Publications by authors named "Andreas Thiel"

120 Publications

Analysis of peripheral inflammatory T cell subsets and their effector function in patients with Birdshot Retinochoroiditis.

Sci Rep 2021 Apr 21;11(1):8604. Epub 2021 Apr 21.

Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität Zu Berlin, Augustenburger Platz 1, 13353, Berlin, Germany.

Birdshot Retinochoroiditis (BSRC) is a progressive non-infectious intraocular inflammation that affects choroid and retina. Inflammatory processes have adverse effects on vision by affecting photoreceptor-bearing cells that do not regenerate. This study aimed at characterizing inflammatory CD4 and CD8 T cell subsets in the peripheral blood of active and inactive BSRCs. Furthermore, we correlated phenotypical and functional immunological analyses with clinical data. We observed a slight increase of terminally differentiated effector memory CD8 T cells expressing CD45RA (T) in blood of inactive, compared to active BSRCs. Moreover, we identified a trend for a decreased population of T2 cells and increased T1 frequencies in active BSRCs, a typical sign of ongoing autoimmune processes. Functional assays demonstrated severe and overall impairment of effector function of both, CD4 and CD8 inflammatory T cells, which might reflect T cell exhaustion. Although the eye is the main site of inflammation in BSRC, we observed altered T cell subset compositions in the peripheral blood, dependent on the disease status. Our results indicate that T cells may play a major role in BSRC pathology, although our cohort size is too limited for definitve conclusions. Future studies with larger BSRCs have to be performed.
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http://dx.doi.org/10.1038/s41598-021-88013-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8060342PMC
April 2021

High-dimensional single cell mass cytometry analysis of the murine hematopoietic system reveals signatures induced by ageing and physiological pathogen challenges.

Immun Ageing 2021 Apr 20;18(1):20. Epub 2021 Apr 20.

Regenerative Immunology and Aging, BIH Center for Regenerative Therapies (BCRT), Charité Universitätsmedizin Berlin, Berlin, Germany.

Background: Immune ageing is a result of repetitive microbial challenges along with cell intrinsic or systemic changes occurring during ageing. Mice under 'specific-pathogen-free' (SPF) conditions are frequently used to assess immune ageing in long-term experiments. However, physiological pathogenic challenges are reduced in SPF mice. The question arises to what extent murine experiments performed under SPF conditions are suited to analyze immune ageing in mice and serve as models for human immune ageing. Our previous comparisons of same aged mice with different microbial exposures, unambiguously identified distinct clusters of immune cells characteristic for numerous previous pathogen encounters in particular in pet shop mice.

Results: We here performed single cell mass cytometry assessing splenic as secondary and bone marrow as primary lymphoid organ-derived leukocytes isolated from young versus aged SPF mice in order to delineate alterations of the murine hematopoietic system induced during ageing. We then compared immune clusters from young and aged SPF mice to pet shop mice in order to delineate alterations of the murine hematopoietic system induced by physiological pathogenic challenges and those caused by cell intrinsic or systemic changes during ageing. Notably, distinct immune signatures were similarly altered in both pet shop and aged SPF mice in comparison to young SPF mice, including increased frequencies of memory T lymphocytes, effector-cytokine producing T cells, plasma cells and mature NK cells. However, elevated frequencies of CD4 T cells, total NK cells, granulocytes, pDCs, cDCs and decreased frequencies of naïve B cells were specifically identified only in pet shop mice. In aged SPF mice specifically the frequencies of splenic IgM plasma cells, CD8 T cells and CD4 CD25 Treg were increased as compared to pet shop mice and young mice.

Conclusions: Our study dissects firstly how ageing impacts both innate and adaptive immune cells in primary and secondary lymphoid organs. Secondly, it partly distinguishes murine intrinsic immune ageing alterations from those induced by physiological pathogen challenges highlighting the importance of designing mouse models for their use in preclinical research including vaccines and immunotherapies.
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http://dx.doi.org/10.1186/s12979-021-00230-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8056611PMC
April 2021

An artificial ruthenium-containing β-barrel protein for alkene-alkyne coupling reaction.

Org Biomol Chem 2021 04 18;19(13):2912-2916. Epub 2021 Mar 18.

Institute of Inorganic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany.

A modified Cp*Ru complex, equipped with a maleimide group, was covalently attached to a cysteine of an engineered variant of Ferric hydroxamate uptake protein component: A (FhuA). This synthetic metalloprotein catalyzed the intermolecular alkene-alkyne coupling of 3-butenol with 5-hexynenitrile. When compared with the protein-free Cp*Ru catalyst, the biohybrid catalyst produced the linear product with higher regioselectivity.
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http://dx.doi.org/10.1039/d1ob00279aDOI Listing
April 2021

SLAMF7 and IL-6R define distinct cytotoxic versus helper memory CD8 T cells.

Nat Commun 2020 12 11;11(1):6357. Epub 2020 Dec 11.

Si-M/"Der Simulierte Mensch" a science framework of Technische Universität Berlin and Charité-Universitätsmedizin Berlin, 13353, Berlin, Germany.

The prevailing 'division of labor' concept in cellular immunity is that CD8 T cells primarily utilize cytotoxic functions to kill target cells, while CD4 T cells exert helper/inducer functions. Multiple subsets of CD4 memory T cells have been characterized by distinct chemokine receptor expression. Here, we demonstrate that analogous CD8 memory T-cell subsets exist, characterized by identical chemokine receptor expression signatures and controlled by similar generic programs. Among them, Tc2, Tc17 and Tc22 cells, in contrast to Tc1 and Tc17 + 1 cells, express IL-6R but not SLAMF7, completely lack cytotoxicity and instead display helper functions including CD40L expression. CD8 helper T cells exhibit a unique TCR repertoire, express genes related to skin resident memory T cells (T) and are altered in the inflammatory skin disease psoriasis. Our findings reveal that the conventional view of CD4 and CD8 T cell capabilities and functions in human health and disease needs to be revised.
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http://dx.doi.org/10.1038/s41467-020-19002-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7733515PMC
December 2020

SARS-CoV-2-reactive T cells in healthy donors and patients with COVID-19.

