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https://hdl.handle.net/2440/53766
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Type: | Journal article |
Title: | PECAM-1-regulated signalling thresholds control tolerance in anergic transgenic B-Cells |
Author: | Wong, M. Hayball, J. Jackson, D. |
Citation: | Molecular Immunology, 2008; 45(6):1767-1781 |
Publisher: | Pergamon-Elsevier Science Ltd |
Issue Date: | 2008 |
ISSN: | 0161-5890 1872-9142 |
Statement of Responsibility: | Mae-Xhum Wong, John D. Hayball and Denise E. Jackson |
Abstract: | Platelet Endothelial Cell Adhesion Molecule-1 (PECAM-1/CD31) is an immunoglobulin (Ig)-immunoreceptor tyrosine based inhibitory motif (Ig-ITIM) superfamily member that recruits and activates protein-tyrosine phosphatases, predominantly SHP-2 and to a lesser extent, SHP-1. Previously, we have shown that deletion of PECAM-1 results in a hyper-proliferative B-cell phenotype. We wanted to test whether the Ig-ITIM superfamily member, PECAM-1 maintains peripheral tolerance by regulating signalling thresholds of B-cells that control autoantibody production or relaxed negative selection of autoreactive B-cells in bone marrow. In order to address this issue, we utilised the classical model of lysozyme/immunoglobulin transgenic mouse model that defines thresholds for eliminating or inactivating self-reactive B-cells. In this study, we show that breeding of double transgenes: soluble hen egg lysozyme (HEL) and its corresponding high-affinity receptor (HEL-Ig) onto PECAM-1 null background resulted in a spontaneous loss of B-cell tolerance in vivo. The resultant PECAM-1(-/-) Dbl Tg mice displayed elevated levels of anti-HEL immunoglobulin M (IgM) antibodies in the serum compared to PECAM-1+/+ anergic counterparts. Dbl Tg B-cells lacking PECAM-1 showed enhanced B-cell proliferation and calcium flux responses to LPS, IL-4 alone, IgM cross-linking and IL-4 indicating augmentation of antigen-receptor signalling. Thus, PECAM-1 is important in maintaining peripheral tolerance in Dbl Tg B-cells. |
Keywords: | B-Lymphocytes Bone Marrow Animals Mice, Inbred C57BL Animals, Genetically Modified Mice Calcium Muramidase Lipopolysaccharides Immunoglobulin M Interleukin-4 Autoantibodies Cross-Linking Reagents Lymphocyte Activation Signal Transduction Cell Proliferation Immune Tolerance Platelet Endothelial Cell Adhesion Molecule-1 |
Description: | Crown copyright © 2007 Published by Elsevier Ltd. |
DOI: | 10.1016/j.molimm.2007.09.024 |
Description (link): | http://www.elsevier.com/wps/find/journaldescription.cws_home/253/description#description |
Published version: | http://dx.doi.org/10.1016/j.molimm.2007.09.024 |
Appears in Collections: | Aurora harvest 5 Medicine publications |
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