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Endocrine

pp 1–9 | Cite as

Regulation of B cell homeostasis by Ptpn22 contributes to type 1 diabetes in NOD mice

  • Xiajie Shi
  • Feng Shao
  • Zhixia Li
  • Lin Kang
  • Junbin Liu
  • Stephan Kissler
  • Zhiguang ZhouEmail author
  • Lijing JiaEmail author
  • Peilin ZhengEmail author
Original Article
  • 49 Downloads

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.

Keywords

Type 1 diabetes PTPN22 B cells Autoimmunity 

Abbreviations

T1D

Type 1 diabetes

IAA

Anti-insulin antibodies

Breg

Regulatory B cells

BCR

B cell receptor

Dox

Doxycycline

NOD

Non obese diabetic

WT

Wild type

BrdU

Bromodeoxyuridine

MZ

Marginal zone

FO

Follicular

pDC

Plasmacytoid dendtric cells

Notes

Acknowledgements

This work is supported by the National Natural Science Foundation of China (Grant No. 81670716, 81500600), Hunan Natural Science Fund for Excellent Young Scholars (Grant No. 2019JJ30036), and the Graduate innovation project of Central South University (Grant No. 2018zzts921). The authors declare no conflicts of interest.

Author contributions

All authors have read and approved the final manuscript. P.Z., L.J., and Z.Z. discussed, designed the study and critically edited the manuscript. X.S. and F.S. conducted the experiments, analysed data, and wrote the manuscript. Z.L., L.K., and J.L. contributed to the experiments and discussion. S.K. provided P2 transgenic mice and critically edited the manuscript.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

This article does not contain any studies with human participants performed by any of the authors. All applicable institutional guidelines for the care and use of animals were followed.

Supplementary material

12020_2019_2120_MOESM1_ESM.docx (3 mb)
Supplementary Information

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Metabolism & Endocrinology, The Second Xiangya Hospital, Key Laboratory of Diabetes Immunology, Central South University, Ministry of EducationNational Clinical Research Center for Metabolic DiseasesChangshaChina
  2. 2.Department of Endocrinology, Shenzhen People’s Hospital, The Second Clinical Medical College of Jinan UniversityThe First Affiliated Hospital of Southern University of Science and TechnologyShenzhenChina
  3. 3.Section for Immunobiology, Joslin Diabetes CenterHarvard Medical SchoolBostonUSA

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