Molecular Mechanisms of Graves' Ophthalmopathy. A focus on smoking and radioiodine.

Forskningsoutput: AvhandlingDoktorsavhandling (sammanläggning)

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Sammanfattning

Graves’ disease (GD) is an autoimmune disease characterized by hyperthyroidism and is caused by an interplay
of genetic and environmental factors. One-third of patients with GD develop Graves’ ophthalmopathy (GO). Key
processes in the pathogenesis of GO are inflammation and adipogenesis in orbital tissue. Strong risk factors
associated with the development of GO are smoking and radioiodine treatment for hyperthyroidism. The aim of
this thesis was to explore the molecular mechanisms behind the effects of smoking and radioiodine treatment on
the pathogenesis of GO.
In Study I, microarray results showed upregulation of IL-1ß, IL-6 and adipocyte-related immediate early genes
(IEGs), CYR61 and PTGS2, in intraorbital adipose/connective tissue from smokers compared with nonsmokers
with active GO. We confirmed the results with Reverse transcription polymerase chain reaction (RT-PCR). Using
bioinformatic tools, we investigated whether the overexpressed genes were associated with pathways upregulated
in adipogenesis. We found the overexpressed genes to be significantly associated with pathways involving
inflammation, adipogenesis, and immune responses.
In Study II, we studied the direct effect of cigarette smoke extract (CSE) on the gene expression of IL-1ß, IL-6,
CYR61, and PTGS2 and on the adipogenesis process using an in vitro model. Orbital fibroblasts (OFs) were
isolated from intraorbital adipose/connective tissue from GO patients. The OFs were exposed to CSE, and gene
expression was measured. We found that CSE alone could upregulate the gene expression of IEGs, IL-1ß, and IL-
6 but not the late adipogenic genes SCD and PPARγ. Moreover, we investigated whether simvastatin could
downregulate IEGs, IL-6 and adipogenesis. Simvastatin downregulated IEGs, IL-6, and adipogenesis in OFs.
Additionally, we found that IGF-1 treatment in 3T3-L1 preadipocytes led to mature adipocytes.
In Study III, we investigated the effect of CSE exposure and simvastatin and diclofenac treatment on peripheral
blood mononuclear cells (PBMCs) isolated from newly diagnosed GD patients. We found that CSE exposure
alone could upregulate the expression of PTGS2, IL-1ß, and IL-6 and the release of PGE2, IL-1ß, and IL-6.
Furthermore, the proliferation of B lymphocytes and T lymphocytes was upregulated in response to CSE
exposure. Simvastatin and diclofenac downregulated the gene expression of PTGS2, IL-1ß, and IL-6 and the
release of PGE2, IL-1ß, and IL-6 by PBMCs. Furthermore, the proliferation of B- and T lymphocytes was
downregulated. The effects of simvastatin and diclofenac were even stronger when the treatments were
combined. Additionally, IGF-1-treated PBMCs upregulated the proliferation of B- and T lymphocytes.
In Study IV, GD patients were treated with radioiodine (RI). Thyrotropin receptor autoantibody (TRAb) levels were
measured 3 months after treatment. DNA was collected using buccal swabs. We found that TRAb levels were
significantly increased in 70% percent of the patients 3 months after RI treatment. TRAb levels were significantly
elevated in the proportion of patients who developed GO after RI treatment compared to those GD patients that did
not develop GO after RI treatment. A single nucleotide polymorphism (SNP) rs231775 in the CTLA-4 gene was
associated with TRAb levels in GD patients after RI treatment.
Originalspråkengelska
KvalifikationDoktor
Tilldelande institution
  • Institutionen för kliniska vetenskaper, Malmö
Handledare
  • Lantz, Mikael, handledare
  • Planck, Tereza, Biträdande handledare
  • Åsman, Peter, Biträdande handledare
Tilldelningsdatum2021 juni 9
UtgivningsortLund
Förlag
ISBN (tryckt)978-91-8021-065-2
StatusPublished - 2021

Bibliografisk information

Defence details
Date: 2021-06-09
Time: 09:00
Place: Agardh föreläsningssal, CRC, Jan Waldenströms gata 35, Skånes Universitetssjukhus i Malmö. Join by Zoom: https://lu-se.zoom.us/j/61634174546
External reviewer (s)
Name: Bek, Toke
Title: MD, PhD
Affiliation: University of Århus, Denmark

Ämnesklassifikation (UKÄ)

  • Oftalmologi
  • Endokrinologi och diabetes
  • Cell- och molekylärbiologi

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