HPA axis and cortisol

HPA axis and aging in depression: systematic review and meta-analysis.: One of the most consistent findings in the biology of depression is an altered activity of the hypothalamic-pituitary-adrenal (HPA) axis. However, data concerning this issue have never been examined with a focus on the older population. Here we present a systematic review and meta-analysis, based on studies investigating levels of cortisol, adrenocorticotropic hormone (ACTH) and corticotropin-releasing hormone (CRH) in depressed participants older than 60 and compared with healthy controls. We f

The HPA axis in bipolar disorder: Systematic review and meta-analysis.: Objectives: To provide a quantitative and qualitative synthesis of the available evidence on the role of Hypothalamic-Pituitary-Adrenal (HPA) axis in the pathophysiology of Bipolar Disorder (BD). Methods: Meta-analysis and meta-regression of case-control studies examining the levels of cortisol, ACTH, CRH levels. Systematic review of stress reactivity, genetic, molecular and neuroimaging studies related to HPA axis activity in BD. Results: Forty-one studies were included in the meta-analyses. BD

Depression and hypothalamic-pituitary-adrenal activation: a quantitative summary of four decades of research.: Objectives: To summarize quantitatively the literature comparing hypothalamic-pituitary-adrenal (HPA) axis function between depressed and nondepressed individuals and to describe the important sources of variability in this literature. These sources include methodological differences between studies, as well as demographic or clinical differences between depressed samples. Methods: The current study used meta-analytic techniques to compare 671 effect sizes (cortisol, adrenocorticotropic hormone,

The stress-buffering effect of acute exercise: Evidence for HPA axis negative feedback.: According to the cross-stressor adaptation hypothesis, physically trained individuals show lower physiological and psychological responses to stressors other than exercise, e.g. psychosocial stress. Reduced stress reactivity may constitute a mechanism of action for the beneficial effects of exercise in maintaining mental health. With regard to neural and psychoneuroendocrine stress responses, the acute stress-buffering effects of exercise have not been investigated yet. A sample of highly traine

Hypothalamic-pituitary-adrenal axis dysregulation and cortisol activity in obesity: A systematic review.: Background: Although there is substantial evidence of differential hypothalamic-pituitary-adrenal (HPA) axis activity in both generalized and abdominal obesity, consistent trends in obesity-related HPA axis perturbations have yet to be identified. Objectives: To systematically review the existing literature on HPA activity in obesity, identify possible explanations for inconsistencies in the literature, and suggest methodological improvements for future study. Data sources: Included papers used

Cortisol stress reactivity across psychiatric disorders: A systematic review and meta-analysis.: The hypothalamus-pituitary-adrenal (HPA) axis and its end product cortisol are essential for an adequate response to stress. Considering the role of stress as a risk factor for psychiatric disorders, it is not surprising that cortisol stress reactivity has frequently been investigated in patients versus healthy individuals. However, the large heterogeneity in measures of the cortisol stress response has hampered a systematic evaluation of the evidence. We here report of a systematic literature r

Yoga, mindfulness-based stress reduction and stress-related physiological measures: A meta-analysis.

Background and objectives: Practices that include yoga asanas and mindfulness-based stress reduction for the management of stress are increasingly popular; however, the neurobiological effects of these practices on stress reactivity are not well understood. Many studies investigating the effects of such practices fail to include an active control group. Given the frequency with which people are selecting such interventions as a form of self-management, it is important to determine their effectiveness. Thus, this review investigates the effects of practices that include yoga asanas, with and without mindfulness-based stress reduction, compared to an active control, on physiological markers of stress. Materials and methods: A systematic review and meta-analysis of randomised controlled trials published in English compared practices that included yoga asanas, with and without mindfulness-ba…

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Stress-related and basic determinants of hair cortisol in humans: A meta-analysis.

