THE PATHOGENESIS OF GRAVES' DISEASE

doi:10.1016/S0889-8529(05)70299-1

Endocrinology and Metabolism Clinics of North America

Volume 27, Issue 1, 1 March 1998, Pages 73-89

https://doi.org/10.1016/S0889-8529(05)70299-1 Get rights and content

Graves' disease is an autoimmune condition of the thyroid. Ultimately, the hyperthyroidism manifested by patients affected by the disease is caused by the production of autoantibodies against the thyrotropin receptor (TSH-R), which mimic the effects of the hormone on thyroid cells, thereby stimulating autonomous production of thyroxine and triiodothyronine. However, the derangement of immune function ultimately leading to the production of these pathologic autoantibodies is complex, involving B and T cells and several autoantigens in addition to TSH-R. Best known among these autoantigens are thyroid peroxidase (TPO) and thyroglobulin, although increasing evidence suggests the involvement of other thyroid proteins. This article discusses current theories regarding the pathogenesis of Graves' disease, autoimmunity, possible predisposing and precipitating factors, the nature and character of the autoantigens involved, and prospects for specific immunotherapy for this autoimmune disease.

Section snippets

EPIDEMIOLOGY

Autoimmune thyroid disease is the most common of the organ-specific autoimmune diseases, with spontaneous hypothyroidism being approximately fivefold more common than Graves' disease.¹¹³ The annual incidence of Graves' disease in the Whickham study,¹¹³ a population-based survey in England, was approximately 80 per 100,000 women per year, with most other surveys reporting incidence rates ranging from 15 to 50 per 100,000 persons per year.11, 23, 27, 37, 38 The annual incidence in English men was

AUTOIMMUNE ASPECTS OF GRAVES' DISEASE

Evidence for the autoimmune basis of Graves' disease first emerged with the detection of a long-acting thyroid stimulator in the serum of patients, and the recognition that it was distinct from TSH.¹ The serum-stimulated iodine release from the thyroid glands of guinea pigs occurred more slowly and for a longer period than did pituitary release of TSH. Subsequently, identification of long-acting thyroid stimulator as an IgG⁶² and of TSH-R as the target for the antibody occurred over several

AUTOANTIGENS IN GRAVES' DISEASE

Patients with Graves' disease commonly have antibodies to several thyroidal antigens. The most important and frequent of these are directed toward TSH-R. Other antigens that are frequent targets in the disease include TPO and thyroglobulin, and recent studies suggest that the thyroidal iodide transporter may also represent an autoantigen.31, 81, 96 Whereas anti–TSH-R antibodies are clearly important in the pathogenesis of the disease, anti-TPO and anti-thyroglobulin seem to have little role,

ALTERED IMMUNE SYSTEM FUNCTION IN GRAVES' DISEASE

Evidence for abnormalities in immune system function is commonly found in patients with Graves' disease. This includes the presence of circulating autoantibodies directed against a variety of antigens, discussed previously. Circulating levels of various cytokines, including the interleukins 1, 4, 8, and 10 and interferon gamma, are also present in the peripheral blood of patients with Graves' disease at higher than normal concentrations.49, 52 The source of these circulating cytokines is

IMMUNE TOLERANCE AND SELF-RECOGNITION IN GRAVES' DISEASE

The most widely accepted concept for the development of autoimmune disease is that it arises as a failure of the immune system to distinguish self from nonself, triggering a cascade of humoral and cell-mediated responses against the offending autoantigen. The induction of self-tolerance is a complex and incompletely understood phenomenon involving both the elimination of (by apoptosis) and the induction of anergy or unresponsiveness in self-reactive T cells in the thymus and peripheral tissues.

Infection

Infectious processes can potentially initiate autoimmune phenomena if the infecting agent possesses antigens sufficiently similar to host antigens to elicit a cross-reactive response. The leading candidate as an infective trigger of Graves' disease is Yersinia enterocolitica. Immunization of animals with coat proteins of this bacteria can induce antibodies that cross-react with recombinant TSH-R extracellular domain.70, 71, 127 Evidence also exists for subclinical and persistent infection with

MODULATORS OF THE AUTOIMMUNE PROCESS

Treatment of Graves' disease has remained largely unchanged during the last four decades and consists of thyroid ablation, either with radioactive iodine or surgery, or treatment with antithyroid drugs. None of these therapies is ideal, having either a high rate of iatrogenic hypothyroidism or a high rate of treatment failure.³⁴ Modification of the underlying disease process holds promise of curing Graves' disease without the adverse effects of current treatment strategies.

