Project Details
Description
Project Summary/Abstract
The autoimmune thyroid diseases (AITD), Graves’ disease (GD) and Hashimoto’s thyroiditis (HT), are the most
common autoimmune diseases. Because their mechanisms are not fully understood, AITD are treated
symptomatically (hormone replacement in HT or hormone suppression in GD) and as a result, patients are often
difficult to manage. Therefore, new therapies are needed that target the autoimmune mechanisms causing AITD.
AITD are complex diseases caused by interactions between susceptibility genes and environmental triggers. We
and others have mapped & confirmed several AITD genes, including thyroglobulin (Tg). We have also shown
that interferon alpha (IFNα), produced during viral infections, is the key cytokine triggering AITD. The current
proposal aims to dissect the genetic and environmental mechanisms causing AITD in order to target them with
novel therapies. Our focus is on genetic mechanisms predisposing to AITD (Aim 1), environmental triggers of
AITD (Aim 2), and medication triggers of AITD (Aim 3). In Aim 1 we will test the hypothesis that missense SNPs
in Tg that are associated with AITD predispose to AITD by increasing Tg misfolding and enhancing its
degradation into immunogenic peptides. We will use a novel muse model of AITD developed by us, in which
autoimmune thyroiditis is induced by immunization with human Tg cDNA in a non-replicating Adenovirus vector.
This model enables us to test the effects of different Tg SNPs shown to be susceptible or protective for AITD,
and to assess in vivo mechanisms by which these Tg variants trigger AITD. In Aim 2 we will test the hypothesis
that IFNα triggers AITD by engaging the autophagic degradation of Tg into immunogenic peptides. We will use
cell lines and a mouse model with thyroid over-expression of IFNα to define the autophagy-lysosomal pathways
of Tg degradation; we will also test the immunogenicity of the generated Tg peptides in mouse models and
PBMC’s from AITD patients. This aim will define a new unifying mechanism for triggering autoimmunity by IFNα-
mediated autoantigen degradation. In Aim 3 we will test the hypothesis that Programmed death-ligand 1 (PD-
L1) expressed on thyrocytes has intrinsic activity protecting them from intracellular stress during inflammation,
and that Immune Checkpoint Inhibitors (ICI’s) trigger thyroiditis by blocking these intrinsic protective effects of
PD-L1. We will use thyroid cell lines with down- and up-regulated PD-L1 expression and mouse models to define
the pathways controlled by PD-L1 in thyrocytes as well as the role of thyroid PD-L1 during inflammation. This
aim will define the mechanisms of ICI-induced thyroiditis as well as the role of thyroidal PD-L1 in AITD.
Collectively, the studies in this proposal will help advance our long-term goal, to design targeted mechanism-
based therapies for autoimmune thyroid diseases.
Status | Finished |
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Effective start/end date | 9/1/22 → 6/30/23 |
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