Reversing Tolerance in Isotype Switch-Competent Anti-Insulin B Lymphocytes.

Williams JM, Bonami RH, Hulbert C, Thomas JW
J Immunol. 2015 195 (3): 853-64

PMID: 26109644 · PMCID: PMC4506889 · DOI:10.4049/jimmunol.1403114

Autoreactive B lymphocytes that escape central tolerance and mature in the periphery are a liability for developing autoimmunity. IgG insulin autoantibodies that predict type 1 diabetes and complicate insulin therapies indicate that mechanisms for tolerance to insulin are flawed. To examine peripheral tolerance in anti-insulin B cells, we generated C57BL/6 mice that harbor anti-insulin VDJH-125 site directed to the native IgH locus (VH125(SD)). Class switch-competent anti-insulin B cells fail to produce IgG Abs following T cell-dependent immunization of VH125(SD) mice with heterologous insulin, and they exhibit markedly impaired proliferation to anti-CD40 plus insulin in vitro. In contrast, costimulation with LPS plus insulin drives robust anti-insulin B cell proliferation. Furthermore, VH125(SD) mice produce both IgM and IgG2a anti-insulin Abs following immunization with insulin conjugated to type 1 T cell-independent Brucella abortus ring test Ag (BRT). Anti-insulin B cells undergo clonal expansion in vivo and emerge as IgM(+) and IgM(-) GL7(+)Fas(+) germinal center (GC) B cells following immunization with insulin-BRT, but not BRT alone. Analysis of Igκ genes in VH125(SD) mice immunized with insulin-BRT reveals that anti-insulin Vκ from the preimmune repertoire is selected into GCs. These data demonstrate that class switch-competent anti-insulin B cells remain functionally silent in T cell-dependent immune responses, yet these B cells are vulnerable to reversal of anergy following combined BCR/TLR engagement that promotes Ag-specific GC responses and Ab production. Environmental factors that lead to infection and inflammation could play a critical yet underappreciated role in driving loss of tolerance and promoting autoimmune disease.

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

MeSH Terms (17)

Animals Autoantibodies Autoimmunity B-Lymphocytes CD40 Antigens Diabetes Mellitus, Type 1 Immune Tolerance Immunoglobulin G Immunoglobulin M Insulin Insulin Antibodies Lipopolysaccharides Mice Mice, Inbred C57BL Mice, Transgenic Molecular Sequence Data VDJ Exons

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