Stefan H E Kaufmann

Max Planck Institute for Infection Biology, Berlín, Berlin, Germany

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Publications (700)4157.34 Total impact

  • Anca Dorhoi, Stefan H E Kaufmann
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    ABSTRACT: Tuberculosis (TB), a chronic bacterial infectious disease caused by Mycobacterium tuberculosis (Mtb), typically affects the lung and causes profound morbidity and mortality rates worldwide. Recent advances in cellular immunology emphasize the complexity of myeloid cell subsets controlling TB inflammation. The specialization of myeloid cell subsets for particular immune processes has tailored their roles in protection and pathology. Among myeloid cells, dendritic cells (DCs) are essential for the induction of adaptive immunity, macrophages predominantly harbor Mtb within TB granulomas and polymorphonuclear neutrophils (PMNs) orchestrate lung damage. However, within each myeloid cell population, diverse phenotypes with unique functions are currently recognized, differentially influencing TB pneumonia and granuloma functionality. More recently, myeloid-derived suppressor cells (MDSCs) have been identified at the site of Mtb infection. Along with PMNs, MDSCs accumulate within the inflamed lung, interact with granuloma-residing cells and contribute to exuberant inflammation. In this review, we discuss the contribution of different myeloid cell subsets to inflammation in TB by highlighting their interactions with Mtb and their role in lung pathology. Uncovering the manifold nature of myeloid cells in TB pathogenesis will inform the development of future immune therapies aimed at tipping the inflammation balance to the benefit of the host. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    European Journal of Immunology 07/2015; DOI:10.1002/eji.201545493 · 4.52 Impact Factor
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    ABSTRACT: Mycobacterium tuberculosis remains a health concern due to its ability to enter a non-replicative dormant state linked to drug resistance. Understanding transitions into and out of dormancy will inform therapeutic strategies. We implemented a universally applicable, label-free approach to estimate absolute cellular protein concentrations on a proteome-wide scale based on SWATH mass spectrometry. We applied this approach to examine proteomic reorganization of M. tuberculosis during exponential growth, hypoxia-induced dormancy, and resuscitation. The resulting data set covering >2,000 proteins reveals how protein biomass is distributed among cellular functions during these states. The stress-induced DosR regulon contributes 20% to cellular protein content during dormancy, whereas ribosomal proteins remain largely unchanged at 5%-7%. Absolute protein concentrations furthermore allow protein alterations to be translated into changes in maximal enzymatic reaction velocities, enhancing understanding of metabolic adaptations. Thus, global absolute protein measurements provide a quantitative description of microbial states, which can support the development of therapeutic interventions. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cell host & microbe 06/2015; DOI:10.1016/j.chom.2015.06.001 · 12.19 Impact Factor
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    ABSTRACT: The epidemiology of Mycobacterium tuberculosis (Mtb) and M. africanum (Maf) suggests differences in their virulence, but the host immune profile to better understand the pathogenesis of tuberculosis (TB) have not been studied. We compared the transcriptomic and metabolic profiles between Mtb- and Maf-infected TB cases to identify host biomarkers associated with lineages-specific pathogenesis and response to anti-TB chemotherapy. Venous blood samples from Mtb- and Maf-infected patients obtained before and after anti-TB treatment were analyzed for cell composition, gene expression and metabolic profiles. Prior to treatment, similar transcriptomic profiles were seen in Maf- and Mtb-infected patients. In contrast, post treatment, over 1600 genes related to immune responses and metabolic diseases were differentially expressed between the groups. Notably, the upstream regulator hepatocyte nuclear factor 4-alpha (HNF4α), which regulated 15% of these genes, was markedly enriched. Serum metabolic profiles were similar in both group pre-treatment, but the decline in pro-inflammatory metabolites post treatment were most pronounced in Mtb-infected patients. Together, the differences in both peripheral blood transcriptomic and serum metabolic profiles between Maf- and Mtb-infected patients observed over the treatment period, might be indicative of intrinsic host factors related to susceptibility to TB and/or differential efficacy of the standard anti-TB treatment on the two lineages.
