Publications by authors named "Judith Alferink"

44 Publications

Alterations in B cell subsets correlate with body composition parameters in female adolescents with anorexia nervosa.

Sci Rep 2021 Jan 13;11(1):1125. Epub 2021 Jan 13.

Department of Mental Health, University of Münster, Albert-Schweitzer-Campus 1, 48149, Münster, Germany.

Anorexia nervosa (AN) is a severe eating disorder and often associated with altered humoral immune responses. However, distinct B cell maturation stages in peripheral blood in adolescents with AN have not been characterized. Treatment effects and the relationship between clinical and B cell parameters are also not fully understood. Here we investigated the phenotype of circulating B cell subsets and the relationship with body composition in adolescents with AN before (T0, n = 24) and after 6 weeks (T1, n = 20) of treatment. Using multi-parameter flow cytometry, we found increased percentages of antigen-experienced B cells and plasmablasts in patients with AN compared to healthy controls (n = 20). In contrast, percentages of CD1dCD5 B cells and transitional B cells with immunoregulatory roles were reduced at T0 and T1. These B cell frequencies correlated positively with fat mass, fat mass index (FMI), free fat mass index, and body mass index standard deviation score. In addition, scavenger-like receptor CD5 expression levels were downregulated on transitional B cells and correlated with fat mass and FMI in AN. Our findings that regulatory B cell subgroups were reduced in AN and their strong relationship with body composition parameters point toward an impact of immunoregulatory B cells in the pathogenesis of AN.
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http://dx.doi.org/10.1038/s41598-020-80693-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7806719PMC
January 2021

Validation and clinical application of a volumetric absorptive microsampling method for 14 psychiatric drugs.

Bioanalysis 2020 Aug 21;12(16):1129-1147. Epub 2020 Aug 21.

Institut für Pharmazeutische und Medizinische Chemie - Klinische Pharmazie, Westfälische Wilhelms-Universität, Corrensstraße 48, 48149 Münster, Germany.

Volumetric absorptive microsampling offers a hematocrit insensitive way for microsampling. The aim of this study was to develop a method for routine healthcare for 14 antidepressants, antipsychotics and their active metabolites on a single-quadrupole HPLC-MS. A clinical validation study to determine conversion factors from capillary blood to plasma concentration was conducted afterward. The method was validated according to current guidelines except for one substance. Five substances were measured in 49 patient samples and conversion factors could be derived with Passing-Bablok and Bland-Altman analysis. A reliable extraction and analysis method for commonly used antidepressants and antipsychotics was developed and validated. The method with the obtained conversion factors can now be used in routine healthcare.
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http://dx.doi.org/10.4155/bio-2020-0136DOI Listing
August 2020

Cannabinoid Receptor 2 Modulates Maturation of Dendritic Cells and Their Capacity to Induce Hapten-Induced Contact Hypersensitivity.

Int J Mol Sci 2020 Jan 11;21(2). Epub 2020 Jan 11.

Department of Psychiatry, University of Münster, 48149 Münster, Germany.

Contact hypersensitivity (CHS) is an established animal model for allergic contact dermatitis. Dendritic cells (DCs) play an important role in the sensitization phase of CHS by initiating T cell responses to topically applied haptens. The cannabinoid receptors 1 (CB1) and 2 (CB2) modulate DC functions and inflammatory skin responses, but their influence on the capacity of haptenized DCs to induce CHS is still unknown. We found lower CHS responses to 2,4-dinitro-1-fluorobenzene (DNFB) in wild type (WT) mice after adoptive transfer of haptenized and bone marrow (BM) DCs as compared to transfer of WT DCs. In contrast, induction of CHS was not affected in WT recipients after transfer of DCs. In vitro stimulated DCs showed lower CCR7 and CXCR4 expression when compared to WT cells, while in vitro migration towards the chemokine ligands was not affected by CB2. Upregulation of MHC class II and co-stimulatory molecules was also reduced in DCs. This study demonstrates that CB2 modulates the maturation phenotype of DCs but not their chemotactic capacities . These findings and the fact that CHS responses mediated by 2 DCs are reduced suggest that CB2 is a promising target for the treatment of inflammatory skin conditions.
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http://dx.doi.org/10.3390/ijms21020475DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7013892PMC
January 2020

Production of IFNβ by Conventional Dendritic Cells after Stimulation with Viral Compounds and IFNβ-Independent IFNAR1-Signaling Pathways are Associated with Aggravation of Polymicrobial Sepsis.

Int J Mol Sci 2019 Sep 7;20(18). Epub 2019 Sep 7.

Institute of Medical Microbiology and Hospital Hygiene, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany.

Viral infections are associated with increased incidence of severe sepsis. Particularly during the early stages, type I interferons (IFNs) are known mediators of detrimental effects. However, the functional role of early interferon β (IFNβ) and its cellular source during sepsis in the context of preexisting viral infections has not been defined. Using the colon ascendens stent peritonitis (CASP) model, we demonstrate that IFNβ and type I IFN receptor (IFNAR1) mice were less susceptible to sepsis after pre-stimulation with the viral mimetic poly(I:C). Wild type (WT) mice treated with poly(I:C) exhibited altered expression patterns of TNF and IL-12p40 during CASP which were dependent on IFNβ or IFNAR1, suggesting a mechanism for the increased sepsis susceptibility of WT mice. Using a double cytokine reporter mouse model, we present novel data on the simultaneous expression of IFNβ and IL-12p40 on a single cell level during polymicrobial sepsis in vivo. Conventional dendritic cells (cDCs) were identified as primary source of IFNβ and the protective cytokine IL-12p40 after CASP surgery irrespective of poly(I:C) pre-stimulation. These data demonstrated that if polymicrobial sepsis is preceded by a viral infection, IFNβ and IL-12p40 are expressed by polyfunctional cDCs suggesting that these cells can play both detrimental and beneficial roles during sepsis development.
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http://dx.doi.org/10.3390/ijms20184410DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6770674PMC
September 2019

Social Defeat Modulates T Helper Cell Percentages in Stress Susceptible and Resilient Mice.

Int J Mol Sci 2019 Jul 17;20(14). Epub 2019 Jul 17.

Department of Psychiatry, University of Münster, 48149 Münster, Germany.

