Former (till March 2015)

FORMER EXCHANGES BETWEEN PARTNERS (till March 2015)

After having collected circulating leukocytes and serum/plasma of large numbers of

  • Patients with severe depression
  • Patients with bipolar disorder
  • Patients with postpartum psychosis and
  • Patients with schizophrenia

The consortium has developed standard assays for

  1. Monocyte activation

    EMC has identified 10 mutually correlating core genes (cluster 1) and a microRNA identifying pro-inflammatory active monocytes and 10 of such core genes (cluster 2) and a microRNA identifying monocytes that are active in adhesion, cell shape, chemotaxis and cell differentiation.

  2. T cell subset analysis
    1. EMC standardly determines  CD3+ T cells, CD8+  cytotoxic T cells, CD4+  helper T cells, CD4+CD25+ FOXP3+ regulator T cells and TH1, TH2 and TH17 cells and brain trafficking CCR6+ T cells
    2. EMC also determines apart from T cells CD56+ NK cells, CD19+ B cells,  and CD14+ monocytes
  3. Trypcat evaluation
  4. APD and LMU standardly determine the following trypcats: tryptophan (Trp), 5-HIAA (serotonin pathway), Kynurenin (Kyn), and the protective immune suppressive Kynurenin A (KynA) and the toxic, pro-inflammatory 3-OH Kynurenin (3-HK)

  5. Pro-inflammatory cytokines and chemokines
    EMC and EDI have developed a standardized bead assay for measurement of IL-1β, IL-6, CCL2, IL-8, VEGF, GDF-15, s-ICAM-1, Eotaxin, sVCAM in serum.  Development was via exchange between EMC and EDI (Thomas Hoogenboezem, Ing). It turned out that IL-1β and IL-6 need to be measured not in multiplex, but in separate sensitive assay.
  6. Retroviral factors
    1. GNI has developed a standardized assay for the HERV-W antigen, circulating and more prevalent and higher in schizophrenia patients
    2. In the last months there has been an exchange of GNI to RMS (Dr Nadege Gehin)
    3. Aim: To test the pro-inflammatory capacity of HERV-W on the pro-inflammatory cytokine production of monocytes of schizophrenia patients.
      Results: 1. The HER-W antigen did, like LPS, stimulate the monocytes of healthy controls and schizophrenia patients to produce pro-inflammatory cytokines

      2. There were no differences between monocytes of schizophrenia patients and healthy controls in this respect.

  7. Growth factors for myeloid cells, lymphoid cells and neurons

EDI and EMC have developed a standardized bead assay for measurement of for IL-2, sCD25, IL-3, IL-7, SCF, GM-CSF, IGF-BP2, BDNF and EGF in serum. Development was via exchange between EMC and EDI (Thomas Hoogenboezem, Ing).

In the first years of the PSYCHAID project EMC and various partners have in exchanges (i.e. APD to LMU, Mu Myint; LMU-APD (Y. Lopez); EMC-CRL Annemarie Wijkhuijs; CRL-EMC (Richard Mendes, WWU-CRL (Laura Sumaski), EMC-CRL (W. Beumer) carried out the standard assays on the large majority of the collected patient samples. The first steps have later been taken by RMS (which has replaced CRL as partner, since CRL went broke) to construct a web-based protected database for clinical and laboratory data of the patients, enabling partners to carry out complex statistical analyses with the large data set.

EMC and clinical partners are following the central hypothesis that inborn neuro-immuno-endocrine abnormalities determine abnormal brain development and that later acute events, like stress and infections (further changing neuro-immuno-endocrine set points) elicit psychiatric symptoms and autoimmune diseases.

EMC and clinical partners have also tested this central hypothesis in an animal model of behavioral abnormalities via a recruitment (Dr Sinead Gibney), and aims at validating key abnormal molecular pathways and key biomarkers also in these animal models. Sinead had, as biologist, experience in both the study of the neuro-immuno-endocrine aspects of psychiatric disease at the human level and at the experimental animal level. She was the scientist-off-choice to work on the central hypothesis of EMC, which is the idea that psychiatric disorders are part of a larger systemic condition, i.e. an abnormal set point of the neuro-immuno-endocrine system, leading not only to psychiatric disease, but also to an increased risk to develop auto-immunities, chronic infections, metabolic syndrome, diabetes and cardiovascular disease. She has contributed to the performance of the transcriptomic and proteomic assays carried out at EMC on patient material, but has also, and in particular, performed parallel studies on a novel animal model of depressive-like behavior, the NOD mouse, which is a known animal model for endocrine autoimmune diseases and for metabolic disturbances. Dr Barry McGuiness now continues these analyses (see underneath).

PSY has tested it central approach which is the discovery via a non-hypothesis-driven approach molecular signatures in serum/plasma or circulating blood cells specific for a the above mentioned psychiatric conditions or specific for the responsiveness of the given psychiatric conditions for treatment.

In a recruitment Dr Pawel Stocki has, as biochemist, used multi-analyte platforms and advanced Mass Spectrometry, core businesses of PSY, and has carried out experiments following the central approach of PSY. PSY has found signatures specific for disease and therapy outcome. It is not surprising that these molecular signatures are made up of immune factors, growth and differentiation factors, neurotrophic factors, metabolic factors and hormones, thus bridging the gap between the non-hypothesis approach of PSY and the hypothesis driven approach of EMC.

Also  a blood-based biomarker signature for the response to olanzapine treatment in drug-free SZ patients has been constructed in this recruitment (using in total 137 SZ patients) and in particular a molecule in the fatty acid metabolism seems to be decisive in the olanzapine response. Therefore the fatty acid metabolism pathway will be further investigated by Jakub Tomasik (see Present Exchanges)

PSY has also established in an exchange between WWU and PSY (Dr Tillmann Ruland) a blood-based biomarker signature reflecting therapeutic response in MDD patients treated with Venlafaxine +/- add-on therapeutics (n=71) and have performed multiplex immunoassay profiling targeting TH1/TH2-regulated cytokine pathways. Final data analysis is currently ongoing and the outcome will be submitted for publication in 2015.

PSY has conducted multiplexed immunoassays (MAP) and cytomics profiling  (a FACS platform) on serum and PBMC respectively from a Schizophrenia and Asperger cohort (n=30 Asperger patients) and bio-statistical analyses have validated the schizophrenia  MAPs against Asperger syndrome. Many overlapping and non-overlapping (schizophrenia or Asperger specific) proteins have been identified, often belonging to interesting pathways playing an important role in  immune cell functioning, e.g. in the ferritin/transerythrin pathway. The first steps to investigate these interesting pathways also at the transcriptomic level in PBMC have been undertaken in an exchange between PSY and EMC (Dr Jantine Broek). It is planned that this exchange will be continued in the end of 2015.

PSY and EMC have investigated in an exchange EMC-PSY (Dr Karin Weigelt) blood proteome signatures associated with concordant and discordant twins suffering from bipolar disorder. MAPs and Mass Spectrometry-based proteome analysis and statistical analysis (linear modelling) have been completed by December 2014. Data await further integration with clinical and twin data.