Antithyroid autoantibodies

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Antithyroid autoantibodies (or simply antithyroid antibodies) are autoantibodies targeted against one or more components on the thyroid. The most clinically relevant anti-thyroid autoantibodies are anti-thyroid peroxidase antibodies (anti-TPO antibodies, TPOAb), thyrotropin receptor antibodies (TRAb) and thyroglobulin antibodies (TgAb). TRAb's are subdivided into activating, blocking and neutral antibodies, depending on their effect on the TSH receptor. Anti-sodium/iodide (Anti–Na+/I−) symporter antibodies are a more recent discovery and their clinical relevance is still unknown. Graves' disease and Hashimoto's thyroiditis are commonly associated with the presence of anti-thyroid autoantibodies. Although there is overlap, anti-TPO antibodies are most commonly associated with Hashimoto's thyroiditis and activating TRAb's are most commonly associated with Graves' disease. Thyroid microsomal antibodies were a group of anti-thyroid antibodies; they were renamed after the identification of their target antigen (TPO). [1] [2] [3] [4]

Contents

Subtypes

Anti-thyroid antibodies can be subdivided into groups according to their target antigen.

Anti-TPO antibodies

Anti-thyroid peroxidase (anti-TPO) antibodies are specific for the autoantigen TPO, a 105 kDa glycoprotein that catalyses iodine oxidation and thyroglobulin tyrosyl iodination reactions in the thyroid gland. [5] Most antibodies produced are directed to conformational epitopes of the immunogenic carboxyl-terminal region of the TPO protein, although antibodies to linear epitopes have been seen. [4] Anti-TPO antibodies are the most common anti-thyroid autoantibody, present in approximately 90% of Hashimoto's thyroiditis, 75% of Graves' disease and 10–20% of nodular goiter or thyroid carcinoma. Also, 10–15% of normal individuals can have high level anti-TPO antibody titres. [4] [6] [7] High serum antibodies are found in active phase chronic autoimmune thyroiditis. Thus, an antibody titer can be used to assess disease activity in patients that have developed such antibodies. [4] [7] [8] The majority of anti-TPO antibodies are produced by thyroid infiltrating lymphocytes, with minor contributions from lymph nodes and the bone marrow. [9] They cause thyroid cell damage by complement activation and antibody dependent cell cytotoxicity. [7] However, anti-TPO antibodies are not believed to contribute to the destruction of the thyroid. [10]

TSH receptor antibodies

The thyrotropin receptor (TSH receptor) is the antigen for TSH receptor antibodies (TRAbs). It is a seven transmembrane G protein-coupled receptor that is involved in thyroid hormone signalling. TRAbs are grouped depending on their effects on receptor signalling; activating antibodies (associated with hyperthyroidism), blocking antibodies (associated with thyroiditis) and neutral antibodies (no effect on receptor). Activating and blocking antibodies mostly bind to conformational epitopes, whereas neutral antibodies bind to linear epitopes. Binding of the antibody to the amino terminus of the TSH receptor shows stimulatory activity, whereas binding to residues 261-370 or 388-403 block the activity. TRAbs are present in 70–100% of Graves' disease (85–100% for activating antibodies and 75–96% for blocking antibodies) and 1–2% of normal individuals. [1] [2] [11]

Activating TRAbs are characteristic of Graves' disease (autoimmune hyperthyroidism). TPO antibody is measured more easily than the TSH receptor antibody, and so is often used as a surrogate in the diagnosis of Graves' disease. These antibodies activate adenylate cyclase by binding to the TSH receptor. This causes the production of thyroid hormones and subsequent growth and vascularisation of the thyroid. [1] TRAbs are also useful in the diagnosis of Graves' ophthalmopathy. Although the exact mechanism of how TRAbs induce Graves' ophthalmopathy is unknown, it is likely that the antibodies bind to TSH receptors in retro-orbital tissues, causing infiltration of lymphocytes. This inflammatory response leads to cytokine production that causes fibroblasts to produce glycosaminoglycans, leading to ophthalmopathy. [12] [13]

Blocking TRAbs (also known as thyrotropin binding inhibitory immunoglobulins (TBII)) competitively block the activity of TSH on the receptor. This can cause hypothyroidism by reducing the thyrotropic effects of TSH. They are found in Hashimoto's thyroiditis and Graves' disease and may be cause of fluctuation of thyroid function in the latter. During treatment of Graves' disease they may also become the predominant antibody, which can cause hypothyroidism. [2] [13]

