The Unveiling of Hidden T‐Cell Determinants of a Native Antigen by Defined Mediators of Inflammation: Implications for the Pathogenesis of Autoimmunity

A major hypothesis for the induction of autoimmunity invokes the enhanced display of previously hidden (cryptic) epitopes under inflammatory conditions leading to the activation of self‐reactive T cells. However, there is meager data that directly validate the influence of specific immune mediators on the upregulation of the presentation of cryptic determinants in vivo . We tested the effect on well‐defined cryptic epitopes of hen eggwhite lysozyme (HEL) of the availability locally of a cytokine (IL‐2, IL‐4, IL‐6, IL‐10, TNF‐α or granulocyte‐macrophage colony‐stimulating factor) at the antigen delivery site, or of the pretreatment of the immunogen with a cathepsin (Cat B, D, L or S) prior to use in vivo . Each of the three mouse strains (H‐2 b/d/k ) tested revealed a unique profile of T‐cell reactivity to different cryptic epitopes of HEL in response to a particular cytokine or cathepsin. These results provide proof of principle for the reversal of crypticity of self‐epitopes by immune mediators in the local milieu. Moreover, co‐immunization with an antigen and a cytokine offers a simple and reliable tool for studying the role of cryptic epitopes in autoimmunity. Our results also strengthen the rationale for the use of inhibitors of cytokine/cathepsin activity in the treatment of autoimmune diseases.