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Inflammatory monocyte activation is associated with natural T regulatory cell deficiencies and co-occurs with cellular immune defects in major depressive disorder
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13th Psychoimmunology Expert Meeting March 3–6, 2016 / Neurology, psychiatry and brain research 22 (2016) 1–25
Specific alteration of NMDA receptor synaptic trafficking by circulating autoantibodies from schizophrenic patients Laurent Groc *, Julie Je´ze´quel, Emily M. Johansson, He´le`ne Gre´a, Ve´ronique Rogemond, Nora Hamadani, Emmanuel LeGuen, Corentin Rabu, Elodie Mathias, Juan Varela, Delphine Bouchet, Robert H. Yolken, Ryad Tamouza, Josep Dalmau, Je´roˆme Honnorat, Marion Leboyer CNRS – University of Bordeaux, Bordeaux, France *Corresponding author. The flourishing identification of circulating autoantibodies against neuronal receptors in neuropsychiatric patients has fostered new conceptual and clinical frameworks. However, their detection in multiple neurological and psychiatric disorders, as well as in healthy subjects, has cast doubt about their pathological action and use as biomarkers. Here, we purified autoantibodies against glutamate NMDA receptor (IgG type; NMDAR-Ab) from schizophrenic patients ‘and healthy subjects’ sera and examined their impact on their targets. First, we report that circulating levels in schizophrenic patients are lower than those found in anti-NMDA encephalitis patients. These low titers generate detection variability as demonstrated by the heterogenous outcomes from the different methods we used. Strikingly, using single molecule and super-resolution imaging approaches, we report that only NMDAR-Ab from schizophrenic patients strongly, specifically, and acutely alters the dynamic organization of synaptic GluN1-NMDAR and membrane partners in live hippocampal neurons. Thus, circulating NMDAR-Ab are heterogeneous in their molecular pathogenicity, supporting a possible role of pathogenic autoantibodies and calling for great caution in using NMDAR-Ab as diagnostic biomarkers for neuropsychiatric disorders. http://dx.doi.org/10.1016/j.npbr.2015.12.026 Inflammatory monocyte activation is associated with natural T regulatory cell deficiencies and co-occurs with cellular immune defects in major depressive disorder Laura Grosse 1,2,*, Thomas Hoogenboezem 3, Oliver Ambre´e 1, Silja Bellingrath 4, Silke Jo¨rgens 1, Harm J. de Wit 3, Annemarie M. Wijkhuijs 3, Volker Arolt 1, Hemmo A. Drexhage 3 1
Department of Psychiatry, University of Muenster, Germany Radiology Morphological Solutions, Rotterdam, The Netherlands 3 Department of Immunology, Erasmus MC, Rotterdam, The Netherlands 4 Department of Psychology, University of Duisburg-Essen, Germany *Corresponding author. 2
Background: In a previous study, we found an up-regulated inflammatory monocyte gene expression profile in major depressive disorder (MDD) patients aged 28 years and a downregulated inflammatory gene expression profile in MDD patients aged <28 years. In the same sample of patients, we aimed to investigate immune dysregulation in the lymphocyte arm of the immune system, particularly in the context of the described monocyte (de-)activation states. Methods: From deep frozen leukocytes, circulating percentages of monocytes, lymphocytes, B, T, and natural killer (NK) cells, and
various functional subsets of T and T helper (Th) cells (Th1, Th2, Th17, and natural T regulatory cells) were measured in N = 50 MDD patients and N = 58 age- and gender-matched healthy controls (HC). In addition, serum levels of interleukin (IL)-6, sCD25, IL-7, IL3, SCF, IGF-BP2, and EGF were evaluated. Results: MDD patients were in general characterized by an impaired maturation of Th2 cells, Th17 cells, and NK cells and by decreased serum levels of IL-7 and sCD25. MDD patients aged 28 years additionally exhibited decreased percentages of CD4+CD25highFoxP3+ T regulatory cells, next to signs of the above described partial T cell defects. Natural T regulatory cells were inversely associated with the pro-inflammatory state of the monocytes (r = .311; p = .034) that characterized this patient subgroup. Conclusions: Inflammatory monocyte immune activation and partial lymphocyte defects are two partly related phenomena that co-occur within the same MDD patients. http://dx.doi.org/10.1016/j.npbr.2015.12.027
