Tag: glucocorticoid receptors

High-fidelity discrete modeling of the HPA axis: a study of regulatory plasticity in biology

Abstract:

BACKGROUND: The hypothalamic-pituitary-adrenal (HPA) axis is a central regulator of stress response and its dysfunction has been associated with a broad range of complex illnesses including Gulf War Illness (GWI) and Chronic Fatigue Syndrome (CFS). Though classical mathematical approaches have been used to model HPA function in isolation, its broad regulatory interactions with immune and central nervous function are such that the biological fidelity of simulations is undermined by the limited availability of reliable parameter estimates.

METHOD: Here we introduce and apply a generalized discrete formalism to recover multiple stable regulatory programs of the HPA axis using little more than connectivity between physiological components. This simple discrete model captures cyclic attractors such as the circadian rhythm by applying generic constraints to a minimal parameter set; this is distinct from Ordinary Differential Equation (ODE) models, which require broad and precise parameter sets. Parameter tuning is accomplished by decomposition of the overall regulatory network into isolated sub-networks that support cyclic attractors. Network behavior is simulated using a novel asynchronous updating scheme that enforces priority with memory within and between physiological compartments.

RESULTS: Consistent with much more complex conventional models of the HPA axis, this parsimonious framework supports two cyclic attractors, governed by higher and lower levels of cortisol respectively. Importantly, results suggest that stress may remodel the stability landscape of this system, favoring migration from one stable circadian cycle to the other. Access to each regime is dependent on HPA axis tone, captured here by the tunable parameters of the multi-valued logic. Likewise, an idealized glucocorticoid receptor blocker alters the regulatory topology such that maintenance of persistently low cortisol levels is rendered unstable, favoring a return to normal circadian oscillation in both cortisol and glucocorticoid receptor expression.

CONCLUSION: These results emphasize the significance of regulatory connectivity alone and how regulatory plasticity may be explored using simple discrete logic and minimal data compared to conventional methods.

Source: Sedghamiz H, Morris M, Craddock TJA, Whitley D, Broderick G. High-fidelity discrete modeling of the HPA axis: a study of regulatory plasticity in biology. BMC Syst Biol. 2018 Jul 17;12(1):76. doi: 10.1186/s12918-018-0599-1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6050677/ (Full article)

Polymorphism in COMT is associated with IgG3 subclass level and susceptibility to infection in patients with chronic fatigue syndrome

Abstract:

BACKGROUND: Chronic fatigue syndrome (CFS) is considered as a neuroimmunological disease but the etiology and pathophysiology is poorly understood. Patients suffer from sustained exhaustion, cognitive impairment and an increased sensitivity to pain and sensory stimuli. A subset of patients has frequent respiratory tract infections (RRTI). Dysregulation of the sympathetic nervous system and an association with genetic variations in the catechol-O-methyltransferase (COMT) and glucocorticoid receptor genes influencing sympathetic and glucocorticoid metabolism were reported in CFS. Here, we analyzed the prevalence of SNPs of COMT and glucocorticoid receptor-associated genes in CFS patients and correlated them to immunoglobulin levels and susceptibility to RRTI.

METHODS: We analyzed blood cells of 74 CFS patients and 76 healthy controls for polymorphisms in COMT, FKBP5 and CRHR1 by allelic discrimination PCR. Serum immunoglobulins were determined by immunoturbidimetric technique, cortisol levels by ECLIA.

RESULTS: Contrary to previous reports, we found no difference between CFS patients and healthy controls in the prevalence of SNPs for COMT, FKBP5 and CRHR1. In patients with the Met/Met variant of COMT rs4680 we observed enhanced cortisol levels providing evidence for its functional relevance. Both enhanced IgE and diminished IgG3 levels and an increased susceptibility to RRTI were observed in CFS patients with the Met/Met variant. Such an association was not observed in 68 non-CFS patients with RRTI.

CONCLUSION: Our results indicate a relationship of COMT polymorphism rs4680 with immune dysregulation in CFS providing a potential link for the association between stress and infection susceptibility in CFS.