    Genes and Immunity 06/2015; DOI:10.1038/gene.2015.21 · 3.79 Impact Factor
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    January Weiner, Stefan H E Kaufmann, Jeroen Maertzdorf
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    ABSTRACT: Rational vaccine development can benefit from biomarker studies, which help to predict, optimize and evaluate the immunogenicity of vaccines and ultimately provide surrogate endpoints for vaccine trials. Systems biology approaches facilitate acquisition of both simple biomarkers and complex biosignatures. Yet, evaluation of high-throughput (HT) data requires a plethora of tools for data integration and analysis. In this review, we present an overview of methods towards evaluation and integration of large amounts of data collected in vaccine trials from similar and divergent molecular HT techniques, such as transcriptomic, proteomic and metabolic profiling. We will describe a selection of relevant statistical and bioinformatic approaches that are frequently associated with "systems biology." We will present data dimension reduction techniques, functional analysis approaches and methods of integrating heterogeneous HT data. Finally, we will provide a few examples of applications of these techniques in vaccine research and development. Copyright © 2015. Published by Elsevier Ltd.
    Vaccine 05/2015; DOI:10.1016/j.vaccine.2015.04.096 · 3.49 Impact Factor
  • Vaccine 05/2015; DOI:10.1016/j.vaccine.2015.04.078 · 3.49 Impact Factor
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    ABSTRACT: Background. A major barrier to effective tuberculosis (TB) control is our limited understanding of risk factors for TB disease progression. This study examined the role of apoptosis in immunity to TB. Methods. Cell subsets from TB cases and tuberculin skin test positive (TST+) and TST negative (TST−) household contacts (HHC) were analysed for expression of Annexin V and Propidium Iodide by flow cytometry. RNA microarrays were used to determine differences in apoptotic gene expression levels and Multiplex Ligation-dependent Probe Amplification (MLPA) was used to analyse gene expression in HHC who progressed to active TB. Results. T cells from TST+HHC exhibited higher levels of apoptosis than TB cases however TB cases had a higher proportion of late apoptotic cells within the CD3+PD-1+ subset. TB cases had reduced levels of anti-apoptotic genes compared to HHC with a significant reduction in BCL2 associated with disease progression at least 1 year prior to progression. Conclusions. Whilst T cells are clearly able to mount a robust immune response to Mtb there are increased levels of apoptosis seen in effector T cells from TB patients. Dysregulation of several apoptotic genes suggest that apoptosis is a major functional pathway that could be targeted for future host-directed therapeutics.
    The Journal of Infectious Diseases 04/2015; DOI:10.1093/infdis/jiv238 · 5.78 Impact Factor
  • Stefan H E Kaufmann
    Vaccine 04/2015; 33(26). DOI:10.1016/j.vaccine.2015.04.001 · 3.49 Impact Factor
  • J Maertzdorf, S H E Kaufmann, J Weiner
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    ABSTRACT: The immune system has evolved complex and specialized mechanisms to mount specific defense responses against the various types of pathogens it encounters. For the development of new vaccines, it is crucial to gain a better understanding of what these mechanisms are and how they work. The field of vaccinology has adopted high-throughput profiling techniques to gain more detailed insights into the various immune responses elicited by different vaccines and natural infections. From all detailed transcriptional profiles generated today, a general picture of immunological responses emerges. First, almost every type of vaccine induces an early interferon-dominated signature. Second, different vaccine formulations induce distinct transcriptional signatures, representing the highly specialized defense mechanisms that must cope with the different pathogens and insults they cause. Transcriptional profiling has shifted its attention toward early molecular signatures, with a growing awareness that early innate responses are likely critical instructors for the development of adaptive immunity at later time points. Copyright © 2015. Published by Elsevier Ltd.
