Low-dose interleukin 2 antidepressant potentiation in unipolar and bipolar depression: Safety, efficacy, and immunological biomarkers.

Immune-inflammatory mechanisms are promising targets for antidepressant pharmacology. Immune cell abnormalities have been reported in mood disorders showing a partial T cell defect. Following this line of reasoning we defined an antidepressant potentiation treatment with add-on low-dose interleukin 2 (IL-2). IL-2 is a T-cell growth factor which has proven anti-inflammatory efficacy in autoimmune conditions, increasing thymic production of naïve CD4 + T cells, and possibly correcting the partial T cell defect observed in mood disorders. We performed a single-center, randomised, double-blind, placebo-controlled phase II trial evaluating the safety, clinical efficacy and biological responses of low-dose IL-2 in depressed patients with major depressive (MDD) or bipolar disorder (BD). 36 consecutively recruited inpatients at the Mood Disorder Unit were randomised in a 2:1 ratio to receive either aldesleukin (12 MDD and 12 BD) or placebo (6 MDD and 6 BD). Active treatment significantly potentiated antidepressant response to ongoing SSRI/SNRI treatment in both diagnostic groups, and expanded the population of T regulatory, T helper 2, and percentage of Naive CD4+/CD8 + immune cells. Changes in cell frequences were rapidly induced in the first five days of treatment, and predicted the later improvement of depression severity. No serious adverse effect was observed. This is the first randomised control trial (RCT) evidence supporting the hypothesis that treatment to strengthen the T cell system could be a successful way to correct the immuno-inflammatory abnormalities associated with mood disorders, and potentiate antidepressant response.

Depression and suicidality: A link to premature T helper cell aging and increased Th17 cells.

BACKGROUND: Previous research has demonstrated a strong link between immune system abnormalities and Major Depressive Disorder (MDD). High suicide risk is a major complication of MDD and has recently been linked to strong (neuro-)immune alterations, but little is known on the link between circulating immune cell composition and suicidal risk status. METHODS: Here, we assessed percentages of circulating peripheral blood mononuclear cells with focus on T helper cell subsets (memory T helper cells, Th1, Th2, Th17 and T regulatory cells) in a large and well-matched cohort of 153 patients diagnosed with MDD and 153 age and sex matched controls. We explored the association of these cell populations with suicide risk while accounting for age, sex, BMI, depression severity and childhood trauma. RESULTS: Patients with MDD had reduced percentages of NK cells, and higher percentages of B and T cells in line with current literature. Further exploration of T-cells revealed a robustly elevated number of memory T helper cells, regardless of age group. Patients at high risk for suicide had the highest memory T helper cells and additionally showed a robust increase of Th17 cells compared to other suicide risk groups. CONCLUSIONS: The higher abundance of memory T helper cells points towards premature aging of the immune system in MDD patients, even during young adulthood. Patients at high risk for suicide show the clearest immune abnormalities and may represent a clinically relevant subtype of depression.

T-cell defects and postpartum depression.

BACKGROUND: Most studies of immune dysregulation in perinatal mood and anxiety disorders have focused on peripheral cytokines, but literature from non-perinatal mood disorders also implicates T-cell defects. We sought to characterize proportions of T-cell subtypes in women with postpartum depression. MATERIALS AND METHODS: We enrolled 21 women with postpartum depression (PPD), 39 healthy postpartum controls, and 114 healthy non-postpartum women. Blood was collected in sodium-heparin EDTA tubes and was analyzed using flow cytometry. We conducted statistical tests including linear regression analysis that were aimed at determining differences in proportions of T cell populations among groups. RESULTS: Mean counts of T-cells (all CD3+ T cells), T-helper cells, (CD3+CD4+ T cells), and T-cytotoxic cells (CD3+CD8+ T cells) were significantly increased in healthy postpartum women compared to healthy non-postpartum controls (p < 0.001, p = 0.007, and p = 0.002, respectively), but not in women with PPD. The increases in healthy postpartum women were driven by increases in TH1 cells and T regulatory cells, increases that were nonexistent or attenuated in women with postpartum depression. Mean counts of CD4+ T-helper memory cells were also increased in healthy postpartum women (p = 0.009), but slightly decreased in women with PPD (p = 0.066), when compared to healthy non-postpartum controls. CONCLUSIONS: Our study confirms that the postpartum period in healthy women is a time of enhanced T cell activity. Women with postpartum depression failed to show physiological enhanced T-cell activity postpartum, and future research is needed to elucidate etiological mechanisms and consequences.