 

Source: Löbel M, Mooslechner AA, Bauer S, Günther S, Letsch A, Hanitsch LG, Grabowski P, Meisel C, Volk HD, Scheibenbogen C. Polymorphism in COMT is associated with IgG3 subclass level and susceptibility to infection in patients with chronic fatigue syndrome. J Transl Med. 2015 Aug 14;13:264. doi: 10.1186/s12967-015-0628-4. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4536662/ (Full article)

 

Glucocorticoid receptor mediated negative feedback in chronic fatigue syndrome using the low dose (0.5 mg) dexamethasone suppression test

Abstract:

BACKGROUND: Chronic fatigue syndrome (CFS) is associated with hypocortisolism, but it is not yet clear the extent to which enhanced negative feedback may underlie this finding.

METHODS: We undertook a low-dose dexamethasone (0.5 mg) suppression test in 18 CFS patients and 20 matched, healthy controls. We measured salivary cortisol levels at 0800 h, 1200 h, 1600 h and 2000 h before and after the administration of 0.5 mg of dexamethasone.

RESULTS: Basal cortisol output was raised in this group of CFS patients compared to controls. Overall, the percentage suppression following dexamethasone administration was no different between CFS (mean+/-sem: 80.4+/-4.4%) and controls (76.2+/-4.9 %). However, the sub-group of patients with CFS and comorbid depression (n=9) showed a significant hypersuppression of salivary cortisol in response to dexamethasone (89.0+/-1.9%; p<0.05 v controls).

LIMITATIONS: The sub-group analysis was on small numbers and should be considered preliminary. Dexamethasone probes only glucocorticoid medicated negative feedback but does not probe mineralocorticoid feedback, the other main physiological feedback mechanism.

CONCLUSION: We found partial support for the hypothesis of enhanced negative feedback in CFS but only in patients with comorbid depression and also in the context of a sample of patients with elevated basal cortisol levels, which is an atypical finding in the literature.

 

Source: Papadopoulos A, Ebrecht M, Roberts AD, Poon L, Rohleder N, Cleare AJ. Glucocorticoid receptor mediated negative feedback in chronic fatigue syndrome using the low dose (0.5 mg) dexamethasone suppression test. J Affect Disord. 2009 Jan;112(1-3):289-94. doi: 10.1016/j.jad.2008.05.001. Epub 2008 Jun 24. https://www.ncbi.nlm.nih.gov/pubmed/18573538

 

Combinations of single nucleotide polymorphisms in neuroendocrine effector and receptor genes predict chronic fatigue syndrome

Abstract:

OBJECTIVE: This paper asks whether the presence of chronic fatigue syndrome (CFS) can be more accurately predicted from single nucleotide polymorphism (SNP) profiles than would occur by chance.

METHODS: Specifically, given SNP profiles for 43 CFS patients, together with 58 controls, we used an enumerative search to identify an ensemble of conjunctive rules that predict whether a patient has CFS.

RESULTS: The accuracy of the rules reached 76.3%, with the highest accuracy rules yielding 49 true negatives, 15 false negatives, 28 true positives and nine false positives (odds ratio [OR] 8.94, p < 0.0001). Analysis of the SNPs used most frequently in the overall ensemble of rules gave rise to a list of ‘most important SNPs’, which was not identical to the list of ‘most differentiating SNPs’ that one would calculate via studying each SNP independently. The top three genes containing the SNPs accounting for the highest accumulated importances were neuronal tryptophan hydroxylase (TPH2), catechol-O-methyltransferase (COMT) and nuclear receptor subfamily 3, group C, member 1 glucocorticoid receptor (NR3C1).

CONCLUSION: The fact that only 28 out of several million possible SNPs predict whether a person has CFS with 76% accuracy indicates that CFS has a genetic component that may help to explain some aspects of the illness.