Altered adaptive immunity involving T lymphocytes has been found in depressed patients and in stress-induced depression-like behavior in animal models. Peripheral T cells play important roles in homeostasis and function of the central nervous system and thus modulate behavior. However, the T cell phenotype and function associated with susceptibility and resilience to depression remain largely unknown. Here, we characterized splenic T cells in susceptible and resilient mice after 10 days of social defeat stress (SDS). We found equally decreased T cell frequencies and comparably altered expression levels of genes associated with T helper (Th) cell function in resilient and susceptible mice. Interleukin (IL)-17 producing CD4 and CD8 T cell numbers in the spleen were significantly increased in susceptible mice. These animals further exhibited significantly reduced numbers of regulatory T cells (T) and decreased gene expression levels of TGF-β. Mice with enhanced Th17 differentiation induced by conditional deletion of PPARγ in CD4 cells (CD4-PPARγ), an inhibitor of Th17 development, were equally susceptible to SDS when compared to CD4-PPARγ controls. These data indicate that enhanced Th17 differentiation alone does not alter stress vulnerability. Thus, SDS promotes Th17 cell and suppresses T cell differentiation predominantly in susceptible mice with yet unknown effects in immune responses after stress exposure.
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http://dx.doi.org/10.3390/ijms20143512DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6678569PMC
July 2019

Sources of Type I Interferons in Infectious Immunity: Plasmacytoid Dendritic Cells Not Always in the Driver's Seat.

Front Immunol 2019 12;10:778. Epub 2019 Apr 12.

Institute of Medical Microbiology and Hospital Hygiene, University of Düsseldorf, Düsseldorf, Germany.

Type I Interferons (IFNs) are hallmark cytokines produced in immune responses to all classes of pathogens. Type I IFNs can influence dendritic cell (DC) activation, maturation, migration, and survival, but also directly enhance natural killer (NK) and T/B cell activity, thus orchestrating various innate and adaptive immune effector functions. Therefore, type I IFNs have long been considered essential in the host defense against virus infections. More recently, it has become clear that depending on the type of virus and the course of infection, production of type I IFN can also lead to immunopathology or immunosuppression. Similarly, in bacterial infections type I IFN production is often associated with detrimental effects for the host. Although most cells in the body are thought to be able to produce type I IFN, plasmacytoid DCs (pDCs) have been termed the natural "IFN producing cells" due to their unique molecular adaptations to nucleic acid sensing and ability to produce high amounts of type I IFN. Findings from mouse reporter strains and depletion experiments in infection models have brought new insights and established that the role of pDCs in type I IFN production is less important than assumed. Production of type I IFN, especially the early synthesized IFNβ, is rather realized by a variety of cell types and cannot be mainly attributed to pDCs. Indeed, the cell populations responsible for type I IFN production vary with the type of pathogen, its tissue tropism, and the route of infection. In this review, we summarize recent findings from models on the cellular source of type I IFN in different infectious settings, ranging from virus, bacteria, and fungi to eukaryotic parasites. The implications from these findings for the development of new vaccination and therapeutic designs targeting the respectively defined cell types are discussed.
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http://dx.doi.org/10.3389/fimmu.2019.00778DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6473462PMC
August 2020

Mitochondria, Microglia, and the Immune System-How Are They Linked in Affective Disorders?

Front Psychiatry 2018 9;9:739. Epub 2019 Jan 9.

Department of Psychiatry and Psychotherapy, University of Münster, Münster, Germany.

Major depressive disorder (MDD) is a severe mood disorder and frequently associated with alterations of the immune system characterized by enhanced levels of circulating pro-inflammatory cytokines and microglia activation in the brain. Increasing evidence suggests that dysfunction of mitochondria may play a key role in the pathogenesis of MDD. Mitochondria are regulators of numerous cellular functions including energy metabolism, maintenance of redox and calcium homeostasis, and cell death and therefore modulate many facets of the innate immune response. In depression-like behavior of rodents, mitochondrial perturbation and release of mitochondrial components have been shown to boost cytokine production and neuroinflammation. On the other hand, pro-inflammatory cytokines may influence mitochondrial functions such as oxidative phosphorylation, production of adenosine triphosphate, and reactive oxygen species, thereby aggravating inflammation. There is strong interest in a better understanding of immunometabolic pathways in MDD that may serve as diagnostic markers and therapeutic targets. Here, we review the interaction between mitochondrial metabolism and innate immunity in the pathophysiology of MDD. We specifically focus on immunometabolic processes that govern microglial and peripheral myeloid cell functions, both cellular components involved in neuroinflammation in depression-like behavior. We finally discuss microglial polarization and associated metabolic states in depression-associated behavior and in MDD.
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http://dx.doi.org/10.3389/fpsyt.2018.00739DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6333629PMC
January 2019

Interferon β-Mediated Protective Functions of Microglia in Central Nervous System Autoimmunity.

Int J Mol Sci 2019 Jan 7;20(1). Epub 2019 Jan 7.

Department of Psychiatry and Psychotherapy, University of Münster, 48149 Münster, Germany.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) leading to demyelination and axonal damage. It often affects young adults and can lead to neurological disability. Interferon β (IFNβ) preparations represent widely used treatment regimens for patients with relapsing-remitting MS (RRMS) with therapeutic efficacy in reducing disease progression and frequency of acute exacerbations. In mice, IFNβ therapy has been shown to ameliorate experimental autoimmune encephalomyelitis (EAE), an animal model of MS while genetic deletion of IFNβ or its receptor augments clinical severity of disease. However, the complex mechanism of action of IFNβ in CNS autoimmunity has not been fully elucidated. Here, we review our current understanding of the origin, phenotype, and function of microglia and CNS immigrating macrophages in the pathogenesis of MS and EAE. In addition, we highlight the emerging roles of microglia as IFNβ-producing cells and vice versa the impact of IFNβ on microglia in CNS autoimmunity. We finally discuss recent progress in unraveling the underlying molecular mechanisms of IFNβ-mediated effects in EAE.
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http://dx.doi.org/10.3390/ijms20010190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6337097PMC
January 2019

CCL17 exerts a neuroimmune modulatory function and is expressed in hippocampal neurons.

Glia 2018 10 12;66(10):2246-2261. Epub 2018 Sep 12.

Immunology & Environment, Life and Medical Sciences (LIMES) Institute, University of Bonn, Bonn, Germany.