The analysis of hair cortisol concentrations (HCC) is a relatively new strategy to measure long-term cumulative cortisol levels, which is increasingly used in psychoneuroendocrinological research. Here, we conduct a first comprehensive meta-analysis of HCC research based on aggregated data from a total of 124 (sub)samples (66 independent studies; total N=10,289). We seek to answer two central questions: (i) Which covariates and basic features of HCC need to be considered in future research? (ii) What are the main determinants of HCC in terms of chronic stress exposure and mental health? Concerning basic characteristics, our findings identify several covariates to be considered (age, sex, hair washing frequency, hair treatment, oral contraceptive use), confirm a decline of HCC from the first to the second proximal 3cm hair segment, and show positive associations between HCC and short-term…

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Mindfulness mediates the physiological markers of stress: Systematic review and meta-analysis.

Meditation is a popular form of stress management, argued to mediate stress reactivity. However, many studies in this field commonly fail to include an active control group. Given the frequency with which people are selecting meditation as a form of self-management, it is important to validate if the practice is effective in mediating stress-reactivity using well-controlled studies. Thus, we aimed to conduct a meta-analysis investigating the neurobiological effects of meditation, including focused attention, open monitoring and automatic self-transcending subtypes, compared to an active control, on markers of stress. In the current meta-analysis and systematic review, we included randomised controlled trials comparing meditation interventions compared to an active control on physiological markers of stress. Studied outcomes include cortisol, blood pressure, heart-rate, lipids and periphe…

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Meta-analytical assessment of the effects of protocol variations on cortisol responses to the Trier Social Stress Test.

Background: The Trier Social Stress Test (TSST) is one of the most widely used laboratory stress tests. Exposure to this psychosocial stressor has been shown to stimulate an acute cortisol stress response in the majority of healthy individuals, while deviations from the typical pattern, i.e., cortisol reactivity dysfunctions have been linked to an ever-increasing number of negative health outcomes. However, significant variability between labs exists in strength of observed cortisol responses in healthy individuals. This variability raises the question of how to distinguish across labs between cortisol stress response patterns that reflect health risk from those that are due to methodological differences. Thus, we propose a systematic review and meta-analysis that aims at quantifying the effects of methodological variation in study and TSST protocol elements on cortisol stress responses …

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The effects of acute stress on episodic memory: A meta-analysis and integrative review.

A growing body of research has indicated that acute stress can critically impact memory. However, there are a number of inconsistencies in the literature, and important questions remain regarding the conditions under which stress effects emerge as well as basic questions about how stress impacts different phases of memory. In this meta-analysis, we examined 113 independent studies in humans with 6,216 participants that explored effects of stress on encoding, postencoding, retrieval, or postreactivation phases of episodic memory. The results indicated that when stress occurred prior to or during encoding it impaired memory, unless both the delay between the stressor and encoding was very short and the study materials were directly related to the stressor, in which case stress improved encoding. In contrast, postencoding stress improved memory unless the stressor occurred in a different ph…

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Effects of stress on decisions under uncertainty: A meta-analysis.

[Correction Notice: An Erratum for this article was reported in Vol 142(9) of Psychological Bulletin (see record 2016-39486-001). It should have been reported that the inverted u-shaped relationship between cortisol stress responses and decision-making performance was only observed in female, but not in male participants as suggested by the study by van den Bos, Harteveld, and Stoop (2009). Corrected versions of the affected sentences are provided.] The purpose of the present meta-analysis was to quantify the effects that stress has on decisions made under uncertainty. We hypothesized that stress increases reward seeking and risk taking through alterations of dopamine firing rates and reduces executive control by hindering optimal prefrontal cortex functioning. In certain decision situations, increased reward seeking and risk taking is dysfunctional, whereas in others, this is not the ca…

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Physiological concomitants of perseverative cognition: A systematic review and meta-analysis.

