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Activation, adhesion and motility of B lymphocytes in health and disease
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
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 [en]
B cells, activation, motility, IL-4, EBV, Dock10, Cdc42, Rac1 and Rac2
National Category
Immunology
Research subject
Immunology
Identifiers
URN: urn:nbn:se:su:diva-92944ISBN: 978-91-7447-704-7 (print)OAI: oai:DiVA.org:su-92944DiVA: diva2:643482
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
List of papers
1. The STAT6 signaling pathway activated by the cytokines IL-4 and IL-13 induces expression of the Epstein-Barr virus-encoded protein LMP-1 in absence of EBNA-2: implications for the type II EBV latent gene expression in Hodgkin lymphoma
Open this publication in new window or tab >>The STAT6 signaling pathway activated by the cytokines IL-4 and IL-13 induces expression of the Epstein-Barr virus-encoded protein LMP-1 in absence of EBNA-2: implications for the type II EBV latent gene expression in Hodgkin lymphoma
Show others...
2011 (English)In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 117, no 1, 165-174 p.Article in journal (Refereed) Published
Abstract [en]

In line with the B-lymphotropic nature of EBV, the virus is present in several types of B cell lymphomas. EBV expresses a different set of latent genes in the associated tumors, such as EBNA-1 and LMPs (type II latency) in the classical Hodgkin lymphomas (cHL). We have previously reported that exposure of the in vitro EBV-converted, HL-derived cell line KMH2-EBV to CD40-ligand and IL-4 induced the expression of LMP-1. Here we show that exposure to IL-4 or IL-13 alone induced LMP-1 in the absence of EBNA-2. The induction of LMP-1 by IL-4 and IL-13 was mediated by the signal transducer STAT6 and a newly defined high-affinity STAT6-binding site in the LMP-1 promoter. IL-4 induced LMP-1 also in Burkitt lymphoma-derived lines and in tonsillar B cells infected with the EBNA-2-deficient EBV strain P3HR-1. Furthermore, co-culture of EBV-carrying BL cells with activated CD4(+) T cells resulted in the induction of LMP-1 in the absence of EBNA-2. As the Hodgkin/Reed-Sternberg are known to secrete IL-13, to have constitutively activated STAT6, and to be closely surrounded by CD4+ T cells, these mechanisms may be involved in the expression of LMP-1 in the EBV-positive cHLs.

National Category
Immunology
Research subject
Immunology
Identifiers
urn:nbn:se:su:diva-44312 (URN)10.1182/blood-2010-01-265272 (DOI)000285963900026 ()20876453 (PubMedID)
Note

authorCount :8

Available from: 2010-11-05 Created: 2010-11-05 Last updated: 2017-12-12Bibliographically approved
2. B cells devoid of the Rho GTPase Cdc42 coordinate the actin and microtubule cytoskeleton less effectively and form an extrafollicular antibody response
Open this publication in new window or tab >>B cells devoid of the Rho GTPase Cdc42 coordinate the actin and microtubule cytoskeleton less effectively and form an extrafollicular antibody response
Show others...
(English)Manuscript (preprint) (Other academic)
National Category
Immunology
Research subject
Immunology
Identifiers
urn:nbn:se:su:diva-93022 (URN)
Available from: 2013-08-28 Created: 2013-08-28 Last updated: 2013-08-29Bibliographically approved
3. The guanine nucleotide exchange factor Dock10: expression and function in B lymphocytes
Open this publication in new window or tab >>The guanine nucleotide exchange factor Dock10: expression and function in B lymphocytes
(English)Manuscript (preprint) (Other academic)
National Category
Immunology
Research subject
Immunology
Identifiers
urn:nbn:se:su:diva-93024 (URN)
Available from: 2013-08-28 Created: 2013-08-28 Last updated: 2013-08-29Bibliographically approved

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