Chemokines are important signaling molecules in the immune and nervous system. Using a fluorescence reporter mouse model, we demonstrate that the chemokine CCL17, a ligand of the chemokine receptor CCR4, is produced in the murine brain, particularly in a subset of hippocampal CA1 neurons. We found that basal expression of Ccl17 in hippocampal neurons was strongly enhanced by peripheral challenge with lipopolysaccharide (LPS). LPS-mediated induction of Ccl17 in the hippocampus was dependent on local tumor necrosis factor (TNF) signaling, whereas upregulation of Ccl22 required granulocyte-macrophage colony-stimulating factor (GM-CSF). CCL17 deficiency resulted in a diminished microglia density under homeostatic and inflammatory conditions. Further, microglia from naïve Ccl17-deficient mice possessed a reduced cellular volume and a more polarized process tree as assessed by computer-assisted imaging analysis. Regarding the overall branching, cell surface area, and total tree length, the morphology of microglia from naïve Ccl17-deficient mice resembled that of microglia from wild-type mice after LPS stimulation. In line, electrophysiological recordings indicated that CCL17 downmodulates basal synaptic transmission at CA3-CA1 Schaffer collaterals in acute slices from naïve but not LPS-treated animals. Taken together, our data identify CCL17 as a homeostatic and inducible neuromodulatory chemokine affecting the presence and morphology of microglia and synaptic transmission in the hippocampus.
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http://dx.doi.org/10.1002/glia.23507DOI Listing
October 2018

Neurobiology of the major psychoses: a translational perspective on brain structure and function-the FOR2107 consortium.

Eur Arch Psychiatry Clin Neurosci 2019 Dec 28;269(8):949-962. Epub 2018 Sep 28.

Department of Psychiatry and Psychotherapy, University of Münster, Munich, Germany.

Genetic (G) and environmental (E) factors are involved in the etiology and course of the major psychoses (MP), i.e. major depressive disorder (MDD), bipolar disorder (BD), schizoaffective disorder (SZA) and schizophrenia (SZ). The neurobiological correlates by which these predispositions exert their influence on brain structure, function and course of illness are poorly understood. In the FOR2107 consortium, animal models and humans are investigated. A human cohort of MP patients, healthy subjects at genetic and/or environmental risk, and control subjects (N = 2500) has been established. Participants are followed up after 2 years and twice underwent extensive deep phenotyping (MR imaging, clinical course, neuropsychology, personality, risk/protective factors, biomaterials: blood, stool, urine, hair, saliva). Methods for data reduction, quality assurance for longitudinal MRI data, and (deep) machine learning techniques are employed. In the parallelised animal cluster, genetic risk was introduced by a rodent model (Cacna1c deficiency) and its interactions with environmental risk and protective factors are studied. The animals are deeply phenotyped regarding cognition, emotion, and social function, paralleling the variables assessed in humans. A set of innovative experimental projects connect and integrate data from the human and animal parts, investigating the role of microRNA, neuroplasticity, immune signatures, (epi-)genetics and gene expression. Biomaterial from humans and animals are analyzed in parallel. The FOR2107 consortium will delineate pathophysiological entities with common neurobiological underpinnings ("biotypes") and pave the way for an etiologic understanding of the MP, potentially leading to their prevention, the prediction of individual disease courses, and novel therapies in the future.
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http://dx.doi.org/10.1007/s00406-018-0943-xDOI Listing
December 2019

Alterations of the Innate Immune System in Susceptibility and Resilience After Social Defeat Stress.

Front Behav Neurosci 2018 13;12:141. Epub 2018 Jul 13.

Department of Psychiatry, University of Münster, Münster, Germany.

Dysregulation of innate immune responses has frequently been reported in stress-associated psychiatric disorders such as major depression. In mice, enhanced circulating cytokine levels as well as altered innate immune cell numbers have been found after stress exposure. In addition, stress-induced recruitment of peripheral monocytes to the brain has been shown to promote anxiety-like behavior. However, it is yet unclear whether specific differences in the innate immune system are associated with stress susceptibility or resilience in mice. Utilizing chronic social defeat, a model of depression and stress vulnerability, we characterized peripheral and brain-invading myeloid cells in stress-susceptible and resilient animals. In all defeated animals, we found reduced percentages of CD11c dendritic cells (DCs) by flow cytometry in the spleen when compared to non-defeated controls. Exclusively in susceptible mice conventional DCs of the spleen showed up-regulated expression of MHC class II and co-stimulatory CD80 molecules pointing toward an enhanced maturation phenotype of these cells. Susceptible, but not resilient animals further exhibited an increase in inflammatory Ly6C monocytes and higher numbers of spleen-derived CD11b cells that produced the proinflammatory cytokine tumor necrosis factor (TNF) upon lipopolysaccharide (LPS) stimulation. Increased percentages of peripheral CD45 CD11b cells immigrated into the brain of defeated mice, regardless of resilience or susceptibility. However, cellular infiltrates in the brain of susceptible mice contained higher percentages of CC chemokine receptor 2 (CCR2) Ly6C monocytes representing an inflammatory phenotype. Thus, we defined specific stress-related immune signatures involving conventional DCs and inflammatory Ly6C monocytes in susceptible and resilient mice. Together, our findings suggest an impact of the innate immune system in vulnerability to stress-related disorders such as major depression.
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http://dx.doi.org/10.3389/fnbeh.2018.00141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6053497PMC
July 2018

Identification of a novel Dlg2 isoform differentially expressed in IFNβ-producing plasmacytoid dendritic cells.

BMC Genomics 2018 Mar 12;19(1):194. Epub 2018 Mar 12.

Institute of Medical Microbiology and Hospital Hygiene, Heinrich, Heine University of Düsseldorf, Universitätsstraße 1, D-40225, Düsseldorf, Germany.

Background: The murine discs large homolog 2 (DLG2; post synaptic density 93 (PSD-93); Chapsyn-110) is a member of the membrane-associated guanylate kinase (MAGUK) protein family involved in receptor assembly and associated with signaling enzymes on cell membranes. In neurons, DLG2 protein isoforms derived from alternatively spliced transcripts have been described to bind to NMDA (N-methyl-aspartate) receptors and K channels and to mediate clustering of these channels in the postsynaptic membrane. In myeloid cells of the immune system, such as dendritic cells (DCs), a lack of data exists on the expression or function of DLG2. In cDNA microarray transcriptome analyses, we found Dlg2 highly expressed in a subpopulation of plasmacytoid DCs (pDCs) stimulated to produce type I interferons (IFNs) such as IFNβ.

Results: Using RACE- and RT-PCR as well as immunoprecipitation followed by Western blotting we characterised the differential expression of the Dlg2 splice variants in IFNβ-producing pDCs. Besides Dlg2ɣ this cell population expressed a novel short Dlg2η transcript we termed Dlg2η3. Our expression data were integrated into information from genome databases to obtain a novel and comprehensive overview of the mouse Dlg2 gene architecture. To elucidate the intracellular localisation pattern of protein isoforms, ectopical expression analysis of fluorescently tagged DLG2 splice variants was performed. Here we found an enrichment of the larger isoform DLG2α1 at the plasma membrane while the newly identified shorter (DLG2η) isoform as well as DLG2ɣ were equally distributed throughout the cytoplasm. Additionally, DLG2η was also found in the nucleus. Analysis of Dlg2-knockout mice previously generated by deleting exon 9 surprisingly revealed that the protein for the novel DLG2η isoform was still expressed in the brain and in bone marrow-derived pDCs from mice carrying the homozygous deletion (Dlg2 ).

