5
Immunopathogenesis of Graves’ ophthalmopathy: The role of the TSH receptor

https://doi.org/10.1016/j.beem.2011.10.003Get rights and content

Graves’ ophthalmopathy is an inflammatory autoimmune disorder of the orbit. The close clinical and temporal relationships between Graves’ hyperthyroidism and ophthalmopathy have long suggested that both conditions derive from a single systemic process and share the thyrotropin receptor as a common autoantigen. This receptor is expressed not only in thyroid follicular cells, but also in orbital fibroblasts with higher levels measured in orbital cells from ophthalmopathy patients than in cells from normal individuals. Recent studies from several laboratories have shown that thyrotropin receptor activation in orbital fibroblasts enhances hyaluronic acid synthesis and adipogenesis, both cellular functions that appear to be upregulated in the diseased orbit. The phosphoinositide 3-kinase/Akt signaling cascade, along with other effector pathways including adenylyl cyclase/cAMP, appears to mediate these processes. Future therapies for this condition may involve inhibition of thyrotropin receptor signaling in orbital fibroblasts.

Introduction

Graves’ orbitopathy (GO) is an inflammatory autoimmune disorder of the orbit.1 The immune basis of the disease is suggested by a perivascular and diffuse infiltration of CD4+ and CD8 + T cells, B cells, plasma cells and macrophages.2 In addition, the connective tissues are extensively remodeled with enlargement of the extra-ocular muscles and orbital adipose tissues.3, 4, 5, 6 Underlying these changes are excessive production of hyaluronic acid (HA) and new fat cell development. While GO affects primarily patients with a history of Graves’ hyperthyroidism, it is also encountered in euthyroid and hypothyroid individuals with laboratory evidence of autoimmune thyroid disease. While the onset of GO occasionally precedes or follows that of hyperthyroidism by several years, these conditions most commonly occur simultaneously or within 18 months of each other.7 Owing to the close clinical and temporal relationships between Graves’ hyperthyroidism and GO, investigators have long hypothesized that both autoimmune conditions derive from a single systemic process and share the thyrotropin receptor (TSHR) as a common autoantigen. In this review, we will explore current evidence that autoimmunity directed against TSHR on orbital cells sets in motion the connective tissue changes within the orbit that lead to the clinical disease.

Section snippets

The target cell in GO

Evidence from several laboratories suggests that orbital fibroblasts are the autoimmune target cells in GO.8, 9, 10, *11 Early studies found that orbital-infiltrating CD8 + T cells recognize orbital fibroblasts and not eye muscle extracts, and that they respond by proliferation via major histocompatibility complex (MHC) class II and CD40 signaling.9 Unlike eye muscle cells, orbital fibroblasts express human leukocyte antigen (HLA)-DR, suggesting that they may act as antigen-presenting cells.12

TSHR as autoantigen in GO

TSHR on thyroid follicular cells serves as the autoimmune target in Graves’ hyperthyroidism and antibodies directed against this cell surface receptor stimulate the over-production of thyroid hormones.16 Clinical observations suggesting that the same receptor may be the primary target in GO include that TSHR-directed autoantibodies (TRAb) can be detected in essentially all patients with GO, including euthyroid patients,17 that levels of TRAb correlate with the severity and clinical activity of

TSHR structure and function

TSHR is a glycoprotein hormone receptor which, along with luteinizing hormone receptor (LHR) and follicle-stimulating hormone receptor (FSHR), is a member of the G protein-coupled receptor (GPCR) family.16 TSHR contains a large extracellular domain (ectodomain) that is mainly responsible for recognition and binding to the ligand, a seven-transmembrane domain, and an intracellular domain (endodomain) bound to G-protein subunits, mainly the Gαs and Gαq. Upon stimulation, both subunits trigger

TSHR antibodies

Sera from individual patients with Graves’ disease contain a mixture of TRAb.*34, 38 The ultimate clinical expression of the disease appears to be influenced by the particular varieties and affinities of TRAb present. The production of specific human, mouse and hamster monoclonal TSHR antibodies has allowed their use as probes to better understand TRAb binding sites and signaling pathways. TRAb can be classified as stimulating (TSAb), blocking (TBAb), or neutral depending on their respective

The potential role of TRAb in orbital tissue remodeling

Signs and symptoms experienced by patients with GO include proptosis (forward protrusion of the eyes), conjunctival and eyelid swelling and erythema, diplopia, and ocular pain. These features derive from expansion of the orbital adipose tissues and extra-ocular muscle bodies within the inflexible bony orbit. The resulting increase in orbital pressure displaces the orbit forward and hinders venous drainage, facilitating the accumulation of inflammatory mediators.1 Orbital inflammation in GO

Possible interactions between TSHR and IGF-1R

The IGF-1R, as well as the structurally related insulin receptor (IR), contains two α- and 2 β-chains that form a heterotetrameric structure linked by covalent disulphide bridges.59, 60 These receptors may also exist as hybrid dimers consisting of one α- β-dimer of each receptor type. Binding of either IGF-1 or insulin initiates dimerization, autophosphorylation, and activation of the receptor complex. Subsequent phosphorylation of tyrosine substrates leads to binding and activation of the

Novel TSHR-directed therapy for GO

Recent information concerning the structure of TSHR and its similarities to LHR and FSHR has led to the development of a generation of small molecule ligands (SML) of TSHR. Drs. Susanne Neumann and Marvin Gershengorn (Clinical Endocrinology Branch, National Institutes of Health, Bethesda, Maryland) have used molecular modeling, high-throughput screening and functional experiments to identify SML that inhibit TSH- and TSAb-stimulated signaling, as well as constitutive signaling of thyrocyte TSHR.

