Collaborative meta-analysis finds no evidence of a strong interaction between stress and 5-HTTLPR genotype contributing to the development of depression

The hypothesis that the S allele of the 5-HTTLPR serotonin transporter promoter region is associated with increased risk of depression, but only in individuals exposed to stressful situations, has generated much interest, research, and controversy since first proposed in 2003. Multiple meta-analyses combining results from heterogeneous analyses have not settled the issue. To determine the magnitude of the interaction and the conditions under which it might be observed, we performed new analyses on 31 datasets containing 38 802 European-ancestry subjects genotyped for 5-HTTLPR and assessed for depression and childhood maltreatment or other stressful life events, and meta-analyzed the results. Analyses targeted two stressors (narrow, broad) and two depression outcomes (current, lifetime). All groups that published on this topic prior to the initiation of our study and met the assessment and sample size criteria were invited to participate. Additional groups, identified by consortium members or self-identified in response to our protocol (published prior to the start of analysis1) with qualifying unpublished data were also invited to participate. A uniform data analysis script implementing the protocol was executed by each of the consortium members. Our findings do not support the interaction hypothesis. We found no subgroups or variable definitions for which an interaction between stress and 5-HTTLPR genotype was statistically significant. In contrast, our findings for the main effects of life stressors (strong risk factor) and 5-HTTLPR genotype (no impact on risk) are strikingly consistent across our contributing studies, the original study reporting the interaction, and subsequent meta-analyses. Our conclusion is that if an interaction exists in which the S allele of 5-HTTLPR increases risk of depression only in stressed individuals, then it is not broadly generalizable, but must be of modest effect size and only observable in limited situations

Genome-wide association study of circulating interleukin 6 levels identifies novel loci

Interleukin 6 (IL-6) is a multifunctional cytokine with both pro- and anti-inflammatory properties with a heritability estimate of up to 61%. The circulating levels of IL-6 in blood have been associated with an increased risk of complex disease pathogenesis. We conducted a two-staged, discovery and replication meta genome-wide association study (GWAS) of circulating serum IL-6 levels comprising up to 67428 (ndiscovery=52654 and nreplication=14774) individuals of European ancestry. The inverse variance fixed effects based discovery meta-analysis, followed by replication led to the identification of two independent loci, IL1F10/IL1RN rs6734238 on chromosome (Chr) 2q14, (Pcombined=1.8x10-11), HLA-DRB1/DRB5 rs660895 on Chr6p21 (Pcombined=1.5x10-10) in the combined meta-analyses of all samples. We also replicated the IL6R rs4537545 locus on Chr1q21 (Pcombined=1.2x10-122). Our study identifies novel loci for circulating IL-6 levels uncovering new immunological and inflammatory pathways that may influence IL-6 pathobiology.</p

Generation and analysis of transgenic mice expressing ovalbumin as a neo-self antigen under control of the myelin basic protein promoter

In this project two novel murine autoimmune models were to be established in an attempt to further investigate the nervous system disorders of Multiple Sclerosis and Guillain Barré Syndrome. Previous experimental autoimmune encephalomyelitis (EAE) and experimental autoimmune neuritis (EAN) models have demonstrated that T cells play a major role in these diseases. Which roles CD4 and CD8 T cells specifically have in the initiation, propagation and termination of an autoimmune nervous system disorder remains controversial. To this end two transgenic mice specifically expressing the neo-antigen (Ag) ovalbumin (OVA) in either the central nervous system (CNS) or peripheral nervous system (PNS) were to be generated. The myelin basic protein (MBP) is a major component of the myelin sheath both within the CNS and the PNS. Therefore the MBP promoter was employed for its distinct regulatory elements to facilitate exclusive CNS or PNS OVA expression. The adoptive transfer of OVA specific MHCI restricted (OT-I) and MHCII restricted (OT-II) TCR Tg T cells extended the OVA Tg mouse model by allowing potentially encephalitogenic T cells to be tracked in vivo. Specificity for the target Ag should enable the dynamic role of antigen specific T cells in neuroinflammatory diseases to be revealed in more detail.Im Rahmen der vorliegenden Arbeit wurden zwei neue Mausmodelle für Autoimmunerkrankungen etabliert, um weitere Fortschritte bei der Aufklärung der zellulären und molekularen Interaktionen bei den Erkrankungen des Nervensystems Multiple Sklerose und Guillain Barré Syndrom zu erzielen. In früheren Experimenten mit EAE (experimentelle autoimmune Enzephalomyelitis) und EAN (experimentelle autoimmune Neuritis) konnte bereits gezeigt werden, dass T-Zellen eine Hauptrolle bei diesen Erkrankungen spielen, wobei jedoch die Bedeutung von CD4 bzw. CD8 T-Zellen im Einzelnen noch nicht aufgeklärt ist. Zu diesem Zwecke sollten zwei transgene (Tg) Mauslinien generiert werden, die speziell entweder im peripheren (PNS) oder im zentralen (ZNS) Nervensystem das Zielantigen OVA exprimieren. MBP ist eine Hauptkomponente der Myelinscheide sowohl im ZNS als auch im PNS. Daher kam der Myelin Basic Protein (MBP) Promoter zum Einsatz, dessen unterschiedliche regulatorischen Elemente eine Expression von intaktem OVA ausschließlich im ZNS bzw. ausschließlich im PNS steuern können. Eine Erweiterung dieser OVA tg Mausmodelle stellte der adoptive Transfer von OVA spezifischen MHCI-restringierten OTI und MHCII-restringierten OTII T-Zellen dar, da es so möglich wurde, potentiell enzephalitogene T-Zellen in vivo zu verfolgen. Dadurch sollte ebenfalls eine detailliertere Darstellung der dynamischen Rolle von antigenspezifischen T-Zellen bei neuroinflammatorischen Erkrankungen ermöglicht werden

