Etiology of autoimmune disease: how T cells escape self-tolerance

Despite central and peripheral regulatory mechanisms designed to prevent self-reactivity, autoimmune disease is a common condition. This article explores several ways in which both high and low affinity T cells can avoid negative selection. The concept of intramolecular sequestration indicates that there will be a hierarchy of presentation of different antigenic determinants derived from a protein antigen, such that some determinants will be efficiently presented whereas others will be poorly presented or not presented at all. Generally, only well-presented determinants will induce tolerance among T cells with sufficient affinity/avidity. Escape from this negative regulation can occur via effects of the antigen processing and presentation system denying determinants access to the peptide-binding grooves of major histo-compatibility complex molecules. Another escape mechanism involves avoidance of the regulatory circuitry.