Increased level of serum cytokines, chemokines and adipokines in patients with schizophrenia is associated with disease and metabolic syndrome

SummaryAt present there are strong indications of a shared vulnerability factor for schizophrenia (SZ), diabetes and the metabolic syndrome (metS). In this study we focus on an aberrantly activated monocyte/macrophage system as the shared factor.We measured in SZ patients (n=144), the serum levels of monocyte/macrophage cytokines/chemokines/adipokines CCL2, CCL4, IL-1β, TNF-α, IL-6, PTX3, leptin, adiponectin, PAI-1, OPG and ICAM-1 and compared these levels to healthy controls (HC) (n=138). Using multivariate analysis, we studied the effect of the presence of the disease SZ, the components of the metS including BMI, the levels of lipids (HDL cholesterol and triglycerides (TG)), diabetes (hyperglycemia) and the use of antipsychotic medication, on the serum levels of these immune compounds.We found all measured immune compounds with the exception of PAI-1 and OPG to be elevated in the SZ patient population. Multivariate analysis showed that elevations were linked to gender (ICAM-1, leptin, TNF-α and adiponectin), an increased BMI (leptin, adiponectin), hyperglycemia/diabetes (CCL4, and OPG), reduced HDL-cholesterol or increased levels of TG (adiponectin and PTX3) or the metS (CCL2, leptin and adiponectin). IL-1β and IL-6 were the only immune compounds raised in the serum of patients not affected by any of the included factors.Although many of the immune compounds were found linked to (components of) the metS, the most dominant linkage was found with the disease schizophrenia, confirming earlier reports on increased monocyte/macrophage activation as a key component for understanding the pathogenesis of schizophrenia

An activated set point of T-cell and monocyte inflammatory networks in recent-onset schizophrenia patients involves both pro- and anti-inflammatory forces

We recently described a pro-inflammatory gene expression signature in the monocytes of 60% of patients with recent-onset schizophrenia (SCZ). Here we investigated whether the T-cell system is also in a pro-inflammatory state. A detailed fluorescence-activated cell sorting (FACS) analysis, e. g. of CD3(+) CD25(+) T cells, IFN-gamma(+), IL-4(+), IL-17A(+) (CD4(+)) lymphocytes and CD4(+) CD25(high)FoxP3(+) regulatory T cells, was performed on peripheral blood of 26 patients with recent-onset SCZ (in 19 of whom the inflammatory gene expression signature of the monocyte had been determined) and in age-/gender-matched healthy controls. Various relevant T-cell cytokines, e.g. sCD25, IFN-gamma, IL-17A and IL-4, were measured in serum by a multiplex assay. We detected : (a) not only higher percentages of pro-inflammatory-prone monocytes, activated CD3(+) CD25(+) T cells and pro-inflammatory Th17 cells in patients, but also higher percentages of anti-inflammatory CD4(+) CD25(high)FoxP3(+) regulatory T cells and IL-4(+) lymphocytes; (b) that this activated T-cell set point was reflected in significantly raised serum levels of sCD25; (c) that the up-regulation of IL-4(+)-containing lymphocytes was predominantly found in patients characterized by a monocyte pro-inflammatory set point; and (d) that regulatory T-cell and Th17-cell numbers were higher in patients irrespective of the pro-inflammatory state of the monocytes. Our data do not support the concept that the T-cell system is in a simple pro-inflammatory state in recent-onset SCZ, but do show that the monocyte and T-cell networks are activated and involve both pro-and anti-inflammatory forces. This suggests control within an activated inflammatory system

An Inflammatory Gene-Expression Fingerprint in Monocytes of Autoimmune Thyroid Disease Patients