    Vaccine 04/2015; DOI:10.1016/j.vaccine.2015.03.075 · 3.49 Impact Factor
  • Anca Dorhoi, Yonghong Feng, Stefan H E Kaufmann
    The Journal of Infectious Diseases 03/2015; DOI:10.1093/infdis/jiv156 · 5.78 Impact Factor
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    ABSTRACT: The immune response upon infection with the pathogen Mycobacterium tuberculosis is poorly understood, hampering the discovery of new treatments and the improvements in diagnosis. In the last years, a blood transcriptional signature in tuberculosis has provided knowledge on the immune response occurring during active tuberculosis disease. This signature was absent in the majority of asymptomatic individuals who are latently infected with M. tuberculosis (referred to as latent). Using modular and pathway analyses of the complex data has shown, now in multiple studies, that the signature of active tuberculosis is dominated by overexpression of interferon-inducible genes (consisting of both type I and type II interferon signaling), myeloid genes, and inflammatory genes. There is also downregulation of genes encoding B and T-cell function. The blood signature of tuberculosis correlates with the extent of radiographic disease and is diminished upon effective treatment suggesting the possibility of new improved strategies to support diagnostic assays and methods for drug treatment monitoring. The signature suggested a previously under-appreciated role for type I interferons in development of active tuberculosis disease, and numerous mechanisms have now been uncovered to explain how type I interferon impedes the protective response to M. tuberculosis infection. © 2015 The Medical Research Council. Immunological Reviews published by John Wiley & Sons Ltd.
    Immunological Reviews 03/2015; 264(1). DOI:10.1111/imr.12269 · 12.91 Impact Factor
  • Stefan H E Kaufmann, Thomas G Evans, Willem A Hanekom
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    ABSTRACT: We need a global strategy for the development of better tuberculosis vaccines. Copyright © 2015, American Association for the Advancement of Science.
    Science translational medicine 02/2015; 7(276):276fs8. DOI:10.1126/scitranslmed.aaa4730 · 14.41 Impact Factor
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    ABSTRACT: TRANSVAC was a collaborative infrastructure project aimed at enhancing European translational vaccine research and training. The objective of this four year project (2009-2013), funded under the European Commission's (EC) seventh framework programme (FP7), was to support European collaboration in the vaccine field, principally through the provision of transnational access (TNA) to critical vaccine research and development (R&D) infrastructures, as well as by improving and harmonising the services provided by these infrastructures through joint research activities (JRA). The project successfully provided all available services to advance 29 projects and, through engaging all vaccine stakeholders, successfully laid down the blueprint for the implementation of a permanent research infrastructure for early vaccine R&D in Europe. Copyright © 2015. Published by Elsevier Ltd.
    Vaccine 02/2015; DOI:10.1016/j.vaccine.2015.01.079 · 3.49 Impact Factor
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    ABSTRACT: The probabilistic expression of cytokine genes in differentiated T helper (Th) cell populations remains ill defined. By single-cell analyses and mathematical modeling, we show that one stimulation featured stable cytokine nonproducers as well as stable producers with wide cell-to-cell variability in the magnitude of expression. Focusing on interferon-γ (IFN-γ) expression by Th1 cells, mathematical modeling predicted that this behavior reflected different cell-intrinsic capacities and not mere gene-expression noise. In vivo, Th1 cells sort purified by secreted IFN-γ amounts preserved a quantitative memory for both probability and magnitude of IFN-γ re-expression for at least 1 month. Mechanistically, this memory resulted from quantitatively distinct transcription of individual alleles and was controlled by stable expression differences of the Th1 cell lineage-specifying transcription factor T-bet. Functionally, Th1 cells with graded IFN-γ production competence differentially activated Salmonella-infected macrophages for bacterial killing. Thus, individual Th cells commit to produce distinct amounts of a given cytokine, thereby generating functional intrapopulation heterogeneity. Copyright © 2015 Elsevier Inc. All rights reserved.
