The Link between Graves’ Disease and Hashimoto’s Thyroiditis: A Role for Regulatory T Cells

Hyperthyroidism in Graves’ disease is caused by thyroid-stimulating autoantibodies to the TSH receptor (TSHR), whereas hypothyroidism in Hashimoto’s thyroiditis is associated with thyroid peroxidase and thyroglobulin autoantibodies. In some Graves’ patients, thyroiditis becomes sufficiently extensive to cure the hyperthyroidism with resultant hypothyroidism. Factors determining the balance between these two diseases, the commonest organ-specific autoimmune diseases affecting humans, are unknown. Serendipitous findings in transgenic BALB/c mice, with the human TSHR A-subunit targeted to the thyroid, shed light on this relationship. Of three transgenic lines, two expressed high levels and one expressed low intrathyroidal A-subunit levels (Hi- and Lo-transgenics, respectively). Transgenics and wild-type littermates were depleted of T regulatory cells (Treg) using antibodies to CD25 (CD4+ T cells) or CD122 (CD8+ T cells) before TSHR-adenovirus immunization. Regardless of Treg depletion, high-expressor transgenics remained tolerant to A-subunit-adenovirus immunization (no TSHR antibodies and no hyperthyroidism). Tolerance was broken in low-transgenics, although TSHR antibody levels were lower than in wild-type littermates and no mice became hyperthyroid. Treg depletion before immunization did not significantly alter the TSHR antibody response. However, Treg depletion (particularly CD25) induced thyroid lymphocytic infiltrates in Lo-transgenics with transient or permanent hypothyroidism (low T4, elevated TSH). Neither thyroid lymphocytic infiltration nor hypothyroidism developed in similarly treated wild-type littermates. Remarkably, lymphocytic infiltration was associated with intermolecular spreading of the TSHR antibody response to other self thyroid antigens, murine thyroid peroxidase and thyroglobulin. These data suggest a role for Treg in the natural progression of hyperthyroid Graves’ disease to Hashimoto’s thyroiditis and hypothyroidism in humans.

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Studies in Mice Deficient for the Autoimmune Regulator (Aire) and Transgenic for the Thyrotropin Receptor Reveal a Role for Aire in Tolerance for Thyroid Autoantigens

Endocrinology ◽

10.1210/en.2008-1690 ◽

2009 ◽

Vol 150 (6) ◽

pp. 2948-2956 ◽

Cited By ~ 24

Author(s):

Alexander V. Misharin ◽

Yuji Nagayama ◽

Holly A. Aliesky ◽

Basil Rapoport ◽

Sandra M. McLachlan

Keyword(s):

Hashimoto’S Thyroiditis ◽

Hashimoto's Thyroiditis ◽

Thyroid Peroxidase ◽

Graves Disease ◽

Binding Motif ◽

Wild Type ◽

Autoimmune Regulator ◽

The Third ◽

A Subunit ◽

Thyroid Autoantigens

The autoimmune regulator (Aire) mediates central tolerance for many autoantigens, and autoimmunity occurs spontaneously in Aire-deficient humans and mice. Using a mouse model of Graves’ disease, we investigated the role of Aire in tolerance to the TSH receptor (TSHR) in Aire-deficient and wild-type mice (hyperthyroid-susceptible BALB/c background). Mice were immunized three times with TSHR A-subunit expressing adenovirus. The lack of Aire did not influence T-cell responses to TSHR protein or TSHR peptides. However, antibody levels were higher in Aire-deficient than wild-type mice after the second (but not the third) immunization. After the third immunization, hyperthyroidism persisted in a higher proportion of Aire-deficient than wild-type mice. Aire-deficient mice were crossed with transgenic strains expressing high or low-intrathyroidal levels of human TSHR A subunits. In the low-expressor transgenics, Aire deficiency had the same effect on the pattern of the TSHR antibody response to immunization as in nontransgenics, although the amplitude of the response was lower in the transgenics. High-expressor A-subunit transgenics were unresponsive to immunization. We examined intrathymic expression of murine TSHR, thyroglobulin, and thyroid peroxidase (TPO), the latter two being the dominant autoantigens in Hashimoto’s thyroiditis (particularly TPO). Expression of the TSHR and thyroglobulin were reduced in the absence of Aire. Dramatically, thymic expression of TPO was nearly abolished. In contrast, the human A-subunit transgene, lacking a potential Aire-binding motif, was unaffected. Our findings provide insight into how varying intrathymic autoantigen expression may modulate thyroid autoimmunity and suggest that Aire deficiency may contribute more to developing Hashimoto’s thyroiditis than Graves’ disease.

