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B cells devoid of the Rho GTPase Cdc42 coordinate the actin and microtubule cytoskeleton less effectively and form an extrafollicular antibody response
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
Karolinska Institutet.
Karolinska Institutet.
Karolinska Institutet.
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(English)Manuscript (preprint) (Other academic)
National Category
Immunology
Research subject
Immunology
Identifiers
URN: urn:nbn:se:su:diva-93022OAI: oai:DiVA.org:su-93022DiVA: diva2:643850
Available from: 2013-08-28 Created: 2013-08-28 Last updated: 2013-08-29Bibliographically approved
In thesis
1. Activation, adhesion and motility of B lymphocytes in health and disease
Open this publication in new window or tab >>Activation, adhesion and motility of B lymphocytes in health and disease
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

B cells can be activated by T cell-dependent stimuli, such as CD40 ligation and cytokines, which induce extensive proliferation, class switch recombination and somatic hypermutation.

Epstein-Barr virus (EBV) can also induce B cell activation by mimicking T cell help through its main oncoprotein, latent membrane protein 1 (LMP-1). It is regulated by another EBV-encoded protein, EBV nuclear antigen 2 (EBNA-2), which is absent in Hodgkin and Burkitt lymphomas. We have studied LMP-1 induction by cytokines in vitro and shown that LMP-1 is induced through the transcription factor signal transducer and activator of transcription (STAT6) and a newly defined high-affinity STAT6-binding site.

When IL-4 is added together with lipopolysaccharide (LPS) or α-CD40 to B cells, it induces homotypic round and tight aggregates in vitro, whereas LPS alone does not induce such morphological changes. I describe here attempts to identify the molecules that regulate these responses.

I have shown that the Rho GTPase Cdc42 controls the spreading of B cells, whereas two other molecules in the same family, Rac1 and Rac2, control homotypic adhesion. Further, I have shown by conditional deletion of Cdc42 in B cells that it is important in the humoral immune response.  Dock10 is a guanosine nucleotide exchange factor (GEF) for Cdc42. It is expressed through all differentiation stages of B cell development. However, targeted deletion of Dock10 in B cells does not result in an aberrant phenotype. Furthermore, by studying conditional knockout mice for Dock10, Cdc42, Rac1 and Rac2, I have elucidated the mechanism of cytoskeletal changes during B cell activation, leading to adhesion and motility.

My results may lead to a better understanding of normal B cell activation and of EBV infection, which is associated with many human tumours and may help to understand cancer development and progression in B cells.

Place, publisher, year, edition, pages
Stockholm: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, 2013. 64 p.
Keyword
B cells, activation, motility, IL-4, EBV, Dock10, Cdc42, Rac1 and Rac2
National Category
Immunology
Research subject
Immunology
Identifiers
urn:nbn:se:su:diva-92944 (URN)978-91-7447-704-7 (ISBN)
Public defence
2013-10-04, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 10:00 (English)
Opponent
Supervisors
Note

At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 2: Manuscript. Paper 3: Manuscript.

Available from: 2013-09-12 Created: 2013-08-26 Last updated: 2013-09-09Bibliographically approved

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