The effect of resistance training on markers of immune function and inflammation in previously sedentary women recovering from breast cancer : a randomized controlled trial

The purpose of this randomized controlled trial was to determine the effects of resistance training (RT) on markers of inflammation and immune function in breast cancer survivors. Thirty-nine breast cancer survivors were randomly assigned to a RT (n = 20) or control (n = 19) group. RT performed supervized exercise three times per week. Natural killer cell (NK) and natural killer T-cell (NKT) function, and markers of inflammation (serum TNFa, IL-6, IL-10, and CRP) were measured before and after training. Changes in NK and NKT cell function were analyzed using ANCOVA, with the change score the dependent variable, and the baseline value of the same variable the covariate. Effect sizes (ES) were calculated via partial eta-squared. We found a significant reduction, and large associated ESs, in the RT group compared to the control group for change in NK cell expression of TNF-a (p = 0.005, ES = 0.21) and NKT cell expression of TNFa (p = 0.04, ES = 0.12). No differences were observed in any serum marker. Significant improvements in all measurements of strength were found in RT compared to control (

Guidelines for the standardized collection of blood-based biomarkers in psychiatry: Steps for laboratory validity - a consensus of the Biomarkers Task Force from the WFSBP

Recently, there has been a major shift in the field of psychiatry towards the exploration of complex relationships between blood-based biomarkers and the pathophysiology of psychiatric and neuropsychiatric disorders. However, issues with study reproducibility, validity and reliability have hindered progress towards the identification of clinically relevant biomarkers for psychiatry. The achievement of laboratory validity is a crucial first step for the posterior development of clinical validity. There is evidence that the variability observed in blood-based research studies may be minimised with the implementation of standardised pre-analytical methods and uniform clinical protocols (i.e., pre-venipuncture). It has been documented that errors made in the pre-analytical phase account for 46-68.2% of laboratory testing errors. Thus, standardising clinical assessment, ethical procedures and pre-analytical phase of clinical research is essential for the reproducibility, validity and reliability of blood marker assessment, and reducing the risk of invalid test results. Various other areas of research have already moved towards guidelines for the standardised collection of blood-based biomarkers. Here we aim to provide a set of guidelines that we believe would improve biomarker research: (1) pre-venipuncture information and documentation, (2) ethics of participant consent and (3) pre-analytical methods. Ultimately, we hope this will assist study planning and will improve data comparison across studies allowing for the discovery of biomarkers in psychiatry with both laboratorial and clinical validity

Large-scale evidence for an association between low-grade peripheral inflammation and brain structural alterations in major depression in the BiDirect study

