Knijff, E.M.

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

2010-01-01T00:00:00Z

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.

A discriminating messenger RNA signature for bipolar disorder formed by an aberrant expression of inflammatory genes in monocytes (Article)

2008-04-01T00:00:00Z

Context: Mood disturbances are associated with an activated inflammatory response system. Objective: To identify a discriminating and coherent expression pattern of proinflammatory genes in monocytes of patients with bipolar disorder. Design: A quantitative polymerase chain reaction (Q-PCR) case-control gene expression study on purified monocytes of bipolar patients, the offspring of bipolar patients, and healthy control participants after having selected 22 discriminating inflammatory genes using whole genome analyses. Setting: Academic research setting in the Netherlands. Patients: Forty-two bipolar patients with 25 healthy controls, 54 offspring of a bipolar parent (13 had a mood disorder and 3 developed one during follow-up), and 70 healthy children underwent Q-PCR. Main Outcome Measure: Inflammatory gene expression levels in monocytes. Results: We detected in the monocytes of bipolar patients a coherent mutually correlating set (signature) of 19 aberrantly expressed (P<.01) messenger RNAs of inflammatory (PDE4B, IL1B, IL6, TNF, TNFAIP3, PTGS2, and PTX3), trafficking (CCL2, CCL7, CCL20, CXCL2, CCR2, and CDC42), survival (BCL2A1 and EMP1), and mitogen-activated protein kinase pathway (MAPK6, DUSP2, NAB2, and ATF3) genes. Twenty-three of 42 bipolar patients (55%) had a positive signature test result vs 7 of 38 healthy controls (18%) (positive test result: positivity for PDE4B, ie, a messenger RNA 1 SD higher than the mean level found in healthy controls, plus 25% of the other genes with similar positive findings). Positive signature test results were also present in 11 of 13 offspring with a mood disorder (85%), 3 of 3 offspring developing a mood disorder (100%), and 17 of 38 euthymic offspring (45%) vs 13 of 70 healthy children (19%). Lithium carbonate and antipsychotic treatment down-regulated the gene expression of most inflammatory genes. Conclusions: The monocytes of a large proportion of bipolar patients and offspring of bipolar parents showed an inflammatory gene expression signature. This coherent set of genes opens new avenues for biomarker development with possibilities for disease prediction in individuals genetically at risk and for the subclassification of bipolar patients who could possibly benefit from anti-inflammatory treatment.

Bipolar Disorder: not only in the Brain - immunological aspects (Doctoral Thesis)

2006-10-25T00:00:00Z

The main objective of this thesis was to obtain more insight in the role of the immune system in the pathogenesis of bipolar disorder by investigating various aberrancies in the immune system of patients with bipolar disorder. In Chapter 1 some general concepts, important for the perception of this thesis, are presented. Background information on bipolar disorder, the immune system, and the hypothalamus pituitary adrenal axis is given. Bipolar disorder is a severe and chronic mood disorder with a prevalence ranging from .3-3.7% (generally 1.3-1.6%) and a complex etiology. There is increasing evidence that the immune system plays a significant role in the pathophysiology of mood disorders, but research in this field particularly focussed on major depression. In this chapter an overview of earlier published research on immune abnormalities in mood disorders, especially bipolar disorder, is given. It is clear that not all immune findings point in the same direction, mainly due to diverse methodological approaches. Consequently, much of the involved mechanisms need further clarification. Also the role of lithium is mentioned, a potent mood stabilizer with immune modulating capacity.