Panels of inflammation biomarkers, growth factors and kynurenine metabolites aid in stratification of depressed patients Angelos Halaris Loyola University Chicago Stritch School of Medicine, Maywood, IL, USA Objectives: Depressive disorders are highly heterogeneous disorders. This heterogeneity contributes greatly to diagnostic inaccuracies, a very low percentage of remitters after the initial antidepressant drug trial, and poor predictability of suicidality, treatment response and requirement for prolonged maintenance treatment. Methods: Males and females (20–65 years of age) meeting DSM-IV criteria for primary major depressive disorder (MDD) and were physically healthy were considered. Thirty patients met inclusion criteria and were enrolled. After baseline assessments they were started on escitalopram on an open label basis. Healthy control subjects were enrolled throughout the period the MDD subjects were recruited. Rating scales were used to assess depression, state and trait anxiety, state and trait anger, stress perception, somatosensory amplification, quality of life. Inflammation biomarkers and growth factors were measured by ‘‘Evidence InvestigatorTM’’ (Randox Technologies). Pentraxin-3 and hsCRP were measured by ELISA. Tryptophan and kynurenines were measured by HPLC. Quinolinic acid was analyzed using GCMS. SPSS version 20 was used for the analyses. Distributions for all biomarkers were analyzed for normality, skewedness, kurtosis, and homoscedasticity of the residuals prior to analysis. Biomarkers found to have skewed distributions were analyzed through nonparametric methods. Cluster analyses were conducted by Dr. Henk Meijerink. Results: We observed correlations between specific symptoms of MDD and some of the biomarkers studied. Depressed mood correlated significantly with IFNg while weight loss correlated significantly with TNFa levels. QUIN correlated significantly with guilt and QUIN/3HK correlated significantly with guilt and psychomotor agitation. Pentaxin-3 correlated with anxiety. VEGF and hsCRP predicted treatment outcome. Conclusions: This is the first report that in MDD patients correlations are observed between specific depressive symptom scores and inflammation, growth factors and kynurenine metabolites. These results once confirmed in a larger cohort can lead to
13th Psychoimmunology Expert Meeting March 3–6, 2016 / Neurology, psychiatry and brain research 22 (2016) 1–25
Specific alteration of NMDA receptor synaptic trafficking by circulating autoantibodies from schizophrenic patients Laurent Groc *, Julie Je´ze´quel, Emily M. Johansson, He´le`ne Gre´a, Ve´ronique Rogemond, Nora Hamadani, Emmanuel LeGuen, Corentin Rabu, Elodie Mathias, Juan Varela, Delphine Bouchet, Robert H. Yolken, Ryad Tamouza, Josep Dalmau, Je´roˆme Honnorat, Marion Leboyer CNRS – University of Bordeaux, Bordeaux, France *Corresponding author. The flourishing identification of circulating autoantibodies against neuronal receptors in neuropsychiatric patients has fostered new conceptual and clinical frameworks. However, their detection in multiple neurological and psychiatric disorders, as well as in healthy subjects, has cast doubt about their pathological action and use as biomarkers. Here, we purified autoantibodies against glutamate NMDA receptor (IgG type; NMDAR-Ab) from schizophrenic patients ‘and healthy subjects’ sera and examined their impact on their targets. First, we report that circulating levels in schizophrenic patients are lower than those found in anti-NMDA encephalitis patients. These low titers generate detection variability as demonstrated by the heterogenous outcomes from the different methods we used. Strikingly, using single molecule and super-resolution imaging approaches, we report that only NMDAR-Ab from schizophrenic patients strongly, specifically, and acutely alters the dynamic organization of synaptic GluN1-NMDAR and membrane partners in live hippocampal neurons. Thus, circulating NMDAR-Ab are heterogeneous in their molecular pathogenicity, supporting a possible role of pathogenic autoantibodies and calling for great caution in using NMDAR-Ab as diagnostic biomarkers for neuropsychiatric disorders. http://dx.doi.org/10.1016/j.npbr.2015.12.026 Inflammatory monocyte activation is associated with natural T regulatory cell deficiencies and co-occurs with cellular immune defects in major depressive disorder Laura Grosse 1,2,*, Thomas Hoogenboezem 3, Oliver Ambre´e 1, Silja Bellingrath 4, Silke Jo¨rgens 1, Harm J. de Wit 3, Annemarie M. Wijkhuijs 3, Volker Arolt 1, Hemmo A. Drexhage 3 1
