Lisa Westerberg Group
The overall goal of our research is to understand how a compromised immune system leads to immunodeficiency with high incidence of autoimmunity and hematological cancers. We have a particular focus on how inborn mutations in actin regulators affect immune cell-cell communication, trafficking, and maintenance of genomic stability. Our research aims at revealing critical mechanisms for correct regulation of the immune system in health and disease and to identifying new targets for therapy.
Understanding the Immune system by studying Immunodeficiency 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 critical mechanisms for correct function of the immune system and have revealed novel therapeutic approaches.
A journey from the cytoplasm to the nucleus with actin regulators in immune cells
We have focused on understanding the role of the evolutionary conserved WASp family of actin regulators and their interacting partners in immune cells. 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, thrombocytopenia, 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 and other groups 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 (Kritikou et al, JCI Insight 2021; Keszei et al, J Clin Invest 2018; Baptista et al, Nat Comms 2016). Using patient samples and experimental models, we are currently investigating how WASp and its interacting partners coordinate receptor signal to gene transcription and chromatin remodeling in the nucleus. A focus is the role of nuclear localization of WASp family members and actin in immune cells (Kuznetov et al, Genome Med 2017). We here combine advanced tissue culture assays and flow cytometry, unique molecular biology tools, and high resolution microscopy.
Immunodeficiency and lymphoma – two sides of the same coin?
We are using gene editing techniques of immune cells to understand the relation of cell transformation and specific genetic mutations identified in primary immunodeficiency patients and lymphoma patients. By analysis of the actin sensor MKL1/MRTFA, we found that its overactivity leads to changed expression of integrins and decreased cell-to-cell contact. This was associated with increased cell proliferation, genomic instability and lymphoma cell growth in vitro and in vivo (Record et al, Haematologica 2020). Increased activity of WASp in X-linked neutropenia leads to aberrant cell division and genomic instability of B cells and, interestingly, is associated with generation of more terminally differentiated plasma cells (He et al, J Allergy Clin Immunol 2021; Westerberg et al, J Exp Med 2010). We are using and collecting samples from primary immunodeficiency patients and pediatric lymphoma patients to understand clonal events at single cell level that lead to cell transformation.
Finding new treatments based on experimental research
Based on our findings, we are testing if modulating actin regulators can be used in therapeutic approaches for Wiskott-Aldrich syndrome and in personalized and generalized cancer immune therapy. We here make use of ex vivo drug screening combined with in vivo experimental models.
Immunodeficiency in extreme environments
Using our knowledge and methodology from studies of primary immunodeficiency and lymphoma patients, we have started to collect cells and samples from volunteers exposed to short term and long term loss of gravity (microgravity). We are using transcriptomics and proteomics combined with high resolution microscopy to understand how immune cells and the immune system are affected in the absence of gravity.
Pia Dosenovic Project
PhD 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)
- Marton Keszei, PhD, 2013-2019
- Hanna Brauner, MD PhD, 2016-2018
- Sven Petersen, PhD, 2011-2012
- Anton Sendel, MD PhD, 2014-2020
- Joanna Kritikou, PhD, 2012-2017
- Carin Dahlberg, PhD, 2010-2015
- Marisa Baptista, PhD, 2009-2014
- Romulo Galvani, PhD, Fiocruz, Brazil 2019-2020
- Liu Jing, MD, CSC visiting scholar, Ningxia Medical University, China 2019-2020
- Larissa Vasconcelos Fontes, MSc, PhD student, Fiocruz, Brazil 2018-2019
Master and Undergraduate students
- Eliot Gouget, Master student 2021
- Shin-Yu (Timas) Kung, Master student 2020
- Anna Angelopoulou, Master student 2020
- 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
- New York University Abu Dhabi: Dr. Piergiorgio Percipalle
- University College London, UK: Dr. Siobhan Burns
- University College London, UK: Dr. Adrian Thrasher
- Leuven University Hospital, Belgium: Dr. Peter Vandenberghe
- Harvard Medical School, USA: Dr. Scott Snapper
- Fiocruz Institute, Brazil: Dr. Vinicius Cotta-de-Almeida
- University of South Florida, USA: Dr. Jolan Walter
- Columbia University, USA: Dr. Jordan Orange
- University of Maryland, USA: Dr. Wenxia Song
- Center for Pediatric Hematology, Oncology, Immunology, Russia: Dr. Anna Shcherbina
- National Institute of Health, USA: Dr. Luigi Notarangelo
- 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
- Icahn School of Medicine at Mount Sinai, USA: Dr. Charlotte Cunningham-Rundles
- University of Milan, Italy: Dr. Anna Villa
- Institute of Biomedical Problems of the Russian Academy of Sciences: Dr. Sergey Ponomarev
- Umeå University, Sweden: Dr. Mattias Forsell
- Karolinska Institutet, Sweden: Drs. Mikael Karlsson, John Andersson, Claudia Kutter, Magnus Björkholm, Liv Eidsmo, Susanne Nylén, Fredrik Wermeling, Klas Kärre, Hans-Erik Claesson, Lena Ström, Evren Alici, Robert Månsson, and Ola Winqvist.