PROSPECTS FOR SPECIFIC IMMUNOTHERAPY

Currently, intervening to modify the autoimmune process requires the use of agents which affect many aspects of immunity. The use of blockers or activators of specific T-cell receptors may, in the future, provide a means to affect more specifically the autoimmune process without altering the immune response to exogenous antigens. By presenting MHC/antigen complexes via antigen-presenting cells, modified to reduce the expression of costimulatory molecules, it may be possible to induce apoptosis

CONCLUSIONS

Understanding of Graves' disease, its etiology and pathogenesis, and the underlying immune system abnormalities associated with it has advanced rapidly during the 40 years since Adams and Purves first described the long-acting thyroid stimulator. Despite this new information, current therapeutic options differ little from those available in the 1950s. Recent advances in our understanding of immune system regulation and of self-tolerance in particular hold promise that, in the future, we may be

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THE PATHOGENESIS OF GRAVES' DISEASE

Section snippets

EPIDEMIOLOGY

AUTOIMMUNE ASPECTS OF GRAVES' DISEASE

AUTOANTIGENS IN GRAVES' DISEASE

ALTERED IMMUNE SYSTEM FUNCTION IN GRAVES' DISEASE

IMMUNE TOLERANCE AND SELF-RECOGNITION IN GRAVES' DISEASE

Infection

MODULATORS OF THE AUTOIMMUNE PROCESS

PROSPECTS FOR SPECIFIC IMMUNOTHERAPY

CONCLUSIONS

J Lab Clin Med

Int J Immunopharmacol

J Biol Chem

Cell Immunol

Lancet

Baillieres Clin Endocrinol Metab

Biochem Biophys Res Commun

Biochem Biophys Res Commun

Adv Neuroimmunol

Life Sci

Lancet

J Biol Chem

Mayo Clin Proc

Biochem Biophys Res Commun

Abnormal responses in the assay of thyrotropin

Proc Univ Otago Med School

Somatostatin antisense oligodeoxynucleotide-mediated stimulation of lymphocyte proliferation in culture

Endocrinology

Detection of IL-12, IL-13, and IL-15 messenger ribonucleic acid in the thyroid of patients with autoimmune thyroid disease

J Clin Endocrinol Metab

Antithyroid drugs and Graves' disease: A prospective randomized evaluation of the efficacy of treatment duration

J Clin Endocrinol Metab

The effect of iodine on lymphocytic thyroiditis in the thymectomized buffalo rat

Endocrinology

The effect of iodide ingestion on the development of spontaneous lymphocytic thyroiditis in the diabetes-prone BB/W rat

Endocrinology

Blocking type antithyrotropin receptor antibody in patients with nongoitrous hypothyroidism: Its incidence and characteristics of action

J Clin Endocrinol Metab

Activated and interferon-gamma producing thyroid-derived T cells are detected in Graves' disease, thyroid autonomy as well as in non-toxic multinodular goiter

Eur J Endocrinol

Induction of autoimmune thyroiditis in chickens by dietary iodine

Science

Decrease of incidence of toxic nodular goitre in a region of Switzerland after full correction of mild iodine deficiency

Eur J Endocrinol

Total and age-specific incidence of Graves' thyrotoxicosis, toxic nodular goitre and solitary toxic adenoma in Malmo, 1970–74

J Intern Med

Increased incidence of thyrotoxicosis in Malmo during the years 1988–1990 as compared to the years 1970–1974

J Intern Med

Induction of autoimmune diabetes by oral administration of autoantigen

Science

Thyroid hormone and immunological studies in endemic goiter

J Clin Endocrinol Metab

Identification of thyroid blocking antibodies and receptor epitopes in autoimmune hypothyroidism by affinity purification using synthetic TSH receptor peptides

Autoimmunity

Appearance of thyroid stimulating antibody and Graves' disease after radioiodine therapy for toxic nodular goitre

Clin Endocrinol

Detection of antibodies blocking thyrotropin effect using Chinese hamster ovary cells transfected with the cloned human TSH receptor

J Endocrinol Invest

Does infection initiate Graves' disease? A population based 10 year study

Autoimmunity

Cytolytic T cells with Th1-like cytokine profile predominate in retroorbital lymphocytic infiltrates of Graves' ophthalmopathy

J Clin Endocrinol Metab

Radioiodine and the immune system

Thyroid

Histomorphological aspects of the development of thyroid autoimmune diseases: Consequences for our understanding of endocrine ophthalmopathy

Thyroid

Detecting unsuspected thyroid dysfunction by the free thyroxine index

Arch Intern Med

Immunoglobulin allotypes (GM and KM) and their interactions with HLA antigens in autoimmune diseases: A review

Autoimmunity

Iodine content of rat thyroglobulin affects its antigenicity in inducing lymphocytic thyroiditis in the BB/W or rat

Autoimmunity

Autoimmune thyroid disease: Immunological, pathological and clinical aspects

Crit Rev Clin Lab Sci

The management of hyperthyroidism

N Engl J Med

The structure of thyroid autoantigens

Autoimmunity

Graves' disease in Olmsted County, Minnesota, 1935 through 1967