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          Institute: MPI für molekulare Biomedizin     Collection: Yearbook 2013     Display Documents

ID: 648348.0, MPI für molekulare Biomedizin / Yearbook 2013
Altered BCR signalling quality predisposes to autoimmune disease and a pre-diabetic state
Authors:Konigsberger, S.; Prodohl, J.; Stegner, D.; Weis, V.; Andreas, M.; Stehling, M.; Schumacher, T.; Bohmer, R.; Thielmann, I.; van Eeuwijk, J.M.; Nieswandt, B.; Kiefer, F.
Date of Publication (YYYY-MM-DD):2012-08-01
Title of Journal:EMBO J
Issue / Number:15
Start Page:3363
End Page:3374
Review Status:Internal review
Audience:Not Specified
Abstract / Description:The spleen tyrosine kinase family members Syk and Zap-70 are pivotal signal transducers downstream of antigen receptors and exhibit overlapping expression patterns at early lymphocytic developmental stages. To assess their differential kinase fitness in vivo, we generated mice, which carry a Zap-70 cDNA knock-in controlled by intrinsic Syk promoter elements that disrupts wild-type Syk expression. Kinase replacement severely compromised Erk1/2-mediated survival and proper selection of developing B cells at central and peripheral checkpoints, demonstrating critical dependence on BCR signalling quality. Furthermore, ITAM- and hemITAM-mediated activation of platelets and neutrophils was completely blunted, while surprisingly FcgammaR-mediated phagocytosis in macrophages was retained. The alteration in BCR signalling quality resulted in preferential development and survival of marginal zone B cells and prominent autoreactivity, causing the generation of anti-insulin antibodies and age-related glomerulonephritis. Development of concomitant fasting glucose intolerance in knock-in mice highlights aberrant B cell selection as a potential risk factor for type 1 diabetes, and suggests altered BCR signalling as a mechanism to cause biased cellular and Ig repertoire selection, ultimately contributing to B cell-mediated autoimmune predisposition
Free Keywords:A; Glucose; Macrophages; Mice; Neutrophils; Phagocytosis; Spleen; Tyrosine
External Publication Status:published
Document Type:Article
Communicated by:keuker
Affiliations:MPI für molekulare Biomedizin
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