The Role of TSH Receptor, PPAR-r, IGF-1R, IGF and Cytokines in Different Stages of Graves’Ophthalmopathy

The recruitment status of this study is unknown because the information has not been verified recently.
Verified June 2005 by National Taiwan University Hospital.
Recruitment status was  Recruiting
Sponsor:
Information provided by:
National Taiwan University Hospital
ClinicalTrials.gov Identifier:
NCT00174057
First received: September 13, 2005
Last updated: NA
Last verified: June 2005
History: No changes posted
  Purpose

The exact mechanism of the pathogenesis of Graves’ ophthalmopathy is still unknown. Histopathologically, extraocular muscle inflammation and orbital fat inflammation are two prominent changes. In the past year, we had investigated the morphological features of the Müller muscle in patients with thyroid lid retraction using the special stain and immunohistochemistry. In our findings, the smooth muscle cells, in the diseased group, were replaced by variable adipose and fibrosis tissues.

In recent years, TSHR, has been verified to express in orbital connective tissue and extra-ocular muscle. From functional studies and an increase in adipogenesis in cultured fibroblasts with expression of TSHR protein, the role not only the target but effector cells in orbital fibroblasts were validated. Quantitative RT-PCR may help to differentiate whether a less extent of expression at the end stage or low protein amount to be detected.

In recent years, the diverse phenotypes of orbital fibroblasts, with regard to expression of Thy-1 protein or not, had been reported from several studies, the investigators believed heterogeneity in orbital fibroblast may determine the clinical presentation of Graves’ophthalmopathy. We also are curious to know if the phenotypic heterogeneity of the fibroblasts in the ocular adnexal and orbital tissues correlates to distinct morphological features of adipogenesis and fibrosis.

Moreover, increased CD40 expression in skin fibroblasts were noted from patients with systemic sclerosis. Expression of IGF-I and IGF-IR seemed to be up-regulated in processes of several fibrotic diseases. A nuclear transcription factor, PPAR-γ, has been verified to have a close relationship with adipogenesis. We hypothesize that some immunological processes involve the ocular adnexal and orbital tissues, which result in various ophthalmological manifestations.

The purpose of this study is to investigate the different stage of the ocular adnexal and orbital tissues to identify the pathogenesis of Graves' ophthalmopathy by frozen sections with Immunohistochemistry, mRNA expression of TSH receptor, PPAR-γ, IGF-1R, and IGF-1 and different cytokines using quantitative RT-PCR and flow cytometry at the acute and stable stage in GO.


Condition
Graves' Ophthalmopathy

Study Type: Observational
Study Design: Observational Model: Case Control
Time Perspective: Cross-Sectional

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Further study details as provided by National Taiwan University Hospital:

Estimated Enrollment: 50
Study Start Date: August 2005
Estimated Study Completion Date: July 2006
Detailed Description:

The exact mechanism of the pathogenesis of Graves’ ophthalmopathy (GO) is still unknown. Histopathologically, extraocular muscle inflammation due to lymphoid infiltration, edema and interstitial fibrosis, and increased glycosaminoglycan deposition and orbital fat inflammation are two prominent changes. There are various manifestations including ocular adnexal tissues inflammation, proptosis, lid retraction, extraocular movement limitation and compressive optic neuropathy. In the past year, we had investigated the morphological features of the Müller muscle in patients with thyroid lid retraction using the special stain and immunohistochemistry in formalin-fixed paraffin-embbeded (FFPE) sections. In our findings, the smooth muscle cells, in the diseased group, were replaced by variable adipose and fibrosis tissues. Two distinct features in the disease group seem to be notable for further investigation.

In recent years, TSHR, a putative autoantigen, has been verified to express in orbital connective tissue and extra-ocular muscle. In addition, they were further demonstrated to express on the surface of cultured orbital fibroblasts and orbital adipose tissue, in patients with GO in several laboratories. From functional studies and an increase in adipogenesis in cultured fibroblasts with expression of TSHR protein, the role not only the target but effector cells in orbital fibroblasts were validated7. We used immunohistochemistry to verify the existence of TSHR on the fibroblasts within the Müller muscle, and the positive staining is manifested in only18 % of patients. It may due to a less extent of expression at the end stage. We are very curious to know if there any difference on the expression of TSHR between orbital specimens from patients with acute and those with stable stage. Quantitative RT-PCR may help to differentiate whether a less extent of expression at the end stage or low protein amount to be detected.

In recent years, the diverse phenotypes of orbital fibroblasts, with regard to expression of Thy-1 protein or not, had been reported from several studies, the investigators believed heterogeneity in orbital fibroblast may determine the clinical presentation of Graves’ ophthalmopathy. We also are curious to know if the phenotypic heterogeneity of the fibroblasts in the ocular adnexal and orbital tissues correlates to distinct morphological features of adipogenesis and fibrosis. In addition, systemic or local pro-inflammatory cytokines may contribute to turn on and turn off the expression of different roles of the fibroblasts.

Moreover, increased CD40 expression in skin fibroblasts were noted from patients with systemic sclerosis. Expression of IGF-I and IGF-IR seemed to be up-regulated in processes of several fibrotic diseases. A nuclear transcription factor, PPAR-γ, has been verified to have a close relationship with adipogenesis. In our previous study, the smooth muscle cells, in the diseased Mullers’ muscle, were replaced by variable adipose and fibrosis tissues. The increased adipose and fibrosis tissue ex vivo of the Müller’ muscle may result from over-action of some biochemical markers in the fibroblasts infiltrating around muscle cells. We hypothesize that some immunological processes involve the ocular adnexal and orbital tissues, which result in various ophthalmological manifestations.

The purpose of this study is to investigate the different stage ( acute or stable stage) of the ocular adnexal and orbital tissues ( including orbital fat, extraocular muscles, orbicularis muscles and eyelid fat) to identify and validate the pathogenesis of Graves ophthalmopathy by frozen sections of the ocular adnexal and orbital tissues with Immunohistochemistry (IHA) (Thy-1 and PPARγ), mRNA expression of TSH receptor, PPAR-γ, IGF-1R, and IGF-1 and different cytokines (IL-1β, IL-4, IL-6, IL-8) using quantitative RT-PCR and flow cytometry at the acute and stable stage in GO.

  Eligibility

Ages Eligible for Study:   20 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:patients with Graves ophthalmopathy -

Exclusion Criteria:no

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  Contacts and Locations
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Please refer to this study by its ClinicalTrials.gov identifier: NCT00174057

Locations
Taiwan
Shu Lang Liao Recruiting
Taipei, Taiwan
Contact: Shu Lang Liao, MD    886-2-23123456 ext 5729    lang89@ha.mc.ntu.edu.tw   
Principal Investigator: Luke L-K Lin, PhD         
Sponsors and Collaborators
National Taiwan University Hospital
Investigators
Study Director: Shu Lang Liao, MD National Taiwan University Hospital
  More Information

No publications provided

ClinicalTrials.gov Identifier: NCT00174057     History of Changes
Other Study ID Numbers: 9461700644
Study First Received: September 13, 2005
Last Updated: September 13, 2005
Health Authority: Taiwan: Department of Health

Keywords provided by National Taiwan University Hospital:
Graves' ophthalmopathy
real time PCR
cytokines
Tsh receptor

Additional relevant MeSH terms:
Graves Ophthalmopathy
Graves Disease
Eye Diseases
Eye Diseases, Hereditary
Exophthalmos
Orbital Diseases
Goiter
Thyroid Diseases
Endocrine System Diseases
Hyperthyroidism
Autoimmune Diseases
Immune System Diseases

ClinicalTrials.gov processed this record on September 16, 2014