BRFAA - Biomedical Research Foundation Academy Of Athens
Biomedical Research Foundation Academy Of AthensAcademy Of Athens

LUPUSCARE

Project Summary

Objectives and Work Packages

Team Members

Research

  1. Publications
  2. Meetings
  3. Flyer
  4. Videos

Educational Material for SLE Patients

Awards


Project Summary

Systemic lupus erythematosus (SLE) is a heterogeneous disease affecting predominantly women of the childbearing age. In lupus, an interplay of environmental, genetic and epigenetic factors lead to perturbation of complex biological networks culminating into diverse clinical phenotypes of varying severity. High throughput methods have allowed an “initial glimpse” into pathogenesis and have laid the foundations for a molecular-based taxonomy for personalized therapy. Based on our experience with the molecular characterization of SLE, a recently completed RNA-sequencing analysis of 150 patients, and our track- record of “paradigm shift” trials in SLE, we integrate data from multi-tissue analyses with novel technologies to improve its diagnosis, monitoring and therapy, and ask fundamental pathogenetic questions in systemic autoimmunity. We design gene expression panels and “expression profile”/“clinical trait” correlation matrices for diagnostics, personalized immunotherapy and improved clinical trial design. In a systematic multi-tissue approach, we also examine the role of somatic mutations in enhancing immune hyperactivity and the risk for lymphoma. The staggering (7–9:1) female predominance I lupus is explored through elaborate genomic, epigenomic and microbiota analyses of families. Finally, we are pursuing the innovative hypothesis that the fundamental abnormalities of SLE lie within the bone marrow hematopoietic stem cells (HSCs) - from which all cells that participate in the pathogenesis of SLE originate, and establish it as a unifying pathogenetic mechanism. By a combination of novel experimental analyses with single cell genomics, multi –Omics, humanized animal models, genome editing and an “organ on-a-chip” device, we seek to validate HSCs as a therapeutic target. This work provides unique insights on how the immune system recognizes self-constituents preserving its homeostasis, and how DNA damage, gender and HSCs impact on disease biology.

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Objectives and Work Packages

  1. Develop novel tests for the early diagnosis, monitoring and classification of SLE patients into more homogenous groups for personalized therapy (WP1)
  2. Explore a novel pathogenetic mechanisms in autoimmunity: the role of DNA damage and somatic mutations in enhancing immune hyperactivity and  the risk of lymphoma and infections in SLE (WP2)
  3. Elucidate the female predominance of human SLE in family trios (WP3) 
  4. Explore Hematopoietic Stem Cells (HSCs) as a common denominator/unifying disease mechanism and as novel therapeutic target in SLE, (WP4).

 

 

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Team Members

Dimitrios Boumpas MD, FACP, FACR
University Faculty, Affiliated Investigator

Professor Dimitrios Boumpas, MD, FACP, Member Academia Europaea  is a professor of Medicine at the Medical School, University of Athens, Director of the 4th Department of Internal Medicine, Attikon University Hospital and an affiliated investigator in BRFAA. His primary clinical and research interests are in the areas of human autoimmunity with emphasis on systemic lupus erythematosus (SLE). His work on the treatment of lupus nephritis has shaped immunosuppressive therapy for autoimmune rheumatic diseases internationally. Dr Boumpas work on the pathogenesis of SLE has elucidated the role of peripheral tolerance and innate immunity, and the contribution of polymorphisms of genes associated with disease susceptibility through functional genetics and construction of gene networks for the disease by the use of high-throughput technology with validation in animal models and humans with SLE. He has published over 267 peer-reviewed scientific papers and books chapters, and has edited a monograph on SLE with over 12,300 citations (h-index = 61). His research was funded by both National and European Union research funds including an ERC advanced Grant (LupusCare). Dr. Boumpas is Chair of European Task force on SLE that develops guidelines for the management and coordinates clinical trials and research on SLE. He is Associate Editor of Annals of Rheumatic Diseases.He is past Chair of the European Research Council Panel for Advanced Grants on Diagnostics Tools, Therapies and Public Health (LS-7) ,  Vice-chair of  the ERC Synergy Grants and has served on the EU ESRFI Committee for Translational Research Infrastructures.

 