Conclusion: We describe a novel splice variant of the mouse Dlg2 gene termed Dlg2η and define the differential expression pattern of DLG2 isoforms in IFNβ-producing pDCs. The presence of DLG2η protein in the CNS of Dlg2 mice might influence the phenotype of these mice and has to be taken into account in the interpretation of results regarding the functional role of DLG2 in neuronal postsynaptic membranes.
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http://dx.doi.org/10.1186/s12864-018-4573-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6389146PMC
March 2018

Doxycycline inhibits experimental cerebral malaria by reducing inflammatory immune reactions and tissue-degrading mediators.

PLoS One 2018 13;13(2):e0192717. Epub 2018 Feb 13.

Institute of Medical Microbiology, Immunology and Parasitology, University Hospital Bonn, Bonn, Germany.

Malaria ranks among the most important infectious diseases worldwide and affects mostly people living in tropical countries. Mechanisms involved in disease progression are still not fully understood and specific treatments that might interfere with cerebral malaria (CM) are limited. Here we show that administration of doxycycline (DOX) prevented experimental CM (ECM) in Plasmodium berghei ANKA (PbA)-infected C57BL/6 wildtype (WT) mice in an IL-10-independent manner. DOX-treated mice showed an intact blood-brain barrier (BBB) and attenuated brain inflammation. Importantly, if WT mice were infected with a 20-fold increased parasite load, they could be still protected from ECM if they received DOX from day 4-6 post infection, despite similar parasitemia compared to control-infected mice that did not receive DOX and developed ECM. Infiltration of T cells and cytotoxic responses were reduced in brains of DOX-treated mice. Analysis of brain tissue by RNA-array revealed reduced expression of chemokines and tumour necrosis factor (TNF) in brains of DOX-treated mice. Furthermore, DOX-administration resulted in brains of the mice in reduced expression of matrix metalloproteinase 2 (MMP2) and granzyme B, which are both factors associated with ECM pathology. Systemic interferon gamma production was reduced and activated peripheral T cells accumulated in the spleen in DOX-treated mice. Our results suggest that DOX targeted inflammatory processes in the central nervous system (CNS) and prevented ECM by impaired brain access of effector T cells in addition to its anti-parasitic effect, thereby expanding the understanding of molecular events that underlie DOX-mediated therapeutic interventions.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0192717PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5811026PMC
April 2018

The C-C Chemokines CCL17 and CCL22 and Their Receptor CCR4 in CNS Autoimmunity.

Int J Mol Sci 2017 Nov 2;18(11). Epub 2017 Nov 2.

Department of Psychiatry, University of Münster, 48149 Münster, Germany.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). It affects more than two million people worldwide, mainly young adults, and may lead to progressive neurological disability. Chemokines and their receptors have been shown to play critical roles in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), a murine disease model induced by active immunization with myelin proteins or transfer of encephalitogenic CD4⁺ T cells that recapitulates clinical and neuropathological features of MS. Chemokine ligand-receptor interactions orchestrate leukocyte trafficking and influence multiple pathophysiological cellular processes, including antigen presentation and cytokine production by dendritic cells (DCs). The C-C class chemokines 17 (CCL17) and 22 (CCL22) and their C-C chemokine receptor 4 (CCR4) have been shown to play an important role in homeostasis and inflammatory responses. Here, we provide an overview of the involvement of CCR4 and its ligands in CNS autoimmunity. We review key clinical studies of MS together with experimental studies in animals that have demonstrated functional roles of CCR4, CCL17, and CCL22 in EAE pathogenesis. Finally, we discuss the therapeutic potential of newly developed CCR4 antagonists and a humanized anti-CCR4 antibody for treatment of MS.
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http://dx.doi.org/10.3390/ijms18112306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5713275PMC
November 2017

Altered B Cell Homeostasis in Patients with Major Depressive Disorder and Normalization of CD5 Surface Expression on Regulatory B Cells in Treatment Responders.

J Neuroimmune Pharmacol 2018 03 13;13(1):90-99. Epub 2017 Sep 13.

Department of Psychiatry and Psychotherapy, University of Münster, Albert-Schweitzer-Campus 1, 48149, Münster, Germany.

Pro-inflammatory activity and cell-mediated immune responses have been widely observed in patients with major depressive disorder (MDD). Besides their well-known function as antibody-producers, B cells play a key role in inflammatory responses by secreting pro- and anti-inflammatory factors. However, homeostasis of specific B cell subsets has not been comprehensively investigated in MDD. In this study, we characterized circulating B cells of distinct developmental steps including transitional, naïve-mature, antigen-experienced switched, and non-switched memory cells, plasmablasts and regulatory B cells by multi-parameter flow cytometry. In a 6-weeks follow-up, circulating B cells were monitored in a small group of therapy responders and non-responders. Frequencies of naïve lgDCD27 B cells, but not lgDCD27 memory B cells, were reduced in severely depressed patients as compared to healthy donors (HD) or mildly to moderately depressed patients. Specifically, B cells with immune-regulatory capacities such as CD1dCD5 B cells and CD24CD38 transitional B cells were reduced in MDD. Also Bm1-Bm5 classification in MDD revealed reduced Bm2' cells comprising germinal center founder cells as well as transitional B cells. We further found that reduced CD5 surface expression on transitional B cells was associated with severe depression and normalized exclusively in clinical responders. This study demonstrates a compromised peripheral B cell compartment in MDD with a reduction in B cells exhibiting a regulatory phenotype. Recovery of CD5 surface expression on transitional B cells in clinical response, a molecule involved in activation and down-regulation of B cell responses, further points towards a B cell-dependent process in the pathogenesis of MDD.
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http://dx.doi.org/10.1007/s11481-017-9763-4DOI Listing
March 2018

Chemokine CCL17 is expressed by dendritic cells in the CNS during experimental autoimmune encephalomyelitis and promotes pathogenesis of disease.

Brain Behav Immun 2017 Nov 19;66:382-393. Epub 2017 Jun 19.