Rumination about the past and worries about the future (perseverative cognition) are extremely common, although pervasive and distressing, dysfunctional cognitive processes. Perseverative cognition is not only implicated in psychological health, contributing to mood worsening and psychopathology but, due to its ability to elicit prolonged physiological activity, is also considered to play a role in somatic health. Although there is emerging evidence that such negative and persistent thoughts have consequences on the body, this association has not yet been quantified. The aim of this study was to meta-analyze available studies on the physiological concomitants of perseverative cognition in healthy subjects. Separate meta-analyses were performed on each examined physiological parameter. Sixty studies were eligible for the analyses. Associations emerged between perseverative cognition and h…

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Genome wide association identifies common variants at the SERPINA6/SERPINA1 locus influencing plasma cortisol and corticosteroid binding globulin.

Variation in plasma levels of cortisol, an essential hormone in the stress response, is associated in population-based studies with cardio-metabolic, inflammatory and neuro-cognitive traits and diseases. Heritability of plasma cortisol is estimated at 30-60% but no common genetic contribution has been identified. The CORtisol NETwork (CORNET) consortium undertook genome wide association meta-analysis for plasma cortisol in 12,597 Caucasian participants, replicated in 2,795 participants. The results indicate that <1% of variance in plasma cortisol is accounted for by genetic variation in a single region of chromosome 14. This locus spans SERPINA6, encoding corticosteroid binding globulin (CBG, the major cortisol-binding protein in plasma), and SERPINA1, encoding α1-antitrypsin (which inhibits cleavage of the reactive centre loop that releases cortisol from CBG). Three partially independen…

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Cognitive appraisals and emotions predict cortisol and immune responses: a meta-analysis of acute laboratory social stressors and emotion inductions.

Models of stress and health suggest that emotions mediate the effects of stress on health; yet meta-analytic reviews have not confirmed these relationships. Categorizations of emotions along broad dimensions such as valence (e.g., positive and negative affect) may obscure important information about the effects of specific emotions on physiology. Within the context of the integrated specificity model, we present a novel theoretical framework that posits that specific emotional responses associated with specific types of environmental demands influence cortisol and immune outcomes in a manner that would have likely promoted the survival of our ancestors. We analyzed experiments from 66 journal articles that directly manipulated social stress or emotions and measured subsequent cortisol or immune responses. Judges rated experiments for the extent to which participants would experience theo…

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Cortisol and post-traumatic stress disorder in adults: systematic review and meta-analysis.

Background: Post-traumatic stress disorder (PTSD) has inconsistently been associated with lower levels of cortisol. Aims: To compare basal cortisol levels in adults with current PTSD and in people without psychiatric disorder. Method: Systematic review and meta-analysis. Standardised mean differences (SMD) in basal cortisol levels were calculated and random-effects models using inverse variance weighting were applied. Results: Across 37 studies, 828 people with PTSD and 800 controls did not differ in cortisol levels (pooled SMD=-0.12, 95% CI=-0.32 to 0.080). Subgroup analyses revealed that studies assessing plasma or serum showed significantly lower levels in people with PTSD than in controls not exposed to trauma. Lower levels were also found in people with PTSD when females were included, in studies on physical or sexual abuse, and in afternoon samples. Conclusions: Low cortisol levels…

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Hypothalamic-pituitary-gut axis dysregulation in irritable bowel syndrome: plasma cytokines as a potential biomarker?

Background & aims: Irritable bowel syndrome (IBS) is a functional disorder with an etiology that has been linked to both psychological stress and infection. The primary aim of this study was to examine the hypothalamic-pituitary-adrenal axis in patients with IBS and to relate such response to plasma cytokine profiles. Methods: A total of 151 subjects, 76 patients and 75 controls, were recruited. The patients with IBS were diagnosed according to Rome II criteria. Forty-nine patients and 48 matched controls had cytokine levels measured, and a subset of 21 patients and 21 controls also underwent a corticotropin-releasing hormone (CRH) stimulation test with plasma levels of adrenocorticotropic hormone (ACTH) and cortisol measured. The remaining 27 patients and 27 controls underwent a dexamethasone (1 mg) challenge. Results: Cortisol and the proinflammatory cytokines interleukin (IL)-6 (toget…

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Psychological stress reactivity and future health and disease outcomes: A systematic review of prospective evidence.