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Pathology

Diagnosing and Managing Hashimoto’s Disease - Advances in Medical Diagnosis, Treatment, and Care ◽

10.4018/978-1-5225-9655-4.ch003 ◽

2020 ◽

pp. 16-24

Keyword(s):

T Cells ◽

Hashimoto’S Thyroiditis ◽

Plasma Cells ◽

Lymphocytic Infiltration ◽

Lymphoid Cells ◽

Hashimoto's Thyroiditis ◽

Gamma Delta T Cells ◽

Cellular Infiltration ◽

Pyramidal Lobe ◽

Grade Iii

Grossly, thyroid enlargement in Hashimoto's thyroiditis (HT) is generally symmetrical, often with a characteristic conspicuous pyramidal lobe. The tissue involved by HT is pinkish-tan to frankly yellowish in color and tends to have a rubbery firmness. There is no necrosis or calcification. The capsule is intact and non-adherent to peri-thyroid structures. Microscopically, there is a diffuse process consisting of a combination of epithelial cell destruction, lymphoid cellular infiltration, and fibrosis. Lymphocytes are predominantly T-cells and plasma cells. Most infiltrating T-cells have α/β T-cell receptors. Gamma/delta T-cells are rare. Hashimoto's thyroiditis has been graded based on lymphocytic infiltration seen on cytology, into Grades 0-III, where Grade 0 means no lymphoid cells and Grade III severe lymphoid cell infiltration. Deposits of dense material representing IgG are found along the basement membrane on electron microscopy. This chapter explores the pathology of Hashimoto's disease.

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Differential autoantibody responses to thyroid peroxidase in patients with Graves' disease and Hashimoto's thyroiditis

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.77.4.1098 ◽

1993 ◽

Vol 77 (4) ◽

pp. 1098-1101 ◽

Cited By ~ 10

Author(s):

M. Bermann

Keyword(s):

Hashimoto’S Thyroiditis ◽

Hashimoto's Thyroiditis ◽

Thyroid Peroxidase ◽

Graves Disease

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Differential autoantibody responses to thyroid peroxidase in patients with Graves' disease and Hashimoto's thyroiditis.

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jcem.77.4.8408460 ◽

1993 ◽

Vol 77 (4) ◽

pp. 1098-1101 ◽

Cited By ~ 1

Author(s):

M Bermann ◽

M Magee ◽

R J Koenig ◽

M M Kaplan ◽

P Arscott ◽

...

Keyword(s):

Hashimoto’S Thyroiditis ◽

Hashimoto's Thyroiditis ◽

Thyroid Peroxidase ◽

Graves Disease

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Thyroid cells in Graves' disease and Hashimoto's thyroiditis stimulate allogeneic T cells when pretreated with phorbol ester

Clinical Endocrinology ◽

10.1111/j.1365-2265.1992.tb02322.x ◽

1992 ◽

Vol 37 (3) ◽

pp. 274-281 ◽

Cited By ~ 7

Author(s):

N. Tandon ◽

A. P. Weetman

Keyword(s):

T Cells ◽

Phorbol Ester ◽

Hashimoto’S Thyroiditis ◽

Hashimoto's Thyroiditis ◽

Graves Disease ◽

Thyroid Cells

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Cytomorphologic spectrum of Hashimoto's thyroiditis and its clinical correlation: A retrospective study of 52 patients

CytoJournal ◽

10.4103/1742-6413.131741 ◽

2014 ◽

Vol 11 ◽

pp. 9 ◽

Cited By ~ 13

Author(s):

Shirish S. Chandanwale ◽

Charusheela R. Gore ◽

Sunita A. Bamanikar ◽

Nidhi Gupta ◽

Kanika Gupta

Keyword(s):