Department of Psychiatry, University of Münster, 48149 Münster, Germany; Cells in Motion, Cluster of Excellence EXC 1003, University of Münster, 48149 Münster, Germany. Electronic address:

The CC chemokine ligand 17 (CCL17) and its cognate CC chemokine receptor 4 (CCR4) are known to control leukocyte migration, maintenance of T17 cells, and regulatory T cell (T) expansion in vivo. In this study we characterized the expression and functional role of CCL17 in the pathogenesis of experimental autoimmune encephalomyelitis (EAE). Using a CCL17/EGFP reporter mouse model, we could show that CCL17 expression in the CNS can be found in a subset of classical dendritic cells (DCs) that immigrate into the CNS during the effector phase of MOG-induced EAE. CCL17 deficient (CCL17) mice exhibited an ameliorated disease course upon MOG-immunization, associated with reduced immigration of IL-17 producing CD4 T cells and peripheral DCs into the CNS. CCL17 DCs further showed equivalent MHC class II and costimulatory molecule expression and an equivalent capacity to secrete IL-23 and induce myelin-reactive T17 cells when compared to wildtype DCs. In contrast, their transmigration in an in vitro model of the blood-brain barrier was markedly impaired. In addition, peripheral T cells were enhanced in CCL17 mice at peak of disease pointing towards an immunoregulatory function of CCL17 in EAE. Our study identifies CCL17 as a unique modulator of EAE pathogenesis regulating DC trafficking as well as peripheral T cell expansion in EAE. Thus, CCL17 operates at distinct levels and on different cell subsets during immune response in EAE, a property harboring therapeutic potential for the treatment of CNS autoimmunity.
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http://dx.doi.org/10.1016/j.bbi.2017.06.010DOI Listing
November 2017

Prefrontal brain responsiveness to negative stimuli distinguishes familial risk for major depression from acute disorder.

J Psychiatry Neurosci 2017 Sep;42(5):343-352

From the Department of Psychiatry, University of Münster, Münster, Germany (Opel, Redlich, Grotegerd, Dohm, Zaremba, Meinert, Bürger, Plümpe, Alferink, Arolt, Dannlowski); the Cluster of Excellence EXC 1003, Cells in Motion, University of Münster, Münster, Germany (Alferink); the Department of Clinical Radiology, University of Münster, Münster, Germany (Heindel, Kugel); the kbo-Inn-Salzach-Klinikum, Wasserburg am Inn, Germany (Zwanzger); the Department of Psychiatry, Ludwig-Maximilian-University, Munich, Germany (Zwanzger); and the Department of Psychiatry, University of Marburg, Marburg, Germany (Dannlowski).

Background: Identifying reliable trait markers of familial risk for major depressive disorder (MDD) is a challenge in translational psychiatric research. In individuals with acute MDD, dysfunctional connectivity patterns of prefrontal areas have been shown repeatedly. However, it has been unclear in which neuronal networks functional alterations in individuals at familial risk for MDD might be present and to what extent they resemble findings previously reported in those with acute MDD.

Methods: We investigated differences in blood oxygen level-dependent (BOLD) response of the medial orbitofrontal cortex (OFC) and dorsolateral prefrontal cortex (DLPFC) to aversive stimuli between acute MDD and familial risk for the disorder in healthy first-degree relatives of acutely depressed patients with MDD (HC-FH+), healthy age- and sex-matched controls without any family history of depression (HC-FH-), and acutely depressed patients with MDD with (MDD-FH+) and without a family history of depression (MDD-FH-) during a frequently used emotional face-matching paradigm. Analyses of task-specific network connectivity were conducted in terms of psychophysiological interactions (PPI).

Results: The present analysis included a total of 100 participants: 25 HC-FH+, 25 HC-FH-, 25 MDD-FH+ and 25 MDD-FH-. Patients with MDD exhibited significantly increased activation in the medial OFC to negative stimuli irrespective of familial risk status, whereas healthy participants at familial risk and patients with MDD alike showed significant hypoactivation in the DLPFC compared with healthy participants without familial risk. The PPI analyses revealed significantly enhanced task-specific coupling between the medial OFC and differing cortical areas in individuals with acute MDD and those with familial risk for the disorder.

Limitations: The main limitation of our study is its cross-sectional design.

Conclusion: Whereas hypoactivation during negative emotion processing in the DLPFC appears as a common feature in both healthy high-risk individuals and acutely depressed patients, activation patterns of the medial OFC and its underlying connectivity seem to distinguish familial risk from acute disorder.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5573576PMC
http://dx.doi.org/10.1503/jpn.160198DOI Listing
September 2017

Attachment style moderates theory of mind abilities in depression.

J Affect Disord 2017 Apr 20;213:156-160. Epub 2017 Feb 20.

Leiden University, Faculty of Social and Behavioural Sciences, Institute of Psychology, Cognitive Psychology Unit, Leiden Institute for Brain and Cognition, Leiden, The Netherlands.

Introduction: Being able to understand other people's emotions and intentions is crucial for social interactions and well-being. Deficits in theory of mind (ToM) functioning hamper this ability and have been observed in depression and other neuropsychiatric disorders. However, results of previous research in depression have been inconclusive, possibly due to the presence of comorbid disorders and the disregarding of other modulating factors.

Methods: Thirty-eight patients with a major depressive disorder (MDD) and forty healthy matched controls were assessed with a ToM task using animated triangles. Results were correlated with attachment styles, empathy abilities and neurocognitive performance.

Results: Our findings show that 1) healthy female controls performed significantly stronger on the ToM task than female MDD patients, 2) these performance differences were driven by attachment styles and 3) depression severity did not impact task performance.

Limitations: The pharmacological treatment of the majority of patients might limit the generalizability of this study.

Discussion: Results indicate a gender-specific impact of attachment styles on ToM performance. Future studies should investigate whether impairments in social cognitive tasks pose a risk factor for depression and/or interactional styles or vice versa. Moreover, with regard to remediation programs gender-specific needs should be taken into account.
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http://dx.doi.org/10.1016/j.jad.2017.02.021DOI Listing
April 2017

Differential Abnormal Pattern of Anterior Cingulate Gyrus Activation in Unipolar and Bipolar Depression: an fMRI and Pattern Classification Approach.

Neuropsychopharmacology 2017 Jun 16;42(7):1399-1408. Epub 2017 Feb 16.

Department of Psychiatry, University of Münster, Münster, Germany.

