Lisa Westerberg Group
The overall goal of our research is to increase the understanding of actin regulators in immune cells and their role in immunodeficiency diseases. We expect to reveal critical mechanisms for maintenance of a correctly regulated immune system in health and disease and identify new targets for therapy.
Understanding the Immune system by studying Immunodeficiency Diseases
The immune system is never at rest. Our immune cells constantly remodel their actin cytoskeleton to migrate into tissues to kill pathogens and cancer cells or to communicate with other immune cells via cell-to-cell interaction. My group is investigating how inborn errors in actin dynamics leads to development of severe immunodeficiency disease, autoimmunity, and cancer.
We investigate primary immunodeficiency to understand the immune system and with the long-term goal to identify new treatments for these diseases. Primary immunodeficiencies are diseases in which part of the body's immune system is missing or does not function properly. Most primary immunodeficiencies are genetic disorders and the majority are diagnosed in children under the age of one. Translational studies of primary immunodeficiency diseases in patients and gene-targeted experimental models have increased our understanding of the cause for disease and led to development of new therapeutic approaches, including bone marrow transplantation and gene therapy. Understanding primary immunodeficiency diseases has also increased our knowledge of critical mechanisms for correct function of the immune system.
We have focused on the evolutionary conserved WASp family of actin regulators and their interacting partners. WASp is uniquely expressed in hematopoietic lineage cells and is mutated in two severe immunodeficiency diseases. Wiskott-Aldrich syndrome is caused by loss-of-function mutations in WASp and patients suffer from life-threating infections and are at risk to develop autoimmunity and cancer. In contrast to WAS, X-linked neutropenia (XLN) is caused by gain-of-function mutations predicted to lead to a constitutively-active WASp. XLN patients suffer from severe congenital neutropenia and are at risk to develop malignancies. Recent data from our group challenges the view that WASp deficiency leads to hypo-responsive immune cells. Instead, our data suggests that WASp-associated immunodeficiency leads to a breach in tolerance by activation of the ‘wrong’ cells at incorrect sites.
Our working hypothesis based on our published and preliminary data is that small changes in intracellular signaling leading to actin dynamics may have large impact on immune cell homeostasis and the immune response. To address this hypothesis, we combine analysis of experimental models and rare patient samples obtained from national and international collaborators. The overall goal of our research is to increase the understanding of actin regulators and their role in hematopoietic cells, both in the cytoplasm and in the nucleus. We expect to reveal critical mechanisms for maintenance of a correctly regulated immune system in health and disease and to identity new treatment strategies for immunodeficiency and hematological malignancies.
Group Leader
Lisa Westerberg graduated from Stockholm University with a M.Sc. in Molecular Biology and received her Ph.D. in Cell and Molecular Biology in 2003 from Karolinska Institutet where she studied under Professor Eva Severinson. In 2009 she completed her postdoctoral research at Harvard Medical School in the laboratories of Professors Scott Snapper and Luigi Notarangelo.
She joined the faculty at Department of Medicine at Karolinska Institutet, Stockholm in 2009 after receiving an Assistant Professor position appointed by the Swedish Research Council. Dr Westerberg is the treasurer of the Swedish Society for Immunology and coordinates the WASPSTINGS network funded by STINT. Dr Westerberg is a Ragnar Söderberg fellow in Medicine and holds a senior researcher position from the Childhood Cancer fund.
Group Members
Shin-Yu Kung
Master student
Anna Angelopoulou
Master studentPhD students (Co-Supervisor)
Giovanna Perinetti Casoni, PhD student, Karolinska Institutet (main supervisor: Yenan Bryceson)
Shan Wang, MSc, PhD student, Karolinska Institutet (main supervisor: Mikael Karlsson)
Pia Dosenovic Project
”Studies of B cells for development of new vaccines.”
Alumni
Postdocs
Marton Keszei, PhD, 2013-2019
Hanna Brauner, MD PhD, 2016-2018
Sven Petersen, PhD, 2011-2012
PhD students
Anton Sendel, MD PhD, 2014-2020
Joanna Kritikou, PhD, 2012-2017
Carin Dahlberg, PhD, 2010-2015
Marisa Baptista, PhD, 2009-2014
Visiting scientists
Larissa Vasconcelos Fontes, MSc, PhD student, Fiocruz, Brazil, 2018-2019
Master and Undergraduate students
Chiara Geyer, Erasmus student 2017 and Master student 2019
Christoph Haase, Erasmus student 2019
Mathias Percipalle, Internship 2019
Tijana Nikic, Amgen scholar student 2019
Meike Thiemann, Bachelor student 2018
Alva Casey, Amgen scholar student 2018
Lena Bohaumilitzky, Erasmus student 2017
Stamatina Rentouli, Erasmus student 2016-2017
Elena Griseti, Master student 2017
Alexander Schäffer, Master student 2017
Deborah Sandfort, Bachelor student 2016-2017