The clinical and physiological relevance of neutral antibodies remains unclear. However, they may be involved in prolonging the TSH receptor half-life. [2]

Thyroglobulin (TG) antibodies

Thyroglobulin antibodies are specific for thyroglobulin, a 660 kDa matrix protein involved in the process of thyroid hormone production. They are found in 70% of Hashimoto's thyroiditis, 60% of idiopathic hypothyroidism, 30% of Graves' disease, a small proportion of thyroid carcinoma and 3% of normal individuals. [1] [3] Anti-TPO antibodies are present in 99% of cases where thyroglobulin antibodies are present, however only 35% of anti-TPO antibody positive cases also demonstrate thyroglobulin antibodies. [14]

Anti–Na+/ I− symporter

Anti-Na+/I− symporter antibodies are a more recent discovery of possible thyroid autoantibodies and their role in thyroid disease remains uncertain. They are present in approximately 20% of Graves' disease and 24% of Hashimoto's thyroiditis. [1]

Pathogenesis

The production of antibodies in Graves' disease is thought to arise by activation of CD4+ T-cells, followed by B-cell recruitment into the thyroid. These B-cells produce antibodies specific to the thyroid antigens. In Hashimoto's thyroiditis, activated CD4+ T-cells produce interferon-γ, causing the thyroid cells to display MHC class II molecules. This expands the autoreactive T-cell repertoire and prolongs the inflammatory response. [15]

While anti-thyroid antibodies are used to track the presence of autoimmune thyroiditis, they are generally not considered to contribute directly to the destruction of the thyroid. [10]

Effect on human reproduction

The presence of anti-thyroid antibodies is associated with an increased risk of unexplained subfertility (odds ratio 1.5 and 95% confidence interval 1.1–2.0), miscarriage (odds ratio 3.73, 95% confidence interval 1.8–7.6), recurrent miscarriage (odds ratio 2.3, 95% confidence interval 1.5–3.5), preterm birth (odds ratio 1.9, 95% confidence interval 1.1–3.5) and maternal postpartum thyroiditis (odds ratio 11.5, 95% confidence interval 5.6–24). [16]

History

In 1912 Hakaru Hashimoto described hypothyroidism and goiter associated with thyroid lymphoid infiltration. In 1956 the anti-Tg antibody was detected in similar cases, elucidating the autoimmune cause of these characteristics. Later the same year, activating TSH receptor antibodies were discovered. Thyroid microsomal antibodies were discovered in 1964, which were subsequently renamed anti-TPO antibodies due to the identification of their autoantigen. [1]

Related Research Articles

<span class="mw-page-title-main">Hyperthyroidism</span> Thyroid gland disease that involves an overproduction of thyroid hormone

Hyperthyroidism is the condition that occurs due to excessive production of thyroid hormones by the thyroid gland. Thyrotoxicosis is the condition that occurs due to excessive thyroid hormone of any cause and therefore includes hyperthyroidism. Some, however, use the terms interchangeably. Signs and symptoms vary between people and may include irritability, muscle weakness, sleeping problems, a fast heartbeat, heat intolerance, diarrhea, enlargement of the thyroid, hand tremor, and weight loss. Symptoms are typically less severe in the elderly and during pregnancy. An uncommon but life-threatening complication is thyroid storm in which an event such as an infection results in worsening symptoms such as confusion and a high temperature; this often results in death. The opposite is hypothyroidism, when the thyroid gland does not make enough thyroid hormone.

<span class="mw-page-title-main">Thyroid</span> Endocrine gland in the neck; secretes hormones that influence metabolism

The thyroid, or thyroid gland, is an endocrine gland in vertebrates. In humans, it is in the neck and consists of two connected lobes. The lower two thirds of the lobes are connected by a thin band of tissue called the isthmus (pl.: isthmi). The thyroid gland is a butterfly-shaped gland located in the neck below the Adam's apple. Microscopically, the functional unit of the thyroid gland is the spherical thyroid follicle, lined with follicular cells (thyrocytes), and occasional parafollicular cells that surround a lumen containing colloid. The thyroid gland secretes three hormones: the two thyroid hormones – triiodothyronine (T3) and thyroxine (T4) – and a peptide hormone, calcitonin. The thyroid hormones influence the metabolic rate and protein synthesis and growth and development in children. Calcitonin plays a role in calcium homeostasis. Secretion of the two thyroid hormones is regulated by thyroid-stimulating hormone (TSH), which is secreted from the anterior pituitary gland. TSH is regulated by thyrotropin-releasing hormone (TRH), which is produced by the hypothalamus.