    Immunity 12/2014; 42(1). DOI:10.1016/j.immuni.2014.12.018 · 19.75 Impact Factor
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    ABSTRACT: Background. The recombinant BCG ΔureC::hly (rBCG) vaccine candidate induces improved protection against tuberculosis over parental BCG (pBCG) in preclinical studies and has successfully completed a phase 2a clinical trial. However, the mechanisms responsible for the superior vaccine efficacy of rBCG are still incompletely understood. Here, we investigated the underlying biological mechanisms elicited by the rBCG vaccine candidate relevant to its protective efficacy. Methods. THP-1 macrophages were infected with pBCG or rBCG, and inflammasome activation and autophagy were evaluated. In addition, mice were vaccinated with pBCG or rBCG, and gene expression in the draining lymph nodes was analyzed by microarray at day 1 after vaccination. Results. BCG-derived DNA was detected in the cytosol of rBCG-infected macrophages. rBCG infection was associated with enhanced absent in melanoma 2 (AIM2) inflammasome activation, increased activation of caspases and production of interleukin (IL)-1β and IL-18, as well as induction of AIM2-dependent and stimulator of interferon genes (STING)-dependent autophagy. Similarly, mice vaccinated with rBCG showed early increased expression of Il-1β, Il-18, and Tmem173 (transmembrane protein 173; also known as STING). Conclusions. rBCG stimulates AIM2 inflammasome activation and autophagy, suggesting that these cell-autonomous functions should be exploited for improved vaccine design.
    The Journal of Infectious Diseases 12/2014; DOI:10.1093/infdis/jiu675 · 5.78 Impact Factor
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    ABSTRACT: Introduction Accurate, simple and cost-effective diagnostic tests are needed for diagnosis of active tuberculosis (TB). Serodiagnosis is attractive as it can be harnessed for point-of-care tests. Methods We evaluated, in a blinded fashion, the sensitivity and specificity of serologic IgG, IgA and/or IgM responses to Apa, HSP16.3, HSP20, PE35, Tpx and LAM in 42 HIV-negative South African pulmonary TB patients and 67 control individuals. The status of latent Mycobacterium tuberculosis infection (LTBI) among controls was defined through the TST and IFN-γ release assays. We evaluated 47 definite LTBI (IGRA+/LTBI), 8 putative LTBI (IGRA–/TST+) and 12 TB-uninfected (non-LTBI) subjects. Results In contrast to anti-PE35 IgA, anti-PE35 IgG and particularly anti-Apa IgA, performances of anti-LAM IgG and selected anti-protein antibodies were less affected by inclusion of LTBI participants into the analysis. Anti-LAM IgG showed with a sensitivity/specificity of 71.4%/86.6% (p<0.001) the best discrimination between TB and non-TB subjects. Selected five-antibody-combinations (including anti-LAM IgG, anti-LAM IgA and anti-Tpx IgG) further improved this performance to an accuracy exceeding 86%. Conclusions Antibody responses to some M. tuberculosis antigens often also reflect latent infection explaining the poor performance of antibody-based tests for active TB in TB endemic settings. Our results suggest that rather a combination of serological responses against selected protein and non-protein antigens and different Ig classes should be investigated for TB serodiagnostics.
    Journal of Infection 12/2014; DOI:10.1016/j.jinf.2014.05.014 · 4.02 Impact Factor
  • Anca Dorhoi, Stefan H.E. Kaufmann
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    ABSTRACT: Pro- and anti-inflammatory mechanisms contribute equally to establishment and progression of tuberculosis.•Inflammatory mediators exhibit distinct roles at various stages of tuberculosis. Therefore in-depth temporal characterization of inflammation can provide guidelines for future interventions.•Inflammatory events are conditioned by distinct inflammatory microenvironments and depend on lung anatomy and physiological imprints.•Granuloma caseation, tissue liquefaction and lung cavitation form the basis for disease transmission.