Thyroid Function ◽

Hashimoto’S Thyroiditis ◽

Lymphocytic Infiltration ◽

Needle Aspiration ◽

Clinical Findings ◽

Hashimoto's Thyroiditis ◽

Thyroid Peroxidase ◽

Follicular Hyperplasia ◽

Number Of Patients ◽

Antibody Profile

Background: Hashimoto's thyroiditis (HT) is an autoimmune disease and it is more prevalent in Asians. The incidence of HT seems to be increasing in the recent times. It is one of the most common cause of hypothyroidism. The purpose of this study is to review the cytomorphologic spectrum of HT and correlate it with clinical findings including thyroid function and antibody profile. Materials and Methods: We retrospectively analyzed the fine-needle aspiration (FNA) features of 52 HT patients. Based on cytomorphologic features patients were categorized into three groups. Clinical findings including thyroid function and thyroid peroxidase (TPO) antibody profile were correlated with cytomorphologic features in all three groups. Results: Majority of the patients were females and in 2nd, 3rd and 4th decades. Diffuse goiter and thyroid hypofunction were the common findings. Significant number of patients had thyroid hyperfunction. Increased lymphocytes on the background and lymphocytic infiltration of thyroid follicular cell clusters in cytology smears were diagnostic of HT. The 32 patients showed elevated titers of TPO antibodies. In the early stages and mild form of the disease, results of thyroid function and anti TPO antibodies are quite variable. Conclusions: HT is a disease of young and middle age and mostly occur in females. Clinical findings alone may not be adequate for definitive diagnosis. FNA is the gold standard for diagnosis. In the presence of abundant colloid, follicular hyperplasia or co-existing neoplasm, careful interpretation of cytology smears should be done. Aspiration from more than one site minimizes the diagnostic pitfalls.

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Evaluation of APRIL in serum of patients with Hashimoto’s Thyroiditis

Revista Científica da Faculdade de Medicina de Campos ◽

10.29184/1980-7813.rcfmc.269.vol.16.n1.2021 ◽

2021 ◽

Vol 16 (1) ◽

pp. 46-51

Author(s):

Adriana Carvalho Santos ◽

Paulo Travassos Neto ◽

Lia Rafaella Ballard Kuhnert ◽

Marcelo Ribeiro Alves ◽

Rita Vasconcellos ◽

...

Keyword(s):

T Cells ◽

Hashimoto’S Thyroiditis ◽

Molecular Mechanisms ◽

Cytotoxic T Cells ◽

Hashimoto's Thyroiditis ◽

Control Group ◽

Thyroid Peroxidase ◽

Healthy Donors ◽

Specific Receptors

Hashimoto’s thyroiditis (HT) is an autoimmune and inflammatory disease in which antibodies are directed against the thyroid gland leading to chronic inflammation and hypothyroidism. The autoimmunity against thyroid antigens can be associated to genetic background and environmental factors. Thyroid peroxidase (TPO) and thyroglobulin (TG) are the major autoantigens for characterizing the disease. HT is related to the activation of autoreactive CD4+ T cells, CD8+ cytotoxic T cells and antithyroid antibody producing-B cells. Among several cytokines related to the pathogenesis of HT, a proliferation-inducing ligand (APRIL) has been studied in the context of the establishment and/or maintenance of autoimmune diseases. The role of APRIL in the pathogenesis of HT is still poorly understood. Therefore, the present study aimed to compare APRIL serum concentration in HT patients and healthy donors by ELISA. We observed a significant decrease in APRIL concentration in HT patients when compared to the control group, and a positive correlation between APRIL level and age. Our results suggest that the APRIL molecule can compose the cytokine profile along the inflammatory response in HT, however, other investigations should be proposed to understand its molecular mechanisms via specific receptors and other regulatory loops.

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Cytomorphological Spectrum of Thyroiditis: A Review of 110 Cases

Journal of Thyroid Research ◽

10.1155/2018/5246516 ◽

2018 ◽

Vol 2018 ◽

pp. 1-7 ◽

Cited By ~ 2

Author(s):

Shirish S. Chandanwale ◽

Rahul Nair ◽

Anushree Gambhir ◽

Supreet Kaur ◽

Aditi Pandey ◽

...