Department of Psychiatry, University of Muenster, Germany Radiology Morphological Solutions, Rotterdam, The Netherlands 3 Department of Immunology, Erasmus MC, Rotterdam, The Netherlands 4 Department of Psychology, University of Duisburg-Essen, Germany *Corresponding author. 2
Background: In a previous study, we found an up-regulated inflammatory monocyte gene expression profile in major depressive disorder (MDD) patients aged 28 years and a downregulated inflammatory gene expression profile in MDD patients aged <28 years. In the same sample of patients, we aimed to investigate immune dysregulation in the lymphocyte arm of the immune system, particularly in the context of the described monocyte (de-)activation states. Methods: From deep frozen leukocytes, circulating percentages of monocytes, lymphocytes, B, T, and natural killer (NK) cells, and
various functional subsets of T and T helper (Th) cells (Th1, Th2, Th17, and natural T regulatory cells) were measured in N = 50 MDD patients and N = 58 age- and gender-matched healthy controls (HC). In addition, serum levels of interleukin (IL)-6, sCD25, IL-7, IL3, SCF, IGF-BP2, and EGF were evaluated. Results: MDD patients were in general characterized by an impaired maturation of Th2 cells, Th17 cells, and NK cells and by decreased serum levels of IL-7 and sCD25. MDD patients aged 28 years additionally exhibited decreased percentages of CD4+CD25highFoxP3+ T regulatory cells, next to signs of the above described partial T cell defects. Natural T regulatory cells were inversely associated with the pro-inflammatory state of the monocytes (r = .311; p = .034) that characterized this patient subgroup. Conclusions: Inflammatory monocyte immune activation and partial lymphocyte defects are two partly related phenomena that co-occur within the same MDD patients. http://dx.doi.org/10.1016/j.npbr.2015.12.027
Panels of inflammation biomarkers, growth factors and kynurenine metabolites aid in stratification of depressed patients Angelos Halaris Loyola University Chicago Stritch School of Medicine, Maywood, IL, USA Objectives: Depressive disorders are highly heterogeneous disorders. This heterogeneity contributes greatly to diagnostic inaccuracies, a very low percentage of remitters after the initial antidepressant drug trial, and poor predictability of suicidality, treatment response and requirement for prolonged maintenance treatment. Methods: Males and females (20–65 years of age) meeting DSM-IV criteria for primary major depressive disorder (MDD) and were physically healthy were considered. Thirty patients met inclusion criteria and were enrolled. After baseline assessments they were started on escitalopram on an open label basis. Healthy control subjects were enrolled throughout the period the MDD subjects were recruited. Rating scales were used to assess depression, state and trait anxiety, state and trait anger, stress perception, somatosensory amplification, quality of life. Inflammation biomarkers and growth factors were measured by ‘‘Evidence InvestigatorTM’’ (Randox Technologies). Pentraxin-3 and hsCRP were measured by ELISA. Tryptophan and kynurenines were measured by HPLC. Quinolinic acid was analyzed using GCMS. SPSS version 20 was used for the analyses. Distributions for all biomarkers were analyzed for normality, skewedness, kurtosis, and homoscedasticity of the residuals prior to analysis. Biomarkers found to have skewed distributions were analyzed through nonparametric methods. Cluster analyses were conducted by Dr. Henk Meijerink. Results: We observed correlations between specific symptoms of MDD and some of the biomarkers studied. Depressed mood correlated significantly with IFNg while weight loss correlated significantly with TNFa levels. QUIN correlated significantly with guilt and QUIN/3HK correlated significantly with guilt and psychomotor agitation. Pentaxin-3 correlated with anxiety. VEGF and hsCRP predicted treatment outcome. Conclusions: This is the first report that in MDD patients correlations are observed between specific depressive symptom scores and inflammation, growth factors and kynurenine metabolites. These results once confirmed in a larger cohort can lead to