Targeting Anti-Insulin B Cell Receptors Improves Receptor Editing in Type 1 Diabetes-Prone Mice.

Bonami RH, Thomas JW
J Immunol. 2015 195 (10): 4730-41

PMID: 26432895 · PMCID: PMC4637270 · DOI:10.4049/jimmunol.1500438

Autoreactive B lymphocytes that commonly arise in the developing repertoire can be salvaged by receptor editing, a central tolerance mechanism that alters BCR specificity through continued L chain rearrangement. It is unknown whether autoantigens with weak cross-linking potential, such as insulin, elicit receptor editing, or whether this process is dysregulated in related autoimmunity. To resolve these issues, we developed an editing-competent model in which anti-insulin Vκ125 was targeted to the Igκ locus and paired with anti-insulin VH125Tg. Physiologic, circulating insulin increased RAG-2 expression and was associated with BCR replacement that eliminated autoantigen recognition in a proportion of developing anti-insulin B lymphocytes. The proportion of anti-insulin B cells that underwent receptor editing was reduced in the type 1 diabetes-prone NOD strain relative to a nonautoimmune strain. Resistance to editing was associated with increased surface IgM expression on immature (but not transitional or mature) anti-insulin B cells in the NOD strain. The actions of mAb123 on central tolerance were also investigated, because selective targeting of insulin-occupied BCR by mAb123 eliminates anti-insulin B lymphocytes and prevents type 1 diabetes. Autoantigen targeting by mAb123 increased RAG-2 expression and dramatically enhanced BCR replacement in newly developed B lymphocytes. Administering F(ab')2123 induced IgM downregulation and reduced the frequency of anti-insulin B lymphocytes within the polyclonal repertoire of VH125Tg/NOD mice, suggesting enhanced central tolerance by direct BCR interaction. These findings indicate that weak or faulty checkpoints for central tolerance can be overcome by autoantigen-specific immunomodulatory therapy.

Copyright © 2015 by The American Association of Immunologists, Inc.

MeSH Terms (17)

Animals Antibodies, Monoclonal Autoantigens Autoimmunity B-Lymphocytes Diabetes Mellitus, Type 1 DNA-Binding Proteins Immune Tolerance Immunoglobulin kappa-Chains Immunoglobulin M Immunomodulation Insulin Mice Mice, Inbred C57BL Mice, Inbred NOD Molecular Sequence Data Receptors, Antigen, B-Cell

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