Abstract

The random nature of immunoglobulin gene segment rearrangement inevitably leads to the generation of self‐reactive B cells. Avoidance of destructive autoimmune reactions is necessary in order to maintain physiological homeostasis. However, current central and peripheral tolerance concepts fail to explain the massive number of autoantibody‐borne autoimmune diseases. Moreover, recent studies have shown that in physiological mouse models autoreactive B cells were neither clonally deleted nor kept in an anergic state, but were instead able to mount autoantibody responses. We propose that activation of autoreactive B cells is induced by polyvalent autoantigen complexes that can occur under physiological conditions. Repeated encounter of autoantigen complexes leads to the production of affinity‐matured autoreactive IgM that protects its respective self‐targets from degradation. We refer to this novel mechanism as adaptive tolerance. This article discusses the discovery of adaptive tolerance and the unexpected role of high affinity IgM autoantibodies.