Background: Acute psychological stress activates the sympatho-adrenal medullary (SAM) system and hypothalamo-pituitary adrenal (HPA) axis. The relevance of this stress reactivity to long-term health and disease outcomes is of great importance. We examined prospective studies in apparently healthy adults to test the hypothesis that the magnitude of the response to acute psychological stress in healthy adults is related to future health and disease outcomes. Methods: We searched Medline Complete, PsycINFO, CINAHL Complete and Embase up to 15 Aug 2019. Included studies were peer-reviewed, English-language, prospective studies in apparently healthy adults. The exposure was acute psychological stress reactivity (SAM system or HPA axis) at baseline. The outcome was any health or disease outcome at follow-up after ≥1 year. Results: We identified 1719 papers through database searching and 1 addi…

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Endocrine and immunomodulatory effects of social isolation and loneliness across adulthood.

Experimental and observational evidence agreed on two interconnected biological mechanisms responsible for the links between social isolation/loneliness and health: alterations in the activity of the hypothalamic-pituitary-adrenal (HPA) axis and compromised functioning of the innate immune system. However, most existing studies did not consider the simultaneous impact of social isolation and loneliness on biological outcomes. Further, they only assessed one biological outcome at a time and did not test any moderation by age, despite empirical and theoretical evidence supporting the plausibility of this hypothesis. To address these gaps in the literature, we tested the associations between two indicators of social isolation (living status and frequency of social contacts) and loneliness and daily cortisol secretion and two markers of systemic inflammation (C-reactive protein [CRP] and int…

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Specific reduction in cortisol stress reactivity after social but not attention-based mental training.

Psychosocial stress is a public health burden in modern societies. Chronic stress-induced disease processes are, in large part, mediated via the activation of the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic-adrenal-medullary system. We asked whether the contemplative mental training of different practice types targeting attentional, socio-affective (for example, compassion), or socio-cognitive abilities (for example, perspective-taking) in the context of a 9-month longitudinal training study offers an effective means for psychosocial stress reduction. Using a multimethod approach including subjective, endocrine, autonomic, and immune markers and testing 313 participants in a standardized psychosocial laboratory stressor, we show that all three practice types markedly reduced self-reported stress reactivity in healthy participants. However, only the training of intersubj…

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Evidence for a differential role of HPA-axis function, inflammation and metabolic syndrome in melancholic versus atypical depression.

The hypothalamic-pituitary-adrenal (HPA) axis and the inflammatory response system have been suggested as pathophysiological mechanisms implicated in the etiology of major depressive disorder (MDD). Although meta-analyses do confirm associations between depression and these biological systems, effect sizes vary greatly among individual studies. A potentially important factor explaining variability is heterogeneity of MDD. Aim of this study was to evaluate the association between depressive subtypes (based on latent class analysis) and biological measures. Data from 776 persons from the Netherlands Study of Depression and Anxiety, including 111 chronic depressed persons with melancholic depression, 122 with atypical depression and 543 controls were analyzed. Inflammatory markers (C-reactive protein, interleukin-6, tumor necrosis factor-α), metabolic syndrome components, body mass index (B…

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Wives' and husbands' cortisol reactivity to proximal and distal dimensions of couple conflict.

Poor marital quality has been linked repeatedly to spouses' health problems, with alterations to physiological stress response systems, such as the hypothalamic-pituitary-adrenocortical (HPA) axis, as one putative mechanism. This study assessed wives' and husbands' HPA axis (i.e., cortisol) reactivity to marital criticism during laboratory-based conflict discussions, in the context of marital aggression experienced during the previous year. Ninety-five couples provided one saliva sample prior to-and three samples following-a triadic family conflict discussion involving their teenage child. Marital criticism during the conflict discussion was related to heightened HPA reactivity for husbands only. For wives, an interaction emerged between criticism during the conflict and previous-year marital aggression: only those wives who had experienced high levels of marital aggression demonstrated …

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Short telomeres in depression and the general population are associated with a hypocortisolemic state.

