Altered BCR signalling quality predisposes to autoimmune disease and a pre-diabetic state

摘要: The spleen tyrosine kinase family members Syk and Zap-70 are pivotal signal transducers downstream of antigen receptors exhibit overlapping expression patterns at early lymphocytic developmental stages. To assess their differential fitness in vivo, we generated mice, which carry a cDNA knock-in controlled by intrinsic promoter elements that disrupts wild-type expression. Kinase replacement severely compromised Erk1/2-mediated survival proper selection developing B cells central peripheral checkpoints, demonstrating critical dependence on BCR signalling quality. Furthermore, ITAM- hemITAM-mediated activation platelets neutrophils was completely blunted, while surprisingly FcγR-mediated phagocytosis macrophages retained. alteration quality resulted preferential development marginal zone prominent autoreactivity, causing the generation anti-insulin antibodies age-related glomerulonephritis. Development concomitant fasting glucose intolerance mice highlights aberrant cell as potential risk factor for type 1 diabetes, suggests altered mechanism to cause biased cellular Ig repertoire selection, ultimately contributing cell-mediated autoimmune predisposition.