Primary hormonogenic sites as conserved autoepitopes on thyroglobulin in murine autoimmune thyroiditis. Secondary role of iodination.
We hypothesized earlier that conserved T cell epitopes and those unique to mouse thyroglobulin (MTg) contributed to its total thyroiditogenicity in murine autoimmune thyroiditis. Recent studies of synthetic peptides from human Tg (HTg) revealed no immunodominant epitopes. The role of iodine residues, considered by some to render Tg immunogenic, became unclear, since only one 12-mer peptide contained thyroxine (T4) positioned at hormonogenic site 2553. It primed T cells for thyroiditis transfer, but noniodinated peptide containing thyronine (T0) was not compared. To determine 1) whether other primary hormonogenic sites were likewise immunogenic and 2) whether iodination was requisite for this and other sites to be an autoepitope, we derivatized three pairs of 12-mer peptides, 1-12, 2549-2560, 2559-2570, containing T0 or T4 at positions 5, 2553, or 2567, respectively. The six peptides were used to stimulate MTg-primed cells in vitro and to immunize mice. None directly induced thyroiditis; peptide Abs were the lowest in mice given hT0(2567) or hT4(2567). Of the three T4-containing peptides, hT4(5) and hT4(2553), but not hT4(2567), stimulated MTg-primed or HTg-primed T cells in vitro, with hT4(2553) being the stronger. Comparing hT0(2553) with hT4(2553), both activated MTg-primed, or peptide-primed, T cells to transfer thyroiditis. The marked immunogenicity of noniodinated hT0(2553) and the poor antigenicity of hT4(5) and hT4(2567) demonstrate that immunogenicity of a conserved hormonogenic site is dependent more on its amino acid sequence than on T4 substitution. Iodination may enhance antigenicity and/or binding affinity, but it is not required for a Tg hormonogenic site to be an autoepitope.
D000595:Amino Acid Sequence; D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis; D003429:Cross Reactions; D004195:Disease Models, Animal; D000939:Epitopes / Q000032:analysis*; D005260:Female; D006801:Humans; D007116:Immunization, Passive; D007455:Iodine / Q000737:chemistry; D051379:Mice; D008808:Mice, Inbred CBA; D008969:Molecular Sequence Data; D013601:T-Lymphocytes / Q000276:immunology*; D013954:Thyroglobulin / Q000737:chemistry / Q000276:immunology*; D013963:Thyroid Hormones / Q000096:biosynthesis*; D013967:Thyroiditis, Autoimmune / Q000276:immunology*; D013970:Thyronines / Q000096:biosynthesis / Q000276:immunology; D013974:Thyroxine / Q000096:biosynthesis / Q000276:immunology
D001323:Autoantibodies; D000939:Epitopes; D013963:Thyroid Hormones; D013970:Thyronines; D013954:Thyroglobulin; D007455:Iodine; D013974:Thyroxine