Distinguishing bipolar disorder from major depressive disorder is a major challenge in psychiatric treatment. Consequently, there has been growing interest in identifying neuronal biomarkers of disorder-specific pathophysiological processes to differentiate affective disorders. Thirty-six depressed bipolar patients, 36 depressed unipolar patients, and 36 matched healthy controls (HCs) participated in an fMRI experiment. Emotional faces served as stimuli in a matching task. We investigated neural activation towards angry, fearful, and happy faces focusing on prototypical regions related to emotion processing, ie, the amygdala and the anterior cingulate gyrus (ACG). Furthermore, we employed a whole-brain and a multivariate pattern classification analysis. Unipolar patients showed abnormally reduced ACG activation toward happy and fearful faces compared with bipolar patients and HCs respectively. Furthermore, the whole-brain analysis revealed significantly increased activation in bipolar patients compared with unipolar patients in the fearful condition in the right frontal and parietal cortex. Moreover, the multivariate pattern classification analysis yielded significant classification rates of up to 72% based on ACG activation elicited by fearful faces. Our results question the rather 'amygdalocentric' neurobiological models of mood disorders. We observed patterns of abnormally reduced ventral and supragenual ACG activation, potentially indicating impaired bottom-up emotion processing and automatic emotion regulation specifically in unipolar but not in bipolar individuals.
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http://dx.doi.org/10.1038/npp.2017.36DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5436122PMC
June 2017

Alemtuzumab treatment alters circulating innate immune cells in multiple sclerosis.

Neurol Neuroimmunol Neuroinflamm 2016 Dec 12;3(6):e289. Epub 2016 Oct 12.

Department of Neurology (C.C.G., T.R., A.S.-M., N.M., L.K., H.W., S.G.M.), University Hospital Münster; Department of Psychiatry (D.A., K.S., S.J., V.A., J.A.) and Cluster of Excellence EXC 1003, Cells in Motion (D.A., K.S., H.W., S.G.M.), University of Münster; Institute of Medical Microbiology and Hospital Hygiene (S.S.), University of Düsseldorf; and Department of Neurology (S.W., B.G.), Clinics Osnabrück, Germany.

Objective: To characterize changes in myeloid and lymphoid innate immune cells in patients with relapsing-remitting multiple sclerosis (MS) during a 6-month follow-up after alemtuzumab treatment.

Methods: Circulating innate immune cells including myeloid cells and innate lymphoid cells (ILCs) were analyzed before and 6 and 12 months after onset of alemtuzumab treatment. Furthermore, a potential effect on granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-23 production by myeloid cells and natural killer (NK) cell cytolytic activity was determined.

Results: In comparison to CD4 T lymphocytes, myeloid and lymphoid innate cell subsets of patients with MS expressed significantly lower amounts of CD52 on their cell surface. Six months after CD52 depletion, numbers of circulating plasmacytoid dendritic cells (DCs) and conventional DCs were reduced compared to baseline. GM-CSF and IL-23 production in DCs remained unchanged. Within the ILC compartment, the subset of CD56 NK cells specifically expanded under alemtuzumab treatment, but their cytolytic activity did not change.

Conclusions: Our findings demonstrate that 6 months after alemtuzumab treatment, specific DC subsets are reduced, while CD56 NK cells expanded in patients with MS. Thus, alemtuzumab specifically restricts the DC compartment and expands the CD56 NK cell subset with potential immunoregulatory properties in MS. We suggest that remodeling of the innate immune compartment may promote long-term efficacy of alemtuzumab and preserve immunocompetence in patients with MS.
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http://dx.doi.org/10.1212/NXI.0000000000000289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5063395PMC
December 2016

Cannabinoid Receptor 2 Modulates Susceptibility to Experimental Cerebral Malaria through a CCL17-dependent Mechanism.

J Biol Chem 2016 09 29;291(37):19517-31. Epub 2016 Jul 29.

From the Institute of Molecular Psychiatry, Medical Faculty, and

Cerebral malaria is a severe and often fatal complication of Plasmodium falciparum infection. It is characterized by parasite sequestration, a breakdown of the blood-brain barrier, and a strong inflammation in the brain. We investigated the role of the cannabinoid receptor 2 (CB2), an important modulator of neuroinflammatory responses, in experimental cerebral malaria (ECM). Strikingly, mice with a deletion of the CB2-encoding gene (Cnr2(-/-)) inoculated with Plasmodium berghei ANKA erythrocytes exhibited enhanced survival and a diminished blood-brain barrier disruption. Therapeutic application of a specific CB2 antagonist also conferred increased ECM resistance in wild type mice. Hematopoietic derived immune cells were responsible for the enhanced protection in bone marrow (BM) chimeric Cnr2(-/-) mice. Mixed BM chimeras further revealed that CB2-expressing cells contributed to ECM development. A heterogeneous CD11b(+) cell population, containing macrophages and neutrophils, expanded in the Cnr2(-/-) spleen after infection and expressed macrophage mannose receptors, arginase-1 activity, and IL-10. Also in the Cnr2(-/-) brain, CD11b(+) cells that expressed selected anti-inflammatory markers accumulated, and expression of inflammatory mediators IFN-γ and TNF-α was reduced. Finally, the M2 macrophage chemokine CCL17 was identified as an essential factor for enhanced survival in the absence of CB2, because CCL17 × Cnr2 double-deficient mice were fully susceptible to ECM. Thus, targeting CB2 may be promising for the development of alternative treatment regimes of ECM.
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http://dx.doi.org/10.1074/jbc.M116.746594DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5016688PMC
September 2016

Reduced locomotor activity and exploratory behavior in CC chemokine receptor 4 deficient mice.

Behav Brain Res 2016 11 25;314:87-95. Epub 2016 Jul 25.

Department of Psychiatry, University of Münster, Münster, Germany; Cluster of Excellence EXC 1003, Cells in Motion, University of Münster, Münster, Germany.

Chemokines and their receptors are key regulators of immune cell trafficking and activation. Recent findings suggest that they may also play pathophysiological roles in psychiatric diseases like depression and anxiety disorders. The CC chemokine receptor 4 (CCR4) and its two ligands, CCL17 and CCL22, are functionally involved in neuroinflammation as well as anti-infectious and autoimmune responses. However, their influence on behavior remains unknown. Here we characterized the functional role of the CCR4-CCL17 chemokine-receptor axis in the modulation of anxiety-related behavior, locomotor activity, and object exploration and recognition. Additionally, we investigated social exploration of CCR4 and CCL17 knockout mice and wild type (WT) controls. CCR4 knockout (CCR4(-/-)) mice exhibited fewer anxiety-related behaviors in the elevated plus-maze, diminished locomotor activity, exploratory behavior, and social exploration, while their recognition memory was not affected. In contrast, CCL17 deficient mice did not show an altered behavior compared to WT mice regarding locomotor activity, anxiety-related behavior, social exploration, and object recognition memory. In the dark-light and object recognition tests, CCL17(-/-) mice even covered longer distances than WT mice. These data demonstrate a mechanistic or developmental role of CCR4 in the regulation of locomotor and exploratory behaviors, whereas the ligand CCL17 appears not to be involved in the behaviors measured here. Thus, either CCL17 and the alternative ligand CCL22 may be redundant, or CCL22 is the main activator of CCR4 in these processes. Taken together, these findings contribute to the growing evidence regarding the involvement of chemokines and their receptors in the regulation of behavior.
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http://dx.doi.org/10.1016/j.bbr.2016.07.041DOI Listing
November 2016

Cutting Edge: IFN-β Expression in the Spleen Is Restricted to a Subpopulation of Plasmacytoid Dendritic Cells Exhibiting a Specific Immune Modulatory Transcriptome Signature.

