Immune Tolerance for Insulin in Developing B Lymphocytes

Abstract

The bulk of the developing B cell repertoire consists of autoreactive specificities; accordingly, effective maintenance of immune tolerance at this stage is critical for the prevention of autoimmune disease, the third most prevalent disease category in the U.S. Using bone marrow culture, we provide the first evidence that functional silencing, manifested by reduced surface IgM, impaired Ca2+ mobilization, and impaired proliferation, occurs in developing anti-insulin B cells exposed to insulin, a key type 1 diabetes autoantigen. This form of anergy occurs following short-term insulin exposure, and removal of antigen restores normal immature B cell function, suggesting that a high degree of functional elasticity is maintained. Development of a novel Igê-targeted BCR transgenic model reveals that a second mechanism of tolerance, receptor editing, can additionally censor immature anti-insulin B cells by replacing the autoreactive BCR specificity. These data therefore indicate that low concentrations of small molecules trigger developing B cell tolerance and highlight a potential therapeutic window for insulin autoimmunity, as the involvement of B cells in type 1 diabetes is increasingly appreciated.