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|Title:||PECAM-1-regulated signalling thresholds control tolerance in anergic transgenic B-Cells|
|Citation:||Molecular Immunology, 2008; 45(6):1767-1781|
|Publisher:||Pergamon-Elsevier Science Ltd|
|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; Antigens, CD31; Interleukin-4; Autoantibodies; Cross-Linking Reagents; Lymphocyte Activation; Signal Transduction; Cell Proliferation; Immune Tolerance|
|Description:||Crown copyright © 2007 Published by Elsevier Ltd.|
|Appears in Collections:||Medicine publications|
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