Nature 2020 11 29;587(7833):270-274. Epub 2020 Jul 29.

Institute of Virology, Charité-Universitätsmedizin Berlin, Berlin, Germany.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the rapidly unfolding coronavirus disease 2019 (COVID-19) pandemic. Clinical manifestations of COVID-19 vary, ranging from asymptomatic infection to respiratory failure. The mechanisms that determine such variable outcomes remain unresolved. Here we investigated CD4 T cells that are reactive against the spike glycoprotein of SARS-CoV-2 in the peripheral blood of patients with COVID-19 and SARS-CoV-2-unexposed healthy donors. We detected spike-reactive CD4 T cells not only in 83% of patients with COVID-19 but also in 35% of healthy donors. Spike-reactive CD4 T cells in healthy donors were primarily active against C-terminal epitopes in the spike protein, which show a higher homology to spike glycoproteins of human endemic coronaviruses, compared with N-terminal epitopes. Spike-protein-reactive T cell lines generated from SARS-CoV-2-naive healthy donors responded similarly to the C-terminal region of the spike proteins of the human endemic coronaviruses 229E and OC43, as well as that of SARS-CoV-2. This results indicate that spike-protein cross-reactive T cells are present, which were probably generated during previous encounters with endemic coronaviruses. The effect of pre-existing SARS-CoV-2 cross-reactive T cells on clinical outcomes remains to be determined in larger cohorts. However, the presence of spike-protein cross-reactive T cells in a considerable fraction of the general population may affect the dynamics of the current pandemic, and has important implications for the design and analysis of upcoming trials investigating COVID-19 vaccines.
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http://dx.doi.org/10.1038/s41586-020-2598-9DOI Listing
November 2020

The H-Y Antigen in Embryonic Stem Cells Causes Rejection in Syngeneic Female Recipients.

Stem Cells Dev 2020 09 25;29(18):1179-1189. Epub 2020 Aug 25.

Transplant and Stem Cell Immunobiology Lab, Department of Surgery, University of California, San Francisco, California, USA.

Pluripotent stem cells are promising candidates for cell-based regenerative therapies. To avoid rejection of transplanted cells, several approaches are being pursued to reduce immunogenicity of the cells or modulate the recipient's immune response. These include gene editing to reduce the antigenicity of cell products, immunosuppression of the host, or using major histocompatibility complex-matched cells from cell banks. In this context, we have investigated the antigenicity of H-Y antigens, a class of minor histocompatibility antigens encoded by the Y chromosome, to assess whether the gender of the donor affects the cell's antigenicity. In a murine transplant model, we show that the H-Y antigen in undifferentiated embryonic stem cells (ESCs), as well as ESC-derived endothelial cells, provokes T- and B cell responses in female recipients.
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http://dx.doi.org/10.1089/scd.2019.0299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7482111PMC
September 2020

An Investigation of Psychosis Subgroups With Prognostic Validation and Exploration of Genetic Underpinnings: The PsyCourse Study.

JAMA Psychiatry 2020 05;77(5):523-533

Department of Psychiatry, Ruhr University Bochum, LWL University Hospital, Bochum, Germany.

Importance: Identifying psychosis subgroups could improve clinical and research precision. Research has focused on symptom subgroups, but there is a need to consider a broader clinical spectrum, disentangle illness trajectories, and investigate genetic associations.

Objective: To detect psychosis subgroups using data-driven methods and examine their illness courses over 1.5 years and polygenic scores for schizophrenia, bipolar disorder, major depression disorder, and educational achievement.

Design, Setting, And Participants: This ongoing multisite, naturalistic, longitudinal (6-month intervals) cohort study began in January 2012 across 18 sites. Data from a referred sample of 1223 individuals (765 in the discovery sample and 458 in the validation sample) with DSM-IV diagnoses of schizophrenia, bipolar affective disorder (I/II), schizoaffective disorder, schizophreniform disorder, and brief psychotic disorder were collected from secondary and tertiary care sites. Discovery data were extracted in September 2016 and analyzed from November 2016 to January 2018, and prospective validation data were extracted in October 2018 and analyzed from January to May 2019.

Main Outcomes And Measures: A clinical battery of 188 variables measuring demographic characteristics, clinical history, symptoms, functioning, and cognition was decomposed using nonnegative matrix factorization clustering. Subtype-specific illness courses were compared with mixed models and polygenic scores with analysis of covariance. Supervised learning was used to replicate results in validation data with the most reliably discriminative 45 variables.

Results: Of the 765 individuals in the discovery sample, 341 (44.6%) were women, and the mean (SD) age was 42.7 (12.9) years. Five subgroups were found and labeled as affective psychosis (n = 252), suicidal psychosis (n = 44), depressive psychosis (n = 131), high-functioning psychosis (n = 252), and severe psychosis (n = 86). Illness courses with significant quadratic interaction terms were found for psychosis symptoms (R2 = 0.41; 95% CI, 0.38-0.44), depression symptoms (R2 = 0.28; 95% CI, 0.25-0.32), global functioning (R2 = 0.16; 95% CI, 0.14-0.20), and quality of life (R2 = 0.20; 95% CI, 0.17-0.23). The depressive and severe psychosis subgroups exhibited the lowest functioning and quadratic illness courses with partial recovery followed by reoccurrence of severe illness. Differences were found for educational attainment polygenic scores (mean [SD] partial η2 = 0.014 [0.003]) but not for diagnostic polygenic risk. Results were largely replicated in the validation cohort.

Conclusions And Relevance: Psychosis subgroups were detected with distinctive clinical signatures and illness courses and specificity for a nondiagnostic genetic marker. New data-driven clinical approaches are important for future psychosis taxonomies. The findings suggest a need to consider short-term to medium-term service provision to restore functioning in patients stratified into the depressive and severe psychosis subgroups.
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http://dx.doi.org/10.1001/jamapsychiatry.2019.4910DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042925PMC
May 2020

The role of environmental stress and DNA methylation in the longitudinal course of bipolar disorder.