    Seminars in Immunology 10/2014; 26(6). DOI:10.1016/j.smim.2014.10.002 · 6.12 Impact Factor
  • Jeroen Maertzdorf, Stefan H E Kaufmann, January Weiner
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    ABSTRACT: Accurate and rapid diagnosis of active tuberculosis (TB) disease is still hampered by inadequate tools. Although current assays relying on single-marker readouts mostly display inadequate sensitivity and/or specificity, host-related multimarker signatures are especially poorly developed. As a consequence, research programs have been initiated to search for combinations of markers-so-called biosignatures with superior performance. Many such investigations harness high-throughput platforms to analyze the host response during infection and disease. A major challenge for these activities is the analysis of vast amounts of data produced. Specialized bioinformatic tools are being applied to identify the most robust biosignatures for classification of exposed and diseased individuals and prognosis of risk of disease in endemic areas. Validation of the most promising biosignatures in ongoing multicohort studies will bring us a step closer to the identification of an accurate unified signature.
    Cold Spring Harbor Perspectives in Medicine 10/2014; 5(1). DOI:10.1101/cshperspect.a018531 · 7.56 Impact Factor
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    ABSTRACT: Tuberculosis (TB) diagnosis in low-income countries is mainly done by microscopy. Hence, little is known about the diversity of Mycobacterium spp. in TB infections. Different genotypes or lineages of Mycobacterium tuberculosis vary in virulence and induce different inflammatory and immune responses. Trained Cricetomys rats show a potential for rapid diagnosis of TB. They detect over 28 % of smear-negative, culture-positive TB. However, it is unknown whether these rats can equally detect sputa from patients infected with different genotypes of M. tuberculosis. A 4-month prospective study on diversity of Mycobacterium spp. was conducted in Dar es Salaam, Tanzania. 252 sputa from 161 subjects were cultured on Lowenstein-Jensen medium and thereafter tested by rats. Mycobacterial isolates were subjected to molecular identification and multispacer sequence typing (MST) to determine species and genotypes. A total of 34 Mycobacterium spp. isolates consisting of 32 M. tuberculosis, 1 M. avium subsp. hominissuis and 1 M. intracellulare were obtained. MST analyses of 26 M. tuberculosis isolates yielded 10 distinct MST genotypes, including 3 new genotypes with two clusters of related patterns not grouped by geographic areas. Genotype MST-67, shared by one-third of M. tuberculosis isolates, was associated with the Mwananyamala clinic. This study shows that diverse M. tuberculosis genotypes (n = 10) occur in Dar es Salaam and trained rats detect 80 % of the genotypes. Sputa with two M. tuberculosis genotypes (20 %), M. avium hominissuis and M. intracellulare were not detected. Therefore, rats detect sputa with different M. tuberculosis genotypes and can be used to detect TB in resource-poor countries.
    Current Microbiology 10/2014; 70(2). DOI:10.1007/s00284-014-0705-6 · 1.36 Impact Factor
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    ABSTRACT: Lung granulomas develop upon Mycobacterium tuberculosis (Mtb) infection as a hallmark of human tuberculosis (TB). They are structured aggregates consisting mainly of Mtb-infected and -uninfected macrophages and Mtb-specific T cells. The production of NO by granuloma macrophages expressing nitric oxide synthase-2 (NOS2) via l-arginine and oxygen is a key protective mechanism against mycobacteria. Despite this protection, TB granulomas are often hypoxic, and bacterial killing via NOS2 in these conditions is likely suboptimal. Arginase-1 (Arg1) also metabolizes l-arginine but does not require oxygen as a substrate and has been shown to regulate NOS2 via substrate competition. However, in other infectious diseases in which granulomas occur, such as leishmaniasis and schistosomiasis, Arg1 plays additional roles such as T-cell regulation and tissue repair that are independent of NOS2 suppression. To address whether Arg1 could perform similar functions in hypoxic regions of TB granulomas, we used a TB murine granuloma model in which NOS2 is absent. Abrogation of Arg1 expression in macrophages in this setting resulted in exacerbated lung granuloma pathology and bacterial burden. Arg1 expression in hypoxic granuloma regions correlated with decreased T-cell proliferation, suggesting that Arg1 regulation of T-cell immunity is involved in disease control. Our data argue that Arg1 plays a central role in the control of TB when NOS2 is rendered ineffective by hypoxia.
