A pilot study on immuno-psychiatry in the 22q11.2 deletion syndrome: A role for Th17 cells in psychosis?

BACKGROUND: A growing body of evidence supports a role for immune alterations in Schizophrenia Spectrum Disorders (SSD). A high prevalence (25-40%) of SSD has been found in patients with 22q11.2 deletion syndrome (22q11.2DS), which is known for T-cell deficits due to thymus hypoplasia. This study is the first to explore the association between the T-cell subsets and psychotic symptoms in adults with 22q11.2DS. METHODS: 34 individuals (aged 19-38 yrs.) with 22q11.2DS and 34 healthy age- and gender matched control individuals were included. FACS analysis of the blood samples was performed to define T-cell subsets. Ultra-high risk for psychosis or diagnosis of SSD was determined based on CAARMS interviews and DSM-5 criteria for SSD. Positive psychotic symptom severity was measured based on the PANSS positive symptoms subscale. RESULTS: A partial T-cell immune deficiency in 22q11.2DS patients was confirmed by significantly reduced percentages of circulating T and T-helper cells. Significantly higher percentages of inflammatory Th1, Th17, and memory T-helper cells were found in adults with 22q11.2DS. Most importantly an increased Th17 percentage was found in adults with psychotic symptoms as compared to non-psychotic adults with 22q11.2DS, and Th17 percentage were related to the presence of positive psychotic symptoms. CONCLUSIONS: Given the literature on the role of T cells and in particular of Th17 cells and IL-17 in hippocampus development, cognition and behavior, these results support the hypothesis for a role of Th17 cells in the development and/or regulation of psychotic symptoms in 22q11.2DS. This pilot study underlines the importance to further study the role of T-cell defects and of Th17 cells in the development of psychiatric symptoms. It also supports the possibility to use 22q11.2DS as a model to study T-cell involvement in the development of SSD.

High prevalence of cardiovascular disease in South Asians: Central role for brown adipose tissue?

Cardiovascular disease (CVD) is the leading cause of death in modern society. Interestingly, the risk of developing CVD varies between different ethnic groups. A particularly high risk is faced by South Asians, representing over one-fifth of the world's population. Here, we review potential factors contributing to the increased cardiovascular risk in the South Asian population and discuss novel therapeutic strategies based on recent insights. In South Asians, classical ('metabolic') risk factors associated with CVD are highly prevalent and include central obesity, insulin resistance, type 2 diabetes, and dyslipidemia. A contributing factor that may underlie the development of this disadvantageous metabolic phenotype is the presence of a lower amount of brown adipose tissue (BAT) in South Asian subjects, resulting in lower energy expenditure and lower lipid oxidation and glucose uptake. As it has been established that the increased prevalence of classical risk factors in South Asians cannot fully explain their increased risk for CVD, other non-classical risk factors must underlie this residual risk. In South Asians, the prevalence of "inflammatory" risk factors including visceral adipose tissue inflammation, endothelial dysfunction, and HDL dysfunction are higher compared with Caucasians. We conclude that a potential novel therapy to lower CVD risk in the South Asian population is to enhance BAT volume or its activity in order to diminish classical risk factors. Furthermore, anti-inflammatory therapy may lower non-classical risk factors in this population and the combination of both strategies may be especially effective.

Enhanced responsiveness to T-cell help causes loss of B-lymphocyte tolerance to a ß-cell neo-self-antigen in type 1 diabetes prone NOD mice.

Self-reactive B lymphocytes contribute to type 1 diabetes pathogenesis as APC and auto-Ab producers in NOD mice and humans. To shed light on the mechanisms responsible for the breakdown in B-lymphocyte self-tolerance to ß-cell Ag, we utilised a model whereby hen-egg lysozyme (HEL)-specific Ig Tg (IgHEL-Tg)-Tg B lymphocytes were allowed to develop in or were transferred into mice expressing the HEL Tg under an insulin promoter (insHEL-Tg). IgHEL-Tg B lymphocytes enhanced type 1 diabetes susceptibility of insHEL-Tg NOD mice. A comparison of the tolerogenic activity of IgHEL-Tg B lymphocytes with NOD and non-autoimmune-prone C57BL/6 genetic backgrounds showed that both were rendered anergic in the presence of insHEL when competing with polyclonal B lymphocytes. Nevertheless, NOD IgHEL-Tg B lymphocytes transferred into insHEL-Tg mice were more readily susceptible to rescue from anergy than their C57BL/6 counterparts, following provision of in vivo T-cell help. The different tolerogenic outcomes were an intrinsic property of B lymphocytes rather than being related to the quality of T-cell help, with the defective response being at least partially controlled by genes mapping to insulin-dependent diabetes (Idd) susceptibility loci on Chromosome 1 (Idd5) and 4 (Idd9/11).

Inflammatory cytokines and growth factors were not associated with psychosis liability or childhood trauma.