Int J Bipolar Disord 2020 Feb 12;8(1). Epub 2020 Feb 12.

Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, 68159, Mannheim, Germany.

Background: Stressful life events influence the course of affective disorders, however, the mechanisms by which they bring about phenotypic change are not entirely known.

Methods: We explored the role of DNA methylation in response to recent stressful life events in a cohort of bipolar patients from the longitudinal PsyCourse study (n = 96). Peripheral blood DNA methylomes were profiled at two time points for over 850,000 methylation sites. The association between impact ratings of stressful life events and DNA methylation was assessed, first by interrogating methylation sites in the vicinity of candidate genes previously implicated in the stress response and, second, by conducting an exploratory epigenome-wide association analysis. Third, the association between epigenetic aging and change in stress and symptom measures over time was investigated.

Results: Investigation of methylation signatures over time revealed just over half of the CpG sites tested had an absolute difference in methylation of at least 1% over a 1-year period. Although not a single CpG site withstood correction for multiple testing, methylation at one site (cg15212455) was suggestively associated with stressful life events (p < 1.0 × 10). Epigenetic aging over a 1-year period was not associated with changes in stress or symptom measures.

Conclusions: To the best of our knowledge, our study is the first to investigate epigenome-wide methylation across time in bipolar patients and in relation to recent, non-traumatic stressful life events. Limited and inconclusive evidence warrants future longitudinal investigations in larger samples of well-characterized bipolar patients to give a complete picture regarding the role of DNA methylation in the course of bipolar disorder.
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http://dx.doi.org/10.1186/s40345-019-0176-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7013010PMC
February 2020

Blockade of the costimulatory CD28-B7 family signal axis enables repeated application of AAV8 gene vectors.

J Thromb Haemost 2020 05 2;18(5):1075-1080. Epub 2020 Mar 2.

Baxalta Innovations GmbH, A Member of the Takeda Group of Companies, Vienna, Austria.

Adeno-associated virus serotype 8 (AAV8) gene therapy has shown efficacy in several clinical trials and is considered a highly promising technology to treat monogenic diseases such as hemophilia A and B. However, a major drawback of AAV8 gene therapy is that it can be applied only once because anti-AAV8 immunity develops after the first treatment. Readministration may be required in patients who are expected to need redosing, eg, due to organ growth, or to boost suboptimal expression levels, but no redosing protocol has been established. We have developed a preventive immune-suppressive protocol for a human factor IX (FIX) vector with an intended dose of ~5 × 10  vg/kg that inhibits the development of anti-AAV8 neutralizing-antibody (NAb) responses and anti-AAV8 T-cell responses using CTLA4-IgG (abatacept). In a preclinical model, transient treatment with abatacept during initial human FIX gene therapy efficiently inhibited the generation of AAV8-specific cellular and humoral responses, and thus permitted redosing of FIX. Furthermore, our data suggest that by suppression of anti-AAV8 NAb responses after the second higher dose (4 × 10  vg/kg) this protocol can be used to enable redosing up to such high doses. An additional advantage of CTLA4-IgG blocking CD28-mediated signals is its potential suppression of AAV8-specific cytotoxic CD8 T-cell responses, which are believed to kill transduced hepatocytes and might interfere with a successful readministration. Redosing protocols using approved drugs would be beneficial for patients because they could effortlessly be applied in clinical trials and enable safe and efficient treatment options for patients undergoing AAV8 gene therapy.
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http://dx.doi.org/10.1111/jth.14757DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7318590PMC
May 2020

High-Pressure Crystallography as a Guide in the Design of Single-Molecule Magnets.

Inorg Chem 2020 Feb 16;59(3):1682-1691. Epub 2020 Jan 16.

Department of Chemistry , Aarhus University , Langelandsgade 140 , DK-8000 Aarhus C , Denmark.

Single-molecule magnet materials owe their function to the presence of significant magnetic anisotropy, which arises from the interplay between the ligand field and spin-orbit coupling, and this is responsible for setting up an energy barrier for magnetic relaxation. Therefore, chemical control of magnetic anisotropy is a central challenge in the quest to synthesize new molecular nanomagnets with improved properties. There have been several reports of design principles targeting such control; however, these principles rely on idealized geometries, which are rarely obtained in crystal structures. Here, we present the results of high-pressure single-crystal diffraction on the single-ion magnet, Co(SPh)(PPh), in the pressure range of 0-9.2 GPa. Upon pressurization a sequence of small geometrical distortions of the central CoS moeity are observed, enabling a thorough analysis of the magneto-structural correlations. The magneto-structural correlations are investigated by theoretical analyses of the pressure-dependent experimental molecular structures. We observed a significant increase in the magnitude of the zero-field splitting parameter , from -54.6 cm to -89.7 cm, which was clearly explained from the reduction of the energy difference between the essential d and d orbitals, and structurally assigned to the change of an angle of compression of the CoS moeity.
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http://dx.doi.org/10.1021/acs.inorgchem.9b02794DOI Listing
February 2020

Selective depletion of plasma cells in vivo based on the specificity of their secreted antibodies.

Eur J Immunol 2020 02 12;50(2):284-291. Epub 2019 Nov 12.

Deutsches RheumaForschungszentrum Berlin - a Leibniz Institute, Berlin, Germany.