Despina Sanoudou, PhD FACMG
Associate Professor

Dr Despina Sanoudou is an Associate Professor at the 4th Department of Internal Medicine, “Attikon Hospital” - Medical School, National and Kapodistrian University of Athens. She studied Molecular Biology, obtained her PhD at the University of Cambridge, worked as a Post-doctoral Fellow at the Children’s Hospital of Boston, and got certified in Clinical Molecular Diagnostics (American Board of Medical Genetics and Genomics). She previously served as an Instructor at the Harvard Medical School, as a Principal Investigator at the Biomedical Research Foundation of the Academy of Athens, and an Assistant Professor at the Medical School of the University of Athens. She has also been an Honorary Senior Research Fellow at the Imperial College of London, a Visiting Scholar at the Boston University Medical School, and an Advisor to the Sir Magdi Yacoub Research Foundation. Her research team (has employed >30 young scientists to date) focuses on the discovery of novel diagnostic and prognostic markers, the identification of novel therapeutic targets, and the evaluation of chemical compounds against cardiovascular and neurological diseases. Her expertise lie in the areas of Human Genetics, Genomics, Pharmacogenomics, Drug Discovery, Biological Drugs, and Personalized Medicine. The results of this work have been published in over 82 scientific articles and book chapters (H-IndexGoogle = 34 and 3,826 citations), 200 oral and 210 written presentations in scientific meetings worldwide. This work has been funded by competitive research grants from the European Union, the Leducq Foundation, the Greek Secretariat for Research and Technology, the Hellenic Cardiological Society, Fondation Sante, the John S. Latsis Public Benefit Foundation and more.

Dr Sanoudou serves as an evaluator of research grant applications at the European Commission and other international funding organizations. She is also an Associate Editor of the journal Metabolism, Guest Editor at the Journal of Precision Medicine and Current Pharmaceutical Design, an Editorial Board member of 7 publishers, and a reviewer in 38 scientific journals. She has organized multiple international and national conferences and training programs and she has founded a Science High School Outreach Program in Greece, which has hosted 4,000 students to date. Furthermore, she teaches at 3rd, 4th and 6th year Medical students, as well as at 9 MSc programs in biosciences and international courses.
Dr Sanoudou has received a series of awards including the L’Oreal-UNESCO award for Young Women in Science, an American Society of Human Genetics education award, a Panhellenic Association of Bioscientists award, multiple Hellenic Cardiological Society and Greek Society of Pharmacology scientific awards and others.

 

Panayotis Verginis, PhD
Investigator - Assistant Professor Level

Dr Panos Verginis received his Ph.D. in Immunology from Memorial University of Newfoundland (St. John’s, Canada) and he then moved to USA for post-doctoral training in Dr. Harald von Boehmer laboratory at the Dana-Farber Cancer Institute, Harvard Medical School (Boston, Massachussetts, U.S.A.). He then repatriated in Greece in 2008 as a research associate at the laboratory of Autoimmunity and Inflammation (Institute of Molecular Biology and Biotechnology, Heraklion, Crete, Greece) where he led the Immunoregulation group. In 2012, he joined the Biomedical Research Foundation of the Academy of Athens.
His primary research interests are in the area of immune regulation with emphasis on the maintenance and re-establishment of immunological tolerance. While in USA, he pioneered the establishment of antigen-specific regulatory T cells whereas in Crete, he delineated novel regulatory cellular subsets (i.e myeloid-derived suppressor cells – MDSCs) in the regulation of autoimmune diseases.
The laboratory uses a variety of animal models of autoimmunity, transplantation and cancer and employs a wide-range of state-of-the-art immunological techniques. Through collaborations with groups with well-established patient cohorts, he explores the relevance of the findings in the context of immune mediated human diseases.

 

George K. Bertsias, MD, PhD
Assistant Professor in Rheumatology-Clinical Immunology, University of Crete, Medical School
Staff physician, Department of Rheumatology, Clinical Immunology and Allergy, University Hospital of Iraklio
Principal Investigator, Laboratory of Rheumatology, Autoimmunity and Inflammation, UoC, Medical School

George K. Bertsias is an Assistant Professor in rheumatology and clinical immunology and a principal investigator at the Laboratory of Autoimmunity and Inflammation, Medical School, University of Crete, Heraklion, Greece, and the Institute of Molecular Biology and Biotechnology (IMBB), Foundation for Research and Technology–Hellas (FORTH), Heraklion, Greece. He received his MD from the University of Crete in 2002 and later received a MSc and PhD in Immunology from the same institution. Dr Bertsias then trained in Internal Medicine and Clinical Immunology-Rheumatology and became board certified in 2011. He received postdoctoral training at the National Institute of Arthritis and Musculoskeletal and Skin Diseases, and National Institute of Human Genome Research Institute, National Institutes of Health in Bethesda, United states. Dr Bertsias is an active member of EULAR, the European League Against Rheumatism, study group and Task Force on SLE. His main scientific interests are in systemic autoimmune diseases, including aspects of the disease epidemiology and outcomes, treatment guidelines recommendations and immune regulation through lymphocyte costimulatory receptors.

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Research

Publications

Mitochondrial Oxidative Damage Underlies Regulatory T Cell Defects in Autoimmunity
Themis Alissafi, Lydia Kalafati, Maria Lazari, Anastasia Filia, Ismini Kloukina, Maria Manifava, Jong-Hyung Lim, Vasileia Ismini Alexaki, Nicholas T Ktistakis, Triantafyllos Doskas, George A Garinis, Triantafyllos Chavakis, Dimitrios T Boumpas, Panayotis Verginis
Cell Metab. 2020 Jul 22;S1550-4131(20)30359-4. doi: 10.1016/j.cmet.2020.07.001.