Editorial: Activation and de-activation of inflammatory pathways. The disequilibrium of immune-neuro-endocrine networks in psychiatric disorders.

In this issue of BBI Melbourne et al describe a reduced activity of the JAK-STAT1 pathway in leukocytes of early and acute schizophrenia patients. This editorial discusses the report of Melbourne et al as being in accord with the view that active forms of schizophrenia are characterized by a de-activation of the Th1 driven M1/JAK-STAT1 mediated pro-inflammatory pathway in myeloid cells (macrophages, dendritic cells and microglia). Myeloid cells can be inflammatory activated and de-activated via various different molecular pathways (leading to various types of macrophages, such as e.g. various M1, various M2 and atherosclerosis related macrophages). There are data in the literature that pathways related to the Th17 driven MAP-kinase pro-inflammatory M1 pathway are activated in the myeloid cells of early and acute schizophrenia. The question thus arises what the intracellular molecular processes are which drive the complex inflammatory set points of macrophages and microglia in early and acute forms of schizophrenia.

A pilot study on immuno-psychiatry in the 22q11.2 deletion syndrome: A role for Th17 cells in psychosis?

BACKGROUND: A growing body of evidence supports a role for immune alterations in Schizophrenia Spectrum Disorders (SSD). A high prevalence (25-40%) of SSD has been found in patients with 22q11.2 deletion syndrome (22q11.2DS), which is known for T-cell deficits due to thymus hypoplasia. This study is the first to explore the association between the T-cell subsets and psychotic symptoms in adults with 22q11.2DS. METHODS: 34 individuals (aged 19-38 yrs.) with 22q11.2DS and 34 healthy age- and gender matched control individuals were included. FACS analysis of the blood samples was performed to define T-cell subsets. Ultra-high risk for psychosis or diagnosis of SSD was determined based on CAARMS interviews and DSM-5 criteria for SSD. Positive psychotic symptom severity was measured based on the PANSS positive symptoms subscale. RESULTS: A partial T-cell immune deficiency in 22q11.2DS patients was confirmed by significantly reduced percentages of circulating T and T-helper cells. Significantly higher percentages of inflammatory Th1, Th17, and memory T-helper cells were found in adults with 22q11.2DS. Most importantly an increased Th17 percentage was found in adults with psychotic symptoms as compared to non-psychotic adults with 22q11.2DS, and Th17 percentage were related to the presence of positive psychotic symptoms. CONCLUSIONS: Given the literature on the role of T cells and in particular of Th17 cells and IL-17 in hippocampus development, cognition and behavior, these results support the hypothesis for a role of Th17 cells in the development and/or regulation of psychotic symptoms in 22q11.2DS. This pilot study underlines the importance to further study the role of T-cell defects and of Th17 cells in the development of psychiatric symptoms. It also supports the possibility to use 22q11.2DS as a model to study T-cell involvement in the development of SSD.

Evidence of microglial activation following exposure to serum from first-onset drug-naïve schizophrenia patients.

Abnormal activation of brain microglial cells is widely implicated in the pathogenesis of schizophrenia. Previously the pathophysiology of microglial activation was considered to be intrinsic to the central nervous system. We hypothesised that due to their perivascular localization, microglia can also be activated by factors present in circulating blood. Through application of high-content functional screening, we show that peripheral blood serum from first-onset drug-naïve schizophrenia patients is sufficient to provoke microglial cell signalling network responses in vitro which are indicative of proinflammatory activation. We further explore the composition of the serum for the presence of analytes, with the potential to activate microglia, and the utility of the resultant microglial cellular phenotype for novel drug discovery.