Keyword(s):

Thyroid Function ◽

Hashimoto’S Thyroiditis ◽

Thyroid Function Test ◽

Lymphocytic Infiltration ◽

Hashimoto's Thyroiditis ◽

Thyroid Peroxidase ◽

Thyroid Follicular Cell ◽

Cell Clusters ◽

Thyroid Peroxidase Antibodies ◽

Function Test

Introduction. Different types of thyroiditis may share some parallel clinical and biochemical features. Timely intervention can significantly reduce morbidity and mortality. Aim. Aim of this study is to find the frequency of various thyroiditis, study the cytomorphological features and correlate with clinical findings including radiological findings, thyroid function test, and anti-thyroid peroxidase antibodies (Anti-TPO antibodies). Materials and Methods. The study included consecutive 110 cases of thyroiditis. Detailed cytomorphological features were studied and correlated with ultrasonography findings, thyroid function test, anti-thyroid peroxidase antibodies (anti-TPO) and histopathological features where thyroidectomy specimens were received for histopathological examination. Results. The majority were Hashimoto’s thyroiditis (n=100) and females (n=103). Other forms of thyroiditis were Hashimoto’s thyroiditis with colloid goiter (n=5), De Quervain’s thyroiditis (n=3), and one case each of postpartum thyroiditis and Hashimoto’s thyroiditis with associated malignancy. The majority of patients were in the age group of 21–40 (n=70) and the majority (n=73) had diffuse enlargement of thyroid. The majority of patients were hypothyroid (n=52). The serum anti-TPO antibodies were elevated in 47 patients out of 71 patients. In the 48 patients who underwent ultrasonography, 38 were diagnosed as having thyroiditis. The most consistent cytomorphological features seen in fine-needle aspiration smears of Hashimoto’s thyroiditis were increased background lymphocytes, lymphocytic infiltration of thyroid follicular cell clusters, and Hurthle cells. Conclusion. The diagnostic cytological features in Hashimoto’s thyroiditis are increased background lymphocytes, lymphocytic infiltration of thyroid follicular cell clusters, and Hurthle cells. FNAC remains the “Gold Standard” for diagnosing Hashimoto’s thyroiditis. Clinical history, thyroid function, and biochemical parameters are the key for diagnosis of other forms of thyroiditis.

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Immunoglobulin Gκ Antithyroid Peroxidase Antibodies in Hashimoto’s Thyroiditis: Epitope-Mapping Analysis1

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jcem.82.8.4124 ◽

1997 ◽

Vol 82 (8) ◽

pp. 2639-2644 ◽

Cited By ~ 3

Author(s):

Barbara Czarnocka ◽

Marek Janota-Bzowski ◽

Richard S. McIntosh ◽

M. Suhail Asghar ◽

Philip F. Watson ◽

...

Keyword(s):

Hashimoto’S Thyroiditis ◽

Autoimmune Thyroid Disease ◽

Epitope Mapping ◽

Mapping Method ◽

Hashimoto's Thyroiditis ◽

Thyroid Peroxidase ◽

Graves Disease ◽

Autoimmune Thyroid ◽

Immunodominant Region ◽

High Affinity

Patients with autoimmune thyroid disease frequently have high affinity antibodies to thyroid peroxidase (TPO), although the role they play in disease pathogenesis is not known. We have previously prepared 37 monoclonal anti-TPO IgGκ Fab fragments from two patients with Hashimoto’s thyroiditis and demonstrated the similarity of these Fab sequences to those published previously, mainly derived from patients with Graves’ disease. In this paper, we describe epitope mapping of these Fabs using a previously characterized panel of murine monoclonal antibody (mAb) and show that the Fabs bind to two neighboring epitopes on native TPO. Although the epitope-mapping method differs from that used to characterize previously published TPO-reactive Fab sequences, it indicates a similarly restricted response to neighboring epitopes in both Graves’ disease and Hashimoto’s thyroiditis. The epitope mapping included mAb 47, which binds to a linear TPO peptide of known sequence in addition to native TPO. Although TPO-reactive Fab did not inhibit the binding of mAb 47, mAb 47 did inhibit the binding of Fab, indicating the likely site of the immunodominant region on native TPO. These results confirm the restricted nature of TPO antibody and further delineate the immunodominant region of native TPO as defined by the mAb.

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