Antigen processing and T cell repertoires as crucial aleatory features in induction of autoimmunity

Induction of self-reactive T cell responses leading eventually to autoimmune pathology involves several key events: (1) availability of a determinant cross-reactive with the pathogenic self or foreign determinant upon processing of native antigen; the foreign molecule bearing the related determinant may have additional processing sites flanking the determinant, or at least different ones (the same determinant may only be available on the native self molecule under inflammatory conditions) (2) a T cell bearing T cell receptor (TCR) capable of response to the autoantigen; (3) ability of the processed self determinant to bind efficiently to the appropriate major histocompatibility complex (MHC) molecule as well as to interact with the appropriate TCR, coordinated with the absence of competitively dominant determinants; and (4) the lack of regulation. At any step of this cascade of interactions, the conditions could either favour induction of an autoreactive T cell response or the process may be truncated/stalled at any step without any adverse effect. A major component determining the outcome of the above interactions is the aleatory nature of the antigen processing events. Experiments highlighting these aleatory events are the focus of this report.