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Absence of the adaptor protein Shb potentiates the TH2 response in a mouse model of atopic dermatitis
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
2014 (English)In: Immunology, ISSN 0019-2805, E-ISSN 1365-2567, Vol. 143, no 1, 33-41 p.Article in journal (Refereed) Published
Abstract [en]

Aberrant regulation of T helper (Th) cell maturation is associated with a number of autoimmune conditions, including allergic disorders and rheumatoid arthritis. The Src homology domain protein B (Shb) adaptor protein was recently implicated as a regulator of Th cell differentiation. Shb is an integral component of the T-cell receptor (TCR) signalling complex and in the absence of Shb the TCR is less responsive to stimulation, resulting in the preferential development of Th2 responses under conditions of in vitro stimulation. In the present study, we extend those observations to an in vivo situation using a murine model of atopic dermatitis. Shb knockout mice develop more pronounced symptoms of atopic dermatitis with increased localized oedema, epidermal hyperplasia and IgE production. Dermal infiltration of mast cells, eosinophils, CD4(+) Th cells and F4/80(+) macrophages was also significantly increased in Shb-deficient mice. This correlated with elevated transcription of the hallmark Th2 cytokines interleukin-4 and interleukin-5. The loss of Shb therefore alters TCR signalling ability, thereby favouring the development of Th2-driven inflammation and exacerbating symptoms of allergy.

Place, publisher, year, edition, pages
2014. Vol. 143, no 1, 33-41 p.
Keyword [en]
atopic dermatitis, Th2 responses, T cell receptor signaling
National Category
Cell and Molecular Biology
Research subject
Medical Cell Biology
Identifiers
URN: urn:nbn:se:uu:diva-209338DOI: 10.1111/imm.12286ISI: 000340385000004OAI: oai:DiVA.org:uu-209338DiVA: diva2:656793
Available from: 2013-10-17 Created: 2013-10-17 Last updated: 2017-12-06Bibliographically approved
In thesis
1. Consequences of Shb Deficiency on Hematopoietic Cell Function
Open this publication in new window or tab >>Consequences of Shb Deficiency on Hematopoietic Cell Function
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The adaptor protein Shb has been implicated in the signaling of several tyrosine kinase receptors and previous studies have suggested a role for Shb in the signal transduction of T cells. Shb associates with the T cell receptor (TCR) and partakes in the signal propagation of activated T lymphocytes. In order to explore Shb’s influence on TCR signaling in vivo, T cell development and function was studied in a Shb knockout mouse. The loss of Shb led to aberrant TCR signaling in both thymocytes and peripheral CD4+ TH cells, with elevated basal phosphorylation of key components in the signal cascade. Shb was found to be dispensable for thymocyte development, but its absence resulted in a TH2 bias in in vitro stimulated peripheral CD4+ TH cells. As imbalances in TH2 responses are linked to allergic diseases, we further explored Shb’s role in immune regulation in a mouse model of atopic dermatitis. Shb knockout mice exhibit more aggravated signs of atopic dermatitis, including increased immune cell recruitment to the affected areas and elevated mRNA levels of typical TH2 cytokines.

The effect of Shb on hematopoiesis in general was determined by examining populations of long-term hematopoietic stem cells (LT-HSCs) and hematopoietic progenitor cells in bone marrow of Shb knockout and wild type mice. Shb deficient bone marrow was found to contain significantly fewer relative numbers of LT-HSCs due to a proliferative defect. The reduced cell cycle activity of Shb LT-HSCs could further be linked to an abnormal regulation of the focal adhesion kinase/Rac1/p21-activated kinase pathway. Since alterations in LT-HSC proliferative abilities may have implications for leukemia development, BCR-Abl induced myeloid neoplasia was investigated in the absence of Shb. Shb deficiency confers a more aggressive progression of BCR-Abl induced myeloid neoplasia characterized by an increased peripheral blood neutrophilia and a deregulated cytokine profile. In addition, focal adhesion kinase and STAT3 signaling is hyperactivated in Shb knockout leukemic cells.

In conclusion, Shb appears to be a multifunctional signaling mediator that controls several responses in hematopoietic cells, under homeostatic as well as disease conditions.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2013. 81 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 937
Keyword
hematopoiesis, hematopoietic stem cells, myeloid neoplasia, T cells, atopic dermatitis, cell signaling
National Category
Cell and Molecular Biology
Research subject
Medical Cell Biology
Identifiers
urn:nbn:se:uu:diva-209339 (URN)978-91-554-8780-5 (ISBN)
Public defence
2013-11-30, A1:107a, BMC, Husargatan 3, Uppsala, 09:15 (English)
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Supervisors
Available from: 2013-11-08 Created: 2013-10-17 Last updated: 2014-01-23

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Gustafsson, KarinWillebrand, ElsaWelsh, Michael

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