Psychosis is a multifactorial condition arising from an interaction between genetic liability and exposure to environmental risk factors, in particular childhood trauma. Furthermore, accumulating evidence supports a role for the immune system in the aetiology of psychosis. Increased peripheral levels of pro-inflammatory cytokines and reduced neurotrophic factors are found in patients with psychosis. Childhood trauma is highly prevalent in psychosis patients and is also associated with increased pro-inflammatory cytokines and reduced neurotrophic factors. Recent studies suggest the increase in pro-inflammatory cytokines and decrease in neurotrophic factors seen in psychosis may be attributable to the effects of child maltreatment. The aim of this study was to improve understanding of the relation between childhood trauma, inflammation and psychosis. We examined separate and interaction effects of psychosis liability and childhood trauma on serum levels of BDNF, CCL-2, CRP, IFN-γ, IGFBP2, IL-6, PDGF, SCF and TNF-α in 40 patients with recent onset psychosis, 13 patients at Ultra-High Risk (UHR) for psychosis, 31 unaffected siblings of psychosis patients and 41 healthy controls. Childhood trauma was assessed retrospectively with the Childhood Trauma Questionnaire (CTQ). No statistically significant effects of psychosis liability or childhood trauma on concentrations of cytokines or growth factors in peripheral blood were found, nor were there any statistically significant interaction effects of psychosis liability with childhood trauma on serum levels of cytokines and growth factors.

Self-esteem moderates affective and psychotic responses to social stress in psychosis: A virtual reality study.

BACKGROUND: Higher liability to psychosis is associated with low self-esteem and increased sensitivity to social stress. Recently, we reported a positive relation between liability to psychosis and affective and psychotic responses to social stress. This study investigated how self-esteem moderates paranoia, peak subjective distress and stress reactivity of people with different psychosis liability in response to social stressors in virtual reality. METHODS: Ninety-four individuals with lower (41 siblings and 53 controls) and 75 persons with higher psychosis liability (55 with recent onset psychotic disorder and 20 at ultra-high risk for psychosis) explored five times a virtual café with various social stressors (crowdedness, ethnic minority status, and hostility). They rated momentary paranoia (State Social Paranoia Scale) after each experiment and subjective distress on a visual analogue scale before and after the experiments. Positive and negative self-esteem were assessed with the Self-Esteem Rating Scale. RESULTS: Momentary paranoia, peak subjective distress, and reactivity to social stressors were associated with negative self-esteem, but not positive self-esteem. Effects of both positive and negative self-esteem on psychotic and affective stress responses, but not stress reactivity, became significantly stronger when individuals were exposed to more stressful environments. Effects of self-esteem on momentary paranoia and peak subjective distress did not differ between the high liability and low liability group. Persons with lower psychosis liability had a stronger effect of negative self-esteem on stress reactivity than persons with higher liability. CONCLUSIONS: Positive and negative self-esteem may play an important role in affective and psychotic responses to social stress.

Anxiety Partially Mediates Cybersickness Symptoms in Immersive Virtual Reality Environments.

The use of virtual reality (VR) in psychological treatment is expected to increase. Cybersickness (CS) is a negative side effect of VR exposure and is associated with treatment dropout. This study aimed to investigate the following: (a) if gender differences in CS can be replicated, (b) if differences in anxiety and CS symptoms between patients and controls can be replicated, and (c) whether the relationship between exposure to VR and CS symptoms is mediated by anxiety. A sample (N = 170) of participants with different levels of psychosis liability was exposed to VR environments. CS and anxiety were assessed with self-report measures before and after the VR experiment. This study replicated gender differences in CS symptoms, most of which were present before exposure to VR. It also replicated findings that a significant correlation between anxiety and CS can be found in healthy individuals, but not in patients. In a VR environment, anxiety partially mediated CS symptoms, specifically nausea and disorientation. A partial explanation for the differences found between patients and controls may lie in a ceiling effect for the symptoms of CS. A second explanation may be the partial overlap between CS symptoms and physiological anxiety responses. CS symptoms reported at baseline cannot be explained by exposure to VR, but are related to anxiety. Caution is required when interpreting studies on both CS and anxiety, until the specificity in measurements has been improved. Since anxiety mediated the CS symptoms, CS is expected to decline during treatment together with the reduction of anxiety.

Self-reported Cognitive Biases Moderate the Associations Between Social Stress and Paranoid Ideation in a Virtual Reality Experimental Study.

