Antithyroid autoantibodies (or simply antithyroid antibodies) are

autoantibodies An autoantibody is an antibody (a type of protein) produced by the immune system that is directed against one or more of the individual's own proteins. Many autoimmune diseases (notably lupus erythematosus) are associated with such antibodies. ...

targeted against one or more components on the

thyroid 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 thyroid isthmus. The ...

. The most clinically relevant anti-thyroid autoantibodies are anti-

thyroid peroxidase Thyroid peroxidase, also called thyroperoxidase (TPO) 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 re ...

antibodies (anti-TPO antibodies, TPOAb),

thyrotropin receptor The thyrotropin receptor (or TSH receptor) is a receptor (and associated protein) that responds to thyroid-stimulating hormone (also known as "thyrotropin") and stimulates the production of thyroxine (T4) and triiodothyronine (T3). The TSH recep ...

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 Graves' disease (german: Morbus Basedow), 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 thyro ...

and

Hashimoto's thyroiditis 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. Early on, symptoms may not be noticed. Over time, the thyroid may enlarg ...

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).

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 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". ...

TPO, a 105kDa glycoprotein that catalyses iodine oxidation and thyroglobulin tyrosyl iodination reactions in the thyroid gland. Most antibodies produced are directed to conformational epitopes of the

immunogenic Immunogenicity is the ability of a foreign substance, such as an antigen, to provoke an immune response in the body of a human or other animal. It may be wanted or unwanted: * Wanted immunogenicity typically relates to vaccines, where the injectio ...

carboxyl-terminal The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain ( protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...

region of the TPO protein, although antibodies to linear epitopes have been seen. Anti-TPO antibodies are the most common anti-thyroid autoantibody, present in approximately 90% of

, 75% of Graves' disease and 10-20% of nodular goiter or

thyroid carcinoma Thyroid neoplasm is a neoplasm or tumor of the thyroid. It can be a benign tumor such as thyroid adenoma,Chapter 20 in: 8th edition. or it can be a malignant neoplasm (thyroid cancer), such as papillary, follicular, medullary or anaplastic t ...

. Also, 10-15% of normal individuals can have high level anti-TPO antibody titres. High serum antibodies are found in active phase chronic autoimmune thyroiditis. Thus, an

antibody titer Titer (American English) or titre (British English) is a way of expressing concentration. Titer testing employs serial dilution to obtain approximate quantitative information from an analytical procedure that inherently only evaluates as positiv ...

can be used to assess disease activity in patients that have developed such antibodies. The majority of anti-TPO antibodies are produced by thyroid infiltrating

lymphocyte A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocytes include natural killer cells (which function in cell-mediated, cytotoxic innate immunity), T cells (for cell-mediated, cytotoxic a ...

s, with minor contributions from lymph nodes and the bone marrow. They cause thyroid cell damage by complement activation and antibody dependent cell cytotoxicity. However, anti-TPO antibodies are not believed to contribute to the destruction of the thyroid.

TSH receptor antibodies

The

(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

(85-100% for activating antibodies and 75-96% for blocking antibodies) and 1-2% of normal individuals. 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. TRAbs are also useful in the diagnosis of

Graves' ophthalmopathy 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 ...

. 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 Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in au ...

production that causes

fibroblast A fibroblast is a type of biological cell that synthesizes the extracellular matrix and collagen, produces the structural framework ( stroma) for animal tissues, and plays a critical role in wound healing. Fibroblasts are the most common cells ...

s to produce

glycosaminoglycans Glycosaminoglycans (GAGs) or mucopolysaccharides are long, linear polysaccharides consisting of repeating disaccharide units (i.e. two-sugar units). The repeating two-sugar unit consists of a uronic sugar and an amino sugar, except in the case ...

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

Thyroglobulin (TG) antibodies

Thyroglobulin antibodies are specific for thyroglobulin, a 660kDa 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. 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.

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.

Pathogenesis

The production of antibodies in Graves' disease is thought to arise by activation of CD4+ T-cells, followed by

B-cell B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted o ...

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 Interferon gamma (IFN-γ) is a dimerized soluble cytokine that is the only member of the type II class of interferons. The existence of this interferon, which early in its history was known as immune interferon, was described by E. F. Wheelock ...

, causing the thyroid cells to display

MHC class II molecules MHC Class II molecules are a class of major histocompatibility complex (MHC) molecules normally found only on professional antigen-presenting cells such as dendritic cells, mononuclear phagocytes, some endothelial cells, thymic epithelial cells, ...

. This expands the autoreactive T-cell repertoire and prolongs the inflammatory response. 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.

Effect on human reproduction

The presence of anti-thyroid antibodies is associated with an increased risk of

unexplained subfertility Unexplained infertility is infertility that is idiopathic in the sense that its cause remains unknown even after an infertility work-up, usually including semen analysis in the man and assessment of ovulation and fallopian tubes in the woman.merck ...

(

odds ratio An odds ratio (OR) is a statistic that quantifies the strength of the association between two events, A and B. The odds ratio is defined as the ratio of the odds of A in the presence of B and the odds of A in the absence of B, or equivalently (due ...

1.5 and 95%

confidence interval In frequentist statistics, a confidence interval (CI) is a range of estimates for an unknown parameter. A confidence interval is computed at a designated ''confidence level''; the 95% confidence level is most common, but other levels, such as 9 ...

1.1–2.0), miscarriage (odds ratio 3.73, 95% confidence interval 1.8–7.6),

recurrent miscarriage Recurrent miscarriage is three or more consecutive pregnancy losses. In contrast, infertility is the inability to conceive. In many cases the cause of RPL is unknown. After three or more losses, a thorough evaluation is recommended by American ...

(odds ratio 2.3, 95% confidence interval 1.5–3.5),

preterm birth Preterm birth, also known as premature birth, is the birth of a baby at fewer than 37 weeks gestational age, as opposed to full-term delivery at approximately 40 weeks. Extreme preterm is less than 28 weeks, very early preterm birth is betwee ...

(odds ratio 1.9, 95% confidence interval 1.1–3.5) and maternal

postpartum thyroiditis 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 a ...

(odds ratio 11.5, 95% confidence interval 5.6–24).

History

In 1912

Hakaru Hashimoto was a Japanese doctor and medical scientist of the Meiji and Taishō periods. He is best known for publishing the first description of the disease that was later named Hashimoto's thyroiditis. Biography Hashimoto was born on 5 May 1881, in th ...

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.

References

{{reflist, 2 Autoantibodies Thyroid Antibodies