Inflammatory gene expression in monocytes of patients with schizophrenia: Overlap and difference with bipolar disorder. A study in naturalistically treated patients

Department of Immunology, Erasmus MC, Rotterdam, The Netherlands.
The International Journal of Neuropsychopharmacology (Impact Factor: 4.01). 11/2010; 13(10):1369-81. DOI: 10.1017/S1461145710000799
Source: PubMed


Accumulating evidence indicates an activated inflammatory response system as a vulnerability factor for schizophrenia (SZ) and bipolar disorder (BD). We aimed to detect a specific inflammatory monocyte gene expression signature in SZ and compare such signature with our recently described inflammatory monocyte gene signature in BD. A quantitative-polymerase chain reaction (Q-PCR) case-control gene expression study was performed on monocytes of 27 SZ patients and compared to outcomes collected in 56 BD patients (all patients naturalistically treated). For Q-PCR we used nine 'SZ specific genes' (found in whole genome analysis), the 19 BD signature genes (previously found by us) and six recently described autoimmune diabetes inflammatory monocyte genes. Monocytes of SZ patients had (similar to those of BD patients) a high inflammatory set point composed of three subsets of strongly correlating genes characterized by different sets of transcription/MAPK regulating factors. Subset 1A, characterized by ATF3 and DUSP2, and subset 1B, characterized by EGR3 and MXD1, were shared between BD and SZ patients (up-regulated in 67% and 51%, and 34% and 41%, respectively). Subset 2, characterized by PTPN7 and NAB2 was up-regulated in the monocytes of 62% BD, but down-regulated in the monocytes of 48% of SZ patients. Our approach shows that monocytes of SZ and BD patients overlap, but also differ in inflammatory gene expression. Our approach opens new avenues for nosological classifications of psychoses based on the inflammatory state of patients, enabling selection of those patients who might benefit from an anti-inflammatory treatment.

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Available from: Nico J M van Beveren, Jan 06, 2016
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    • "The primary evidence that supports the existence of this spectrum is as follows: a) Genetic studies, including the Genome-Wide Association Study (GWAS) with large population samples, that have described genetic variations of the major histocompatibility complex and of genes expressed in tissue with important roles in immune or inflammatory responses (Schizophrenia Working Group of the Psychiatric Genomics, 2014; Shi et al., 2009; Stefansson et al., 2009). There is also evidence of the upregulation of genes linked to inflammation in brain tissue (Drexhage et al., 2010; Saetre et al., 2007). b) Ecological studies that demonstrate an increased presentation of autoimmune illnesses and serious infections in this population (Benros et al., 2011; Torrey et al., 2012). "
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    ABSTRACT: The search for biomarkers in cognition has been the focus of a large part of the research on patients suffering from schizophrenia. The scientific literature is heterogeneous, and few studies establishing an integrative model of pathogenesis and therapeutic response are available in this field. In this review, we aimed to summarize three essential aspects correlated with cognitive performance: 1) the relationship between inflammation and cognition in schizophrenia, 2) the role of prolactin in cognition, and 3) the association between cognition and neurotrophic factors, particularly brain-derived neurotrophic factor (BDNF). Several studies support the association of inflammatory markers with cognitive status in schizophrenia. In recent decades, the development of effective therapies for cognitive impairment in schizophrenia has focused on the search for anti-inflammatory and immunomodulatory medications. Conversely, the implications of prolactin and its functions in cognition, the transition to psychosis and the diagnosis and prognosis of schizophrenia have been established independent of antipsychotic treatment. With regard to neurotrophic factors, a recent study has correlated BDNF levels with cognitive recovery in schizophrenic patients treated with cognitive remediation. We conclude that although there is a diversity of biomarkers focused on cognitive function in schizophrenia, BDNF is the biomarker that has accumulated the vast majority of evidence in the current literature.
    Full-text · Article · Dec 2015 · Schizophrenia Research: Cognition
    • "There is accumulating evidence that cell-mediated immunity plays an important role in the pathogenesis of major mood disorders (Beumer et al., 2012; Drexhage et al., 2010; Miller, 2010; Toben and Baune, 2015). In support of this view, we recently described an up-regulation of a coherent set of immune activation and inflammationrelated genes in circulating monocytes of subgroups of patients with major depressive disorder (Carvalho et al., 2014; Grosse et al., 2015b). "
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    ABSTRACT: 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 down-regulated 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, IL-3, 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(+)CD25(high)FoxP3(+) 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: Deficiencies of the NK and T (regulatory) cell system and inflammatory monocyte immune activation co-occur as partly interrelated phenomena within the same MDD patients.
    No preview · Article · Dec 2015 · Brain Behavior and Immunity
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    • "Focusing on the main cellular producers of these cytokines, such as circulating monocytes and macrophages, may be a better approach to find stable markers for BD. Indeed, studies from our group focusing on gene expression of circulating monocytes found a discriminating pro-inflammatory gene expression in BD patients compared to HC (Drexhage et al. 2010; Padmos et al. 2008). It remains unclear whether these immunological disturbances are related to the mood state, or are a trait phenomenon. "
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    ABSTRACT: Background: This study aimed to examine whether inflammatory gene expression was a trait or a state marker in patients with bipolar disorder (BD). Methods: 69 healthy controls (HC), 82 euthymic BD patients and 8 BD patients with a mood episode (7 depressed, 1 manic) were included from the MOODINFLAME study. Six of the eight patients who had a mood episode were also investigated when they were euthymic (6 of the 82 euthymic patients). Of these participants the expression of 35 inflammatory genes was determined in monocytes using quantitative-polymerase chain reaction, of which a total gene expression score was calculated as well as a gene expression score per sub-cluster. Results: There were no significant differences in inflammatory monocyte gene expression between healthy controls and euthymic patients. Patients experiencing a mood episode, however, had a significantly higher total gene expression score (10.63 ± 2.58) compared to healthy controls (p = .004) and euthymic patients (p = .009), as well as when compared to their own scores when they were euthymic (p = .02). This applied in particular for the sub-cluster 1 gene expression score, but not for the sub-cluster 2 gene expression score. Conclusions: Our study indicates that in BD inflammatory monocyte, gene expression is especially elevated while in a mood episode compared to being euthymic.
    Full-text · Article · Sep 2015
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