Antibody-mediated diseases affect more than 10% of the human population. For most, no cure is available, particularly when the pathogenic antibodies are secreted by long-lived plasma cells resistant to conventional immunosuppressive therapies. Current therapeutic approaches target not only the plasma cells that secrete pathogenic antibodies, but also those providing protective antibodies. Here, in a murine model bearing long-lived plasma cells secreting anti-OVA and -chicken gamma globulin (CGG) antibodies, we describe the first-time use of an antigen-antibody (OVA/anti-CD138 antibody) conjugate for in vivo labeling and selective ablation of plasma cells that secrete antibodies specific for the antigen OVA. The selective depletion also led to a stable reduction of the corresponding serum anti-OVA antibody levels. In contrast, CGG-specific plasma cells and circulating anti-CGG antibody levels remained unchanged. The method described here should enable the development of unique causative treatment strategies for established antibody-mediated diseases sparing humoral immunity.
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http://dx.doi.org/10.1002/eji.201948144DOI Listing
February 2020

Kinship-based social inequality in Bronze Age Europe.

Science 2019 11 10;366(6466):731-734. Epub 2019 Oct 10.

Department of Archaeogenetics, Max Planck Institute for the Science of Human History, 07745 Jena, Germany.

Revealing and understanding the mechanisms behind social inequality in prehistoric societies is a major challenge. By combining genome-wide data, isotopic evidence, and anthropological and archaeological data, we have gone beyond the dominating supraregional approaches in archaeogenetics to shed light on the complexity of social status, inheritance rules, and mobility during the Bronze Age. We applied a deep microregional approach and analyzed genome-wide data of 104 human individuals deriving from farmstead-related cemeteries from the Late Neolithic to the Middle Bronze Age in southern Germany. Our results reveal individual households, lasting several generations, that consisted of a high-status core family and unrelated low-status individuals; a social organization accompanied by patrilocality and female exogamy; and the stability of this system over 700 years.
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http://dx.doi.org/10.1126/science.aax6219DOI Listing
November 2019

The genetic relationship between educational attainment and cognitive performance in major psychiatric disorders.

Transl Psychiatry 2019 08 28;9(1):210. Epub 2019 Aug 28.

Asklepios Specialized Hospital, Göttingen, 37081, Germany.

Cognitive deficits are a core feature of psychiatric disorders like schizophrenia and bipolar disorder. Evidence supports a genome-wide polygenic score (GPS) for educational attainment (GPS) can be used to explain variability in cognitive performance. We aimed to identify different cognitive domains associated with GPS in a transdiagnostic clinical cohort of chronic psychiatric patients with known cognitive deficits. Bipolar and schizophrenia patients from the PsyCourse cohort (N = 730; 43% female) were used. Likewise, we tested whether GPSs for schizophrenia (GPS) and bipolar disorder (GPS) were associated with cognitive outcomes. GPS explained 1.5% of variance in the backward verbal digit span, 1.9% in the number of correctly recalled words of the Verbal Learning and Memory Test, and 1.1% in crystallized intelligence. These effects were robust to the influences of treatment and diagnosis. No significant associations between GPS or GPS with cognitive outcomes were found. Furthermore, these risk scores did not confound the effect of GPS on cognitive outcomes. GPS explains a small fraction of cognitive performance in adults with psychiatric disorders, specifically for domains related to linguistic learning and working memory. Investigating such a proxy-phenotype longitudinally, could give intriguing insight into the disease course, highlighting at what time genes play a more influential role on cognitive performance. Better understanding the origin of these deficits might help identify those patients at risk for lower levels of functioning and poor social outcomes. Polygenic estimates may in the future be part of predictive models for more personalized interventions.
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http://dx.doi.org/10.1038/s41398-019-0547-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6713703PMC
August 2019

MicroRNA-487a-3p functions as a new tumor suppressor in prostate cancer by targeting CCND1.

J Cell Physiol 2020 02 15;235(2):1588-1600. Epub 2019 Jul 15.

Beijing Advanced Innovation Center for Food Nutrition and Human Health, China Agricultural University, Beijing, China.

Prostate cancer (PCa) is one of the major health problems of the aging male. The roles of dysregulated microRNAs in PCa remain unclear. In this study, we mined the public published data and found that miR-487a-3p was significantly downregulated in 38 pairs of clinical prostate tumor tissues compared with the normal tissues. We further verified this result by in situ hybridization on tissue chip and quantitative real-time polymerase chain reaction (qRT-PCR) in PCa/normal cells. miR-487a-3p targeting of cyclin D1 (CCND1) was identified using bioinformatics, qRT-PCR and western blot analyses. The cellular proliferation, cell cycle, migration, and invasion were assessed by cell counting kit-8, flow cytometry analysis and transwell assay. We discovered that overexpression of miR-487a-3p suppressed PCa cell growth, migration, invasion by directly targeting CCND1. Knockdown of CCND1 in PCa cells showed similar results. Meanwhile, the expression level of CCND1 was significantly upregulated in the PCa tissues and cell lines, which presented negative correlation with the expression of miR-487a-3p. More important, we demonstrated significantly reduced growth of xenograft tumors of stable miR-487a-3p-overexpressed human PCa cells in nude mice. Taken together, for the first time, our results revealed that miR-487a-3p as a tumor suppressor of PCa could target CCND1. Our finding might reveal miR-487a-3p could be potentially contributed to the pathogenesis and a clinical biomarker or the new potential therapeutic target of PCa.
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http://dx.doi.org/10.1002/jcp.29078DOI Listing
February 2020

Cytotoxic Effects of Rabbit Anti-thymocyte Globulin Preparations on Primary Human Thymic Epithelial Cells.

Transplantation 2019 11;103(11):2234-2244

Department of Hematology, Oncology and Tumor Immunology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.

Background: Graft-versus-host disease (GvHD) presents a major cause for morbidity and mortality after allogeneic hematopoietic stem cell transplantation. Rabbit-derived antithymocyte globulin (rATG) treatment reduces the incidence of GvHD after allogeneic hematopoietic stem cell transplantation. However, delayed immune reconstitution following rATG treatment, partly caused by hampered thymic function, is being discussed. The present study aims at elucidating possible cytotoxic effects of 2 commonly used rATG preparations on cultured human thymic stroma, especially thymic epithelial cells (TECs).

