Thyroglobulin as an autoantigen: what can we learn about immunopathogenicity from the correlation of antigenic...

Autoantibodies against human thyroglobulin are a hallmark of autoimmune thyroid disease in humans, and are often found in normal subjects. Their pathogenic significance is debated. Several B-cell epitope-bearing peptides have been identified in thyroglobulin. They are generally located away from the cysteine-rich regions of tandem sequence repetition. It is possible that our current epitopic map is incomplete because of the difficulty that proteolytic and recombinant approaches have in restituting conformational epitopes based upon proper pairing between numerous cysteinyl residues. Furthermore, the homology of cysteine-rich repeats with a motif occurring in several proteins, endowed with antiprotease activity, suggests that these regions may normally escape processing and presentation to the immune system, and brings attention to the mechanisms, such as oxidative cleavage, by which such cryptic epitopes may be exposed. A number of T-cell epitope-bearing peptides, endowed with thyroiditogenic power in susceptible mice, were also identified. None of them was dominant, as none was able to prime in vivo lymph node cells that would proliferate or transfer autoimmune thyroiditis to syngeneic hosts, upon stimulation with intact thyroglobulin in vitro. More than half of them are located within the acetylcholinesterase-homologous domain of thyroglobulin, and overlap B-cell epitopes associated with autoimmune thyroid disease, while the others are located within cysteine-rich repeats. The immunopathogenic, non-dominant character of these epitopes also favours the view that the development of autoimmune thyroid disease may involve the unmasking of cryptic epitopes, whose exposure may cause the breaking of peripheral tolerance to thyroglobulin. Further research in this direction seems warranted.