Altered BCR signalling quality predisposes to autoimmune disease and a pre-diabetic state.
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 FcγR-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.
Mammalian Cell Signaling Laboratory, Department of Vascular Cell Biology, Max Planck Institute for Molecular Biomedicine, Münster, Germany.
Sebastian
S
Königsberger
Jan
J
Prodöhl
David
D
Stegner
Vanessa
V
Weis
Martin
M
Andreas
Martin
M
Stehling
Theresa
T
Schumacher
Ruben
R
Böhmer
Ina
I
Thielmann
Judith M M
JM
van Eeuwijk
Bernhard
B
Nieswandt
Friedemann
F
Kiefer
D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics*; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000502:physiology; D002478:Cells, Cultured; D055879:Gene Knock-In Techniques; D015322:Gene Rearrangement, B-Lymphocyte / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011236:Prediabetic State / Q000235:genetics*; D011505:Protein-Tyrosine Kinases / Q000235:genetics; D051562:Proto-Oncogene Proteins c-bcr / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics; D000072377:Syk Kinase; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000235:genetics
D047908:Intracellular Signaling Peptides and Proteins; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse; D051746:ZAP-70 Protein-Tyrosine Kinase; C497262:Zap70 protein, mouse; C496614:Bcr protein, mouse; D051562:Proto-Oncogene Proteins c-bcr