Xiajie Shi1, Feng Shao1, Zhixia Li1, Lin Kang2, Junbin Liu1, Stephan Kissler3, Zhiguang Zhou4, Lijing Jia5, Peilin Zheng6,7. 1. Department of Metabolism & Endocrinology, The Second Xiangya Hospital, Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, Hunan, 410011, China. 2. Department of Endocrinology, Shenzhen People's Hospital, The Second Clinical Medical College of Jinan University, The First Affiliated Hospital of Southern University of Science and Technology, Shenzhen, 518020, China. 3. Section for Immunobiology, Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA. 4. Department of Metabolism & Endocrinology, The Second Xiangya Hospital, Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, Hunan, 410011, China. zhouzhiguang@csu.edu.cn. 5. Department of Endocrinology, Shenzhen People's Hospital, The Second Clinical Medical College of Jinan University, The First Affiliated Hospital of Southern University of Science and Technology, Shenzhen, 518020, China. jialijing2012@126.com. 6. Department of Metabolism & Endocrinology, The Second Xiangya Hospital, Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, Hunan, 410011, China. plzheng83@163.com. 7. Department of Endocrinology, Shenzhen People's Hospital, The Second Clinical Medical College of Jinan University, The First Affiliated Hospital of Southern University of Science and Technology, Shenzhen, 518020, China. plzheng83@163.com.
Abstract
PURPOSE: A coding variant in PTPN22 (C1858T) is one of the most important genetic risk factors in type 1 diabetes (T1D). The role of the PTPN22 risk allele in B cells is still incompletely understood and has not been investigated directly in T1D. This study aimed to explore the role of PTPN22 in the homeostasis of B cells and its influence in T1D. METHODS: Wild-type (WT) and Ptpn22 inducible knockdown (KD) NOD mice were treated with 200 μg/ml doxycycline at the age of 10 weeks for 1-2 months. B cell compositions in the bone marrow, peritoneal cavity and spleen were examined. The pathogenicity of Ptpn22 KD B cells was explored by adoptive cell transfer. RESULTS: Ptpn22 silencing increased the frequency of recirculating mature B cells in the bone marrow, decreased the frequency of B-1a cells in the peritoneal cavity and suppressed the formation of marginal zone B cells and plasma cells in the spleen. Changes in the composition of the peripheral B cell compartment caused by altered cell proliferation while rates of apoptosis were not affected. Significantly, co-transfer of Ptpn22 KD B cells with NY8.3 diabetogenic T cells diminished the frequency of diabetes in recipient NOD.scid mice compared with co-transfer of WT B cells. CONCLUSIONS: Our study constitutes the first functional study of Ptpn22 in B cells in NOD mice. Our findings suggest that Ptpn22 variation contributes to T1D by modifying the B cell compartment and support a gain-of-function for the PTPN22 disease variant.
PURPOSE: A coding variant in PTPN22 (C1858T) is one of the most important genetic risk factors in type 1 diabetes (T1D). The role of the PTPN22 risk allele in B cells is still incompletely understood and has not been investigated directly in T1D. This study aimed to explore the role of PTPN22 in the homeostasis of B cells and its influence in T1D. METHODS: Wild-type (WT) and Ptpn22 inducible knockdown (KD) NOD mice were treated with 200 μg/ml doxycycline at the age of 10 weeks for 1-2 months. B cell compositions in the bone marrow, peritoneal cavity and spleen were examined. The pathogenicity of Ptpn22 KD B cells was explored by adoptive cell transfer. RESULTS: Ptpn22 silencing increased the frequency of recirculating mature B cells in the bone marrow, decreased the frequency of B-1a cells in the peritoneal cavity and suppressed the formation of marginal zone B cells and plasma cells in the spleen. Changes in the composition of the peripheral B cell compartment caused by altered cell proliferation while rates of apoptosis were not affected. Significantly, co-transfer of Ptpn22 KD B cells with NY8.3 diabetogenic T cells diminished the frequency of diabetes in recipient NOD.scid mice compared with co-transfer of WT B cells. CONCLUSIONS: Our study constitutes the first functional study of Ptpn22 in B cells in NOD mice. Our findings suggest that Ptpn22 variation contributes to T1D by modifying the B cell compartment and support a gain-of-function for the PTPN22 disease variant.
Entities:
Keywords:
Autoimmunity; B cells; PTPN22; Type 1 diabetes