Breaking Tolerance to Thyroid Antigens: Changing Concepts in Thyroid Autoimmunity
TL;DR: The goal of inducing self-tolerance to prevent autoimmune thyroid disease will require accurate prediction of at-risk individuals together with an antigen-specific, not blanket, therapeutic approach.
Abstract: Thyroid autoimmunity involves loss of tolerance to thyroid proteins in genetically susceptible individuals in association with environmental factors. In central tolerance, intrathymic autoantigen presentation deletes immature T cells with high affinity for autoantigen-derived peptides. Regulatory T cells provide an alternative mechanism to silence autoimmune T cells in the periphery. The TSH receptor (TSHR), thyroid peroxidase (TPO), and thyroglobulin (Tg) have unusual properties ("immunogenicity") that contribute to breaking tolerance, including size, abundance, membrane association, glycosylation, and polymorphisms. Insight into loss of tolerance to thyroid proteins comes from spontaneous and induced animal models: 1) intrathymic expression controls self-tolerance to the TSHR, not TPO or Tg; 2) regulatory T cells are not involved in TSHR self-tolerance and instead control the balance between Graves' disease and thyroiditis; 3) breaking TSHR tolerance involves contributions from major histocompatibility complex molecules (humans and induced mouse models), TSHR polymorphism(s) (humans), and alternative splicing (mice); 4) loss of tolerance to Tg before TPO indicates that greater Tg immunogenicity vs TPO dominates central tolerance expectations; 5) tolerance is induced by thyroid autoantigen administration before autoimmunity is established; 6) interferon-α therapy for hepatitis C infection enhances thyroid autoimmunity in patients with intact immunity; Graves' disease developing after T-cell depletion reflects reconstitution autoimmunity; and 7) most environmental factors (including excess iodine) "reveal," but do not induce, thyroid autoimmunity. Micro-organisms likely exert their effects via bystander stimulation. Finally, no single mechanism explains the loss of tolerance to thyroid proteins. The goal of inducing self-tolerance to prevent autoimmune thyroid disease will require accurate prediction of at-risk individuals together with an antigen-specific, not blanket, therapeutic approach.
Citations
More filters
TL;DR: Thyroid dysfunction during pembrolizumab treatment of NSCLC is common and is characterized by early-onset, frequently preceded by transient hyperthyroidism, closely associated with anti-thyroid antibodies, and may be associated with improved outcomes.
463 citations
Cites background from "Breaking Tolerance to Thyroid Antig..."
...Although a breakdown of self-tolerance is suspected to lead to thyroid autoimmunity [20], the mechanisms of how PD-1 blockade may reveal such auto-immunity remain unclear....
[...]
TL;DR: autoantibodies can be classified into the following categories: mimic receptor stimulation, blocking of neural transmission, induction of altered signaling, triggering uncontrolled microthrombosis, cell lysis, neutrophil activation, and (7) induction of inflammation.
Abstract: Autoantibodies are frequently observed in healthy individuals In a minority of these individuals, they lead to manifestation of autoimmune diseases, such as rheumatoid arthritis or Graves’ disease Overall, more than 25% of the population is affected by autoantibody-driven autoimmune disease Pathways leading to autoantibody-induced pathology greatly differ among different diseases, and autoantibodies directed against the same antigen, depending on the targeted epitope, can have diverse effects To foster knowledge in autoantibody-induced pathology and to encourage development of urgently needed novel therapeutic strategies we here categorized autoantibodies according to their effects According to our algorithm, autoantibodies can be classified into the following categories: (1) Mimic receptor stimulation, (2) blocking of neural transmission, (3) induction of altered signaling, triggering uncontrolled (4) microthrombosis, (5) cell lysis, (6) neutrophil activation and (7) induction of inflammation These mechanisms in relation to disease, as well as principles of autoantibody generation and detection are reviewed herein
318 citations
Cites background from "Breaking Tolerance to Thyroid Antig..."
...The highly glycosylated extracellular TSHR A-subunit, formed by intramolecular cleavage of the holoreceptor, is shed and is the autoantigen primarily responsible for TSAb induction in Graves’ disease (80–82) (Figure 3B)....