Methods: A primary TEC culture was established and the binding and cytotoxicity of 2 rATG preparations to the aforementioned cells were assessed by flow cytometry and immunofluorescence analyses. The release of several cytokines by cultured thymic stroma cells in response to rATG was analyzed via multiplex enzyme-linked immunosorbent assays.

Results: Both preparations showed a comparable dose-dependent binding to TECs and exerted a similar complement-independent, dose-dependent cytotoxicity. rATG exposure further resulted in hampered secretion of interleukin (IL)-7, IL-15, and IL-6, cytokines being involved in thymic T cell development and proliferation. Pretreatment with keratinocyte growth factor diminished rATG-induced cytotoxicity of TECs and restored their IL-7 and IL-15 secretion.

Conclusions: Cytotoxic effects on TECs link the rATG-induced thymic damage to the delayed T cell reconstitution, witnessed after rATG treatment. Our data support a combination treatment of rATG and thymus-protective strategies such as keratinocyte growth factor to simultaneously offer sufficient GvHD prophylaxis and overcome delayed T cell reconstitution caused by thymic damage.
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http://dx.doi.org/10.1097/TP.0000000000002799DOI Listing
November 2019

The Role of Pre-existing Cross-Reactive Central Memory CD4 T-Cells in Vaccination With Previously Unseen Influenza Strains.

Front Immunol 2019 4;10:593. Epub 2019 Apr 4.

Berlin-Brandenburg Center for Regenerative Therapies, Charité University Medicine Berlin, Berlin, Germany.

Influenza vaccination is a common approach to prevent seasonal and pandemic influenza. Pre-existing antibodies against close viral strains might impair antibody formation against previously unseen strains-a process called original antigenic sin. The role of this pre-existing cellular immunity in this process is, despite some hints from animal models, not clear. Here, we analyzed cellular and humoral immunity in healthy individuals before and after vaccination with seasonal influenza vaccine. Based on influenza-specific hemagglutination inhibiting (HI) titers, vaccinees were grouped into HI-negative and -positive cohorts followed by in-depth cytometric and TCR repertoire analysis. Both serological groups revealed cross-reactive T-cell memory to the vaccine strains at baseline that gave rise to the majority of vaccine-specific T-cells post vaccination. On the contrary, very limited number of vaccine-specific T-cell clones was recruited from the naive pool. Furthermore, baseline quantity of vaccine-specific central memory helper T-cells and clonotype richness of this population directly correlated with the vaccination efficacy. Our findings suggest that the deliberate recruitment of pre-existing cross-reactive cellular memory might help to improve vaccination outcome.
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http://dx.doi.org/10.3389/fimmu.2019.00593DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6458262PMC
July 2020

Altered naive CD4 T cell homeostasis in myasthenia gravis and thymoma patients.

J Neuroimmunol 2019 02 11;327:10-14. Epub 2019 Jan 11.

Department of Experimental Neurology, Charité - Universitätsmedizin Berlin, Germany; Department of Neurology, Charité - Universitätsmedizin Berlin, Germany; NeuroCure Clinical Research Center, Charité - Universitätsmedizin Berlin, Germany.

In Myasthenia Gravis (MG) thymic pathologies are often present and thymectomy is used as treatment. By flow cytometry we elucidated alterations of naïve CD4 T cell homeostasis in MG patients and patients with thymoma. MG patients showed increased absolute numbers of CD31naïve CD4 T cells. Thymoma patients displayed a significantly higher fraction of peripheral blood CD31naive T cells. We show an altered naive CD4 T cell homeostasis in MG patients that might predispose to autoimmunity. Aberrant generation of T cells in thymoma can be detected by an increased frequency of CD31naive CD4 T cells in the periphery.
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http://dx.doi.org/10.1016/j.jneuroim.2019.01.005DOI Listing
February 2019

The influence of religious activity and polygenic schizophrenia risk on religious delusions in schizophrenia.

Schizophr Res 2019 08 3;210:255-261. Epub 2019 Jan 3.

Department of Psychiatry, Psychotherapy and Psychosomatics, Clinical Center Wilhelmshaven, Wilhelmshaven 26389, Germany.

Background: Religious delusions are a common symptom in patients experiencing psychosis, with varying prevalence rates of religious delusions across cultures and societies. To enhance our knowledge of this distinct psychotic feature, we investigated the mutually-adjusted association of genetic and environmental factors with occurrence of religious delusions.

Methods: We studied 262 adult German patients with schizophrenia or schizoaffective disorder. Association with lifetime occurrence of religious delusions was tested by multiple logistic regression for the following putative predictors: self-reported degree of religious activity, DSM-IV diagnosis, sex, age, education level, marital status, presence of acute delusion at the time of interview and an individual polygenic schizophrenia-risk score (SZ-PRS, available in 239 subjects).

Results: Of the 262 patients, 101 (39%) had experienced religious delusions. The risk of experiencing religious delusions was significantly increased in patients with strong religious activity compared to patients without religious affiliation (OR = 3.6, p = 0.010). Low or moderate religious activity had no significant effect. The same analysis including the SZ-PRS confirmed the effect of high religious activity on occurrence of religious delusions (OR = 4.1, p = 0.008). Additionally, the risk of experiencing religious delusions increased with higher SZ-PRS (OR 1.4, p = 0.020, using pT = 0.05 for SZ-PRS calculation). None of the other variables were significantly associated with lifetime occurrence of religious delusions.

Conclusions: Our results suggest that strong religious activity and high SZ-PRS are independent risk factors for the occurrence of religious delusions in schizophrenia and schizoaffective disorder.
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http://dx.doi.org/10.1016/j.schres.2018.12.025DOI Listing
August 2019

A longitudinal approach to biological psychiatric research: The PsyCourse study.

Am J Med Genet B Neuropsychiatr Genet 2019 03 2;180(2):89-102. Epub 2018 Aug 2.

Department of Psychiatry, Klinikum Bremen-Ost, Bremen, Germany.

