Parameters influencing generation of cryptic pathogenic T-cell epitopes in thyroglobulin

Dai, Yang (2002) Parameters influencing generation of cryptic pathogenic T-cell epitopes in thyroglobulin. Doctoral (PhD) thesis, Memorial University of Newfoundland.

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Abstract

Thyroglobulin (Tg) is a major autoantigen in autoimmune thyroiditis, a T-cell-mediated, organ-specific autoimmune disorder. Immunization with Tg or some Tg peptides can activate thyroiditogenic T cells and cause experimental autoimmune thyroiditis (EAT) in mice. Most of the identified pathogenic Tg peptides have been characterized as cryptic epitopes due to their insufficient presentation following processing of Tg in vivo and in vitro. The main goal of this study was to examine whether modification of Tg processing could enhance generation of cryptic T-cell epitopes. Two physiologically relevant parameters that could modify Tg processing were tested: the first was the formation of immune complexes (IC) of Tg with Tg-specific Abs; and the other was the increased iodination of Tg. -- It is shown that generation of the non-dominant pathogenic Tg epitope (2549-2560), containing thyroxine (T4) at position 2553 (T4(2553)), is augmented in APC that internalize ICs of Tg with selected Tg-specific IgG mAbs. The enhancing effects of certain mAbs on the generation of T4(2553) is FcR-dependent, but FcR-mediated internalization of Tg is not sufficient for generation of T4(2553). The data rather suggest a mAb effect on Tg processing within APC. Interestingly, one of Tg-specific mAbs, 55H8, suppressed the generation of T4(2553) following processing Tg-mAb ICs. The suppressive role of 55H8 on activation of T4(2553)-specific T-cells was further investigated. It was found that 55H8 can bind to the T4(2553) peptide within Ak MHC and prevent recognition of the peptide by T4(2553)-specific T-cells. These two studies indicate that Tg-specific Abs may regulate the course of AT by enhancing or suppressing activation of Tg-reactive pathogenic T-cells. It was shown that highly iodinated thyroglobulin (I-Tg) exhibits higher immunopathogenicity than normal Tg in mice. Processing of I-Tg in LNC in vivo, or in macrophages and dendritic cells, but not B cells, in vitro, promoted presentation of the cryptic pathogenic Tg peptide (2495-2511) to T cells. This study demonstrates that generation of non-iodinated, cryptic but pathogenic determinants during processing of I-Tg, may contribute to the development of AT. In conclusion, the studies describe general mechanisms as to how autoantibodies may regulate process of T-cell-mediated autoimmune diseases and how environmental factors such as excess iodine may trigger autoimmune responses.

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