Contrasting expression pattern of RNA-sensing receptors TLR7, RIG-I and MDA5 in interferon-positive and interferon-negative patients with primary Sjögren's syndrome.

OBJECTIVE: The interferon (IFN) type I signature is present in over half of patients with primary Sjögren's syndrome (pSS) and associated with higher disease-activity and autoantibody presence. Plasmacytoid dendritic cells (pDCs) are considered as the main source of enhanced IFN type I expression. The objective of this study was to unravel the molecular pathways underlying IFN type I bioactivity in pDCs of patients with pSS. METHODS: Blood samples from 42 healthy controls (HC) and 115 patients with pSS were stratified according to their IFN type I signature. CD123+BDCA4+ pDCs and CD14+ monocytes were isolated from peripheral blood mononuclear cells (PBMCs). Genome-wide microarray analysis was conducted on sorted pDCs in a small sample set, followed by validation of differentially expressed genes of interest in pDCs and monocytes. RESULTS: We found an upregulation of endosomal toll-like receptor (TLR) 7, but not TLR9, in IFN-positive (IFNpos) pDCs (p<0.05) and monocytes (p=0.024). Additionally, the downstream signalling molecules MyD88, RSAD2 and IRF7 were upregulated, as were the cytoplasmic RNA-sensing receptors DDX58/retinoic acid inducible gene-I (RIG-I) and IFIH1/melanoma differentiation associated gene-5 (MDA5). In vitro triggering of the TLR7-pathway in HC PBMCs induced upregulation of DDX58/RIG-I and IFIH1/MDA5, and downregulated TLR9. The upregulation of TLR7, its downstream signalling pathway, DDX58/RIG-I and IFIH1/MDA5 were confined to patients with IFN-positive pSS. IFN-negative patients had a contrasting expression pattern-TLR7 normal, and decreased TLR9, RIG-I and MDA5. CONCLUSIONS: Here we conclude a contrasting expression pattern of the RNA-sensing receptors TLR7, RIG-I and MDA5 in pDCs and monocytes of patients with IFNpos pSS. This profile could explain the pathogenic IFN production and might reveal novel therapeutic targets in these patients.

Th17 cells correlate positively to the structural and functional integrity of the brain in bipolar depression and healthy controls.

Abnormalities of T cell-mediated immune activation, in the absence of active somatic immune diseases, have consistently been reported in mood disorders. Apart from being important players in the regulation of cells of the immune system, T cells are essential for normal brain development. We here report studies on the relationship between circulating levels of T helper cells and structural and functional brain imaging in depressed bipolar patients. Since the CCL20-CCR6 axis is an important entry to the brain we differentiated the various T helper cell subpopulations on the basis of their chemokine receptor expression. METHODS: FACS staining was performed for Th1, Th2, Th17, Th22 and T regulatory cells on frozen leukocytes of 25 consecutively admitted inpatients affected by a major depressive episode, without psychotic features, in the course of Bipolar Disorder I and 21 healthy controls. The frequency of the T helper populations was associated with DTI and fMRI data acquired on a Philips 3.0 Tesla scanner. Tract based spatial statistic was used to obtain measures of white matter integrity (fractional anisotropy, axial, radial and mean diffusivity) from a standard DTI sequence with 35 directions. Patients were also studied for fMRI through a moral valence decision task were subjects had to decide whether morally tuned stimuli were positive or negative. RESULTS: The percentage of circulating Th17 (CCR6+CXCR3negCCR4+CCR10neg) cells correlated positively with higher fractional anisotropy in fiber tracts contributing to the functional integrity of the brain both in patients and healthy controls, while the frequency of circulating T regulatory (CD4+CD25+FOXP3+) cells correlated positively with higher radial and mean diffusivity in patients. The frequency of circulating T regulatory cells also correlated to lower neuronal responses to negative versus positive morally tuned stimuli in the right dorsolateral prefrontal cortex of patients. Th1 cells correlated negatively with white matter integrity in several tracts (healthy controls), while the cells showed a positive correlation to the levels of pro-inflammatory cytokines (patients). CONCLUSION: This study shows a new putative role for Th17 cells. Th17 cells are not only playing a role in inducing autoimmunity and auto-inflammation, but might also play a counter intuitive anabolic role in the maintenance of the functional and structural integrity of the brain.

