Cumulative autoimmunity: T cell clones recognizing several self-epitopes exhibit enhanced pathogenicity

T cell receptor (TCR) recognition is intrinsically polyspecific. In the field of autoimmunity, recognition of both self- and microbial peptides by a single TCR has led to the concept of molecular mimicry. However, findings made by our group and others clearly demonstrate that a given TCR can also recognize multiple distinct self-peptides. Based on experimental data we argue that recognition of several self-peptides increases the pathogenicity of an autoreactive T cell; a property we refer to as "cumulative autoimmunity." The mechanisms of such increased pathogenicity, and the implications of cumulative autoimmunity regarding the pathophysiology of T cell-mediated autoimmune diseases will be discussed.