16 research outputs found
Studies on the immunoregulation of autoimmune thyroiditis
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
Studies on iodine-accelerated spontaneous autoimmune thyroiditis in NOD.H2h⁴ mice
This thesis has no abstrac