Immunodeficiency Diseases – 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.

A group picture of Lisa Westerberg lab members
Neutrophils by scanning electron microscopy
Neutrophils by scanning electron microscopy Photo: Marton Keszei

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 picture of germinal center (pink-yellow) in B cell follicles (blue) in the spleen
Germinal center (pink-yellow) in B cell follicles (blue) in the spleen Photo: Carin Dahlberg

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 (Vieira, Pinho, Westerberg, Ped Allergy Immunol. 2023; Saeed, Record, Westerberg, Int Rev Cell Mol Biol 2020). 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.

High resolution images for F-actin (blue) in B cells
High resolution images for F-actin (blue) in B cells Photo: Mezida Saeed

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 (He et al, J Allergy Clin Immunol 2022; 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 (Record, Saeed et al, Front Cell Dev Biol. 2021; Kuznetov et al, Genome Med 2017). We here combine advanced tissue culture assays and flow cytometry, unique molecular biology tools, and high resolution microscopy.

Picture of TIRF B celler with myosin
TIRF B celler with myosin Photo: Mezida Saeed

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.

A lab picture of he actin cytoskeleton (red) in a megakaryocyte (nucleus, blue)
The actin cytoskeleton (red) in a megakaryocyte (nucleus, blue) Photo: Rhaissa Vieira

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 (Oliveira et al, Br J Cancer 2023; Oliveira et al, J Leuk Biol 2022; Oliveira, Westerberg, J Leuk Biol 2020). We here make use of ex vivo drug screening combined with in vivo experimental models.

An illustration of mission patch
Mission patch Photo: Julien Record

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) (Gallardo-Dodd, Oertlin, Record et al, Sci Adv 2023; Jacob, Oertlin et al, NPJ Microgravity 2023).  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.

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Publications

Selected publications

Staff and contact

Group leader

All members of the group

Alumni

Postdocs

  • Christian Oertlin, PhD, 2021-2022
  • Mezida Saeed, PhD, 2019-2022
  • Marton Keszei, PhD, 2013-2019
  • Hanna Brauner, MD PhD, 2016-2018
  • Sven Petersen, PhD, 2011-2012

PhD students

  • Mariana Oliveira, PhD, 2016-2021
  • Anton Sendel, MD PhD, 2014-2020
  • Joanna Kritikou, PhD, 2012-2017
  • Carin Dahlberg, PhD, 2010-2015
  • Marisa Baptista, PhD, 2009-2014

Senior Research Specialist

  • Nikolai Kouznetsov, PhD, 2014-2021

Visiting scientists

  • Marcus Rafael Lobo Bezerra, PhD student, Fiocruz, Brazil 2022-2023
  • Lia Goncalves Pinho, PhD student, Fiocruz, Brazil 2021-2023
  • Zhoujie Ding, PhD, VR postdoc 2017-2022
  • Pedro Paranhos Tanaka, PhD student, Fiocruz, Brazil 2021-2022
  • Fabricio Montalvao Ferreira, PhD, Fiocruz, Brazil, 2021-2022
  • 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

  • Giulio Zanette, Master student 2023
  • Katharina Riffelsberger, Master student 2023
  • Elisabet Jené Vinuesa, Bachelor student 2023
  • Evangelos Doukoumopoulos, Master student 2022
  • Marta Domínguez Gargallo, Bachelor student 2022
  • Merve Nida Gökbak, Amgen scholar student 2022
  • Yeon Jae, Summer student 2022
  • Jasper Taal, Erasmus student 2021
  • Sofie Hemström, MD student 2021
  • 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

Collaborators, Funding and Outreach

A presentation of collaborators and contributors. Our group is also actively involved in medical education and our research is featured on several external research websites.

Collaborators

  • 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. John Andersson, Susanne Nylén, Fredrik Wermeling, Claudia Kutter, Galina Selivanova, Mikael Karlsson, Klas Kärre, Yenan Bryceson, Magnus Björkholm, Lena Ström, Liv Eidsmo, Robert Månsson, and Evren Alici. 

