-cell activation, that together contribute to the inflammatory process. Many systemic acute-phase effects are due to the combined action of IL1β, IL6 and TNFα. They play a crucial role in the activation of the hypothalamic-pituitary-adrenal (HPA) axis response to various threats to homeostasis. In addition, they are implicated in the pathophysiology of several diseases, a selection of which includes neurodegenerative disorders, cardiovascular diseases, depression, addictions and pain. Since these and other immune-related disorders are heritable, it can be speculated that part of their genetic background is explained by genetic variation in inflammatory genes producing changes in the amount or structure of these genes. Therefore, genes encoding IL1β, IL6 and TNFα were screened for common functional polymorphisms for association and linkage studies.

Chromosome 2q14–21 contains a cluster of IL1-related genes, including IL1A, IL1B and IL1 receptor antagonist protein (IL1RN). Here, we have focused on IL1B, because of its interaction with IL6 and TNF in the central and peripheral immune response. IL1B has seven exons and is 7 kb in length. In 1992, Pociot et al identified a biallelic (C/T) polymorphism in the IL1B—promoter region (position −511) that affects IL1β secretion in vitro. This marker was used in association studies of the susceptibility to chronic hepatitis B, gastric cancer, multiple cases of sclerosis, Alzheimer's disease and sporadic Parkinson's disease, but association results have been inconsistent across different studies.

IL6 is mapped to chromosome 7p21–24 with an upstream promoter containing 303 bp. It has five exons spanning 4.8 kb in length. A common G/C polymorphism of the IL6 promoter on position −174 has been shown to influence in vivo protein expression. It has been investigated in a wide variety of diseases, including multiple myeloma, coronary heart disease, endometriosis and ovarian cancer. However, linkage studies are contradictory. In addition, this functional marker may be rare in certain populations that make it useless in limited size datasets.

LTA and TNF are located next to each other on chromosome 6p21.3 having three and four exons and spanning 2 and 2.7 kb, respectively. A dimorphism with potential functional relevance (G to A transition at position −308 in the promoter/enhancer region) has been described for the TNF locus. The minor −308A allele was shown to be strongly associated with human leukocyte antigen (HLA)-DR3, known to be related to a TNFα ‘high producer’ phenotype. In support of clinical relevance, the −308A allele is associated with a seven-fold increased risk for cerebral complications of malaria and with a worse prognosis and longer disease duration in dermatitis herpetiformis. However, the same marker was not responsible for differential TNFα production induced by the standard in vitro stimuli.

Although taking into consideration the importance and informativeness of known functional loci in inflammatory genes, it can be assumed that consistent pictures of IL1β, IL6 and TNF genotype-phenotype relationships are yet to emerge. Other functional loci may be present, including polymorphisms which are known but which have not yet been recognized to be functional. A haplotype approach combining known functional polymorphisms with a series of loci chosen for haplotype informativeness could comprehensively capture the potential information content on immune gene functional variants of moderate abundance

The Stress Response

The biological stress response has become well described although much remains to be discovered. Traditionally the stress responses system comprises two arms—the HPA axis and the sympathetic nervous system (SNS), including the sympathoadrenal–medullary (SAM) axis (see Figure 1). Both arms are influenced by the amygdala and the hypothalamus. The first and fastest-acting part of the response is SNS activation, largely equivalent to the fight-flight response of Cannon and the initial stage of Selye's alarm response. The HPA axis is slower to respond in terms of endocrine output.

While the LA acts as the input station of the amygdala, the central nucleus (CE) acts as the main output station, mediating behavioural and autonomic expressions of fear, as well as autonomic and endocrine stress responses by downstream indirect connections to the hypothalamus, to the central grey area, and to the dorsal motor nucleus of the vagus (Rodrigues, LeDoux, & Sapolsky, 2009). There are few direct connections between the LA and the CE. Rather, the information is processed in the B and then projected to the CE. The B also projects to the striatum, mediating behavioural instrumental responses such as avoidance and escape, which are central to coping with the stressor.