<span class="mw-page-title-main">Graves' disease</span> Autoimmune endocrine disease

Graves' disease, also known as toxic diffuse goiter, is an autoimmune disease that affects the thyroid. It frequently results in and is the most common cause of hyperthyroidism. It also often results in an enlarged thyroid. Signs and symptoms of hyperthyroidism may include irritability, muscle weakness, sleeping problems, a fast heartbeat, poor tolerance of heat, diarrhea and unintentional weight loss. Other symptoms may include thickening of the skin on the shins, known as pretibial myxedema, and eye bulging, a condition caused by Graves' ophthalmopathy. About 25 to 30% of people with the condition develop eye problems.

<span class="mw-page-title-main">Hypothyroidism</span> Endocrine disease

Hypothyroidism is a disorder of the endocrine system in which the thyroid gland does not produce enough thyroid hormones. It can cause a number of symptoms, such as poor ability to tolerate cold, a feeling of tiredness, constipation, slow heart rate, depression, and weight gain. Occasionally there may be swelling of the front part of the neck due to goitre. Untreated cases of hypothyroidism during pregnancy can lead to delays in growth and intellectual development in the baby or congenital iodine deficiency syndrome.

<span class="mw-page-title-main">Autoimmunity</span> Immune response against an organisms own healthy cells

In immunology, autoimmunity is the system of immune responses of an organism against its own healthy cells, tissues and other normal body constituents. Any disease resulting from this type of immune response is termed an "autoimmune disease". Prominent examples include celiac disease, post-infectious IBS, diabetes mellitus type 1, Henoch–Schönlein purpura (HSP) sarcoidosis, systemic lupus erythematosus (SLE), Sjögren syndrome, eosinophilic granulomatosis with polyangiitis, Hashimoto's thyroiditis, Graves' disease, idiopathic thrombocytopenic purpura, Addison's disease, rheumatoid arthritis (RA), ankylosing spondylitis, polymyositis (PM), dermatomyositis (DM), and multiple sclerosis (MS). Autoimmune diseases are very often treated with steroids.

Thyroid-stimulating hormone (also known as thyrotropin, thyrotropic hormone, or abbreviated TSH) is a pituitary hormone that stimulates the thyroid gland to produce thyroxine (T4), and then triiodothyronine (T3) which stimulates the metabolism of almost every tissue in the body. It is a glycoprotein hormone produced by thyrotrope cells in the anterior pituitary gland, which regulates the endocrine function of the thyroid.

<span class="mw-page-title-main">Thyroglobulin</span> Protein produced and used by the thyroid

Thyroglobulin (Tg) is a 660 kDa, dimeric glycoprotein produced by the follicular cells of the thyroid and used entirely within the thyroid gland. Tg is secreted and accumulated at hundreds of grams per litre in the extracellular compartment of the thyroid follicles, accounting for approximately half of the protein content of the thyroid gland. Human TG (hTG) is a homodimer of subunits each containing 2768 amino acids as synthesized.

<span class="mw-page-title-main">Hashimoto's thyroiditis</span> Autoimmune disease

Hashimoto's thyroiditis, also known as chronic lymphocytic thyroiditis and Hashimoto's disease, is an autoimmune disease in which the thyroid gland is gradually destroyed. A slightly broader term is autoimmune thyroiditis, identical other than that it is also used to describe a similar condition without a goitre.

Ord's thyroiditis is a common form of thyroiditis, an autoimmune disease where the body's own antibodies fight the cells of the thyroid.

<span class="mw-page-title-main">Thyroid peroxidase</span> Enzyme expressed mainly in the thyroid gland

Thyroid peroxidase, also called thyroperoxidase (TPO), thyroid specific peroxidase or iodide peroxidase, is an enzyme expressed mainly in the thyroid where it is secreted into colloid. Thyroid peroxidase oxidizes iodide ions to form iodine atoms for addition onto tyrosine residues on thyroglobulin for the production of thyroxine (T4) or triiodothyronine (T3), the thyroid hormones. In humans, thyroperoxidase is encoded by the TPO gene.

<span class="mw-page-title-main">Thyroid disease</span> Medical condition

Thyroid disease is a medical condition that affects the function of the thyroid gland. The thyroid gland is located at the front of the neck and produces thyroid hormones that travel through the blood to help regulate many other organs, meaning that it is an endocrine organ. These hormones normally act in the body to regulate energy use, infant development, and childhood development.

