Page 981 - Clinical Immunology_ Principles and Practice ( PDFDrive )

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Autoimmune Thyroid Diseases

Anna L. Mitchell, Simon H.S. Pearce

Autoimmune thyroid disorders are common, and, indeed, as a study estimated that about 80% of the propensity to develop
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group, they are the most prevalent autoimmune disorders in GD is attributable to genetic factors. Further evidence for the
humans. Despite many common underlying features, such as a heritability of GD comes from the observation that it clusters
marked female preponderance, shared susceptibility alleles, and within families. Up to one­quarter of individuals with GD
common autoantigens, Graves disease and autoimmune hypo­ have a first­degree relative with the condition or with another
thyroidism have contrasting clinical characteristics. Over recent autoimmune thyroid disease, such as autoimmune hypothyroid­
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years, our knowledge about the underlying pathogenesis has ism. Should an individual have a sibling with GD, it is estimated
increased as a result of advances in human genomics, molecular that the relative risk (λ s ) of that individual developing GD is
immunology, and the availability of murine models of disease. around 10, which is comparable with that of other heritable
Novel therapies based on this increased understanding are now autoimmune conditions, such as type 1 diabetes, which has a
emerging. λ s of 15.
A number of genetic loci have been shown to contribute
to GD susceptibility (Fig. 70.1). These genes encode proteins
KEY CONCEPTS in biological pathways that regulate immune system activity
Classification of Autoimmune Thyroid Disease or thyroid biology. The major histocompatibility complex
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(MHC) region on chromosome 6p21 has long been associated
Autoimmune hyperthyroidism Graves disease with multiple autoimmune conditions. Human leukocyte antigen
Autoimmune thyroiditis Hashimoto thyroiditis (HLA) genes found within the MHC region play a vital role in
Atrophic thyroiditis
Postpartum thyroiditis pathogen and self­peptide recognition and therefore have a clear
role in immunity and in establishing and maintaining immune
tolerance (Chapter 5).
GRAVES HYPERTHYROIDISM In European populations, the primary association between
MHC and GD is with alleles of the class II MHC genes. The
Graves disease (GD) is a common autoimmune condition that HLA­DR3 allele is detected twice as frequently in subjects with GD
accounts for the majority of cases of hyperthyroidism in the as in healthy controls (i.e., 50% of GD subjects vs 25% of controls).
developed world. Its pathogenesis is unique among the auto­ At the protein level, neutral amino acids alanine or glutamine are
immune endocrinopathies because a key feature is the presence substituted for positively charged arginine at position 74 in the
of stimulating autoantibodies directed against the thyrotropin HLA­DR peptide­binding pocket, which is thought to alter the
(thyroid­stimulating hormone [TSH]) receptor, which mimic binding­pocket configuration, more readily allowing self­peptides
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the action of TSH, a native hormone produced in the pituitary, to enter the antigen binding site. Importantly, 50% of individuals
to drive thyroid overactivity. Interestingly, thyroid dysfunction with GD do not have the HLA-DR3 allele, implying that there
is commonly associated with other extrathyroidal manifestations is unlikely to be a single antigenic epitope responsible for GD.
of GD, the most common being Graves ophthalmopathy (GO). The cytotoxic T lymphocyte antigen­4 (CTLA4) gene (chro­
mosome 2q33) encodes a costimulatory molecule expressed on
Epidemiology the surface of activated T cells, which plays a pivotal role in
GD is one of the most common autoimmune diseases, with a downregulating T­cell responses and in checking T­cell acti­
prevalence of approximately 1% in women in the developed vation, emphasizing the contribution of inhibitory signals in
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world. It is more common in iodine­sufficient countries, where setting immune response thresholds (Chapter 18). The CT60
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it accounts for 60–90% of cases of hyperthyroidism. GD is seven single nucleotide polymorphism (SNP) downstream from the
times more common in women than in men and may affect 3’ untranslated region (3’UTR) was found to influence GD
individuals at any age; however, the peak incidence occurs between susceptibility (odds ratio [OR] 1.5) and has been suggested as
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the ages of 35 and 40 years. a possible etiological variant ; however, the functional effects
of this variant remain poorly defined and contributions from
Etiology other variants, such as at codon 17 in the CTLA­4 signal peptide
GD is a complex genetic condition, implying that environmental remain likely. About 50% of individuals from healthy European
stimuli precipitate disease in genetically predisposed individuals populations carry the autoimmune “susceptible” CTLA4 haplo­
who harbor multiple susceptibility alleles. A large Danish twin type; therefore other important factors are clearly at play. CTLA­4

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