SNS and the SAM Axis

The SNS influences the cardiovascular system, the gastrointestinal (GI) tract, respiration, renal, endocrine, and other systems, while the parasympathetic nervous system contributes by “withdrawing” and inhibiting the SNS. The SNS response is mediated by the locus coeruleus (LC)/noradrenergic system, comprising the noradrenergic cells of the medulla and pons. The CE projects to the brain stem to increase noradrenaline (NA) release from sympathetic nerve endings, sympathetic activation, and activation of the adrenal medulla, resulting in increased adrenaline and NA levels, arousal, and vigilance, that is, enhanced processing of external cues. The SAM system releases catecholamines (mostly adrenaline) into the bloodstream while the SNS with cholinergic preganglionic fibres releases NA from postganglionic axons. SNS innervation of peripheral organs is mediated by efferent preganglionic fibres, with cell bodies in the intermediolateral column of the spinal cord. These synapse in the sympathetic ganglia with postganglionic neurons, which innervate the vascular smooth muscle, heart, skeletal muscles, gut, kidney, fat, etc. Blood pressure and heart rate are elevated and energy resources are diverted to the musculature and away from vegetative functions.

At the same time, the hypothalamus is activated by the amygdala (largely indirectly; Herman et al., 2003) to release corticotropin-releasing hormone (CRH), and HPA activation ensues. Thus the two arms of the stress response system are both closely connected with amygdala and brain-stem function. Through its projections to the amygdala, the SNS enhances long-term storage of aversive emotional memories in the hippocampus and striatum. Noradrenergic responses to stressors may be modulated by higher centres such as the mesocortical/mesolimbic systems (influencing effect and anticipation); the amygdala and hippocampus, modulating the stress output (initiation, propagation, and termination of the response); and the arcuate nucleus, modulating pain.

The HPA Response

CRH is secreted from cells of the medial parvocellular division of the paraventricular nucleus (PVN) of the hypothalamus into the hypophyseal portal system and acts on CRH receptors in the anterior pituitary to release adrenocorticotropic hormone (ACTH) into the systemic circulation. CRH and its receptors are found also in extrahypothalamic structures, including limbic areas and the arousal systems of the LC and spinal cord, as well as in several peripheral tissues—adrenal medulla, heart, prostate, gut, liver, kidney, and testes. CRH receptors comprise two subtypes—CRH-R1, the most abundant in the anterior pituitary but also found throughout the brain, and CRH-R2, found in both peripheral tissues and subcortical brain areas.

ACTH is, together with α-MSH (melanocyte-stimulating hormone) and the endogenous opioids β-endorphin and encephalin, a product of cleavage of the proopiomelanocortin (POMC) molecule. Vasopressin (AVP) may synergistically interact with the CRH system to activate the anterior pituitary, although, by itself, AVP has little corticotropic action (Tsigos & Chrousos, 2002).

There are few direct projections between the amygdala and the PVN. Rather, amygdala influence over HPA activity is mediated by projections of the amygdala to the bed nucleus of the stria terminalis. Additionally, the PVN is influenced by input from the nucleus of the solitary tract, the Raphé nuclei, the subfornical organ, the thalamus, other hypothalamic areas (dorsomedial nucleus, medial preoptic area, lateral hypothalamic area, arcuate nucleus, etc.), the hippocampus, the PFC, and the lateral septum. Thus responses to both psychogenic and systemic stressors are mediated by brain-stem structures, allowing for an integrated response (Herman et al., 2003).

Circulating ACTH from the anterior pituitary leads to secretion from the adrenal cortex of glucocorticoid (GC) hormones, including cortisol and corticosterone. ACTH also stimulates release from the adrenal cortex of the neurosteroid dehydroepiandrosterone, a precursor for testosterone and dihydrotestosterone.

The HPA and SNS arms interact. NA and CRH stimulate each other, partly through α-1-NA receptors, and both systems are self-regulating through autoregulatory feedback loops. Both systems are regulated by the same central neurotransmitter systems and both are stimulated by serotonin and acetylcholine. Negative feedback systems involve GCs, gamma-aminobutyric acid (GABA), ACTH, and opioid peptides. NA-stimulated glycogenolysis is facilitated by GCs, being just one example of the interdependence of the HPA and SAM systems. In addition to facilitating energy mobilization, the HPA axis functions to inhibit the sympathetic and adrenomedullary systems and to terminate the immediate defence response, while promoting behavioural adaptation (de Kloet & Joëls, 2013; Munck, Guyre, & Holbrook, 1984).