J Immunol 2016 06 2;196(11):4447-51. Epub 2016 May 2.

Institute of Medical Microbiology and Hospital Hygiene, University of Düsseldorf, 40225 Düsseldorf, Germany;

Type I IFNs are critical in initiating protective antiviral immune responses, and plasmacytoid dendritic cells (pDCs) represent a major source of these cytokines. We show that only few pDCs are capable of producing IFN-β after virus infection or CpG stimulation. Using IFNβ/YFP reporter mice, we identify these IFN-β-producing cells in the spleen as a CCR9(+)CD9(-) pDC subset that is localized exclusively within the T/B cell zones. IFN-β-producing pDCs exhibit a distinct transcriptome profile, with higher expression of genes encoding cytokines and chemokines, facilitating T cell recruitment and activation. These distinctive characteristics of IFN-β-producing pDCs are independent of the type I IFNR-mediated feedback loop. Furthermore, IFN-β-producing pDCs exhibit enhanced CCR7-dependent migratory properties in vitro. Additionally, they effectively recruit T cells in vivo in a peritoneal inflammation model. We define "professional type I IFN-producing cells" as a distinct subset of pDCs specialized in coordinating cellular immune responses.
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http://dx.doi.org/10.4049/jimmunol.1500383DOI Listing
June 2016

Prediction of Individual Response to Electroconvulsive Therapy via Machine Learning on Structural Magnetic Resonance Imaging Data.

JAMA Psychiatry 2016 Jun;73(6):557-64

Department of Psychiatry, University of Muenster, Muenster, Germany5Department of Psychiatry, University of Marburg, Marburg, Germany.

Importance: Electroconvulsive therapy (ECT) is one of the most effective treatments for severe depression. However, biomarkers that accurately predict a response to ECT remain unidentified.

Objective: To investigate whether certain factors identified by structural magnetic resonance imaging (MRI) techniques are able to predict ECT response.

Design, Setting, And Participants: In this nonrandomized prospective study, gray matter structure was assessed twice at approximately 6 weeks apart using 3-T MRI and voxel-based morphometry. Patients were recruited through the inpatient service of the Department of Psychiatry, University of Muenster, from March 11, 2010, to March 27, 2015. Two patient groups with acute major depressive disorder were included. One group received an ECT series in addition to antidepressants (n = 24); a comparison sample was treated solely with antidepressants (n = 23). Both groups were compared with a sample of healthy control participants (n = 21).

Main Outcomes And Measures: Binary pattern classification was used to predict ECT response by structural MRI that was performed before treatment. In addition, univariate analysis was conducted to predict reduction of the Hamilton Depression Rating Scale score by pretreatment gray matter volumes and to investigate ECT-related structural changes.

Results: One participant in the ECT sample was excluded from the analysis, leaving 67 participants (27 men and 40 women; mean [SD] age, 43.7 [10.6] years). The binary pattern classification yielded a successful prediction of ECT response, with accuracy rates of 78.3% (18 of 23 patients in the ECT sample) and sensitivity rates of 100% (13 of 13 who responded to ECT). Furthermore, a support vector regression yielded a significant prediction of relative reduction in the Hamilton Depression Rating Scale score. The principal findings of the univariate model indicated a positive association between pretreatment subgenual cingulate volume and individual ECT response (Montreal Neurological Institute [MNI] coordinates x = 8, y = 21, z = -18; Z score, 4.00; P < .001; peak voxel r = 0.73). Furthermore, the analysis of treatment effects revealed a increase in hippocampal volume in the ECT sample (MNI coordinates x = -28, y = -9, z = -18; Z score, 7.81; P < .001) that was missing in the medication-only sample.

Conclusions And Relevance: A relatively small degree of structural impairment in the subgenual cingulate cortex before therapy seems to be associated with successful treatment with ECT. In the future, neuroimaging techniques could prove to be promising tools for predicting the individual therapeutic effectiveness of ECT.
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http://dx.doi.org/10.1001/jamapsychiatry.2016.0316DOI Listing
June 2016

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

Int J Neuropsychopharmacol 2015 Sep 12;19(3):pyv103. Epub 2015 Sep 12.

Department of Psychiatry, University of Münster, Germany (Dr Ambrée, Ms Grosse, Dr Alferink, Dr Rothermundt, and Dr Arolt); Department of Psychiatry, Erasmus Medical Center Rotterdam, The Netherlands (Drs Bergink and Birkenhäger); Radiology Morphological Solutions, Rotterdam, The Netherlands (Ms Grosse); Department of Immunology, Erasmus Medical Center Rotterdam, The Netherlands (Dr Drexhage); Cluster of Excellence EXC 1003, Cells in Motion, Münster, Germany (Dr Alferink); Department of Psychiatry, St. Rochus-Hospital, Telgte, Oberhausen, Germany (Dr Rothermundt).

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.
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http://dx.doi.org/10.1093/ijnp/pyv103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4815471PMC
September 2015

Measuring Compounds in Exhaled Air to Detect Alzheimer's Disease and Parkinson's Disease.

PLoS One 2015 13;10(7):e0132227. Epub 2015 Jul 13.

Department of Internal Medicine, Division of Pulmonary Diseases, Philipps-University Marburg, 35043 Marburg, Germany.

Background: Alzheimer's disease (AD) is diagnosed based upon medical history, neuropsychiatric examination, cerebrospinal fluid analysis, extensive laboratory analyses and cerebral imaging. Diagnosis is time consuming and labour intensive. Parkinson's disease (PD) is mainly diagnosed on clinical grounds.

Objective: The primary aim of this study was to differentiate patients suffering from AD, PD and healthy controls by investigating exhaled air with the electronic nose technique. After demonstrating a difference between the three groups the secondary aim was the identification of specific substances responsible for the difference(s) using ion mobility spectroscopy. Thirdly we analysed whether amyloid beta (Aβ) in exhaled breath was causative for the observed differences between patients suffering from AD and healthy controls.

Methods: We employed novel pulmonary diagnostic tools (electronic nose device/ion-mobility spectrometry) for the identification of patients with neurodegenerative diseases. Specifically, we analysed breath pattern differences in exhaled air of patients with AD, those with PD and healthy controls using the electronic nose device (eNose). Using ion mobility spectrometry (IMS), we identified the compounds responsible for the observed differences in breath patterns. We applied ELISA technique to measure Aβ in exhaled breath condensates.

