Studies on the immunoregulation of autoimmune thyroiditis

Kolypetri, Panagiota (2014) Studies on the immunoregulation of autoimmune thyroiditis. Doctoral (PhD) thesis, Memorial University of Newfoundland.

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Abstract

Autoimmune thyroiditis is a chronic disease characterized by mononuclear cell infiltration in the thyroid gland and production of anti-thyroglobulin (Tg) antibodies. In this thesis, we have used the murine models of experimental autoimmune thyroiditis (EAT) and iodide-accelerated spontaneous autoimmune thyroiditis (ISAT) to investigate the immunoregulation of the disease. In the EAT model, we have examined whether putative H2Aᴷ-binding Tg epitopes, located adjacent to cathepsin cleavage sites within mouse Tg would have immunopathogenic properties. The peptides, p2369 and p2439, elicited significant proliferative T cell responses and production of IL-2 and IFN-γ in recall assays using lymph node cells from peptide-primed mice. Both peptides were pathogenic in CBA/J mice after direct challenge with the peptide in CFA and by adoptive transfer of peptideprimed lymph node cells into naïve recipient hosts. In the ISAT model, we have examined whether NOD.H2ᴴ⁴ thyrocytes are highly prone to iodide-mediated apoptosis since such an event could theoretically trigger ISAT in this strain. Our data showed that NOD.H2ᴴ⁴ thyrocytes cultured with low NaI concentrations had significantly higher apoptotic rates compared to CBA/J thyrocytes. Increased apoptosis was associated with an impaired control of oxidative stress mechanisms since the expression of only two genes involved in ROS metabolism and/or anti-oxidant function were upregulated in iodide-treated NOD.H2ᴴ⁴ thyrocytes vs. 22 genes in iodidetreated CBA/J thyrocytes. Next, we examined the immunopathogenicity of the Tg epitope, a.a. 2549-2560 (T4p2553) in NOD.H2ᴴ⁴ mice. The epitope was immunopathogenic in this strain after direct challenge with peptide in CFA. In ISAT, peptide-specific proliferative responses were recorded using only cervical lymph node cells (CLNC) from iodide-fed mice before the onset of the disease. Also, selective enrichment of CD4⁺ IFN-γ⁺ T4p2553-specific cells was observed among CLNC and intrathyroidal lymphocytes. T4p2553 was equally detectable on dendritic cells from CLNC regardless of iodide intake whereas spontaneous T4p2553-specific IgG responses were not detectable. Our data identified for the first time a Tg T-cell epitope as a spontaneous target in ISAT. Lastly, we have examined whether a high salt diet can exacerbate autoimmune thyroiditis because previous studies by other groups had suggested this diet as a predisposing factor for autoimmune diseases in general. Our data showed that high salt intake failed to significantly affect the incidence and severity of SAT in NOD.H2ᴴ⁴ mice or EAT in Tgprimed C57BL/6J and T4p2553-primed CBA/J mice relative to mice on a normal diet. No difference was detected at the Tg-specific IgG levels between the two groups. These data demonstrate that a high salt diet is not a risk factor for all autoimmune diseases.

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