    Proceedings of the National Academy of Sciences 09/2014; 111(38). DOI:10.1073/pnas.1408839111 · 9.81 Impact Factor
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    ABSTRACT: The aryl hydrocarbon receptor (AhR) is a highly conserved ligand-dependent transcription factor that senses environmental toxins and endogenous ligands, thereby inducing detoxifying enzymes and modulating immune cell differentiation and responses. We hypothesized that AhR evolved to sense not only environmental pollutants but also microbial insults. We characterized bacterial pigmented virulence factors, namely the phenazines from Pseudomonas aeruginosa and the naphthoquinone phthiocol from Mycobacterium tuberculosis, as ligands of AhR. Upon ligand binding, AhR activation leads to virulence factor degradation and regulated cytokine and chemokine production. The relevance of AhR to host defence is underlined by heightened susceptibility of AhR-deficient mice to both P. aeruginosa and M. tuberculosis. Thus, we demonstrate that AhR senses distinct bacterial virulence factors and controls antibacterial responses, supporting a previously unidentified role for AhR as an intracellular pattern recognition receptor, and identify bacterial pigments as a new class of pathogen-associated molecular patterns.
    Nature 08/2014; 512(7515). DOI:10.1038/nature13684 · 42.35 Impact Factor

Publication Stats

28k Citations
4,157.34 Total Impact Points

Institutions

  • 1996–2015
    • Max Planck Institute for Infection Biology
      • Department of Immunology
      Berlín, Berlin, Germany
  • 2013
    • University of Melbourne
      Melbourne, Victoria, Australia
  • 2012
    • French National Centre for Scientific Research
      • Institute of Pharmacology and Structural Biology
      Lutetia Parisorum, Île-de-France, France
  • 2011
    • Technische Universität München
      München, Bavaria, Germany
    • Charité Universitätsmedizin Berlin
      Berlín, Berlin, Germany
  • 2009
    • Makerere University
      • School of Medicine
      Kampala, Central Region, Uganda
  • 1990–2008
    • Universität Heidelberg
      • Institute of Immunology and Serology
      Heidelburg, Baden-Württemberg, Germany
  • 2007
    • Vanderbilt University
      Nashville, Michigan, United States
    • London School of Hygiene and Tropical Medicine
      • Department of Immunology and Infection
      London, ENG, United Kingdom
    • University of Greifswald
      • Institute for Microbiology
      Greifswald, Mecklenburg-Vorpommern, Germany
    • University of Lille Nord de France
      Lille, Nord-Pas-de-Calais, France
  • 2006
    • European Federation of Immunological Societies
      Berlín, Berlin, Germany
    • National Institute of Infectious Diseases, Tokyo
      Edo, Tōkyō, Japan
    • Howard Hughes Medical Institute
      Ashburn, Virginia, United States
  • 2005
    • Cornell University
      Итак, New York, United States
  • 1999–2002
    • Humboldt-Universität zu Berlin
      Berlín, Berlin, Germany
    • Fundação de Dermatologia Tropical e Venereologia Alfredo da Matta
      Cachoeirinha, Pernambuco, Brazil
  • 1988–2002
    • Universität Ulm
      • • Institute of Microbiology and Biotechnology
      • • Institute of Medical Microbiology and Hygiene
      Ulm, Baden-Wuerttemberg, Germany
  • 1998–2001
    • University of Wuerzburg
      • Department of Microbiology
      Würzburg, Bavaria, Germany
  • 1995
    • Tokyo Metropolitan Institute of Public Health
      • Department of Veterinary Public Health
      Edo, Tōkyō, Japan
  • 1989
    • University of Freiburg
      Freiburg, Baden-Württemberg, Germany
  • 1984–1988
    • Max Planck Institute of Immunobiology and Epigenetics
      Freiburg, Baden-Württemberg, Germany
  • 1981–1983
    • Freie Universität Berlin
      Berlín, Berlin, Germany