title: Targeting Anti-Insulin B Cell Receptors Improves Receptor Editing in Type 1 Diabetes-Prone Mice.
abstract: 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.
authors.affiliation: Division of Rheumatology and Immunology, Department of Medicine, Vanderbilt University, Nashville, TN 37232; and.
authors.forename: Rachel H
authors.initials: RH
authors.lastname: Bonami
authors.affiliation: Division of Rheumatology and Immunology, Department of Medicine, Vanderbilt University, Nashville, TN 37232; and Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville TN 37232 james.w.thomas@vanderbilt.edu.
authors.forename: James W
authors.initials: JW
authors.lastname: Thomas
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D001324:Autoantigens / Q000276:immunology; D015551:Autoimmunity / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology*; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D003922:Diabetes Mellitus, Type 1 / Q000628:therapy*; D007108:Immune Tolerance / Q000276:immunology*; D007075:Immunoglobulin M / Q000096:biosynthesis / Q000276:immunology; D007145:Immunoglobulin kappa-Chains / Q000276:immunology; D056747:Immunomodulation; D007328:Insulin / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D008969:Molecular Sequence Data; D011947:Receptors, Antigen, B-Cell / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D001324:Autoantigens; D004268:DNA-Binding Proteins; D007075:Immunoglobulin M; D007145:Immunoglobulin kappa-Chains; D007328:Insulin; C499308:Rag2 protein, mouse; D011947:Receptors, Antigen, B-Cell