T Cell Phenotype and T Cell Receptor Repertoire in Patients with Major Depressive Disorder

While a link between inflammation and the development of neuropsychiatric disorders, including major depressive disorder (MDD) is supported by a growing body of evidence, little is known about the contribution of aberrant adaptive immunity in this context. Here, we conducted in-depth characterization of T cell phenotype and T cell receptor (TCR) repertoire in MDD. For this cross- sectional case–control study, we recruited antidepressant-free patients with MDD without any somatic or psychiatric comorbidities (n = 20), who were individually matched for sex, age, body mass index, and smoking status to a non-depressed control subject (n = 20). T cell phenotype and repertoire were interrogated using a combination of flow cytometry, gene expression analysis, and next generation sequencing. T cells from MDD patients showed significantly lower surface expression of the chemokine receptors CXCR3 and CCR6, which are known to be central to T cell differentiation and trafficking. In addition, we observed a shift within the CD4+ T cell compartment characterized by a higher frequency of CD4+CD25highCD127low/− cells and higher FOXP3 mRNA expression in purified CD4+ T cells obtained from patients with MDD. Finally, flow cytometry-based TCR Vβ repertoire analysis indicated a less diverse CD4+ T cell repertoire in MDD, which was corroborated by next generation sequencing of the TCR β chain CDR3 region. Overall, these results suggest that T cell phenotype and TCR utilization are skewed on several levels in patients with MDD. Our study identifies putative cellular and molecular signatures of dysregulated adaptive immunity and reinforces the notion that T cells are a pathophysiologically relevant cell population in this disorder

Blunted autonomic reactivity to pharmacological panic challenge under long-term escitalopram treatment in healthy men.

Background: Central serotonergic pathways influence brain areas involved in vagal cardiovascular regulation and, thereby, influence sympathetic efferent activity. Selective serotonin reuptake inhibitors (SSRIs) affect multiple serotonergic pathways, including central autonomic pathways. However, only a few studies have assessed SSRI-mediated effects on autonomic reactivity in healthy individuals using heart rate variability (HRV). Methods: The present study assessed the influence of long-Term treatment with escitalopram (ESC) on autonomic reactivity to an intravenous application of 50 μg cholecystokinin tetrapeptide (CCK-4) in 30 healthy young men using a double-blind, placebo (PLA)-controlled, randomized, within-subject cross-over design. Main outcome measures were time- and frequencydomain HRV parameters, assessed at both baseline and immediately after CCK-4 application. Results: Results showed substantial effects for the treatment . CCK-4 challenge interaction with respect to heart rate (p pn2 = 0.499), SDNN (p pn2 = 576), RMSSD (p = 0.015; pn2 = 194), NN50% (p = 0.008; pn2 = 0.224), and LF% (p = 0.014; pn2 = 0.196), and moderate effects with respect HF% (p = 0.099; pn2 = 0.094), with PLA subjects showing a higher increase in HR and SDNN and a higher decrease in RMSSD, NN50, LF and HF than subjects in the ESC condition. Thus, ESC treatment significantly blunted the autonomic reactivity to CCK-4. Secondary analysis indicated no effect of the 5-HTTLPR polymorphism on CCK-4-induced autonomic response. Conclusions: Our results support findings suggesting an effect of SSRI treatment on autonomic regulation and provide evidence that ESC treatment is associated with blunted autonomic reactivity in healthy men

