Epitope dominance: evidence for reciprocal determinant spreading to glutamic acid decarboxylase in non‐obese diabetic mice

Summary: Autoimmunne T‐cell responses to peptide determinants of several autoantigens have recently been characterized. These data suggest that, in some autoimmune models, such as experimental autoimmune encephalomyelitis, T‐cell responses may diversify from a nested set of peptides to include many other peptide regions. A similar immune phenomenon pertaining to autoimmune diabetes (IDDM) is observed in NOD mice. We have explored a similar pattern of T‐cell responses related to age and disease status in NOD mice termed epitope dominance, which describes immune responses toward a pronounced subset of determinants of the autoantigen glutamic acid decarboxylase (GAD). Our studies have identified a total of five GAD epitopes between the 65 and 67 kDa isoforms. The magnitude of T‐cell responses to these various determinants was dependent on the stage of disease as well as on whether mice were protected from disease. The T‐cell responses of these epitopes in NOD mice correlated with the predicted binding of these peptides to the NOD class II molecule I‐A g7 . We therefore propose a model which implicates antigen presenting cells as critical entities in the propagation of dominant responses to the presentation of autoantigens to T cells, particularly in the Thi environment of the NOD mouse. This hypothesis presents a new framework for the discussion and interpretation of the kinetics of T‐cell responses to different peptide epitopes in autoimmune diseases such as IDDM.