Deficiencies of the T and natural killer cell system in major depressive disorder: T regulatory cell defects are associated with inflammatory monocyte activation.

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.

Volume, metabolites and neuroinflammation of the hippocampus in bipolar disorder - A combined magnetic resonance imaging and positron emission tomography study.

BACKGROUND: The hippocampus is one of the brain regions that is involved in several pathophysiological theories about bipolar disorder (BD), such as the neuroinflammation theory and the corticolimbic metabolic dysregulation theory. We compared hippocampal volume and hippocampal metabolites in bipolar I disorder (BD-I) patients versus healthy controls (HCs) with magnetic resonance imaging (MRI) and spectroscopy (MRS). We post hoc investigated whether hippocampal volume and hippocampal metabolites were associated with microglial activation and explored if potential illness modifying factors affected these hippocampal measurements and whether these were associated with experienced mood and functioning. MATERIALS AND METHODS: Twenty-two BD-I patients and twenty-four HCs were included in the analyses. All subjects underwent psychiatric interviews as well as an MRI scan, including a T1 scan and PRESS magnetic resonance spectroscopy (MRS). Volumetric analysis was performed with Freesurfer. MRS quantification was performed with LC Model. A subgroup of 14 patients and 11 HCs also underwent a successful [(11)C]-(R)-PK11195 neuroinflammation positron emission tomography scan. RESULTS: In contrast to our hypothesis, hippocampal volumes were not decreased in patients compared to HC after correcting for individual whole-brain volume variations. We demonstrated decreased N-acetylaspartate (NAA)+N-acetyl-aspartyl-glutamate (NAAG) and creatine (Cr)+phosphocreatine (PCr) concentrations in the left hippocampus. In the explorative analyses in the left hippocampus we identified positive associations between microglial activation and the NAA+NAAG concentration, between alcohol use and NAA+NAAG concentration, between microglial activation and the depression score and a negative relation between Cr+PCr concentration and experienced occupational disability. Duration of illness associated positively with volume bilaterally. CONCLUSION: Compared to HCs, the decreased NAA+NAAG concentration in the left hippocampus of BD-I patients suggests a decreased neuronal integrity in this region. In addition we found a positive relation between microglial activation and neuronal integrity in vivo, corresponding to a differentiated microglial function where some microglia induce apoptosis while others stimulate neurogenesis.

The dysregulated brain: consequences of spatial and temporal brain complexity for bipolar disorder pathophysiology and diagnosis.

Increasingly, evidence has been accumulating emphasizing the importance of looking at bipolar disorder (BD) from a neurodevelopmental and transdimensional perspective to better understand its origins and its course. In this overview article, the problems facing pathophysiological psychiatric research in BD are addressed and interpreted in the light of brain complexity. Brain complexity can be split into spatial complexity, which constitutes the physiological levels of the central nervous system (i.e., the genetic, molecular, cellular, neuronal circuit and phenomenological levels), and temporal complexity, that is, neurodevelopment. The consequences of this consideration are discussed and suggestions for clinical practice and pathophysiological psychiatric research are made.

Exaggerated Increases in Microglia Proliferation, Brain Inflammatory Response and Sickness Behaviour upon Lipopolysaccharide Stimulation in Non-Obese Diabetic Mice.

