Breakdown of T-cell ignorance: The tolerance failure responsible for mainstream autoimmune diseases?

This article explores the possibility that the major autoimmune diseases come about because of the breakdown of T lymphocyte ignorance – that state in which antigen and lymphocyte have never come together in such a way as to induce tolerance or an immune response. By use of transgenic technique to place a foreign antigen/peptide in various mouse tissues the widespread occurrence of ignorance has been observed and information obtained on when it is likely to occur. Now, with the advent of tetramer technique to enrich specific T cells and the recognition of lymphocyte markers indicating whether or not antigen interaction has taken place, ignorance of genuine self-antigens is being examined in mouse and man. In the absence of thymic deletion it seems that tolerance to self-antigens is brought about either by T cell ignorance or T cell regulatory control. The initiating factor in these major diseases is likely to be a change in the condition of the antigen leading to tolerance failure. There is evidence that it is ignorance that breaks down in Type 1 diabetes and systemic lupus erythematosus. If this proves a general rule, it may be because ignorance is the tolerance mechanism most vulnerable to subversion.