Background: The hypothalamic-pituitary-adrenal (HPA) axis plays a central role in stress regulation, and leukocyte telomere length (TL) has been suggested to represent a cumulative measure of stress. Depression is intimately related with stress and frequently exhibits a dysregulated HPA axis. We aimed to study the relationships between TL and biological and psychological facets of stress in recurrent major depressive disorder and controls. Methods: Leukocyte TL was measured in 91 subjects with recurrent major depressive disorder and 451 control subjects. Stress was assessed from both a biological perspective, by assessing HPA axis function with a weight-adjusted very-low-dose dexamethasone suppression test (DST), and a psychological perspective, with self-report questionnaires. Results: TL was shorter among patients compared with control subjects (277 base pairs, p = .001). Overall, shor…

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Attenuation of cortisol across development for victims of sexual abuse.

Inconsistencies exist in literature examining hypothalamic-pituitary-adrenal (HPA) axis activity in children and adults who have experienced childhood abuse. Hence, the extent and manner to which childhood abuse may disrupt HPA axis development is largely unknown. To address these inconsistencies, the developmental course of nonstress cortisol in a long-term longitudinal study was assessed at six time points from childhood through adolescence and into young adulthood to determine whether childhood abuse results in disrupted cortisol activity. Nonstress, morning cortisol was measured in 84 females with confirmed familial sexual abuse and 89 nonabused, comparison females. Although dynamically controlling for co-occurring depression and anxiety, hierarchical linear modeling (HLM) showed that relative to comparison females, the linear trend for abused females was significantly less steep whe…

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HPA axis reactivity: a mechanism underlying the associations among 5-HTTLPR, stress, and depression.

Background: Recent evidence indicates that individuals who are homozygous for the short (s) allele in the promoter region of the serotonin transporter gene have higher rates of depression and other psychiatric disorders as a function of exposure to increasing levels of stressful life events than do individuals who have one or two copies of the long (l) allele. Despite the reliability of this association, the mechanism by which this polymorphism confers risk for psychopathology in the presence of stress is not understood. This study was designed to examine the formulation that individuals who are homozygous for the s allele are characterized by a greater biological reactivity to stress than are their counterparts who have one or two copies of the l allele. Methods: Girls at high (n = 25) and low (n = 42) risk for depression by virtue of the presence or absence of a family history of this …

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Moderation of psychosocial risk factors through dysfunction of the hypothalamic-pituitary-adrenal stress axis in the onset of chronic widespread musculoskeletal pain: findings of a population-based prospective cohort study.

Objective: To test the hypothesis that abnormalities in the hypothalamic-pituitary-adrenal (HPA) stress-response system would act as an effect moderator between HPA function and the onset of chronic widespread pain (CWP). Methods: We conducted a population-based prospective cohort study. Current pain and psychosocial status were ascertained in 11,000 subjects. Of the 768 eligible subjects free of CWP but at future risk based on their psychosocial profile, 463 were randomly selected, and 267 (57.7%) consented to assessment of their HPA axis function. Diurnal function was measured by assessing levels of salivary cortisol in the morning (9:00 AM) and evening (10:00 PM). Serum cortisol levels were measured after an overnight low-dose (0.25 mg) dexamethasone suppression test and a potentially stressful clinical examination. All subjects were followed up 15 months later to identify cases of ne…

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Gender differences in hypothalamic-pituitary-adrenal (HPA) axis reactivity.