The non-obese diabetic (NOD) mouse, an established model for autoimmune diabetes, shows an exaggerated reaction of pancreas macrophages to inflammatory stimuli. NOD mice also display anxiety when immune-stimulated. Chronic mild brain inflammation and a pro-inflammatory microglial activation is critical in psychiatric behaviour. OBJECTIVE: To explore brain/microglial activation and behaviour in NOD mice at steady state and after systemic lipopolysaccharide (LPS) injection. METHODS: Affymetrix analysis on purified microglia of pre-diabetic NOD mice (8-10 weeks) and control mice (C57BL/6 and CD1 mice, the parental non-autoimmune strain) at steady state and after systemic LPS (100 µg/kg) administration. Quantitative PCR was performed on the hypothalamus for immune activation markers (IL-1ß, IFNγ and TNFα) and growth factors (BDNF and PDGF). Behavioural profiling of NOD, CD1, BALB/c and C57BL/6 mice at steady state was conducted and sickness behaviour/anxiety in NOD and CD1 mice was monitored before and after LPS injection. RESULTS: Genome analysis revealed cell cycle/cell death and survival aberrancies of NOD microglia, substantiated as higher proliferation on BrdU staining. Inflammation signs were absent. NOD mice had a hyper-reactive response to novel environments with some signs of anxiety. LPS injection induced a higher expression of microglial activation markers, a higher brain pro-inflammatory set point (IFNγ, IDO) and a reduced expression of BDNF and PDGF after immune stimulation in NOD mice. NOD mice displayed exaggerated and prolonged sickness behaviour after LPS administration. CONCLUSION: After stimulation with LPS, NOD mice display an increased microglial proliferation and an exaggerated inflammatory brain response with reduced BDNF and PDGF expression and increased sickness behaviour as compared to controls.

S100B Serum Levels Predict Treatment Response in Patients with Melancholic Depression.

BACKGROUND: There is an ongoing search for biomarkers in psychiatry, for example, as diagnostic tools or predictors of treatment response. The neurotrophic factor S100 calcium binding protein B (S100B) has been discussed as a possible predictor of antidepressant response in patients with major depression, but also as a possible biomarker of an acute depressive state. The aim of the present study was to study the association of serum S100B levels with antidepressant treatment response and depression severity in melancholically depressed inpatients. METHODS: After a wash-out period of 1 week, 40 inpatients with melancholic depression were treated with either venlafaxine or imipramine. S100B levels and Hamilton Depression Rating Scale (HAM-D) scores were assessed at baseline, after 7 weeks of treatment, and after 6 months. RESULTS: Patients with high S100B levels at baseline showed a markedly better treatment response defined as relative reduction in HAM-D scores than those with low baseline S100B levels after 7 weeks (P=.002) and 6 months (P=.003). In linear regression models, S100B was a significant predictor for treatment response at both time points. It is of interest to note that nonresponders were detected with a predictive value of 85% and a false negative rate of 7.5%. S100B levels were not associated with depression severity and did not change with clinical improvement. CONCLUSIONS: Low S100B levels predict nonresponse to venlafaxine and imipramine with high precision. Future studies have to show which treatments are effective in patients with low levels of S100B so that this biomarker will help to reduce patients' burden of nonresponding to frequently used antidepressants.

Clinical characteristics of inflammation-associated depression: Monocyte gene expression is age-related in major depressive disorder.

Increased inflammatory activation might only be present in a subgroup of depressed individuals in which immune processes are especially relevant to disease development. We aimed to analyze demographic, depression, and trauma characteristics of major depressive disorder (MDD) patients with regard to inflammatory monocyte gene expression. Fifty-six naturalistically treated MDD patients (32 ± 12 years) and 57 healthy controls (HC; 31 ± 11 years) were analyzed by the Inventory of Depressive Symptomatology (IDS) and by the Childhood Trauma Questionnaire (CTQ). We determined the expression of 38 inflammatory and immune activation genes including the glucocorticoid receptor (GR)α and GRß genes in purified CD14(+) monocytes using quantitative-polymerase chain reaction (RT-qPCR). Monocyte gene expression was age-dependent, particularly in MDD patients. Increased monocyte gene expression and decreased GRα/ß ratio were only present in MDD patients aged ⩾ 28 years. Post hoc analyses of monocyte immune activation in patients <28 years showed two subgroups: a subgroup with a severe course of depression (recurrent type, onset <15 years) - additionally characterized by panic/arousal symptoms and childhood trauma - that had a monocyte gene expression similar to HC, and a second subgroup with a milder course of the disorder (73% first episode depression, onset ⩾15 years) - additionally characterized by the absence of panic symptoms - that exhibited a strongly reduced inflammatory monocyte activation compared to HC. In conclusion, monocyte immune activation was not uniformly raised in MDD patients but was increased only in patients of 28 years and older.