BACKGROUND: Preliminary research suggests that major depressive disorder (MDD) is associated with structural alterations in the brain, as well as with low-grade peripheral inflammation. However, even though a link between inflammatory processes and altered brain structural integrity has been purported by experimental research, well-powered studies to confirm this hypothesis in patients with MDD have been lacking. We aimed to investigate the potential association between structural brain alterations and low-grade inflammation as interrelated biological correlates of MDD. METHODS: In this cross-sectional study, 514 patients with MDD and 359 healthy controls underwent structural MRI. We used voxel-based morphometry to study local differences in grey matter volume. We also assessed serum levels of high-sensitivity C-reactive protein (hsCRP) in each participant. RESULTS: Compared with healthy controls (age [mean ± standard deviation] 52.57 ± 7.94 yr; 50% male), patients with MDD (49.14 ± 7.28 yr, 39% male) exhibited significantly increased hsCRP levels (Z = −5.562, p < 0.001) and significantly decreased grey matter volume in the prefrontal cortex and the insula. Prefrontal grey matter volume reductions were significantly associated with higher hsCRP levels in patients with MDD (x = 50, y = 50, z = 8; t1,501 = 5.15; k = 92; pFWE < 0.001). In the MDD sample, the significant negative association between hsCRP and grey matter appeared independent of age, sex, body mass index, current smoking status, antidepressant load, hospitalization and medical comorbidities. LIMITATIONS: This study had a cross-sectional design. CONCLUSION: The present study highlights the role of reduced grey matter volume and low-grade peripheral inflammation as interrelated biological correlates of MDD. The reported inverse association between peripheral low-grade inflammation and brain structural integrity in patients with MDD translates current knowledge from experimental studies to the bedside

Guidelines for the standardized collection of blood-based biomarkers in psychiatry: steps for laboratory validity - a consensus of the Biomarkers Task Force from the WFSBP

Recently, there has been a major shift in the field of psychiatry towards the exploration of complex relationships between blood-based biomarkers and the pathophysiology of psychiatric and neuropsychiatric disorders. However, issues with study reproducibility, validity and reliability have hindered progress towards the identification of clinically relevant biomarkers for psychiatry. The achievement of laboratory validity is a crucial first step for the posterior development of clinical validity. There is evidence that the variability observed in blood-based research studies may be minimised with the implementation of standardised pre-analytical methods and uniform clinical protocols (i.e., pre-venipuncture). It has been documented that errors made in the pre-analytical phase account for 46-68.2% of laboratory testing errors. Thus, standardising clinical assessment, ethical procedures and pre-analytical phase of clinical research is essential for the reproducibility, validity and reliability of blood marker assessment, and reducing the risk of invalid test results. Various other areas of research have already moved towards guidelines for the standardised collection of blood-based biomarkers. Here we aim to provide a set of guidelines that we believe would improve biomarker research: (1) pre-venipuncture information and documentation, (2) ethics of participant consent and (3) pre-analytical methods. Ultimately, we hope this will assist study planning and will improve data comparison across studies allowing for the discovery of biomarkers in psychiatry with both laboratorial and clinical validity.Ana C. Andreazza, Isabelle Laksono, Brisa S. Fernandes, Catherine Toben, Piotr Lewczuk ... Bernhard T. Baune ... etal

Naive CD8 T-cells initiate spontaneous autoimmunity to a sequestered model antigen of the central nervous system

In multiple sclerosis, CD8 T-cells are thought play a key pathogenetic role, but mechanistic evidence from rodent models is limited. Here, we have tested the encephalitogenic potential of CD8 T-cells specific for the model antigen ovalbumin (OVA) sequestered in oligodendrocytes as a cytosolic molecule. We show that in these ‘ODC-OVA’ mice, the neo-self antigen remains invisible to CD4 cells expressing the OVA-specific OT-II receptor. In contrast, OVA is accessible to naïve CD8 T-cells expressing the OT-I T-cell receptor, during the first 10 days of life, resulting in antigen release into the periphery. Introduction of OT-I as a second transgene leads to fulminant demyelinating experimental autoimmune encephalomyelitis with multiple sclerosis-like lesions, affecting cerebellum, brainstem, optic nerve and spinal cord. OVA-transgenic oligodendrocytes activate naïve OT-I cells in vitro, and both major histocompatibility complex class I expression and the OT-I response are further up-regulated by interferon-γ (IFN-γ). Release of IFN-γ into the circulation of ODC-OVA/OT-I double transgenic mice precedes disease manifestation, and pathogenicity of OT-I cells transferred into ODC-OVA mice is largely IFN-γ dependent. In conclusion, naïve CD8 T-cells gaining access to an ‘immune-privileged’ organ can initiate autoimmunity via an IFN-γ-assisted amplification loop even if the self-antigen in question is not spontaneously released for presentation by professional antigen presenting cells.Shin-Young Na, Yi Cao, Catherine Toben, Lars Nitschke, Christine Stadelmann, Ralf Gold, Anneliese Schimpl, and Thomas Hüni