In current diagnostic systems, schizophrenia and bipolar disorder are still conceptualized as distinct categorical entities. Recently, both clinical and genomic evidence have challenged this Kraepelinian dichotomy. There are only few longitudinal studies addressing potential overlaps between these conditions. Here, we present design and first results of the PsyCourse study (N = 891 individuals at baseline), an ongoing transdiagnostic study of the affective-to-psychotic continuum that combines longitudinal deep phenotyping and dimensional assessment of psychopathology with an extensive collection of biomaterial. To provide an initial characterization of the PsyCourse study sample, we compare two broad diagnostic groups defined by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) classification system, that is, predominantly affective (n = 367 individuals) versus predominantly psychotic disorders (n = 524 individuals). Depressive, manic, and psychotic symptoms as well as global functioning over time were contrasted using linear mixed models. Furthermore, we explored the effects of polygenic risk scores for schizophrenia on diagnostic group membership and addressed their effects on nonparticipation in follow-up visits. While phenotypic results confirmed expected differences in current psychotic symptoms and global functioning, both manic and depressive symptoms did not vary between both groups after correction for multiple testing. Polygenic risk scores for schizophrenia significantly explained part of the variability of diagnostic group. The PsyCourse study presents a unique resource to research the complex relationships of psychopathology and biology in severe mental disorders not confined to traditional diagnostic boundaries and is open for collaborations.
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http://dx.doi.org/10.1002/ajmg.b.32639DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6585634PMC
March 2019

Investigating polygenic burden in age at disease onset in bipolar disorder: Findings from an international multicentric study.

Bipolar Disord 2019 02 28;21(1):68-75. Epub 2018 Jun 28.

Institute of Psychiatric Phenomics and Genomics (IPPG), University Hospital, LMU Munich, Munich, Germany.

Objectives: Bipolar disorder (BD) with early disease onset is associated with an unfavorable clinical outcome and constitutes a clinically and biologically homogenous subgroup within the heterogeneous BD spectrum. Previous studies have found an accumulation of early age at onset (AAO) in BD families and have therefore hypothesized that there is a larger genetic contribution to the early-onset cases than to late onset BD. To investigate the genetic background of this subphenotype, we evaluated whether an increased polygenic burden of BD- and schizophrenia (SCZ)-associated risk variants is associated with an earlier AAO in BD patients.

Methods: A total of 1995 BD type 1 patients from the Consortium of Lithium Genetics (ConLiGen), PsyCourse and Bonn-Mannheim samples were genotyped and their BD and SCZ polygenic risk scores (PRSs) were calculated using the summary statistics of the Psychiatric Genomics Consortium as a training data set. AAO was either separated into onset groups of clinical interest (childhood and adolescence [≤18 years] vs adulthood [>18 years]) or considered as a continuous measure. The associations between BD- and SCZ-PRSs and AAO were evaluated with regression models.

Results: BD- and SCZ-PRSs were not significantly associated with age at disease onset. Results remained the same when analyses were stratified by site of recruitment.

Conclusions: The current study is the largest conducted so far to investigate the association between the cumulative BD and SCZ polygenic risk and AAO in BD patients. The reported negative results suggest that such a polygenic influence, if there is any, is not large, and highlight the importance of conducting further, larger scale studies to obtain more information on the genetic architecture of this clinically relevant phenotype.
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http://dx.doi.org/10.1111/bdi.12659DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6585855PMC
February 2019

Simultaneous Presence of Non- and Highly Mutated Keyhole Limpet Hemocyanin (KLH)-Specific Plasmablasts Early after Primary KLH Immunization Suggests Cross-Reactive Memory B Cell Activation.

J Immunol 2018 06 7;200(12):3981-3992. Epub 2018 May 7.

Zellbiologie, Deutsches Rheuma-Forschungszentrum, ein Institut der Leibniz-Gemeinschaft, 10117 Berlin, Germany;

There are currently limited insights into the progression of human primary humoral immunity despite numerous studies in experimental models. In this study, we analyzed a primary and related secondary parenteral keyhole limpet hemocyanin (KLH) immunization in five human adults. The primary challenge elicited discordant KLH-specific serum and blood effector B cell responses (i.e., dominant serum KLH-specific IgG and IgM levels versus dominant KLH-specific IgA plasmablast frequencies). Single-cell IgH sequencing revealed early appearance of highly (>15 mutations) mutated circulating KLH-specific plasmablasts 2 wk after primary KLH immunization, with simultaneous KLH-specific plasmablasts carrying non- and low-mutated IgH sequences. The data suggest that the highly mutated cells might originate from cross-reactive memory B cells (mBCs) rather than from the naive B cell repertoire, consistent with previous reported mutation rates and the presence of KLH-reactive mBCs in naive vaccinees prior to immunization. Whereas upon secondary immunization, serum Ab response kinetics and plasmablast mutation loads suggested the exclusive reactivation of KLH-specific mBCs, we, however, detected only little clonal overlap between the peripheral KLH-specific secondary plasmablast IgH repertoire and the primary plasmablast and mBC repertoire, respectively. Our data provide novel mechanistic insights into human humoral immune responses and suggest that primary KLH immunization recruits both naive B cells and cross-reactive mBCs, whereas secondary challenge exclusively recruits from a memory repertoire, with little clonal overlap with the primary response.
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http://dx.doi.org/10.4049/jimmunol.1701728DOI Listing
June 2018

2-Methyl-2,4-pentanediol (MPD) boosts as detergent-substitute the performance of ß-barrel hybrid catalyst for phenylacetylene polymerization.

Beilstein J Org Chem 2017 31;13:1498-1506. Epub 2017 Jul 31.

Institute of Biotechnology, RWTH Aachen University, Worringer Weg 3, 52074 Aachen, Germany.