Introduction: Cognitive biases are associated with psychosis liability and paranoid ideation. This study investigated the moderating relationship between pre-existing self-reported cognitive biases and the occurrence of paranoid ideation in response to different levels of social stress in a virtual reality environment. Methods: This study included 170 participants with different levels of psychosis liability (55 recent onset psychosis, 20 ultrahigh risk for psychosis, 42 siblings of psychotic patients, and 53 controls). All participants were exposed to virtual environments with different levels of social stress. The level of experienced paranoia in the virtual environments was measured with the State Social Paranoia Scale. Cognitive biases were assessed with a self-report continuous measure. Also, cumulative number of cognitive biases was calculated using dichotomous measures of the separate biases, based on general population norm scores. Results: Higher belief inflexibility bias (Z = 2.83, P < .001), attention to threat bias (Z = 3.40, P < .001), external attribution bias (Z = 2.60, P < .001), and data-gathering bias (Z = 2.07, P < .05) were all positively associated with reported paranoid ideation in the social virtual environments. Level of paranoid response increased with number of cognitive biases present (B = 1.73, P < .001). The effect of environmental stressors on paranoid ideation was moderated by attention to threat bias (Z = 2.78, P < .01) and external attribution bias (Z = 2.75, P < .01), whereas data-gathering bias and belief inflexibility did not moderate the relationship. Conclusion: There is an additive effect of separate cognitive biases on paranoid response to social stress. The effect of social environmental stressors on paranoid ideation is further enhanced by attention to threat bias and external attribution bias.

Social environments and interpersonal distance regulation in psychosis: A virtual reality study.

BACKGROUND: Experimentally studying the influence of social environments on mental health and behavior is challenging, as social context is difficult to standardize in laboratory settings. Virtual Reality (VR) enables studying social interaction in terms of interpersonal distance in a more ecologically valid manner. Regulation of interpersonal distance may be abnormal in patients with psychotic disorders and influenced by environmental stress, symptoms or distress. AIMS: To investigate interpersonal distance in people with a psychotic disorder and at ultrahigh risk for psychosis (UHR) compared to siblings and controls in virtual social environments, and explore the relationship between clinical characteristics and interpersonal distance. METHODS: Nineteen UHR patients, 52 patients with psychotic disorders, 40 siblings of patients with a psychotic disorder and 47 controls were exposed to virtual cafés. In five virtual café visits, participants were exposed to different levels of social stress, in terms of crowdedness, ethnicity and hostility. Measures on interpersonal distance, distress and state paranoia were obtained. Baseline measures included trait paranoia, social anxiety, depressive, positive and negative symptoms. RESULTS: Interpersonal distance increased when social stressors were present in the environment. No difference in interpersonal distance regulation was found between the groups. Social anxiety and distress were positively associated with interpersonal distance in the total sample. CONCLUSION: This VR paradigm indicates that interpersonal distance regulation in response to environmental social stressors is unaltered in people with psychosis or UHR. Environmental stress, social anxiety and distress trigger both people with and without psychosis to maintain larger interpersonal distances in social situations.

High psychosis liability is associated with altered autonomic balance during exposure to Virtual Reality social stressors.

BACKGROUND: Social stressors are associated with an increased risk of psychosis. Stress sensitisation is thought to be an underlying mechanism and may be reflected in an altered autonomic stress response. Using an experimental Virtual Reality design, the autonomic stress response to social stressors was examined in participants with different liability to psychosis. METHOD: Fifty-five patients with recent onset psychotic disorder, 20 patients at ultra-high risk for psychosis, 42 siblings of patients with psychosis and 53 controls were exposed to social stressors (crowdedness, ethnic minority status and hostility) in a Virtual Reality environment. Heart rate variability parameters and skin conductance levels were measured at baseline and during Virtual Reality experiments. RESULTS: High psychosis liability groups had significantly increased heart rate and decreased heart rate variability compared to low liability groups both at baseline and during Virtual Reality experiments. Both low frequency (LF) and high frequency (HF) power were reduced, while the LF/HF ratio was similar between groups. The number of virtual social stressors significantly affected heart rate, HF, LF/HF and skin conductance level. There was no interaction between psychosis liability and amount of virtual social stress. CONCLUSION: High liability to psychosis is associated with decreased parasympathetic activity in virtual social environments, which reflects generally high levels of arousal, rather than increased autonomic reactivity to social stressors.

Environmental Social Stress, Paranoia and Psychosis Liability: A Virtual Reality Study.

The impact of social environments on mental states is difficult to assess, limiting the understanding of which aspects of the social environment contribute to the onset of psychotic symptoms and how individual characteristics moderate this outcome. This study aimed to test sensitivity to environmental social stress as a mechanism of psychosis using Virtual Reality (VR) experiments. Fifty-five patients with recent onset psychotic disorder, 20 patients at ultra high risk for psychosis, 42 siblings of patients with psychosis, and 53 controls walked 5 times in a virtual bar with different levels of environmental social stress. Virtual social stressors were population density, ethnic density and hostility. Paranoia about virtual humans and subjective distress in response to virtual social stress exposures were measured with State Social Paranoia Scale (SSPS) and self-rated momentary subjective distress (SUD), respectively. Pre-existing (subclinical) symptoms were assessed with the Community Assessment of Psychic Experiences (CAPE), Green Paranoid Thoughts Scale (GPTS) and the Social Interaction Anxiety Scale (SIAS). Paranoia and subjective distress increased with degree of social stress in the environment. Psychosis liability and pre-existing symptoms, in particular negative affect, positively impacted the level of paranoia and distress in response to social stress. These results provide experimental evidence that heightened sensitivity to environmental social stress may play an important role in the onset and course of psychosis.