 

Source: Goertzel BN, Pennachin C, de Souza Coelho L, Gurbaxani B, Maloney EM, Jones JF. Combinations of single nucleotide polymorphisms in neuroendocrine effector and receptor genes predict chronic fatigue syndrome. Pharmacogenomics. 2006 Apr;7(3):475-83. https://www.ncbi.nlm.nih.gov/pubmed/16610957

 

Glucocorticoids and glucocorticoid receptors: mediators of fatigue?

Abstract:

Fatigue is a common problem; when chronic and disabling, subjects can be categorized as having chronic fatigue syndrome (CFS). Whilst it is most likely a multifactorial condition of biopsychosocial origin, the nature of the pathophysiological component remains unclear. There has been a wealth of interest in the possible hypothalamo-pituitary-adrenal (HPA) axis dysfunction in CFS, and whether such changes may mediate fatigue.

On balance, there appears to be reduced cortisol output in a proportion of patients, together with heightened negative feedback and glucocorticoid receptor function. There is evidence for impaired adrenocorticotropic hormone (ACTH) and cortisol responses to a variety of challenges. However, there is no evidence for a specific or uniform dysfunction of the HPA axis.

Evidence that these changes may be related to symptom production comes from randomized controlled trials of glucocorticoid replacement therapy, which have shown improvements in fatigue and disability. Given the many factors that may impinge on the HPA axis in CFS, such as inactivity, sleep disturbance, psychiatric comorbidity, medication and ongoing stress, it seems likely that there is not a single or specific change to the HPA axis in CFS and that the observed HPA axis disturbances are of multifactorial etiology. This is further supported by a comparison of neuroendocrine findings in other conditions in which fatigue is prominent, showing both similarities and differences with the pattern in CFS.

 

Source: Cleare AJ. Glucocorticoids and glucocorticoid receptors: mediators of fatigue? Acta Neuropsychiatr. 2003 Dec;15(6):341-53. doi: 10.1046/j.1601-5215.2003.00050.x. http://www.ncbi.nlm.nih.gov/pubmed/26983770

 

Increased sensitivity to glucocorticoids in peripheral blood mononuclear cells of chronic fatigue syndrome patients, without evidence for altered density or affinity of glucocorticoid receptors

Abstract:

BACKGROUND: In this study we tested the hypothesis that the increased sensitivity to glucocorticoids in chronic fatigue syndrome (CFS)-patients can be attributed to an altered functioning of their glucocorticoid receptors (GR).

METHODS: For this purpose, affinity and distribution of the GR were studied in purified, peripheral blood mononuclear cells (PBMC) of 10 CFS patients and 14 controls along with the responsiveness of these cells to glucocorticoids in vitro.

RESULTS: Affinity (Kd) and number of GR was not different in PBMC of CFS patients when compared with the controls (Kd, 12.9 +/- 8.9 nmol vs 18.8 +/- 16.2 nmol and GR number, 4,839 +/- 2,824/ cell vs 4,906 +/- 1,646/cell). Moreover, RT-PCR revealed no differences in GR messenger RNA expression. Nevertheless, PBMC from CFS patients showed an increased sensitivity to glucocorticoids in vitro. In CFS patients 0.01 micromol dexamethasone suppressed PBMC proliferation by 37%, whereas the controls were only suppressed by 17% (P < 0.01). Addition of phorbol 12-myristate 13-acetate to the cultures rendered the cells resistant to dexamethasone with regard to proliferation and IL-10 and IFN-gamma production, but not to IL-2 and TNF-alpha production in both patients and controls. No difference between patients and controls was observed in this respect

CONCLUSIONS: In conclusion, PBMC of CFS patients display an increased sensitivity to glucocorticoids, which cannot be explained by number or affinity of the GR but should rather be attributed to molecular processes beyond the actual binding of the ligand to the GR.

 

Source: Visser J, Lentjes E, Haspels I, Graffelman W, Blauw B, de Kloet R, Nagelkerken L. Increased sensitivity to glucocorticoids in peripheral blood mononuclear cells of chronic fatigue syndrome patients, without evidence for altered density or affinity of glucocorticoid receptors. J Investig Med. 2001 Mar;49(2):195-204. http://www.ncbi.nlm.nih.gov/pubmed/11288761