Covering hydrophobic regions with stabilization agents to solubilize purified transmembrane proteins is crucial for their application in aqueous media. The small molecule 2-methyl-2,4-pentanediol (MPD) was used to stabilize the transmembrane protein (FhuA) utilized as host for the construction of a rhodium-based biohybrid catalyst. Unlike commonly used detergents such as sodium dodecyl sulfate or polyethylene polyethyleneglycol, MPD does not form micelles in solution. Molecular dynamics simulations revealed the effect and position of stabilizing MPD molecules. The advantage of the amphiphilic MPD over micelle-forming detergents is demonstrated in the polymerization of phenylacetylene, showing a ten-fold increase in yield and increased molecular weights.
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http://dx.doi.org/10.3762/bjoc.13.148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5550818PMC
July 2017

Age dependent differences in the kinetics of γδ T cells after influenza vaccination.

PLoS One 2017 11;12(7):e0181161. Epub 2017 Jul 11.

Berlin-Brandenburg Center for Regenerative Therapies, Charité -Universitätsmedizin Berlin, Augustenburger Platz 1, Berlin, Germany.

Immunosenescence is a hallmark of the aging immune system and is considered the main cause of a reduced vaccine efficacy in the elderly. Although γδ T cells can become activated by recombinant influenza hemagglutinin, their age-related immunocompetence during a virus-induced immune response has so far not been investigated. In this study we evaluate the kinetics of γδ T cells after vaccination with the trivalent 2011/2012 northern hemisphere seasonal influenza vaccine. We applied multi-parametric flow cytometry to a cohort of 21 young (19-30 years) and 23 elderly (53-67 years) healthy individuals. Activated and proliferating γδ T cells, as identified by CD38 and Ki67 expression, were quantified on the days 0, 3, 7, 10, 14, 17, and 21. We observed a significantly lower number of activated and proliferating γδ T cells at baseline and following vaccination in elderly as compared to young individuals. The kinetics changes of activated γδ T cells were much stronger in the young, while corresponding changes in the elderly occurred slower. In addition, we observed an association between day 21 HAI titers of influenza A and the frequencies of Ki67+ γδ T cells at day 7 in the young. In conclusion, aging induces alterations of the γδ T cell response that might have negative implications for vaccination efficacy.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0181161PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5507438PMC
September 2017

HDAC1 links early life stress to schizophrenia-like phenotypes.

Proc Natl Acad Sci U S A 2017 06 22;114(23):E4686-E4694. Epub 2017 May 22.

Department of Psychiatry and Psychotherapy, Medical Center of the University of Munich, 80336 Munich, Germany.

Schizophrenia is a devastating disease that arises on the background of genetic predisposition and environmental risk factors, such as early life stress (ELS). In this study, we show that ELS-induced schizophrenia-like phenotypes in mice correlate with a widespread increase of histone-deacetylase 1 () expression that is linked to altered DNA methylation. overexpression in neurons of the medial prefrontal cortex, but not in the dorsal or ventral hippocampus, mimics schizophrenia-like phenotypes induced by ELS. Systemic administration of an HDAC inhibitor rescues the detrimental effects of ELS when applied after the manifestation of disease phenotypes. In addition to the hippocampus and prefrontal cortex, mice subjected to ELS exhibit increased expression in blood. Moreover, levels are increased in blood samples from patients with schizophrenia who had encountered ELS, compared with patients without ELS experience. Our data suggest that HDAC1 inhibition should be considered as a therapeutic approach to treat schizophrenia.
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http://dx.doi.org/10.1073/pnas.1613842114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5468618PMC
June 2017

HDAC1 links early life stress to schizophrenia-like phenotypes.

Proc Natl Acad Sci U S A 2017 06 22;114(23):E4686-E4694. Epub 2017 May 22.

Department of Psychiatry and Psychotherapy, Medical Center of the University of Munich, 80336 Munich, Germany.

Schizophrenia is a devastating disease that arises on the background of genetic predisposition and environmental risk factors, such as early life stress (ELS). In this study, we show that ELS-induced schizophrenia-like phenotypes in mice correlate with a widespread increase of histone-deacetylase 1 () expression that is linked to altered DNA methylation. overexpression in neurons of the medial prefrontal cortex, but not in the dorsal or ventral hippocampus, mimics schizophrenia-like phenotypes induced by ELS. Systemic administration of an HDAC inhibitor rescues the detrimental effects of ELS when applied after the manifestation of disease phenotypes. In addition to the hippocampus and prefrontal cortex, mice subjected to ELS exhibit increased expression in blood. Moreover, levels are increased in blood samples from patients with schizophrenia who had encountered ELS, compared with patients without ELS experience. Our data suggest that HDAC1 inhibition should be considered as a therapeutic approach to treat schizophrenia.
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http://dx.doi.org/10.1073/pnas.1613842114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5468618PMC
June 2017

CD40L expression by CD4 but not CD8 T cells regulates antiviral immune responses in acute LCMV infection in mice.

Eur J Immunol 2016 11 20;46(11):2566-2573. Epub 2016 Sep 20.

Regenerative Immunology and Aging, Berlin-Brandenburger Center for Regenerative Therapies (BCRT), Charité Universitätsmedizin Berlin, Berlin, Germany.

CD40-CD40 ligand (CD40L) signaling plays multiple indispensable roles in cellular and humoral immunity. Impaired memory T-cell responses in the absence of CD40L have been well documented, but the requirement of this interaction for efficient priming of CD8 T cells especially under inflammatory conditions has been under debate. In contrast to previous publications, we report here that virus-specific CD8 T-cell responses as well as viral clearance are affected not only in the memory but also in the effector phase in CD40L mice infected with lymphocytic choriomeningitis virus (LCMV) Armstrong strain. Interestingly, a considerable part of the LCMV-specific effector and memory T cells consists of CD40L CD8 T cells. However, deficiency of CD40L in CD8 T cells did influence neither the quantity nor the quality of primary T-cell responses in LCMV infection. Virus-specific CD8 T cells in conditional knockout mice, with a selective deletion of the CD40L in CD8 T cells, were fully functional regarding cytokine production and efficient pathogen clearance. Thus, our results unambiguously demonstrate that while CD40L is critical to generate effective primary CD8 T-cell responses also under inflammatory conditions, CD40L expression by CD8 T cells themselves is dispensable in acute LCMV infection.
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http://dx.doi.org/10.1002/eji.201646420DOI Listing
November 2016

Wild immunology assessed by multidimensional mass cytometry.