Context: In monocytes of patients with autoimmune diabetes, we recently identified a gene expression fingerprint of two partly overlapping gene clusters, a PDE4B-associated cluster (consisting of 12 core proinflammatory cytokine/compound genes), a FABP5-associated cluster (three core genes), and a set of nine overlapping chemotaxis, adhesion, and cell assembly genes correlating to both PDE4B and FABP5. Objective: Our objective was to study whether a similar monocyte inflammatory fingerprint as found in autoimmune diabetes is present in autoimmune thyroid disease (AITD). Design and Patients: Quantitative PCR was used for analysis of 28 genes in monocytes of 67 AITD patients and 70 healthy controls. The tested 28 genes were the 24 genes previously found abnormally expressed in monocytes of autoimmune diabetes patients plus four extra genes found in whole-genome analysis of monocytes of AITD patients reported here. Results: Monocytes of 24% of AITD and 50% of latent autoimmune diabetes of adults (LADA) patients shared an inflammatory fingerprint consisting of the set of 24 genes of the PDE4B, FABP5, and overlapping gene sets. This study in addition revealed that FCAR, the gene for the Fc alpha receptor I, and PPBP, the gene for CXCL7, were part of this proinflammatory monocyte fingerprint. Conclusions: Our study provides an important tool to determine a shared, specific proinflammatory state of monocytes in AITD and LADA patients, enabling further research into the role of such proinflammatory cells in the failure to preserve tolerance in these conditions and of key fingerprint genes involved. (J Clin Endocrinol Metab 95: 1962-1971, 2010

Changes in serum adhesion molecules, chemokines, cytokines, and tissue remodeling factors in euthyroid women without thyroid antibodies who are at risk for autoimmune thyroid disease: a hypothesis on the early phases of the endocrine autoimmune reaction

The target glands in spontaneous animal models of endocrine autoimmune disease show, prior to the autoimmune reaction, growth and connective tissue abnormalities, whereas the autoimmune reaction is initiated by an early accumulation of macrophages and dendritic cells in the target glands. The aim of the study was to test the hypothesis that serum factors related to these growth and connective tissue abnormalities and the early accumulation of immune cells, ie, tissue growth/remodeling factors, adhesion molecules, chemokines, and pro- and anti-inflammatory cytokines, are related to thyroid peroxidase autoantibodies (TPO-Abs) seroconversion in subjects at risk to develop autoimmune thyroid disease (AITD). A controlled study on 64 TPO-Ab-negative euthyroid female relatives with at least 1 first- or second-degree relative with documented autoimmune hyper- or hypothyroidism, 32 of whom did and 32 who did not seroconvert to TPO-Ab positivity in 5-year follow-up. The relatives were compared with 32 healthy controls. In all subjects we measured serum levels of chemokine (C-C motif) ligand (CCL)-2, CCL3, CCL4, soluble vascular cell adhesion molecule, soluble intercellular adhesion molecule-1, thrombospondin-1, vascular endothelial growth factor-A, angiopoietin 1 receptor-2, metalloproteinase-13, platelet-derived growth factor-BB, fibronectin, IL-1β, IL-6, TNF-α, IL-10, and growth differentiation factor-15 by multiplex (cytometric bead array) or a single commercial ELISA. Both seroconverting and nonseroconverting family members showed an up-regulation of fibronectin and a down-regulation of platelet-derived growth factor-BB and the adhesion and migration factors CCL2, CCL4, soluble vascular cell adhesion molecule-1, angiopoietin 1 receptor-2, and metalloproteinase-13. The seroconverters differed from the nonseroconverters by an up-regulation of the proinflammatory compounds Il-1β, IL-6, and CCL3. This study shows that euthyroid females within AITD families show a characteristic pattern of abnormalities in serum levels of tissue remodeling factors, growth factors, chemokines, (vascular) adhesion molecules, and cytokines prior to the occurrence of TPO-Abs in serum. The results provide proof of principle that preseroconversion stages and seroconversion to AITD might be predicted using serum analytes related to growth/connective tissue abnormalities and migration/accumulation abnormalities of macrophages and dendritic cell

The mononuclear phagocyte system and its cytokine inflammatory networks in schizophrenia and bipolar disorder

This review describes patients with schizophrenia and bipolar disorder. In such patients, a high inflammatory set point of circulating monocytes at the transcriptome level is observed, involving various inflammatory transcripts forming distinct fingerprints (the transcriptomic monocyte fingerprint in schizophrenia overlaps with that in bipolar disorder, but also differs with it at points). There are increased levels of compounds of the IL-1, IL-6 and TNF system in the serum (be it modest and inconsistent). There is also evidence that the IL-2 system is activated in patients with schizophrenia (and perhaps those with mania), although independently of the activation of the IL-1, IL-6 and TNF systems, suggesting separate inducing mechanisms for monocyte and T-cell activation. It is not yet known whether such T cell activation involves the Th1/Th2/Th17 or Treg systems