Phenotypically distinct anti-insulin B cells repopulate pancreatic islets after anti-CD20 treatment in NOD mice

Boldison, J., Da Rosa, L. C. , Buckingham, L., Davies, J., Wen, L. and Wong, F. S. (2019) Phenotypically distinct anti-insulin B cells repopulate pancreatic islets after anti-CD20 treatment in NOD mice. Diabetologia, 62(11), pp. 2052-2065. (doi: 10.1007/s00125-019-04974-y) (PMID:31444529) (PMCID:PMC6805803)

Abstract

Aims/hypothesis: Autoreactive B cells escape immune tolerance and contribute to the pathogenesis of type 1 diabetes. While global B cell depletion is a successful therapy for autoimmune disease, the fate of autoreactive cells during this treatment in autoimmune diabetes is unknown. We aimed to identify and track anti-insulin B cells in pancreatic islets and understand their repopulation after anti-CD20 treatment. Methods: We generated a double transgenic system, the VH125.hCD20/NOD mouse. The VH125 transgenic mouse, expressing an increased frequency of anti-insulin B cells, was crossed with a human CD20 (hCD20) transgenic mouse, to facilitate B cell depletion using anti-CD20. B cells were analysed using multiparameter and ImageStream flow cytometry. Results: We demonstrated that anti-insulin B cells were recruited to the pancreas during disease progression in VH125.hCD20/NOD mice. We identified two distinct populations of anti-insulin B cells in pancreatic islets, based on CD19 expression, with both populations enriched in the CD138int fraction. Anti-insulin B cells were not identified in the plasma-cell CD138hi fraction, which also expressed the transcription factor Blimp-1. After anti-CD20 treatment, anti-insulin B cells repopulated the pancreatic islets earlier than non-specific B cells. Importantly, we observed that a CD138intinsulin+CD19− population was particularly enriched after B cell depletion, possibly contributing to the persistence of disease still observed in some mice after anti-CD20 treatment. Conclusions/interpretation: Our observations may indicate why the loss of C-peptide is only temporarily delayed following anti-CD20 treatment in human type 1 diabetes.

• Item Type: Articles
• Additional Information: This work was funded by the Medical Research Council (UK) (MR/K021141/1 to FSW). LCDR was funded by a studentship from Cnpq (Conselho Nacional de Pesquisa, Brazil, grant no. 245609/2012–1).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Camargo da Rosa, Dr Larissa
• Authors: Boldison, J., Da Rosa, L. C., Buckingham, L., Davies, J., Wen, L., and Wong, F. S.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Journal Name: Diabetologia
• Publisher: Springer
• ISSN: 0012-186X
• ISSN (Online): 1432-0428
• Published Online: 23 August 2019
• Copyright Holders: Copyright © 2019 The Authors
• First Published: First published in Diabetologia 62(11): 2052-2065
• Publisher Policy: Reproduced under a Creative Commons License