Copeptin response to panic provocation with CO<inf>2</inf> in healthy adults

Repeated panic attacks are the core symptom of panic disorder and severely stressful for patients. Additional to the psychological response, the physiological symptoms are an important aspect of the experienced panic. However, data on the extent of hypothalamic-pituitary-adrenal (HPA)-axis activation during panic attacks is inconsistent. Therefore, in the present study, we aimed at investigating the stress-axis activity in more detail by including Copeptin (CoP) as a stable surrogate parameter for the vasopressinergic hypothalamic activity during experimentally induced panic attacks in healthy adults (N = 21). During a placebo-controlled panic challenge with 35% CO2 compared to normal air inhalation, we measured CoP and the peripheral effector hormones Adrenocorticotropic Releasing Hormone (ACTH) and cortisol in plasma along with the psychological response to panic anxiety. We analyzed hormonal secretion patterns, their correlations and individual panic ratings over time and explored differences between female and male participants. We found a significant CO2-induced increase of CoP plasma levels and psychological panic symptoms after CO2-administration, while no positive correlations of CoP levels with the peripheral HPA-axis hormones and with panic symptoms were present. No differences between female and male participants concerning their psychological response nor their baseline CoP levels, the release of CoP or its increase during the experiment were found. CoP could be a sensitive indicator for an organism's physiologic acute hypothalamic response during stress and panic attacks

Vagal effects of endocrine HPA axis challenges on resting autonomic activity assessed by heart rate variability measures in healthy humans

Background: The hypothalamic-pituitary-adrenal axis (HPA axis) and the autonomic nervous system (ANS) are considered to play the most crucial role in the pathophysiology of stress responsiveness and are increasingly studied together. However, only few studies have simultaneously assessed HPA axis and ANS activity to investigate their direct interaction in pathophysiology, while no study so far has assessed the dynamic interplay between the two systems in healthy subjects through endocrine challenges. Methods: The present study assessed the direct effects of overnight pharmacoendocrine HPA axis challenges with dexamethasone (suppression) and metyrapone (stimulation) on ANS activity at rest as determined by linear and nonlinear measures of heart rate variability (HRV) in 39 young healthy individuals. Results: Findings indicated significant effects of metyrapone, but not dexamethasone on autonomic activity at rest based on HRV measures. HRV after metyrapone was overall significantly reduced in comparison to baseline or post-dexamethasone conditions, while the combined metyrapone-related reduction of HRV measures RMSSD, NN50(%) and HF(%) with concomitant increase of the unifractal scaling coefficient α fast value jointly indicated a specifically diminished vagal activity. Conclusions: We provide first data that HPA axis stimulation (metyrapone) is associated with reduced vagal tone, while HPA axis suppression (dexamethasone) has no effect on autonomic modulation of heart function. Our results support a vital role of the parasympathetic nervous system in the interplay between ANS and HPA axis and, thus, in the modulation of stress-related cardiovascular responsiveness and the susceptibility to stress-related disorders

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<p>While a link between inflammation and the development of neuropsychiatric disorders, including major depressive disorder (MDD) is supported by a growing body of evidence, little is known about the contribution of aberrant adaptive immunity in this context. Here, we conducted in-depth characterization of T cell phenotype and T cell receptor (TCR) repertoire in MDD. For this cross-sectional case–control study, we recruited antidepressant-free patients with MDD without any somatic or psychiatric comorbidities (n = 20), who were individually matched for sex, age, body mass index, and smoking status to a non-depressed control subject (n = 20). T cell phenotype and repertoire were interrogated using a combination of flow cytometry, gene expression analysis, and next generation sequencing. T cells from MDD patients showed significantly lower surface expression of the chemokine receptors CXCR3 and CCR6, which are known to be central to T cell differentiation and trafficking. In addition, we observed a shift within the CD4⁺ T cell compartment characterized by a higher frequency of CD4⁺CD25^highCD127^low/− cells and higher FOXP3 mRNA expression in purified CD4⁺ T cells obtained from patients with MDD. Finally, flow cytometry-based TCR Vβ repertoire analysis indicated a less diverse CD4⁺ T cell repertoire in MDD, which was corroborated by next generation sequencing of the TCR β chain CDR3 region. Overall, these results suggest that T cell phenotype and TCR utilization are skewed on several levels in patients with MDD. Our study identifies putative cellular and molecular signatures of dysregulated adaptive immunity and reinforces the notion that T cells are a pathophysiologically relevant cell population in this disorder.</p