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 Tecnologiaeansson Foundation
- Israeli Wiskott-Aldrich syndrome Association (IWASA)
- 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
- Wenner-Gren foundations
- 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:
Interview about mentorship at the Amgen scholar website:
Two sides of the coin: Cytoskeletal regulation of immune synapses in cancer and primary immune deficiencies.
Saeed MB, Record J, Westerberg LS
International Review of Cell and Molecular Biology. Volume 356, 2020, Pages 1-97
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.
Overactive WASp in X-linked neutropenia leads to aberrant B-cell division and accelerated plasma cell generation.
He M, Saeed MB, Record J, Keszei M, Gonçalves Pinho L, Vasconcelos-Fontes L, D'Aulerio R, Vieira R, Oliveira MMS, Geyer C, Bohaumilitzky L, Thiemann M, Deordieva E, Buedts L, Matias Lopes JP, Pershin D, Hammarström L, Xia Y, Zhao X, Cunningham-Rundles C, Thrasher AJ, Burns SO, Cotta-de-Almeida V, Liu C, Shcherbina A, Vandenberghe P, Westerberg LS.
J Allergy Clin Immunol. 2021 Aug 9:S0091-6749(21)01207-0. doi: 10.1016/j.jaci.2021.07.033. Online ahead of print.PMID: 34384840
The WASp L272P gain-of-function mutation alters dendritic cell coordination of actin dynamics for migration and adhesion.
Oliveira MMS, Kung SY, Moreau HD, Maurin M, Record J, Sanséau D, Nylén S, Lennon-Duménil AM, Westerberg LS.
J Leukoc Biol. 2021 Aug 25. doi: 10.1002/JLB.1AB0821-013RR. Online ahead of print.PMID: 34431547
Constitutive activation of WASp leads to abnormal cytotoxic cells with increased granzyme B and degranulation response to target cells.
Kritikou JS, Oliveira MM, Record J, Saeed MB, Nigam SM, He M, Keszei M, Wagner AK, Brauner H, Sendel A, Sedimbi SK, Rentouli S, Lane DP, Snapper SB, Kärre K, Vandenberghe P, Orange JS, Westerberg LS.
JCI Insight. 2021 Mar 22;6(6):e140273. doi: 10.1172/jci.insight.140273.PMID: 33621210
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, Nagy N, Oliveira MMS, Griseti E, Haase CB, Dahlström J, Boddul S, Wermeling F, Thrasher AJ, Liu C, Andersson J, Claesson HE, Winqvist O, Burns SO, Björkholm M, Westerberg LS.
Haematologica. 2020 May;105(5):1339-1350. doi: 10.3324/haematol.2019.216317. Epub 2019 Oct 3.PMID: 31582539
Constitutive activation of WASp in X-linked neutropenia renders neutrophils hyperactive.
Keszei M, Record J, Kritikou JS, Wurzer H, Geyer C, Thiemann M, Drescher P, Brauner H, Köcher L, James J, He M, Baptista MA, Dahlberg CI, Biswas A, Lain S, Lane DP, Song W, Pütsep K, Vandenberghe P, Snapper SB, Westerberg LS.
J Clin Invest. 2018 Aug 31;128(9):4115-4131. doi: 10.1172/JCI64772. Epub 2018 Aug 20.PMID: 30124469
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, Snapper SB, Percipalle P, Westerberg LS.
Genome Med. 2017 Oct 27;9(1):91. doi: 10.1186/s13073-017-0481-6.PMID: 29078804
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, Worth AJ, Liedén A, Kuo IC, Wallin RP, Snapper SB, Eidsmo L, Scheynius A, Karlsson MC, Bouma G, Burns SO, Forsell MN, Thrasher AJ, Nylén S, Westerberg LS.
Nat Commun. 2016 Jul 18;7:12175. doi: 10.1038/ncomms12175.PMID: 27425374