[...]
...Instead, TSAb and Graves’-like hyperthyroidism can be induced in mice or hamsters by injecting intact eukaryotic cells expressing the TSHR or by injecting plasmid/adenoviral vectors encoding the TSHR or, more efficiently, its A-subunit (77, 87)....
[...]
...First, injecting neonatal BALB/c mice with TSHR A-subunit protein induced tolerance that could not be broken by subsequent immunization with adenovirus encoding A-subunit (124)....
[...]
...Crystallization of both types of mAb with recombinant TSHR-A-subunit protein reveal closely overlapping epitopes with subtle differences expected for a TSAb (M22) and a TBAb (K1-70) (101, 102)....
[...]
...(B) Representation of the TSH holoreceptor including its transmembrane domain (left) and the TSHR A-subunit (right) shed after cleavage....
[...]
TL;DR: Thyroid dysfunction is common in cancer patients treated with pembrolizumab and the mechanism of thyroid destruction appears independent of thyroid autoantibodies and may include T cell, NK cell, and/or monocyte-mediated pathways.
Abstract: Context:
Thyroid immune-related adverse events (irAEs) in patients treated with programmed death receptor-1 (PD-1) blockade are increasingly recognized as one of the most common adverse effects. Our aim was to determine the incidence and examine the potential mechanisms of anti-PD-1–induced thyroid irAEs.
184 citations
Cites background from "Breaking Tolerance to Thyroid Antig..."
...As such, whereas the role of PD-1–dependent T-cell activation may contribute to T cell–mediated destruction of the thyroid in pembrolizumab-treated patients, the role of PD-1 in the autoimmune setting seem less likely, consistent with known antibody-mediatedmechanism for the latter (28)....
[...]
TL;DR: The importance of epigenetic alterations during the development of the most prevalent human autoimmune diseases, such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), systemic sclerosis (SSc), Sjogren’s syndrome (SS), autoimmune thyroid diseases (AITD), and type 1 diabetes (T1D), is reviewed to provide new insights in the pathogenesis of autoimmune diseases.
Abstract: Epigenetic pathways play a pivotal role in the development and function of the immune system. Over the last decade, a growing body of studies has been published out seeking to explain a correlation between epigenetic modifications and the development of autoimmune disorders. Epigenetic changes, such as DNA methylation, histone modifications, and noncoding RNAs, are involved in the pathogenesis of autoimmune diseases mainly by regulating gene expression. This paper reviews the importance of epigenetic alterations during the development of the most prevalent human autoimmune diseases, such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), systemic sclerosis (SSc), Sjogren’s syndrome (SS), autoimmune thyroid diseases (AITD), and type 1 diabetes (T1D), aiming to provide new insights in the pathogenesis of autoimmune diseases and the possibility to develop novel therapeutic approaches targeting the epigenome.
155 citations
TL;DR: There are large differences in thyroid function reference intervals between different populations of pregnant women, which can be explained by variations in assays as well as population-specific factors, such as ethnicity and body mass index.
Abstract: Background: Gestational thyroid dysfunction is common and associated with maternal and child morbidity and mortality. During pregnancy, profound changes in thyroid physiology occur, resulting in different thyroid-stimulating hormone (TSH) and free thyroxine (FT4) reference intervals compared to the nonpregnant state. Therefore, international guidelines recommend calculating trimester- and assay-specific reference intervals per center. If these reference intervals are unavailable, TSH reference intervals of 0.1–2.5 mU/L for the first trimester and 0.2–3.0 mU/L for the second trimester are recommended. In daily practice, most institutions do not calculate institution-specific reference intervals but rely on these fixed reference intervals for the diagnosis and treatment of thyroid disorders during pregnancy. However, the calculated reference intervals for several additional pregnancy cohorts have been published in the last few years and show substantial variation.
Content: We provide a detailed overview of the available studies on thyroid function reference intervals during pregnancy, different factors that contribute to these reference intervals, and the maternal and child complications associated with only minor variations in thyroid function.
