Peptide and Major Histocompatibility Complex–Specific Breaking of Humoral Tolerance to Native Insulin With the B9-23 Peptide in Diabetes-Prone and Normal Mice

Monoclonal antibody blocking the recognition of an insulin peptide–MHC complex modulates type 1 diabetes

“…The major T-cell insulin epitope lies within the amino acid 9-23 peptide of the β-chain (B: [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23]. This peptide can bind within the peptide binding groove of the NOD MHC class II molecule (MHCII), IA g7 , in multiple positions or "registers."…”

“…Similarly, autoimmunity to insulin is essential for the loss of tolerance to the β-cell antigen islet-specific glucose 6 phosphatase catalytic subunit-related protein (IGRP) (11,15), but the converse is not true. The NOD mouse expresses a single MHC class II (MHCII) molecule, IA g7 , whose presence is essential for the development of T1DM (16)(17)(18). We previously suggested that a particular version of IA g7 -insulin B:9-23 complex is crucial for the initiation of islet autoimmunity in the NOD mouse (19)(20)(21)(22) and that a homologous complex involving the structurally related MHCII molecules human leukocyte antigen DQ8 (HLA-DQ8) and HLA-DQ2 may play a similar role in humans (23)(24)(25).…”

Induction and acceleration of insulitis/diabetes in mice with a viral mimic (polyinosinic-polycytidylic acid) and an insulin self-peptide

“…This peptide is recognized by islet-infiltrating T cells of the NOD mouse (22,26), and some of the clones can respond to B:9-23 presented by BALB͞c antigen-presenting cells in addition to NOD antigenpresenting cells (27). In addition, administration of the B:9-23 peptide to BALB͞c mice, but not C57BL͞6 mice, and congenic strains with H-2 d but not H-2 b results in high titers of insulin autoantibodies (28). Note that the induced insulin autoantibodies react with intact insulin and cannot be absorbed with the immunizing B:9-23 insulin peptide.…”

Conserved T cell receptor α-chain induces insulin autoantibodies

“…In addition, the anti-B:9-23 protective 2H6 clone had the J␣-sequence identical to Wegmann clones, but a different V␣-sequence (16). Finally, antigen-presenting cells with both I-A d and I-A g7 (which share the same I-A ␣-chain) are able to present the B:9-23 peptide to the anti-B:9-23 clones, and both BALB/c (I-A d ) and NOD mice (I-A g7 ) respond to immunization with the B:9-23 peptide with generation of high levels of insulin autoantibodies that cannot be absorbed by the immunizing peptide (and thus represent insulin autoantibodies rather than simply peptide autoantibodies) (17). Immunization of NOD mice with the B:9-23 peptide in adjuvant despite inducing insulin autoantibodies prevents diabetes.…”