Hannah Wurzer, Master student 2016
Marissa Franke, Euroscholar student 2016
Laura Köcher, student 2015-2016
Pei Yee Tey, Amgen Scholar student 2016
Jaime James, Master student and Research assistant 2014-2016
Paul Drescher, Bachelor student 2014-2015
Wenqing Yan, Amgen scholar student 2015
Yi Fei Lee, Amgen scholar student 2015
Bettina Mwale, Amgen Scholar student 2014
Katharina Koch, student 2012
Lucy Garner, Amgen Scholar student 2012
Bisera Stepanovska, Amgen Scholar student 2012
Rhea Chatterjea, Amgen Scholar student 2011
Chiao Yin Lim, Amgen Scholar student 2011
Katherine Oliver, Amgen Scholar student 2010
Collaborators
- Harvard Medical School, USA: Dr. Scott Snapper
- New York University Abu Dhabi: Dr Piergiorgio Percipalle
- Fiocruz Institute, Brazil: Dr. Vinicius Cotta-de-Almeida
- National Institute of Health, USA: Dr. Luigi Notarangelo
- University of South Florida, USA: Dr. Jolan Walter
- Baylor College of Medicine, USA: Dr. Jordan Orange
- University of Maryland, USA: Dr. Wenxia Song
- University College London, UK: Drs. Adrian Thrasher and Siobhan Burns
- Leuven University Hospital, Belgium: Dr. Peter Vandenberghe
- University of Milan, Italy: Dr. Anna Villa
- Curie Institute, France: Dr. Ana-Maria Lennon Dumenil
- Huazhong University of Science and Technology, China: Dr. Chaohong Liu
- Chongqing Medical University, China: Dr. Xiaodong Zhao
- Umeå University, Sweden: Dr Mattias Forsell
- Stockholm University, Sweden: Dr. Eva Severinson
- Karolinska Institutet, Sweden: Drs. Mikael Karlsson, John Andersson, Magnus Björkholm, Liv Eidsmo, Susanne Nylén, Fredrik Wermeling, Klas Kärre, Hans-Erik Claesson, Lena Ström, Evren Alici, Robert Månsson, and Ola Winqvist
Funding
We gratefully acknowledge the funding from:
• Childhood Cancer Foundation
• Center for Allergy Research
• Clas Groschinsky Foundation
• European Commission 7th framework program
• Fundação para e a Ciência e Tecnologia
• Jeansson Foundation
• Karolinska Institutet foundations
• Konung Gustaf V:s 80-årsfond
• Magnus Bergvall Foundation
• NovoSeeds Exploratory pre-seed grants
• Olle Engkvist Byggmästare foundation
• Ragnar Söderberg foundation
• Swedish Cancer Society
• Swedish Foundation for International cooperation in research and higher education
• Swedish Medical Society
• Swedish National Space Board
• Swedish Society for Medical Research (SSMF)
• Swedish Research Council
• Åke Olsson foundation
• Åke Wiberg Foundation
For Science and Education
Our group is also actively involved in medical education and our research is featured on several external research websites.
Ragnar Söderberg blogg and Movie:
https://ragnarsoderbergsstiftelse.se/lisa-westerberg
Interview about mentorship at the Amgen scholar website:
http://amgenscholars.com/karolinska-institutet-faculty-mentor-lisa-westerberg-on-mentorship/
Networks:
Joint Brazilian - Swedish Research Collaboration CAPES – STINT network grant with Dr. Vinicius Cotta-de-Almeida, Fiocruz Institute, Brazil
Swedish Research Council and the National Natural Science Foundation of China (NSFC) network grant with Dr. Chaohong Liu, Huazhong University of Science and Technology, China.
Publications
An intronic deletion in megakaryoblastic leukemia 1 is associated with hyperproliferation of B cells in triplets with Hodgkin lymphoma.
Record J, Sendel A, Kritikou JS, Kuznetsov NV, Brauner H, He M, et al
Haematologica 2019 Oct;():
Wiskott-Aldrich syndrome gene mutations modulate cancer susceptibility in the p53± murine model.
Keszei M, Kritikou JS, Sandfort D, He M, Oliveira MMS, Wurzer H, et al
Oncoimmunology 2018 ;7(9):e1468954
Constitutive activation of WASp in X-linked neutropenia renders neutrophils hyperactive.
Keszei M, Record J, Kritikou JS, Wurzer H, Geyer C, Thiemann M, et al
J. Clin. Invest. 2018 08;128(9):4115-4131
Nuclear Wiskott-Aldrich syndrome protein co-regulates T cell factor 1-mediated transcription in T cells.
Kuznetsov NV, Almuzzaini B, Kritikou JS, Baptista MAP, Oliveira MMS, Keszei M, et al
Genome Med 2017 10;9(1):91
IL-2 in the tumor microenvironment is necessary for Wiskott-Aldrich syndrome protein deficient NK cells to respond to tumors in vivo.
Kritikou JS, Dahlberg CI, Baptista MA, Wagner AK, Banerjee PP, Gwalani LA, et al
Sci Rep 2016 08;6():30636
Deletion of Wiskott-Aldrich syndrome protein triggers Rac2 activity and increased cross-presentation by dendritic cells.
Baptista MA, Keszei M, Oliveira M, Sunahara KK, Andersson J, Dahlberg CI, et al
Nat Commun 2016 07;7():12175
Deletion of WASp and N-WASp in B cells cripples the germinal center response and results in production of IgM autoantibodies.
Dahlberg CI, Torres ML, Petersen SH, Baptista MA, Keszei M, Volpi S, et al
J. Autoimmun. 2015 Aug;62():81-92
Wiskott-Aldrich syndrome protein (WASP) and N-WASP are critical for peripheral B-cell development and function.
Westerberg LS, Dahlberg C, Baptista M, Moran CJ, Detre C, Keszei M, et al
Blood 2012 Apr;119(17):3966-74
Activating WASP mutations associated with X-linked neutropenia result in enhanced actin polymerization, altered cytoskeletal responses, and genomic instability in lymphocytes.
Westerberg LS, Meelu P, Baptista M, Eston MA, Adamovich DA, Cotta-de-Almeida V, et al
J. Exp. Med. 2010 Jun;207(6):1145-52