Results: The eNose was able to differentiate between AD, PD and HC correctly. Using IMS, we identified markers that could be used to differentiate healthy controls from patients with AD and PD with an accuracy of 94%. In addition, patients suffering from PD were identified with sensitivity and specificity of 100%. Altogether, 3 AD patients out of 53 participants were misclassified. Although we found Aβ in exhaled breath condensate from both AD and healthy controls, no significant differences between groups were detected.

Conclusion: These data may open a new field in the diagnosis of neurodegenerative disease such as Alzheimer's disease and Parkinson's disease. Further research is required to evaluate the significance of these pulmonary findings with respect to the pathophysiology of neurodegenerative disorders.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0132227PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4500505PMC
April 2016

IFNβ secreted by microglia mediates clearance of myelin debris in CNS autoimmunity.

Acta Neuropathol Commun 2015 Apr 3;3:20. Epub 2015 Apr 3.

Introduction: Multiple sclerosis (MS) is a chronic demyelinating disorder of the central nervous system (CNS) leading to progressive neurological disability. Interferon β (IFNβ) represents a standard treatment for relapsing-remitting MS and exogenous administration of IFNβ exhibits protective effects in experimentally induced CNS autoimmunity. Also, genetic deletion of IFNβ in mice leads to an aggravation of disease symptoms in the MS model of experimental autoimmune encephalomyelitis (EAE). However, neither the underlying mechanisms mediating the beneficial effects nor the cellular source of IFNβ have been fully elucidated.

Results: In this report, a subpopulation of activated microglia was identified as the major producers of IFNβ in the CNS at the peak of EAE using an IFNβ-fluorescence reporter mouse model. These IFNβ expressing microglia specifically localized to active CNS lesions and were associated with myelin debris in demyelinated cerebellar organotypic slice cultures (OSCs). In response to IFNβ microglia showed an enhanced capacity to phagocytose myelin in vitro and up-regulated the expression of phagocytosis-associated genes. IFNβ treatment was further sufficient to stimulate association of microglia with myelin debris in OSCs. Moreover, IFNβ-producing microglia mediated an enhanced removal of myelin debris when co-transplanted onto demyelinated OSCs as compared to IFNβ non-producing microglia.

Conclusions: These data identify activated microglia as the major producers of protective IFNβ at the peak of EAE and as orchestrators of IFNβ-induced clearance of myelin debris.
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http://dx.doi.org/10.1186/s40478-015-0192-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4383054PMC
April 2015

The cannabinoid receptor 2 is involved in acute rejection of cardiac allografts.

Life Sci 2015 Oct 2;138:29-34. Epub 2015 Mar 2.

Institute of Molecular Psychiatry, University of Bonn, Bonn, Germany; Department of Psychiatry and Psychotherapy, University of Münster, Münster, Germany; Cells-in-Motion Cluster of Excellence EXC 1003, University of Münster, Münster , Germany. Electronic address:

Aims: Acute rejection of cardiac allografts is a major risk factor limiting survival of heart transplant recipients. Rejection is triggered by dendritic cell (DC) mediated activation of host T cells, amongst others CD4(+) T helper (TH)1- and TH17 cells. The cannabinoid receptor 2 (CB2) is an important modulator of cellular immune responses. However, its role in cardiac allograft rejection has not been studied so far.

Main Methods: Here, we examined the effect of CB2 on cytokine release by mature DCs and its impact on CD4(+) T cell differentiation by utilizing in vitro generated bone marrow-derived DCs (BM-DCs) and CD4(+) T cells from CB2 knockout (Cnr2(-/-)) mice. We further assessed the functional role of CB2 in acute allograft rejection using Cnr2(-/-) mice in a fully major histocompatibility complex-mismatched mouse cardiac transplantation model.

Key Findings: Cardiac allograft rejection was accelerated in Cnr2(-/-) mice compared to wild type recipients. In vitro stimulation of BM-DCs showed enhanced secretion of the pro-inflammatory cytokines interleukin (IL)-6, IL-1β, tumor necrosis factor (TNF) and the immunomodulatory cytokine TGF-β. Furthermore, secretion of the TH1/TH17 promoting cytokines IL-12 and IL-23 was increased in Cnr2(-/-) BM-DCs. In addition, Cnr2(-/-) CD4(+) T cells showed an enhanced capacity to differentiate into interferon (IFN)-γ- or IL-17-producing effector cells.

Significance: These results demonstrate that CB2 modulates in vitro cytokine responses via DCs and directly via its influence on TH1/TH17 differentiation. These findings and the fact that allograft rejection is enhanced in Cnr2(-/-) mice suggest that CB2 may be a promising therapeutic target in organ transplantation.
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http://dx.doi.org/10.1016/j.lfs.2015.02.012DOI Listing
October 2015

Cannabinoid receptor 2 deficiency results in reduced neuroinflammation in an Alzheimer's disease mouse model.

Neurobiol Aging 2015 Feb 28;36(2):710-9. Epub 2014 Sep 28.

Institute of Molecular Psychiatry, University of Bonn, Bonn, Germany. Electronic address:

Several studies have indicated that the cannabinoid receptor 2 (CB2) plays an important role in neuroinflammation associated with Alzheimer's disease (AD) progression. The present study examined the role of CB2 in microglia activation in vitro as well as characterizing the neuroinflammatory process in a transgenic mouse model of AD (APP/PS1 mice). We demonstrate that microglia harvested from CB2(-/-) mice were less responsive to pro-inflammatory stimuli than CB2(+/+) microglia, based on the cell surface expression of ICAM and CD40 and the release of chemokines and cytokines CCL2, IL-6, and TNFα. Transgenic APP/PS1 mice lacking CB2 showed reduced percentages of microglia and infiltrating macrophages. Furthermore, they showed lowered expression levels of pro-inflammatory chemokines and cytokines in the brain, as well as diminished concentrations of soluble Aβ 40/42. The reduction in neuroinflammation did not affect spatial learning and memory in APP/PS1*CB2(-/-) mice. These data suggest a role for the CB2 in Alzheimer's disease-associated neuroinflammation, independent of influencing Aβ-mediated pathology and cognitive impairment.
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http://dx.doi.org/10.1016/j.neurobiolaging.2014.09.019DOI Listing
February 2015

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

Brain Behav Immun 2015 Feb 20;44:48-56. Epub 2014 Aug 20.

Department of Psychiatry and Psychotherapy, University of Münster, Germany.

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 GRβ 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/β 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.
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http://dx.doi.org/10.1016/j.bbi.2014.08.004DOI Listing
February 2015