GCs stimulate the release of stored energy (gluconeogenesis) by glycogenolysis, lipolysis, and proteolysis and act on several, if not most, organ systems, including the brain, the immune system, and the reproductive endocrine system. GC effects are exerted at cytoplasmic receptors but also have membrane effects via endocannabinoid mobilization (de Kloet & Joëls, 2013). Activated cytoplasmic receptors migrate to the cell nucleus where they interact with DNA to activate specific hormone-response genes, also inhibiting other transcription factors including NF-κB, which are positive regulators of genes involved in the activation and growth of immune cells, among others (Tsigos & Chrousos, 2002).

GCs act on two nuclear receptors, high-affinity mineralocorticoid receptors (MRS) and low-affinity GC receptors (GRs). The levels of circulating GCs activate these receptors differentially, with resting levels stimulating primarily Mrs and high levels stimulating GRs and Mrs This differential activation forms the basis of the inverted U-shaped curve relating GC levels to cognitive performance and organismic function (Herbert et al., 2006). Poor performance is associated with moderate activation of the MRS and no activation of GRs, as well as with high activations of both. Performance is enhanced when most of the MRS and some of the GRs are activated (de Kloet & Joëls, 2013).

Because the GCs are relatively accessible to measurement in blood, urine, saliva, hair, and faeces and because they are relatively stable, they have commonly used indices of the stress response, particularly in field and clinical settings. Measurement of the sympathetic arm and SAM is less straightforward because of the rapidity of the response. Peak serum levels of cortisol are generally found at 15–20 min after the HPA system is activated, allowing a reasonable time for sampling, in contrast to ACTH and sympathetic activation, with rising times of seconds and less stability (Eriksen et al., 1999). GC levels in other tissues and body fluids have different rise times, which need to be taken into account in laboratory or field studies. The development of assays for GCs in hair is particularly useful for estimating the long-term output of the axis (Stalder & Kirschbaum, 2012). Noninvasive measures in the animal laboratory and field studies, primarily in faeces, are increasingly used, avoiding the complications of handling and anaesthesia (Lane, 2006; Rehbinder & Hau, 2006).

Interpretation of GC levels must take into account that much (c. 95%) of the GCs secreted from the adrenal cortex are bound to corticosteroid-binding globulin (CBG; transcortin) (Henley & Lightman, 2011). Thus only about 5% of secreted GCs are available for acting on tissue receptors. CBG levels may themselves be affected by stress. Some stressors in animals (e.g., inescapable shock and chronic social stress) downregulate levels of CBG, increasing free levels of GCs available to the tissues (e.g., Fleshner et al., 1995; Spencer et al., 1996). CBG also binds progesterone, and women on oral contraceptives have elevated levels, lower salivary cortisol levels, and higher total cortisol levels following the Trier Social Stress Test (Kumsta, Entringer, Hellhammer, & Wüst, 2007). The choice of measurement (free, bound, or total GC) will depend on whether the experimenter is concerned with the total output of the HPA axis or only the biologically active component.

In nonstressful situations, CRH and AVP are secreted in a pulsatile fashion with a circadian pattern generated by inputs from the suprachiasmatic nucleus (Lightman et al., 2008; Walker, Terry, & Lightman, 2010). Pulsatile activity increases in the early hours of the active cycle manifest in increased GC levels in the early morning in humans (the opposite in nocturnal species), and a fall through the day, reaching a nadir in the evening. The cycle is affected by factors such as light and feeding schedules, with light being the most potent zeitgeber, and by stressors.

The output of the HPA system is modulated by several factors, including AVP of magnocellular origin, cytokines, inflammatory mediators, and angiotensin II. Furthermore, although adrenocortical secretion of cortisol is primarily under the influence of ACTH, the adrenal cortex also receives innervation from the autonomic nervous system.