Anti-thyroid autoantibodies are autoantibodies targeted against one or
more components on the thyroid. The most clinically relevant anti-thyroid
autoantibodies are anti-thyroid peroxidase antibodies, thyrotropin
receptor antibodies and thyroglobulin antibodies. TRAbs are subdivided into
activating, blocking and neutral antibodies, depending on their effect on
the TSH receptor. Anti-sodium/Iodide 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
TRAbs 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. Subtypes
Anti-thyroid antibodies can be subdivided into groups according to
their target antigen. = Anti-TPO antibodies=
Anti-thyroid peroxidase antibodies are specific for the autoantigen 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 carboxyl-terminal
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 Hashimoto's thyroiditis, 75% of Graves'
disease and 10-20% of nodular goitre or thyroid carcinoma. 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 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 lymphocytes, 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 significantly to the destruction of the thyroid.
= TSH receptor antibodies= The thyrotropin receptor is the antigen
for TSH receptor antibodies. 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,
blocking antibodies and neutral antibodies. 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
and 1-2% of normal individuals. Activating TRAbs are characteristic of
Graves' disease. 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. 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. Blocking TRAbs) 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 halflife.
= Thyroglobulin 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 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.
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, miscarriage, recurrent miscarriage, preterm birth and
maternal Postpartum thyroiditis. History
In 1912 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. References