Funding

We gratefully acknowledge the funding from:

Outreach

Book chapter

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

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.

Team Dosenovic

Research focus

B cell responses are a critical component for the protection against infections provided by vaccines. The activation of B cells is however highly regulated, to make sure the body does not mount immune responses to self-antigens, or develop un-controllable cell division, which could lead to cancer.

To generate vaccines that elicit protective and long-lasting immune responses against pathogens such as HIV-1, influenza and other emerging viruses, we use genetically modified mouse models with B cells expressing human antibodies that enable us to define the trajectory and quality of antigen-specific B cells after immunization.

We are also testing novel approaches for vaccine design such as using anti-idiotypic antibodies to stimulate a pathogen-specific B cell response.

Collectively, our research aims to study B cell responses on the molecular and cellular levels to provide information on B cell regulation that can help develop new vaccines against HIV-1 as well as other genetically variable- and emerging pathogens.

Members

Profile image

Pia Dosenovic

Principal Researcher

Rafael Marques

Research Assistant

Selected publications

Anti-idiotypic antibodies elicit anti-HIV-1-specific B cell responses.
Dosenovic P, Pettersson AK, Wall A, Thientosapol ES, Feng J, Weidle C, et al
J. Exp. Med. 2019 Oct;216(10):2316-2330

Anti-HIV-1 B cell responses are dependent on B cell precursor frequency and antigen-binding affinity.
Dosenovic P, Kara EE, Pettersson AK, McGuire AT, Gray M, Hartweger H, et al
Proc. Natl. Acad. Sci. U.S.A. 2018 05;115(18):4743-4748

Progress toward active or passive HIV-1 vaccination.
Escolano A, Dosenovic P, Nussenzweig MC
J. Exp. Med. 2017 01;214(1):3-16

HIV Vaccine Design to Target Germline Precursors of Glycan-Dependent Broadly Neutralizing Antibodies.
Steichen JM, Kulp DW, Tokatlian T, Escolano A, Dosenovic P, Stanfield RL, et al
Immunity 2016 09;45(3):483-496

Sequential Immunization Elicits Broadly Neutralizing Anti-HIV-1 Antibodies in Ig Knockin Mice.
Escolano A, Steichen JM, Dosenovic P, Kulp DW, Golijanin J, Sok D, et al
Cell 2016 Sep;166(6):1445-1458.e12

Specifically modified Env immunogens activate B-cell precursors of broadly neutralizing HIV-1 antibodies in transgenic mice.
McGuire AT, Gray MD, Dosenovic P, Gitlin AD, Freund NT, Petersen J, et al
Nat Commun 2016 Feb;7():10618

Immunization for HIV-1 Broadly Neutralizing Antibodies in Human Ig Knockin Mice.
Dosenovic P, von Boehmer L, Escolano A, Jardine J, Freund NT, Gitlin AD, et al
Cell 2015 Jun;161(7):1505-15

Antibodies in HIV-1 vaccine development and therapy.
Klein F, Mouquet H, Dosenovic P, Scheid JF, Scharf L, Nussenzweig MC
Science 2013 Sep;341(6151):1199-204

BLyS-mediated modulation of naive B cell subsets impacts HIV Env-induced antibody responses.
Dosenovic P, Soldemo M, Scholz JL, O'Dell S, Grasset EK, Pelletier N, et al
J. Immunol. 2012 Jun;188(12):6018-26

Selective expansion of HIV-1 envelope glycoprotein-specific B cell subsets recognizing distinct structural elements following immunization.
Dosenovic P, Chakrabarti B, Soldemo M, Douagi I, Forsell MN, Li Y, et al
J. Immunol. 2009 Sep;183(5):3373-82

Funding

Current funding:

  • Karolinska Institutet
  • The Swedish Research Council (VR)
  • The European Research Council (ERC starting grant 2019)
  • Knut och Alice Wallenberg Foundation (Wallenberg Academy Fellow)

 

Previous funding:

  • K99 Pathway to Independence Award (NIH)
  • The Swedish Research Council (VR)
  • Karolinska Institutet