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Unravelling the mechanism for development of WASP-associated primary immunodeficiency

Final Report Summary - WASPSTINGS (Unravelling the mechanism for development of WASP-associated primary immunodeficiency)

Westerberg Laboratory
Lab web page: http://ki.se/en/mtc/lisa-westerberg-group

I started the Immunodeficiency group at Karolinska Institutet in 2009 after receiving a VR Assistant Professor grant and after completing 5 years of postdoctoral training at Harvard Medical School. Recent data from my laboratory challenge the concept that WASP deficiency leads to an immune-compromised setting. Our data show that B cells devoid of WASP fail to undergo proper affinity maturation in germinal centers. Instead, we found an increased extrafollicular response in WASP-deficient mice with expansion of B cells that recognize autoantigens (Dahlberg et al, submitted). Moreover, we found that skin pathology is associated with hyperactive CD8+ T cells and increased cross-presentation by dendritic cells (Baptista et al, Immunity under review). Together, these data has led us to postulate the working hypothesis that WASP-associated immunodeficiencies induce a breach in tolerance by activation of the ‘wrong’ cells at incorrect sites. We reason and will test that this altered response is due to strong compensatory mechanisms in cell signaling so that when one molecule is missing (for example WASP) - another pathway is activated that regulate a different cellular response. I believe the next frontier is to understand the cross-talk between different members in the WASP family signalling pathway and their role inside the nucleus. I have during the first 5 years at KI created a large platform of gene-targeted mice in which we are studying WASp family members and their interaction partners in their natural environment of the immune system. We have developed new molecular tools and designed new gene therapy approaches and many of these strains are so far unpublished. The long-term vision with this approach is to bridge the gap between immunology and cell biology and to work close to clinicians in already established collaborations. I expect that my laboratory has contributed with the following groundbreaking findings in 6 years and of interest for the broad scientific community:
Cell biology – Identification of the function of actin regulators such as WASp in the cytoplasm for vesicle dynamics and cellular stress and in the nucleus for chromatin remodelling and maintenance of genetic stability
Immunology – Identification of the role of WASp family members and their molecular regulation in leukocyte biology
Preclinical and clinical trials – Showing proof-of-concept using new Gene Therapy approaches with small interfering RNAs in mice and thereafter translating to clinic as new therapeutic approaches for diseases caused by dominant active proteins
New tools to investigate the immune system – Development of novel gene-targeted models using molecular biology approaches in the forefront of biomedical research

My strategy on the path to becoming a principal investigator has been to: (1) complete research from my postdoctoral work (see Publication list 2 and 5), (2) set up a large methodological platform (Figure 2), and (3) to secure ample funding. In 2012, I became a Ragnar Söderberg fellow in Medicine (SEK 8.000.000) and the Swedish research Council granted me SEK 10.000.000 for highly ranked ERC-StG2012. In 2013, I was recruited to Department of Microbiology, Tumor, and Cell biology where I received a starting grant to design my laboratory exactly to meet our needs. Since I joined Karolinska Institutet in 2009 I have published 5 papers (PNAS 2009, J Exp Med 2010, Blood 2012a and Blood 2012b, PLoS Biology 2013) and 1 commentary (Blood) and my group has 3 more papers in the pipeline where I am senior author and 4 as co-authors. I am actively solidifying my current international collaborations by coordinating the ‘WASPSTINGS’ network funded by STINT and I am organizing a large scientific meeting (see immunology2014.se).