<span class="mw-page-title-main">Thyroiditis</span> Medical condition

Thyroiditis is the inflammation of the thyroid gland. The thyroid gland is located on the front of the neck below the laryngeal prominence, and makes hormones that control metabolism.

<span class="mw-page-title-main">Thyrotropin receptor</span> Mammalian protein found in Homo sapiens

The thyrotropin receptor is a receptor that responds to thyroid-stimulating hormone and stimulates the production of thyroxine (T4) and triiodothyronine (T3). The TSH receptor is a member of the G protein-coupled receptor superfamily of integral membrane proteins and is coupled to the Gs protein.

<span class="mw-page-title-main">Graves' ophthalmopathy</span> Medical condition

Graves’ ophthalmopathy, also known as thyroid eye disease (TED), is an autoimmune inflammatory disorder of the orbit and periorbital tissues, characterized by upper eyelid retraction, lid lag, swelling, redness (erythema), conjunctivitis, and bulging eyes (exophthalmos). It occurs most commonly in individuals with Graves' disease, and less commonly in individuals with Hashimoto's thyroiditis, or in those who are euthyroid.

<span class="mw-page-title-main">Subacute thyroiditis</span> Medical condition

Subacute thyroiditis refers to a temporal classification of the different forms of thyroiditis based on onset of symptoms. The temporal classification of thyroiditis includes presentation of symptoms in an acute, subacute, or chronic manner. There are also other classification systems for thyroiditis based on factors such as clinical symptoms and underlying etiology.

Postpartum thyroiditis refers to thyroid dysfunction occurring in the first 12 months after pregnancy and may involve hyperthyroidism, hypothyroidism or the two sequentially. According to the National Institute of Health, postpartum thyroiditis affects about 8% of pregnancies. There are, however, different rates reported globally. This is likely due to the differing amounts of average postpartum follow times around the world, and due to humans' own innate differences. For example, in Bangkok, Thailand the rate is 1.1%, but in Brazil it is 13.3%. The first phase is typically hyperthyroidism. Then, the thyroid either returns to normal or a woman develops hypothyroidism. Of those women who experience hypothyroidism associated with postpartum thyroiditis, one in five will develop permanent hypothyroidism requiring lifelong treatment.

<span class="mw-page-title-main">Hashimoto's encephalopathy</span> Human disease (neurological condition)

Hashimoto's encephalopathy, also known as steroid-responsive encephalopathy associated with autoimmune thyroiditis (SREAT), is a neurological condition characterized by encephalopathy, thyroid autoimmunity, and good clinical response to corticosteroids. It is associated with Hashimoto's thyroiditis, and was first described in 1966. It is sometimes referred to as a neuroendocrine disorder, although the condition's relationship to the endocrine system is widely disputed. It is recognized as a rare disease by the NIH Genetic and Rare Diseases Information Center.

An antithyroid agent is a hormone inhibitor acting upon thyroid hormones.

Thyroid disease in pregnancy can affect the health of the mother as well as the child before and after delivery. Thyroid disorders are prevalent in women of child-bearing age and for this reason commonly present as a pre-existing disease in pregnancy, or after childbirth. Uncorrected thyroid dysfunction in pregnancy has adverse effects on fetal and maternal well-being. The deleterious effects of thyroid dysfunction can also extend beyond pregnancy and delivery to affect neurointellectual development in the early life of the child. Due to an increase in thyroxine binding globulin, an increase in placental type 3 deioidinase and the placental transfer of maternal thyroxine to the fetus, the demand for thyroid hormones is increased during pregnancy. The necessary increase in thyroid hormone production is facilitated by high human chorionic gonadotropin (hCG) concentrations, which bind the TSH receptor and stimulate the maternal thyroid to increase maternal thyroid hormone concentrations by roughly 50%. If the necessary increase in thyroid function cannot be met, this may cause a previously unnoticed (mild) thyroid disorder to worsen and become evident as gestational thyroid disease. Currently, there is not enough evidence to suggest that screening for thyroid dysfunction is beneficial, especially since treatment thyroid hormone supplementation may come with a risk of overtreatment. After women give birth, about 5% develop postpartum thyroiditis which can occur up to nine months afterwards. This is characterized by a short period of hyperthyroidism followed by a period of hypothyroidism; 20–40% remain permanently hypothyroid.

<span class="mw-page-title-main">Thyroid's secretory capacity</span>

Thyroid's secretory capacity is the maximum stimulated amount of thyroxine that the thyroid can produce in a given time-unit.

References

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