Page 987 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPTEr 70 Autoimmune Thyroid Diseases 953

and orbital pressure is relieved by urgent orbital decompression effect. These data highlight the need to further investigate the
surgery. In patients whose eyelids do not close completely, eye MHC region to clarify its role in AH susceptibility.
ointments and protective eye pads are essential to protect the In common with GD, the CTLA-4 gene also appears to influ­
eyes against corneal damage and ulceration. Once disease activity ence AH susceptibility. Three CTLA-4 polymorphisms have been
has burned out, rehabilitative surgery can greatly improve the associated with AH in a number of populations. An A/G SNP
function and cosmetic appearance of the eyes. Orbital decompres­ located downstream of the 3’UTR (designated CT60), an A/G
sion, strabismus correction, and eyelid surgery are commonly polymorphism at codon 17, and a 106­bp microsatellite repeat
used procedures. 22 in the 3’UTR of exon 3. A locus on chromosome 8q24 containing
the thyroglobulin gene was linked to AH, and a number of SNPs
FUTURE DEVELOPMENTS FOR GRAVES were subsequently studied in AH individuals with modest reported
HYPERTHYROIDISM AND OPHTHALMOPATHY ORs for association of between 1.32 and 1.56. Other loci impli­
cated in AH susceptibility include the tumor necrosis factor
Novel approaches to modulating the immune response in GD (TNF-α) gene, PTPN22, CYP27B1, T­cell receptor (TCR) genes,
and GO as a therapeutic strategy are under investigation. In light and several immunoglobulin genes and cytokine regulatory genes.
of the significant side effects associated with steroid therapy In contrast to GD, environmental factors in AH susceptibility
for GO, steroid­sparing agents, including methotrexate and have been challenging to identify. However, the role of iodine is
mycophenolate mofetil, are of particular interest. Novel biological widely accepted, since population studies have reported an increase
agents have been evaluated to a limited extent in these condi­ in the prevalence of thyroid lymphocytic infiltration and auto­
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tions and are subject to further ongoing studies. Rituximab, antibodies following public health salt iodization programs.
a CD20 monoclonal antibody (mAb) that depletes circulating Infectious agents have also been implicated in susceptibility to
B cells, appeared to be potentially efficacious in early studies; AH. Several studies have identified an increased prevalence of
however, in two randomized controlled trials in individuals with IgG and/or IgA antibodies to virulence­associated outer mem­
moderate to severe active GO, results have been conflicting, and brane proteins of Yersinia enterocolitica in AH patients and in
therefore further studies are now needed. A longer­term goal is relatives of individuals with AH, suggesting that susceptibility
the development of an anti–TSH­R antibody or small molecule genes for Yersinia infection may also confer risk for AH.
antagonist that could block binding of stimulatory TSH­R anti­ The effect of radiation, either “internal” (nuclear “fallout” or
bodies or inhibit TSH­R signaling, thus ameliorating the cause of from RAI treatment) or “external” (radiotherapy or direct
hyperthyroidism. exposure during a nuclear accident), on AH susceptibility has
been extensively studied. Following the nuclear reactor accident
AUTOIMMUNE HYPOTHYROIDISM at Chernobyl, a rise in thyroid autoantibodies was noted 15 years
following exposure; however, this was not accompanied by thyroid
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The most common cause of autoimmune hypothyroidism (AH) dysfunction. Long­term follow­up studies of thyroid function
is chronic (or lymphocytic) autoimmune thyroiditis. There are in Japanese survivors of the atomic bombing of Nagasaki and
two variants, atrophic and goitrous (Hashimoto thyroiditis). Hiroshima have demonstrated a clear link between radiation
exposure and thyroid cancer; however, the association with AH
Epidemiology remains disputed. One study, at 40 years follow­up, demonstrated
In populations living in iodine sufficient areas, AH is common, a significant relationship between dose of radiation exposure at
affecting between 1 and 10% of the population. The prevalence Nagasaki and AH. However, a further study, at more than 50
increases with age, with 3–20% of individuals over 75 years of years of follow­up, showed that radiation exposure did not
age being hypothyroid. Like GD, AH is more common in women correlate with either the occurrence of thyroid autoantibodies
than in men. In a UK community survey, the incidence of or AH. 26
hypothyroidism in women was 3.5/1000/year, which increased
to 13.7/1000/year in women between 75 and 80 years of age. In Immunopathogenesis
men, the incidence was just 0.6/1000/year. 24 The mechanisms by which tolerance to thyroid antigens is
lost in the first instance remain obscure. It appears that both
Etiology a susceptible genetic background and a permissive environ­
AH, like GD, is a complex genetic condition. Familial clustering ment are required before AH develops. Notably, AH is much
provides evidence for a genetic etiology, which, in several studies, more frequent in the autoimmune polyendocrinopathy type 1
appears stronger than that for GD. The λs for AH is estimated (APECED) syndrome than GD, suggesting that central thymic
to be between 10 and 45, suggesting that AH is more heritable T­cell selection, and therefore central tolerance, may be more
compared with GD. In families with autoimmunity, frequently important in AH than in GD. Histologically, lymphocytic
a mixture of individuals affected by AH and GD are seen, sug­ infiltrates can be seen in the thyroid, consisting of both T and
gesting some shared genetic factors. The differing prevalence of B cells (Fig. 70.7). These infiltrates can be diffuse or focal.
AH in different ethnic groups, with AH being more common Scarring and fibrosis may also be seen, with destruction of the
in Caucasian than in black populations, also supports a genetic normal thyroid architecture and an absence of colloid in thyroid
background. Knowledge about the genetics of AH is limited. follicles.
The MHC class II HLA-DR3, ­DR4, and ­DR5 alleles have Both cell­mediated and humoral immune mechanisms are
been associated with AH in Caucasians only. Conflicting results important in the continuing thyroid damage seen in AH. T cells
have been reported for HLA-DQ alleles. One study reported that are known to play a pivotal role in both the initiation and perpetu­
the HLA-DQ alleles DQA1*0301 and DQB1*0201 confer sus­ ation of AH. Studies in which researchers induced hypothyroidism
ceptibility to AH in Caucasians, with certain HLA-DQ alleles in Rag1­deficient transgenic mice that were unable to produce
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(DQA1*0102 and DQB1*0602) reported to confer a protective autoantibodies confirm this. T cells respond to antigen­presenting