Dawe, Kim Isabelle; (1994) T-cell recognition in experimental autoimmune thyroiditis. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

A pathogenic thyroxine containing epitope involved in the induction of experimental autoimmune thyroiditis has been mapped to the C-terminal region of human thyroglobulin. Using thyroglobulin reactive T-cell hybridomas we have been able to define the minimal epitope required for class II restricted recognition, this has been shown to be 9 amino acids in length. Both the iodination and the structure of the thyroxine residue have been shown to be critical for T-cell recognition by thyroglobulin reactive T-cell hybridomas and for subsequent activation. This recognition can be inhibited by the use of antibodies directed to the thyroxine residue of the peptide thus giving us useful clues about the possible three- dimensional structure of the class Il-peptide complex. Potential MHC/TCR binding residues have been identified by the extensive use of substituted peptides we have been able to demonstrate two residues whose substitution abrogates peptide activity, it is not known if these residues bind MHC or TCR. The identified epitope is able to re-activate MTg primed lymph-node cells in vitro and in vivo; such that they are able to transfer disease to naive recipients, however cells primed with thyroglobulin depleted of iodine are unable to recognise thyroxine containing peptide in vitro. Anti-CD4 therapy in vivo following MTg priming is able to specifically down- regulate in vivo and in vitro responses to thyroxine containing peptide. Using a selection of susceptible mouse haplotypes some identification has been made regarding other thyroxine containing residues that may be involved in the induction of experimental disease. The DBA/1 haplotype appears to respond to a thyroxine containing peptide covering position 5 on the thyroglobulin molecule. This is in contrast to the CBA/J which responds to the peptide covering position 2553 following priming with MTg and the SJL which does not seems to recognise thyroxine containing epitopes. The thyroxine containing peptide covering position 2553 can be presented by thyroid epithelial cells in the presence of class II to T-cell hybridomas recognising this region. However, under similar physiological conditions, pathogenic lymph node cells seem unable to recognise these peptide/class II complexes. It has been shown that thyrocytes from high responder strains are susceptible to class II induction by IFN-[gamma] which can act synergistically with TNF-[alpha] to up-regulate levels. Although it appears that levels of class II induced may not differ significantly between high and low responder strains, this implies that there are other factors besides MHC association that may be important in the presentation by thyroid epithelial cells.

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