Monocyte activation, brain-derived neurotrophic factor (BDNF), and S100B in bipolar offspring: a follow-up study from adolescence into adulthood.

OBJECTIVES: There is increasing evidence that both immune and neurochemical alterations are involved in the pathogenesis of bipolar disorder; however, their precise role remains unclear. In this study, we aimed to evaluate neuro-immune changes in a prospective study on children of patients with bipolar disorder. METHODS: Bipolar offspring, from the prospective Dutch bipolar offspring study (n = 140), were evaluated cross-sectionally within a longitudinal context at adolescence, young adulthood, and adulthood. We examined the expression of 44 inflammation-related genes in monocytes, the cytokines pentraxin 3 (PTX3), chemokine ligand 2 (CCL2), and interleukin-1ß (IL-1ß), and brain-derived neurotrophic factor (BDNF) and S100 calcium binding protein B (S100B) in the serum of bipolar offspring and healthy controls. RESULTS: During adolescence, bipolar offspring showed increased inflammatory gene expression in monocytes, high serum PTX3 levels, but normal CCL2 levels. BDNF levels were decreased, while S100B levels were normal. During young adulthood, monocyte activation remained, although to a lesser degree. Serum PTX3 levels remained high, and signs of monocyte migration became apparent through increased CCL2 levels. BDNF and S100B levels were not measured. At adulthood, circulating monocytes had lost their activation state, but CCL2 levels remained increased. Both BDNF and S100B were now increased. Abnormalities were independent of psychopathology state at all stages. CONCLUSIONS: This study suggests an aberrant neuro-immune state in bipolar offspring, which followed a dynamic course from adolescence into adulthood and was present irrespective of lifetime or future mood disorders. We therefore assumed that the aberrant neuro-immune state reflects a general state of vulnerability for mood disorders rather than being of direct predictive value.

Feature-expression heat maps--a new visual method to explore complex associations between two variable sets.

INTRODUCTION: Existing methods such as correlation plots and cluster heat maps are insufficient in the visual exploration of multiple associations between genetics and phenotype, which is of importance to achieve a better understanding of the pathophysiology of psychiatric and other illnesses. The implementation of a combined presentation of effect size and statistical significance in a graphical method, added to the ordering of the variables based on the effect-ordered data display principle was deemed useful by the authors to facilitate in the process of recognizing meaningful patterns in these associations. MATERIALS AND METHODS: The requirements, analyses and graphical presentation of the feature-expression heat map are described. The graphs display associations of two sets of ordered variables where a one-way direction is assumed. The associations are depicted as circles representing a combination of effect size (color) and statistical significance (radius). RESULTS: An example dataset is presented and relation to other methods, limitations, areas of application and possible future enhancements are discussed. CONCLUSION: The feature-expression heat map is a useful graphical instrument to explore associations in complex biological systems where one-way direction is assumed, such as genotype-phenotype pathophysiological models.

Microglia shape corpus callosum axon tract fasciculation: functional impact of prenatal inflammation.

Microglia colonise the brain parenchyma at early stages of development and accumulate in specific regions where they participate in cell death, angiogenesis, neurogenesis and synapse elimination. A recurring feature of embryonic microglial is their association with developing axon tracts, which, together with in vitro data, supports the idea of a physiological role for microglia in neurite development. Yet the demonstration of this role of microglia is lacking. Here, we have studied the consequences of microglial dysfunction on the formation of the corpus callosum, the largest commissure of the mammalian brain, which shows consistent microglial accumulation during development. We studied two models of microglial dysfunction: the loss-of-function of DAP12, a key microglial-specific signalling molecule, and a model of maternal inflammation by peritoneal injection of lipopolysaccharide at embryonic day (E)15.5. We also took advantage of the Pu.1(-/-) mouse line, which is devoid of microglia. We performed transcriptional profiling of maternally inflamed and Dap12-mutant microglia at E17.5. The two treatments principally down-regulated genes involved in nervous system development and function, particularly in neurite formation. We then analysed the developmental consequences of these microglial dysfunctions on the formation of the corpus callosum. We show that all three models of altered microglial activity resulted in the defasciculation of dorsal callosal axons. Our study demonstrates that microglia display a neurite-development-promoting function and are genuine actors of corpus callosum development. It further shows that microglial activation impinges on this function, thereby revealing that prenatal inflammation impairs neuronal development through a loss of trophic support.

