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Autoimmune thyroid disease: new models of cell death in autoimmunity

Key Points

  • Autoimmunity against the thyroid gland generates two opposite pathogenic processes: thyroid hyperplasia in Graves' disease and thyroid destruction in Hashimoto's thyroiditis.

  • Three different mechanisms have been sequentially proposed to be responsible for autoimmune thyrocyte depletion: first, antibody-mediated destruction through immune-complex deposition; second, T-cell-mediated destruction through the release of cytotoxic granules after specific target recognition; and third, death-receptor-mediated induction of apoptosis.

  • The rate of thyrocyte apoptosis dictates the clinical outcome of thyroid autoimmunity. Thyrocyte apoptosis is extremely rare in normal thyroid. It markedly increases during Hashimoto's thyroiditis, but not in Graves' disease. Therefore, regulation of thyrocyte survival is a crucial pathogenic determinant.

  • During Hashimoto's thyroiditis, thyrocytes express death-receptor ligands that might trigger apoptosis of both thyrocytes and infiltrating lymphocytes. So, it is not clear whether lymphocytes kill thyrocytes or vice versa.

  • T-helper lymphocytes produce cytokines that influence both immune and target cells at several levels. The predominance of T-helper type 1 (TH1) or TH2 cytokines might regulate thyrocyte survival through the induction of pro-apoptotic and anti-apoptotic proteins. So, the ability of T-helper cytokines to modify the pattern of apoptotic-related proteins could have a remarkable effect in various immune-mediated conditions.

Abstract

Autoimmunity to thyroid antigens leads to two distinct pathogenic processes with opposing clinical outcomes: hypothyroidism in Hashimoto's thyroiditis and hyperthyroidism in Graves' disease. The high frequency of these diseases and easy accessibility of the thyroid gland has allowed the identification of key pathogenic mechanisms in organ-specific autoimmune diseases. In early investigations, antibody- and T-cell-mediated death mechanisms were proposed as being responsible for autoimmune thyrocyte depletion. Later, studies on apoptosis have provided new insights into autoimmune target destruction, indicating the involvement of death receptors and cytokine-regulated apoptotic pathways in the pathogenesis of thyroid autoimmunity.

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Figure 1: Thyroid autoimmunity produces two opposite pathogenetic processes and clinical outcomes.
Figure 2: Three different mechanisms of thyrocyte depletion in Hashimoto's thyroiditis have been sequentially proposed.
Figure 3: Two independent pathways mediate T-cell cytotoxicity.
Figure 4: Infiltrating T cells might be killed by thyrocytes during Hashimoto's thyroiditis.
Figure 5: Model of thyrocyte fate in thyroid autoimmune diseases.

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Acknowledgements

G.S. and R.D.M. are supported by the Associazione Italiana per la Ricerca sul Cancro.

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Correspondence to Ruggero De Maria.

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DATABASES

LocusLink

APAF-1

BAK

BAX

BCL2

BCL-XL

BID

caspase-3

caspase-8

caspase-9

CD95

CD178

cFLIP

cytochrome c

FAP-1

IFN-γ

IL-1

IL-1β

IL-2

IL-4

IL-5

IL-6

IL-10

IL-12

inducible nitric-oxide syntase

perforin

TGF-β

thyroglobulin

thyroid peroxidase

TNF-α

TNFR superfamily

TRAIL

TRAILR1

TRAILR2

TSH receptor

 OMIM

Graves' disease

Hashimoto's thyroiditis

multiple sclerosis

myasthenia gravis

type 1 diabetes

FURTHER INFORMATION

autoimmune disease

Glossary

CENTRAL TOLERANCE

Autoreactive T cells that react strongly with self-ligands are eliminated during development in the thymus by a process that is known as negative selection.

CRYPTIC EPITOPES

Antigenic peptides that are generated at sub-threshold levels. When cryptic epitopes become visible to the immune system, they might elicit an immune response that is responsible for the autoimmune disease.

GERMINAL CENTRES

Secondary lymphoid follicles that contain reactive B cells which undergo intense proliferation, maturation and death after encountering their specific antigens.

ENDOCRINE OPHTHALMOPATHY

A complex eye disease that is characterized by lymphocyte and chronic inflammatory-cell infiltration in orbital tissues, oedema and proliferation of connective tissue.

GOITRE

Diffuse enlargement of the thyroid gland.

ANERGY

A condition of complete unresponsiveness to antigens that can affect both T and B cells.

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Stassi, G., De Maria, R. Autoimmune thyroid disease: new models of cell death in autoimmunity. Nat Rev Immunol 2, 195–204 (2002). https://doi.org/10.1038/nri750

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