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Immunopathogenesis of Graves’ Disease

  • Chapter
Graves' Disease

Abstract

Hyperthyroidism in Graves’ disease is caused by antibodies to the TSH receptor (TSHR) that mimic the action of TSH. These thyroid stimulating antibodies (TSAb) develop in genetically susceptible individuals because of a breakdown in self-tolerance to the TSHR, a process in which the TSHR itself likely plays a role. Rather than the membrane-bound holoreceptor, the shed, highly glycosylated TSHR A-subunit is the autoantigen in Graves’ disease. Central tolerance involves expression of self-antigen peptides in the thymus and is normally responsible for deleting T cells that bind with high affinity to TSHR peptides. Regulatory T cells provide a backup to central tolerance, together with mechanisms to preclude B cell reactivity to the TSHR. However, all these mechanisms fail in Graves’ patients and lead to the generation of these unusual, high-affinity antibodies, present at low serum concentrations, that stimulate the TSHR. Assays for these antibodies are unconventional and involve either inhibition of TSH binding to its receptor or generation of cAMP from monolayers of TSHR-expressing cells. The epitopes recognized by TSHR antibodies are not linear but conformational. In rare patients, hypothyroidism is caused by TSHR antibodies that block stimulation by TSH (TBAb). Moreover, “switching” from TBAb to TSAb (or vice versa) is sometimes observed. Overall, TSHR antibodies can be of value in monitoring the status of “switch” patients as well as in other situations including the risks of fetal or neonatal hyperthyroidism, prediction of remission, and guidance for the management of Graves’ ophthalmopathy and dermopathy.

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Abbreviations

Aire:

Autoimmune regulator

APECED:

Autoimmune polyendocrinopathy candidiasis-ectodermal dystrophy

APS-1:

Autoimmune polyendocrine syndrome type 1

cAMP:

3′-5′-Cyclic adenosine monophosphate

CD4:

Marker on helper T cells

CD25:

Interleukin-2 receptor α chain

CD122:

Interleukin-2 receptor β chain

CD8:

Marker on cytotoxic T cells

CHO:

Chinese hamster ovary cells

ELISA:

Enzyme-linked immunoassay

ECD:

Extracellular domain of the TSHR

Foxp3:

Forkhead box P3 protein

LATS:

Long-acting thyroid stimulator

LRD:

Leucine-rich repeat domain of the TSHR

LH:

Luteinizing hormone

SNP:

Single nucleotide polymorphism

TBAb:

TSH blocking antibody

TBI:

TSH binding inhibition

Treg:

Regulatory T cells

TSH:

Thyrotropin

TSHR:

Thyrotropin receptor

TMD:

Transmembrane domain of the TSHR

TSAb:

Thyroid stimulating antibody

VNTR:

Variable number of tandem repeats

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  1. Department of Medicine, Cedars-Sinai Medical Center and UCLA, Suite B-131, 8700 Beverly Blvd., Los Angeles, CA, 90048, USA

    Basil Rapoport M.D. & Sandra M. McLachlan Ph.D.

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  1. Basil Rapoport M.D.
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Correspondence to Basil Rapoport M.D. .

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  1. Mayo Clinic College of Medicine, Division of Endocrinology and Metabolism, Mayo Clinic, Rochester, Minnesota, USA

    Rebecca S. Bahn

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Rapoport, B., McLachlan, S.M. (2015). Immunopathogenesis of Graves’ Disease. In: Bahn, R. (eds) Graves' Disease. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-2534-6_2

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