Cytometry A 2017 01 12;91(1):85-95. Epub 2016 Jul 12.

Regenerative Immunology and Aging, BCRT, Charité Universitätsmedizin Berlin, Berlin, Germany.

A great part of our knowledge on mammalian immunology has been established in laboratory settings. The use of inbred mouse strains enabled controlled studies of immune cell and molecule functions in defined settings. These studies were usually performed in specific-pathogen free (SPF) environments providing standardized conditions. In contrast, mammalians including humans living in their natural habitat are continuously facing pathogen encounters throughout their life. The influences of environmental conditions on the signatures of the immune system and on experimental outcomes are yet not well defined. Thus, the transferability of results obtained in current experimental systems to the physiological human situation has always been a matter of debate. Studies elucidating the diversity of "wild immunology" imprintings in detail and comparing it with those of "clean" lab mice are sparse. Here, we applied multidimensional mass cytometry to dissect phenotypic and functional differences between distinct groups of laboratory and pet shop mice as a source for "wild mice". For this purpose, we developed a 31-antibody panel for murine leukocyte subsets identification and a 35-antibody panel assessing various cytokines. Established murine leukocyte populations were easily identified and diverse immune signatures indicative of numerous pathogen encounters were classified particularly in pet shop mice and to a lesser extent in quarantine and non-SPF mice as compared to SPF mice. In addition, unsupervised analysis identified distinct clusters that associated strongly with the degree of pathogenic priming, including increased frequencies of activated NK cells and antigen-experienced B- and T-cell subsets. Our study unravels the complexity of immune signatures altered under physiological pathogen challenges and highlights the importance of carefully adapting laboratory settings for immunological studies in mice, including drug and therapy testing. © 2016 International Society for Advancement of Cytometry.
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http://dx.doi.org/10.1002/cyto.a.22906DOI Listing
January 2017

Highly Predictive Model for a Protective Immune Response to the A(H1N1)pdm2009 Influenza Strain after Seasonal Vaccination.

PLoS One 2016 8;11(3):e0150812. Epub 2016 Mar 8.

Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité University Hospital, Berlin, Germany.

Understanding the immune response after vaccination against new influenza strains is highly important in case of an imminent influenza pandemic and for optimization of seasonal vaccination strategies in high risk population groups, especially the elderly. Models predicting the best sero-conversion response among the three strains in the seasonal vaccine were recently suggested. However, these models use a large number of variables and/or information post- vaccination. Here in an exploratory pilot study, we analyzed the baseline immune status in young (<31 years, N = 17) versus elderly (≥50 years, N = 20) donors sero-negative to the newly emerged A(H1N1)pdm09 influenza virus strain and correlated it with the serological response to that specific strain after seasonal influenza vaccination. Extensive multi-chromatic FACS analysis (36 lymphocyte sub-populations measured) was used to quantitatively assess the cellular immune status before vaccination. We identified CD4+ T cells, and amongst them particularly naive CD4+ T cells, as the best correlates for a successful A(H1N1)pdm09 immune response. Moreover, the number of influenza strains a donor was sero-negative to at baseline (NSSN) in addition to age, as expected, were important predictive factors. Age, NSSN and CD4+ T cell count at baseline together predicted sero-protection (HAI≥40) to A(H1N1)pdm09 with a high accuracy of 89% (p-value = 0.00002). An additional validation study (N = 43 vaccinees sero-negative to A(H1N1)pdm09) has confirmed the predictive value of age, NSSN and baseline CD4+ counts (accuracy = 85%, p-value = 0.0000004). Furthermore, the inclusion of donors at ages 31-50 had shown that the age predictive function is not linear with age but rather a sigmoid with a midpoint at about 50 years. Using these results we suggest a clinically relevant prediction model that gives the probability for non-protection to A(H1N1)pdm09 influenza strain after seasonal multi-valent vaccination as a continuous function of age, NSSN and baseline CD4 count.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0150812PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4782986PMC
August 2016

Siglec-1-positive plasmacytoid dendritic cells (pDCs) in human peripheral blood: A semi-mature and myeloid-like subset imbalanced during protective and autoimmune responses.

Clin Immunol 2016 Feb 7;163:42-51. Epub 2015 Dec 7.

Department of Rheumatology and Clinical Immunology, Charité University Hospital, Charitéplatz 1, 10117, Berlin, Germany; German Rheumatism Research Centre (DRFZ) - a Leibniz Institute, Charitéplatz 1, 10117, Berlin, Germany. Electronic address:

Plasmacytoid dendritic cells (pDCs) play a central role in the pathogenesis of systemic lupus erythematosus (SLE) as IFN-α producers and promoters of T-cell activation or tolerance. Here, we demonstrated by flow-cytometry and confocal microscopy that Siglec-1, a molecule involved in the regulation of adaptive immunoresponses, is expressed in a subset of semi-mature, myeloid-like pDCs in human blood. These pDCs express lower BDCA-2 and CD123 and higher HLA-DR and CD11c than Siglec-1-negative pDCs and do not produce IFN-α via TLR7/TLR9 engagement. In vitro, Siglec-1 expression was induced in Siglec-1-negative pDCs by influenza virus. Proportions of Siglec-1-positive/Siglec-1-negative pDCs were higher in SLE than in healthy controls and correlated with disease activity. Healthy donors immunized with yellow fever vaccine YFV-17D displayed different kinetics of the two pDC subsets during protective immune response. PDCs can be subdivided into two subsets according to Siglec-1 expression. These subsets may play specific roles in (auto)immune responses.
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http://dx.doi.org/10.1016/j.clim.2015.12.001DOI Listing
February 2016