The present study was designed to determine whether there are gender differences in hormonal response patterns to HPA axis activation. To this end, two methods of activating the HPA axis were employed: a standardized psychological stress test and a pharmacological challenge. Healthy subjects (mean age 23.4 years, SD 7.0 years) completed a naloxone challenge and/or the modified Trier Social Stress Test (TSST). For the naloxone challenge, two baseline blood samples were obtained. Placebo was then administered (0 min), followed by increasing doses of intravenous naloxone (50, 100, 200 and 400 microg/kg) at 30-min intervals. Post-placebo blood samples were collected at 15-min intervals for 180 min. The TSST consisted of 5 min of public speaking followed by 5 min of mental arithmetic exercises. Three baseline and five post-TSST blood samples were drawn. Eighty subjects (53 male, 27 female) un…

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Relationship between cortisol responses to stress and personality.

Although there is growing evidence of links between the cortisol stress response and personality, the nature of the relationships and the underlying mechanisms require further clarification. The purpose of this study was to examine associations between personality traits and cortisol responses to stress using the Revised NEO Personality Inventory five-factor model of personality. In total, 68 healthy adults, aged 18-30 years, completed the personality assessment and underwent a laboratory psychological stress test that consisted of a 5 min speech and 5-min of mental arithmetic. Findings showed that in the sample as a whole, less Openness was associated with lower cortisol responses to the challenge. Cortisol responses also corresponded to certain personality dimensions in a gender-specific manner. Blunted cortisol responses were associated with higher Neuroticism in women and with lower …

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Blunted HPA axis response to stress influences susceptibility to posttraumatic stress response in rats.

Background: Posttraumatic stress disorder (PTSD) is associated with low levels of circulating cortisol, and recent studies suggest that cortisol administration may reduce PTSD symptoms. This study investigated the role of cortisol in the manifestation of anxiety- and fear-like symptoms in an animal model of PTSD. Method: Magnitude of changes in prevalence of anxiety-like behaviors on the elevated plus-maze and nonhabituated exaggerated startle reaction were compared in three strains of rats exposed to predator stress, with and without prior corticosterone treatment. Extreme behavioral changes in both paradigms implied an extreme behavioral response (EBR), representing PTSD-like symptoms. Results: Lewis rats exhibited greater baseline anxiety-like behaviors and greater stress-induced increases in anxiety-like behaviors than Fischer F344 or Sprague-Dawley rats, with only minor corticostero…

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Hypothalamic-pituitary-adrenocortical responses to psychological stress and risk for smoking relapse.

Stress is a commonly reported precipitant of relapse to substance use. There is a growing recognition of the need to understand psychobiological alterations in the stress response among chronic drug users, and to determine how they may precipitate relapse. This paper focuses on the hypothalamic-pituitary-adrenocortical (HPA) response to stress among dependent smokers. Nicotine acutely activates the HPA axis, and increased HPA activity has been linked to attenuated CNS nicotinic receptor sensitivity. We will review a series of studies demonstrating that steep decline in cortisol concentrations during early abstinence and hyporesponsiveness to stress predict shorter time to relapse. Our studies show that hormonal associations with smoking relapse tend to be more consistent in men, while intensity of withdrawal symptoms tend to be consistent predictors of smoking relapse in women. We propos…

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Neuroendocrine and viral correlates of premature immunosenescence.

Aging continuously remodels the immune system, a process known as immunosenescence. Here, we review evidence of premature immunosenescence in younger individuals under conditions of chronic psychological stress, chronic inflammation, or exposure to certain persistent viral infections. Chronic stress may accelerate various features of immunosenescence by activating key allostatic systems, notably the hypothalamic-pituitary-adrenal axis and increased cortisol levels. Chronic stress is associated with thymic involution, blunted T cell proliferation, increased serum proinflammatory markers, and shorter telomere lengths. Human cytomegalovirus (CMV) infection has been implicated in accelerating immunosenescence by shrinking the T cell receptor repertoire and causing clonal expansion of senescent CD8(+) CD28(-) T cells with a proinflammatory profile. These factors increase inflammation associat…

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