MxA as a clinically applicable biomarker for identifying systemic interferon type I in primary Sjogren's syndrome.

OBJECTIVE: To establish an easy and practical assay for identifying systemic interferon (IFN) type I bioactivity in patients with primary Sjögren's syndrome (pSS). The IFN type I signature is present in over half of the pSS patients and identifies a subgroup with a higher disease activity. This signature is currently assessed via laborious expression profiles of multiple IFN type I-inducible genes. METHODS: In a cohort of 35 pSS patients, myxovirus-resistance protein A (MxA) was assessed as a potential biomarker for type I IFN activity, using an enzyme immunoassay (EIA) on whole-blood and flow cytometric analyses (fluorescence-activated cell sorting, FACS) of isolated CD14 monocytes. In addition, potential biomarkers such as CD64, CD169 and B cell-activating factor (BAFF) were simultaneously analysed in CD14 monocytes using FACS. The IFNscore, a measure for total type I IFN bioactivity, was calculated using expression values of the IFN type I signature genes--IFI44, IFI44L, IFIT3, LY6E and MX1--in CD14 monocytes, determined by real-time quantitative PCR. RESULTS: IFNscores correlated the strongest with monocyte MxA protein (r=0.741, p<0.001) and whole-blood MxA levels (r=0.764, p<0.001), weaker with CD169 (r=0.495, p<0.001) and CD64 (r=0.436, p=0.007), and not at all with BAFF protein. In particular, whole blood MxA levels correlated with EULAR Sjögren's Syndrome Disease Activity Index scores and numerous clinical pSS parameters. Interestingly, patients on hydroxychloroquine showed reduced MxA levels (EIA, p=0.04; FACS p=0.001). CONCLUSIONS: The MxA assays were excellent tools to assess IFN type I activity in pSS, MxA-EIA being the most practical. MxA levels associate with features of active disease and are reduced in hydroxychloroquine-treated patients, suggesting the clinical applicability of MxA in stratifying patients according to IFN positivity.

Neuroinflammation in bipolar disorder - A [(11)C]-(R)-PK11195 positron emission tomography study.

BACKGROUND: The "monocyte-T-cell theory of mood disorders" regards neuroinflammation, i.e. marked activation of microglia, as a driving force in bipolar disorder. Microglia activation can be visualized in vivo using [(11)C]-(R)-PK11195 PET. Indirect evidence suggests the hippocampus as a potential focus of neuroinflammation in bipolar disorder. We aim to determine if there is increased [(11)C]-(R)-PK11195 binding to activated microglia in the hippocampus of patients with bipolar I disorder when compared to healthy controls. MATERIAL AND METHODS: Fourteen patients with bipolar I disorder and eleven healthy controls were included in the analyses. Dynamic 60-min PET scans were acquired after the injection of [(11)C]-(R)-PK11195. All subjects underwent psychiatric interviews as well as an MRI scan, which was used for anatomic co-registration in the data analysis. The data from the PET scans was analyzed with a two-tissue-compartment model to calculate the binding potential, using the metabolite-corrected plasma and blood curve as input. RESULTS: A significantly increased [(11)C]-(R)-PK11195 binding potential, which is indicative of neuroinflammation, was found in the right hippocampus of the patients when compared to the healthy controls (1.66 (CI 1.45-1.91) versus 1.33 (CI 1.16-1.53); p=0.033, respectively). Although the same trend was observed in the left hippocampus, this difference was not statistically significant. CONCLUSION: This study is the first to demonstrate the presence of focal neuroinflammation in the right hippocampus in bipolar I disorder.