Summary

We present evidence that autoimmunity directed against TSHR on orbital cells sets in motion connective tissue remodeling within the orbit that leads to the various clinical expressions of GO. HA accumulation, expansion of orbital adipose tissues and local inflammation appear to be the salient histologic features of the disease. Orbital fibroblasts express functional TSHR and are considered to be the target cells. Several laboratories have explored the impact of TSHR activation in these cells on

Acknowledgments

This work was supported in part by the National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health (grant number DK77814 to RSB).

References (71)

  • S. Mueller et al.

    The superagonistic activity of bovine thyroid-stimulating hormone (TSH) and the human TR1401 TSH analog is determined by specific amino acids in the hinge region of the human TSH receptor

    Journal of Biological Chemistry

    (2009)
  • R.S. Bahn

    Graves’ ophthalmopathy

    New England Journal of Medicine

    (2010)
  • S.M. McLachlan et al.

    Cell-mediated or humoral immunity in Graves’ ophthalmopathy? Profiles of T-cell cytokines amplified by polymerase chain reaction from orbital tissue

    Journal of Clinical Endocrinology Metabolism

    (1994)
  • T.J. Smith et al.

    Connective tissue, glycosaminoglycans, and diseases of the thyroid

    Endocrine Reviews

    (1989)
  • R.L. Anderson et al.

    Dysthyroid optic neuropathy without extraocular muscle involvement

    Ophthalmic Surgery

    (1989)
  • G. Forbes et al.

    Ophthalmopathy of Graves’ disease: computerized volume measurements of the orbital fat and muscle

    American Journal of Neuroradiology

    (1986)
  • W.M. Wiersinga et al.

    Temporal relationship between onset of Graves’ ophthalmopathy and onset of thyroidal Graves’ disease

    Journal of Endocrinological Investigation

    (1988)
  • S.E. Feldon et al.

    Autologous T-lymphocytes stimulate proliferation of orbital fibroblasts derived from patients with Graves’ ophthalmopathy

    Investigative Ophthalmology and Visual Science

    (2005)
  • B. Grubeck-Loebenstein et al.

    Retrobulbar T cells from patients with Graves’ ophthalmopathy are CD8+ and specifically recognize autologous fibroblasts

    Journal of Clinical Investigation

    (1994)
  • E. Otto et al.

    TSH receptor in endocrine autoimmunity

    Clinical and Experimental Rheumatology

    (1996)
  • B.S. Prabhakar et al.

    Current perspective on the pathogenesis of Graves’ disease and ophthalmopathy

    Endocrine Reviews

    (2003)
  • A. Pappa et al.

    T cells and fibroblasts in affected extraocular muscles in early and late thyroid associated ophthalmopathy

    British Journal of Ophthalmology

    (2000)
  • T.J. Smith et al.

    Orbital fibroblast heterogeneity may determine the clinical presentation of thyroid-associated ophthalmopathy

    Journal of Clinical Endocrinology and Metabolism

    (2002)
  • L. Koumas et al.

    Fibroblast subsets in the human orbit: Thy-1+ and Thy-1- subpopulations exhibit distinct phenotypes

    European Journal of Immunology

    (2002)
  • T.K. Khoo et al.

    Evidence for enhanced Thy-1 (CD90) expression in orbital fibroblasts from patients with Graves’ ophthalmopathy

    Thyroid

    (2008)
  • B. Rapoport et al.

    The thyrotropin (TSH) receptor: interaction with TSH and autoantibodies

    Endocrine Reviews

    (1998)
  • D.H. Khoo et al.

    Graves’ ophthalmopathy in the absence of elevated free thyroxine and triiodothyronine levels: prevalence, natural history, and thyrotropin receptor antibody levels

    Thyroid

    (2000)
  • M.N. Gerding et al.

    Association of thyrotrophin receptor antibodies with the clinical features of Graves’ ophthalmopathy

    Clinical Endocrinology

    (2000)
  • S.D. Lytton et al.

    A novel thyroid stimulating immunoglobulin bioassay is a functional indicator of activity and severity of Graves’ orbitopathy

    Journal of Clinical Endocrinology and Metabolism

    (2010)
  • X.G. Vos et al.

    Frequency and characteristics of TBII-seronegative patients in a population with untreated Graves’ hyperthyroidism: a prospective study

    Clinical Endocrinology (Oxford)

    (2008)
  • A.K. Eckstein et al.

    Thyrotropin receptor autoantibodies are independent risk factors for Graves’ ophthalmopathy and help to predict severity and outcome of the disease

    Journal of Clinical Endocrinology and Metabolism

    (2006)
  • R.S. Bahn et al.

    Thyrotropin receptor expression in cultured Graves’ orbital preadipocyte fibroblasts is stimulated by thyrotropin

    Thyroid

    (1998)
  • A.E. Heufelder et al.

    Evidence for the presence of a functional TSH-receptor in retroocular fibroblasts from patients with Graves’ ophthalmopathy

    Experimental and Clinical Endocrinology

    (1992)
  • K. Starkey et al.

    Adipose thyrotrophin receptor expression is elevated in Graves’ and thyroid eye diseases ex vivo and indicates adipogenesis in progress in vivo

    Journal of Molecular Endocrinology

    (2003)
  • R.S. Bahn et al.

    Thyrotropin receptor expression in Graves’ orbital adipose/connective tissues: potential autoantigen in Graves’ ophthalmopathy

    Journal of Clinical Endocrinology and Metabolism

    (1998)
  • Cited by (102)

    View all citing articles on Scopus
    a

    Tel.: +1 507 284 2462; Fax: +1 507 266 2270.

    View full text