Altered DNA methylation profile in Norwegian patients with Autoimmune Addison's Disease

Bjånesøy, Trine Elholm; Andreassen, Bettina Kulle; Bratland, Eirik; Reiner, Andrew H.; Islam, Shahinul; Husebye, Eystein S.; Bakke, Marit

doi:10.1016/j.molimm.2014.02.018

Cited by 18 publications

(11 citation statements)

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“…In a recent study, Bjanesoy et al (29) identified multiple hypomethylated gene promoter regions in CD4 + T cells isolated from PAI patients. Given that in vitro treatment of NK cells with demethylating agents has been shown to result in decreased surface expression of NKG2D (30), it would be of interest for future studies to examine the DNA methylation profile of NK cells from PAI patients, focusing primarily upon the promoters of genes that encode NK cell activatory receptors.…”

Section: Discussionmentioning

confidence: 99%

Primary adrenal insufficiency is associated with impaired natural killer cell function: a potential link to increased mortality

Bancos

Hazeldine

Chortis

et al. 2017

European Journal of Endocrinology

101

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ObjectiveMortality in patients with primary adrenal insufficiency (PAI) is significantly increased, with respiratory infections as a major cause of death. Moreover, patients with PAI report an increased rate of non-fatal infections. Neutrophils and natural killer (NK) cells are innate immune cells that provide frontline protection against invading pathogens. Thus, we compared the function and phenotype of NK cells and neutrophils isolated from PAI patients and healthy controls to ascertain whether altered innate immune responses could be a contributory factor for the increased susceptibility of PAI patients to infection.Design and methodsWe undertook a cross-sectional study of 42 patients with PAI due to autoimmune adrenalitis (n = 37) or bilateral adrenalectomy (n = 5) and 58 sex- and age-matched controls. A comprehensive screen of innate immune function, consisting of measurements of neutrophil phagocytosis, reactive oxygen species production, NK cell cytotoxicity (NKCC) and NK cell surface receptor expression, was performed on all subjects.ResultsNeutrophil function did not differ between PAI and controls. However, NKCC was significantly reduced in PAI (12.0 ± 1.5% vs 21.1 ± 2.6%, P < 0.0001). Phenotypically, the percentage of NK cells expressing the activating receptors NKG2D and NKp46 was significantly lower in PAI, as was the surface density of NKG2D (all P < 0.0001). Intracellular granzyme B expression was significantly increased in NK cells from PAI patients (P < 0.01).ConclusionsAdrenal insufficiency is associated with significantly decreased NKCC, thereby potentially compromising early recognition and elimination of virally infected cells. This potential impairment in anti-viral immune defense may contribute to the increased rate of respiratory infections and ultimately mortality in PAI.

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Section: Discussionmentioning

confidence: 99%

Primary adrenal insufficiency is associated with impaired natural killer cell function: a potential link to increased mortality

Bancos

Hazeldine

Chortis

et al. 2017

European Journal of Endocrinology

101

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“…This therapy fails to provide the anticipatory rise of cortisol prior to wakening and thus gives a shifted circadian profile while also resulting in acute nonphysiological levels of cortisol in the middle of the day 132 . Patients have altered immune responses in the form of altered circadian patterns of circulating monocytes and natural killer cells 133 , impaired natural killer cell function 134 and hypomethylated CD4+ T cells 135 . In an attempt to rectify these adverse outcomes, modified and dual release preparations 133,136,137 , as well as continuous 138 and pulsatile pump (The Pulses study, ISRCTN67193733) preparations are being trialled.…”

Section: Potential Mechanisms Underlying This Inhibition Include Disrmentioning

confidence: 99%

The human stress response

2019

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The human stress response has evolved to maintain homeostasis under conditions of real or perceived stress. This objective is achieved through autoregulatory neural and hormonal systems in close association with central and peripheral clocks. The hypothalamic-pituitary-adrenal (HPA) axis is a key regulatory pathway in the maintenance of these homeostatic processes. The end product of this pathway-cortisol-is secreted in a pulsatile pattern, with changes in pulse amplitude creating a circadian pattern. During acute stress, cortisol levels rise and pulsatility is maintained. Although the initial rise in cortisol follows a large surge of adrenocorticotropic hormone (ACTH), if long-term inflammatory stress occurs, ACTH returns to near basal levels while cortisol remains raised as a result of increased adrenal sensitivity. In chronic stress, hypothalamic activation of the pituitary changes from corticotropin-releasing hormone dominant to arginine vasopressin dominant, and cortisol remains raised due at least in part to decreased cortisol metabolism. Acute elevations in cortisol are beneficial to promote survival of the fittest as part of the fight or flight response. However, chronic exposure to stress results in reversal of the beneficial effects with long-term cortisol exposure becoming maladaptive, which can lead to a broad range of problems, including the metabolic syndrome, obesity, cancer, mental health disorders, cardiovascular disease and increased susceptibility to infections. Neuroimmunoendocrine modulation in disease states and glucocorticoidbased therapeutics are also discussed.

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“…DNA methylation involves the addition of a methyl group to cytosines by DNA methyl transferases (Dnmts) [74]. DNA methylation varies among tissues and cell type because it is a dynamic process involving methylation and demethylation events [75,76].…”

Section: Dna Dna Methylationmentioning

confidence: 99%