Summary: There are large differences in thyroid function reference intervals between different populations of pregnant women. These differences can be explained by variations in assays—as well as population-specific factors, such as ethnicity and body mass index. The importance of using correct reference intervals is underlined by the fact that even small subclinical variations in thyroid function have been associated with detrimental pregnancy outcomes, including low birth weight and pregnancy loss. It is therefore crucial that institutions do not rely on a fixed universal cutoff concentrations, but calculate their own pregnancy-specific reference intervals.
148 citations
References
More filters
TL;DR: The authors showed that CD4+CD25+ cells contribute to maintaining self-tolerance by downregulating immune response to self and non-self Ags in an Ag-nonspecific manner, presumably at the T cell activation stage.
Abstract: Approximately 10% of peripheral CD4+ cells and less than 1% of CD8+ cells in normal unimmunized adult mice express the IL-2 receptor alpha-chain (CD25) molecules. When CD4+ cell suspensions prepared from BALB/c nu/+ mice lymph nodes and spleens were depleted of CD25+ cells by specific mAb and C, and then inoculated into BALB/c athymic nude (nu/nu) mice, all recipients spontaneously developed histologically and serologically evident autoimmune diseases (such as thyroiditis, gastritis, insulitis, sialoadenitis, adrenalitis, oophoritis, glomerulonephritis, and polyarthritis); some mice also developed graft-vs-host-like wasting disease. Reconstitution of CD4+CD25+ cells within a limited period after transfer of CD4+CD25- cells prevented these autoimmune developments in a dose-dependent fashion, whereas the reconstitution several days later, or inoculation of an equivalent dose of CD8+ cells, was far less efficient for the prevention. When nu/nu mice were transplanted with allogeneic skins or immunized with xenogeneic proteins at the time of CD25- cell inoculation, they showed significantly heightened immune responses to the skins or proteins, and reconstitution of CD4+CD25+ cells normalized the responses. Taken together, these results indicate that CD4+CD25+ cells contribute to maintaining self-tolerance by down-regulating immune response to self and non-self Ags in an Ag-nonspecific manner, presumably at the T cell activation stage; elimination/reduction of CD4+CD25+ cells relieves this general suppression, thereby not only enhancing immune responses to non-self Ags, but also eliciting autoimmune responses to certain self-Ags. Abnormality of this T cell-mediated mechanism of peripheral tolerance can be a possible cause of various autoimmune diseases.
5,929 citations
TL;DR: TSH and the prevalence of antithyroid antibodies are greater in females, increase with age, and are more in whites and Mexican Americans than in blacks, which needs more research to relate these findings to clinical status.
Abstract: NHANES III measured serum TSH, total serum T(4), antithyroperoxidase (TPOAb), and antithyroglobulin (TgAb) antibodies from a sample of 17,353 people aged > or =12 yr representing the geographic and ethnic distribution of the U.S. population. These data provide a reference for other studies of these analytes in the U.S. For the 16,533 people who did not report thyroid disease, goiter, or taking thyroid medications (disease-free population), we determined mean concentrations of TSH, T(4), TgAb, and TPOAb. A reference population of 13,344 people was selected from the disease-free population by excluding, in addition, those who were pregnant, taking androgens or estrogens, who had thyroid antibodies, or biochemical hypothyroidism or hyperthyroidism. The influence of demographics on TSH, T(4), and antibodies was examined. Hypothyroidism was found in 4.6% of the U.S. population (0.3% clinical and 4.3% subclinical) and hyperthyroidism in 1.3% (0.5% clinical and 0.7% subclinical). (Subclinical hypothyroidism is used in this paper to mean mild hypothyroidism, the term now preferred by the American Thyroid Association for the laboratory findings described.) For the disease-free population, mean serum TSH was 1.50 (95% confidence interval, 1.46-1.54) mIU/liter, was higher in females than males, and higher in white non-Hispanics (whites) [1.57 (1.52-1.62) mIU/liter] than black non-Hispanics (blacks) [1.18 (1.14-1.21) mIU/liter] (P < 0.001) or Mexican Americans [1.43 (1.40-1.46) mIU/liter] (P < 0.001). TgAb were positive in 10.4 +/- 0.5% and TPOAb, in 11.3 +/- 0.4%; positive antibodies were more prevalent in women than men, increased with age, and TPOAb were less prevalent in blacks (4.5 +/- 0.3%) than in whites (12.3 +/- 0.5%) (P < 0.001). TPOAb were significantly associated with hypo or hyperthyroidism, but TgAb were not. Using the reference population, geometric mean TSH was 1.40 +/- 0.02 mIU/liter and increased with age, and was significantly lower in blacks (1.18 +/- 0.02 mIU/liter) than whites (1.45 +/- 0.02 mIU/liter) (P < 0.001) and Mexican Americans (1.37 +/- 0.02 mIU/liter) (P < 0.001). Arithmetic mean total T(4) was 112.3 +/- 0.7 nmol/liter in the disease-free population and was consistently higher among Mexican Americans in all populations. In the reference population, mean total T(4) in Mexican Americans was (116.3 +/- 0.7 nmol/liter), significantly higher than whites (110.0 +/- 0.8 nmol/liter) or blacks (109.4 +/- 0.8 nmol/liter) (P < 0.0001). The difference persisted in all age groups. In summary, TSH and the prevalence of antithyroid antibodies are greater in females, increase with age, and are greater in whites and Mexican Americans than in blacks. TgAb alone in the absence of TPOAb is not significantly associated with thyroid disease. The lower prevalence of thyroid antibodies and lower TSH concentrations in blacks need more research to relate these findings to clinical status. A large proportion of the U.S. population unknowingly have laboratory evidence of thyroid disease, which supports the usefulness of screening for early detection.
3,471 citations
TL;DR: Aire-deficient thymic medullary epithelial cells showed a specific reduction in ectopic transcription of genes encoding peripheral antigens, highlighting the importance of thymically imposed “central” tolerance in controlling autoimmunity.
Abstract: Humans expressing a defective form of the transcription factor AIRE (autoimmune regulator) develop multiorgan autoimmune disease. We used aire- deficient mice to test the hypothesis that this transcription factor regulates autoimmunity by promoting the ectopic expression of peripheral tissue- restricted antigens in medullary epithelial cells of the thymus. This hypothesis proved correct. The mutant animals exhibited a defined profile of autoimmune diseases that depended on the absence of aire in stromal cells of the thymus. Aire-deficient thymic medullary epithelial cells showed a specific reduction in ectopic transcription of genes encoding peripheral antigens. These findings highlight the importance of thymically imposed "central" tolerance in controlling autoimmunity.
2,276 citations
"Breaking Tolerance to Thyroid Antig..." refers background in this paper
...The absence of Aire leads to spontaneous thyroiditis in NOD mice, but not in mice on other genetic backgrounds (89)....
[...]
...Aire is a transcription factor that regulates the expression of nu- merous self-proteins in medullary thymic epithelial cells....
[...]
...Niki S, Oshikawa K, Mouri Y, et al. Alteration of intrapancreatic target-organ specificity by abrogation of Aire in NOD mice....
[...]
...Mice engineered to express this naturally occurring Aire mutation (G228W) had partial inhibition of intrathymic expression of some self-antigens (198)....
[...]
...Immunological Basis for Self-Tolerance A. Central tolerance B. Autoimmune regulator (Aire) C. Regulatory T cells D. B-cell tolerance E. Tolerogenic dendritic cells V. Induced Thyroid Autoimmunity A. Conventional approach to induce thyroiditis B....
[...]
TL;DR: The results show that in normal animals tolerance to self-MHC is due to clonal elimination rather than suppression, and indicate that tolerance induction may occur in the thymus at the time immature thymocytes are selected to move into the mature thymocyte pool.
2,187 citations
"Breaking Tolerance to Thyroid Antig..." refers background in this paper
...T cells that recognize self-peptides with high affinity are deleted from the repertoire (74)....
[...]
...Central tolerance is based on negative selection of autoreactive T cells in the thymic medulla (74)....
[...]