Fabrication of a 3D microfluidic cell culture device for bone marrow-on-a-chip. Micro and Nano Engineering
Kefallinou D, Grigoriou M, Boumpas DT, Gogolides E, Tserepi A.
2020/11/01/ 2020;9:100075.

IFNα Impairs Autophagic Degradation of mtDNA Promoting Autoreactivity of SLE Monocytes in a STING-Dependent Fashion
Katerina Gkirtzimanaki, Eleni Kabrani, Dimitra Nikoleri, Alexander Polyzos, Athanasios Blanas, Prodromos Sidiropoulos, Antonis Makrigiannakis, George Bertsias, Dimitrios T Boumpas, Panayotis Verginis
Cell Rep. 2018 Oct 23;25(4):921-933.e5. doi: 10.1016/j.celrep.2018.09.001.

Transcriptome Reprogramming and Myeloid Skewing in Haematopoietic Stem and Progenitor Cells in Systemic Lupus Erythematosus
Maria Grigoriou, Aggelos Banos, Anastasia Filia, Pavlos Pavlidis, Stavroula Giannouli, Vassiliki Karali, Dionysis Nikolopoulos, Antigone Pieta, George Bertsias, Panayotis Verginis, Ioannis Mitroulis, Dimitrios T Boumpas
Ann Rheum Dis.2020 Feb;79(2):242-253. doi: 10.1136/annrheumdis-2019-215782. Epub 2019 Nov 28.

Evolving Phenotype of Systemic Lupus Erythematosus in Caucasians: Low Incidence of Lupus Nephritis, High Burden of Neuropsychiatric Disease and Increased Rates of Late-Onset Lupus in the 'Attikon' Cohort
D Nikolopoulos, M Kostopoulou, A Pieta, T Karageorgas, D Tseronis, K Chavatza, S Flouda, P Rapsomaniki, A Banos, E Kremasmenou, V Tzavara, P Katsimbri, A Fanouriakis, D T Boumpas
Lupus.2020 Apr;29(5):514-522. doi: 10.1177/0961203320908932. Epub 2020 Feb 27.

Combined genetic and transcriptome analysis of patients with SLE: distinct, targetable signatures for susceptibility and severity.
Panousis NI, Bertsias GK, Ongen H, Gergianaki I, Tektonidou MG, Trachana M, Romano-Palumbo L, Bielser D, Howald C, Pamfil C, Fanouriakis A, Kosmara D, Repa A, Sidiropoulos P, Dermitzakis ET, Boumpas DT
Ann Rheum Dis. 2019 Jun 5. pii: annrheumdis-2018-214379. doi: 10.1136/annrheumdis-2018-214379.

REDD1/autophagy pathway promotes thromboinflammation and fibrosis in human systemic lupus erythematosus (SLE) through NETs decorated with tissue factor (TF) and interleukin-17A (IL-17A).
Frangou E, Chrysanthopoulou A, Mitsios A, Kambas K, Arelaki S, Angelidou I, Arampatzioglou A, Gakiopoulou H, Bertsias GK, Verginis P, Ritis K, Boumpas DT.

Sexual dimorphism in SLE: above and beyond sex hormones.
EAA Christou, A Banos, D Kosmara, GK Bertsias and DT Boumpas
Lupus. 2019 Jan;28(1):3-10. doi: 10.1177/0961203318815768. Epub 2018 Dec 1.

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Meetings

LUPUSCARE Kick-off Meeting

Hematopoietic Stem Cells

Bioinformatics Day

Ethics Advisory Board Meeting, April 15, Athens

Lupuscare Meeting WP 1-3 / Workshop, September 9, 2019, BRFAA

Lupuscare Meeting Progress in WP 4, November 8, 2019, BRFAA

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Flyer

THE ERC LUPUSCARE PROGRAMME

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Videos

 

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Educational Material for SLE Patients

Patient Information for the Project "LUPUSCARE" Systemic Lupus Erythematosus (SLE) (Greek)

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Awards

Anastasia Filia, PhD, was one of the 6 Basic Science abstract awardees at European Rheumatology (EULAR) congress 2019 in Madrid

Anastasia Filia, PhD, bioinformatics researcher in Dr Boumpas Lab, was one of the 6 Basic Science abstract awardees at European Rheumatology (EULAR) congress 2019 in Madrid.

Dr Filia, was honoured for her work on the prediction of major organ involvement in systemic lupus erythematosus (SLE). She and her associates used machine learning and RNA sequencing to detect the smallest number of genes predicting organ involvement using blood samples from 150 patients with SLE.

A 25-gene signature was used to predict organ involvement with high accuracy, sensitivity and specificity. Following validation, such a signature could be used in the clinic to determine optimal treatment & management strategies.

Her work was done at BRFAA in collaboration with Drs M Dermitzakis (BRFAA and University of Geneva) and G Bertsias (University of Crete) groups.

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This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement No 742390)”