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      Replicable and Coupled Changes in Innate and Adaptive Immune Gene Expression in Two Case-Control Studies of Blood Microarrays in Major Depressive Disorder

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          Abstract

          Background

          Peripheral inflammation is often associated with major depressive disorder (MDD), and immunological biomarkers of depression remain a focus of investigation.

          Methods

          We used microarray data on whole blood from two independent case-control studies of MDD: the GlaxoSmithKline–High-Throughput Disease-specific target Identification Program [GSK-HiTDiP] study (113 patients and 57 healthy control subjects) and the Janssen–Brain Resource Company study (94 patients and 100 control subjects). Genome-wide differential gene expression analysis (18,863 probes) resulted in a p value for each gene in each study. A Bayesian method identified the largest p-value threshold ( q = .025) associated with twice the number of genes differentially expressed in both studies compared with the number of coincidental case-control differences expected by chance.

          Results

          A total of 165 genes were differentially expressed in both studies with concordant direction of fold change. The 90 genes overexpressed (or UP genes) in MDD were significantly enriched for immune response to infection, were concentrated in a module of the gene coexpression network associated with innate immunity, and included clusters of genes with correlated expression in monocytes, monocyte-derived dendritic cells, and neutrophils. In contrast, the 75 genes underexpressed (or DOWN genes) in MDD were associated with the adaptive immune response and included clusters of genes with correlated expression in T cells, natural killer cells, and erythroblasts. Consistently, the MDD patients with overexpression of UP genes also had underexpression of DOWN genes (correlation > .70 in both studies).

          Conclusions

          MDD was replicably associated with proinflammatory activation of the peripheral innate immune system, coupled with relative inactivation of the adaptive immune system, indicating the potential of transcriptional biomarkers for immunological stratification of patients with depression.

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          Most cited references28

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          Gene Ontology: tool for the unification of biology

          Genomic sequencing has made it clear that a large fraction of the genes specifying the core biological functions are shared by all eukaryotes. Knowledge of the biological role of such shared proteins in one organism can often be transferred to other organisms. The goal of the Gene Ontology Consortium is to produce a dynamic, controlled vocabulary that can be applied to all eukaryotes even as knowledge of gene and protein roles in cells is accumulating and changing. To this end, three independent ontologies accessible on the World-Wide Web (http://www.geneontology.org) are being constructed: biological process, molecular function and cellular component.
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            Systemic infections and inflammation affect chronic neurodegeneration.

            It is well known that systemic infections cause flare-ups of disease in individuals with asthma and rheumatoid arthritis, and that relapses in multiple sclerosis can often be associated with upper respiratory-tract infections. Here we review evidence to support our hypothesis that in chronic neurodegenerative diseases such as Alzheimer's disease, with an ongoing innate immune response in the brain, systemic infections and inflammation can cause acute exacerbations of symptoms and drive the progression of neurodegeneration.
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              The relationship of depression and stressors to immunological assays: a meta-analytic review.

              This is a broad meta-analysis of the relations of both depression and stressors to immunological assays. The number of study samples (greater than 180) and measures (greater than 40) is much more extensive than any so far. Analyses are done by both fixed and random effects. By a fixed-effects analysis, both major depression and naturally occurring acute stressors are associated with (1) an overall leukocytosis, (2) mild reductions in absolute NK-cell counts and relative T-cell proportions, (3) marginal increases in CD4/CD8 ratios, and (4) moderate decreases in T- and NK-cell function. However, the degree of heterogeneity of the studies' results raises questions about their robustness. Therefore, we also did the first random effects analysis to estimate what is likely to appear in future studies. For depression, the analysis showed the immunological correlates included (1) an overall leukocytosis, manifesting as a relative neutrophilia and lymphoenia; (2) increased CD4/CD8 ratios; (3) increased circulating haptoglobin, PGE(2), and IL-6 levels; (4) reduced NK-cell cytotoxicity; and (5) reduced lymphocyte proliferative response to mitogen. For stressors, the random effects analysis showed that future studies are likely to find the following effects: (1) an overall leukocytosis, manifesting as an absolute lymphocytosis; (2) alterations in cytotoxic lymphocyte levels, CD4/CD8 ratios, and natural killer cell cytotoxicity with the direction of change depending on the chronicity of the stressor; (3) a relative reduction of T-cell levels; (3) increased EBV antibody titers; (4) reduced lymphocyte proliferative response and proportion of IL-2r bearing cells following mitogenic stimulation; and (5) increased leukocyte adhesiveness. The random-effects analysis revealed that for both major depression and naturally occurring stressors the following effects are shared: leukocytosis, increased CD4/CD8 ratios, reduced proliferative response to mitogen, and reduced NK cell cytotoxicity. The implications for these findings for disease susceptibility and the pathophysiology of these conditions is discussed. Copyright 2001 Academic Press.
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                Author and article information

                Contributors
                Journal
                Biol Psychiatry
                Biol. Psychiatry
                Biological Psychiatry
                Elsevier
                0006-3223
                1873-2402
                01 January 2018
                01 January 2018
                : 83
                : 1
                : 70-80
                Affiliations
                [a ]Medical Research Council Biostatistics Unit, Cambridge, United Kingdom
                [b ]Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom
                [c ]Cambridgeshire and Peterborough National Health Service Foundation Trust, Cambridge, United Kingdom
                [d ]Roslin Institute, University of Edinburgh, Edinburgh, United Kingdom
                [e ]ImmunoPsychiatry, GlaxoSmithKline Research & Development, Stevenage, United Kingdom
                [f ]Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom
                [g ]Brighton and Sussex Medical School, University of Sussex, Brighton, United Kingdom
                [h ]Centre for Biological Sciences, University of Southampton, Southampton, United Kingdom
                [i ]Rancho BioSciences, San Diego, California
                [j ]Janssen Research & Development, Titusville, New Jersey
                Author notes
                []Address correspondence to Edward T. Bullmore, M.B., Ph.D., Department of Psychiatry, University of Cambridge, Herchel Smith Building for Brain & Mind Sciences, Cambridge Biomedical Campus, Cambridge CB2 0SZ, UK.Department of PsychiatryUniversity of CambridgeHerchel Smith Building for Brain & Mind SciencesCambridge Biomedical CampusCambridge CB2 0SZUK etb23@ 123456cam.ac.uk
                Article
                S0006-3223(17)31617-7
                10.1016/j.biopsych.2017.01.021
                5720346
                28688579
                19343d5e-7670-4a95-b2f5-da4d8ad07e70
                © 2017 Society of Biological Psychiatry. All rights reserved.

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                History
                : 22 June 2016
                : 8 January 2017
                : 12 January 2017
                Categories
                Article

                Clinical Psychology & Psychiatry
                affymetrix,bayesian,biomarker,inflammation,systems,transcriptome
                Clinical Psychology & Psychiatry
                affymetrix, bayesian, biomarker, inflammation, systems, transcriptome

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