However, not only is presence of these antibodies an extremely rare biochemical phenomenon, but also negative TBII testing at that time suggested absence of these and other TSHR autoantibodies. We believe this report is important as not only is it the first to report thyrotoxicosis due to GD, then due to Hashitoxicosis, and then due to GD in the same individuals, but also the cooccurrence of these 2 autoimmune processes highlights the concept that these are not separate processes but parts of the same autoimmune spectrum.
This is an open access article distributed under the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Article of the Year Award: Outstanding research contributions of , as selected by our Chief Editors. Read the winning articles. Journal overview. Academic Editor: Mihail A. Received 29 Mar Accepted 12 May Published 31 May Case Presentation Case 1.
Discussion These are three very interesting patients who presented with 3 phases of thyrotoxicosis, initially with both biochemical and clinical thyrotoxicosis due to GD, followed by off MMI therapy by recurrence of biochemical thyrotoxicosis only due to Hashitoxicosis, and then again with both biochemical and clinical thyrotoxicosis due to GD.
Competing Interests The authors declare that they have no competing interests. References I. Hunter, S. Greene, T. MacDonald, and A. Segni, E. Leonardi, B. Mazzoncini, I. Pucarelli, and A. McLachlan, Y. Nagayama, P.
Pichurin et al. Aust, K. Krohn, N. Morgenthaler et al. Tani, K. Yoshida, H. Fukazawa et al. Desai and S. View at: Google Scholar H. Tamai, H. Uno, Y. Hirota et al. McLachlan and B. Fountoulakis and A. Canning, C. Ruwhof, and H.
Phenekos, A. Vryonidou, A. Arrows indicate elevated TSH values in hypothyroid mice. Thyroid pathology provided the explanation for the hypothyroidism described above.
Consistent with these observations, wild-type littermates and euthyroid Lo-expressor transgenics immunized with TSHR-Ad had normal thyroid histology Fig. Hyperthyroid wild-type mice developed thyroid hyperplasia without infiltrating lymphocytes Fig. Most striking, however, thyroids of hypothyroid Lo-expressor transgenics Treg depleted with anti-CD25 had massive lymphocyte infiltrates, encompassing much of the thyroid Fig.
The extent of thyroid lymphocytic infiltration in both experiments was quantified as the percentage of the thyroid area invaded by lymphocytes. Thyroid lymphocytic infiltration. Data are shown for Lo-expressor transgenics Tgic-Lo and wild-type mice whose T 4 levels are shown in Fig. Thyroid tissue was obtained at euthanasia 4 wk after the third immunization.
The extent percent of the thyroid infiltrated with lymphocytes was estimated without knowledge of the type of mouse or its treatment regimen.
Values for the four transgenic mice with hypothyroidism at the time of euthanasia Fig. Indeed, in association with thyroid lymphocytic infiltration, autoantibodies to murine Tg were present in all anti-CDtreated Lo-expressor transgenics but in no other groups of transgenics or wild-type mice Fig.
Intermolecular autoantibody spreading from the TSHR to other thyroid autoantigens. These groups of animals also had the greatest degree of thyroid lymphocytic infiltration Fig. Data are expressed as the percent positive gated cells.
Because of human diversity as well as for obvious ethical limitations, syngeneic animal models of autoimmune diseases are invaluable investigative tools. Unlike their wild-type littermates, A-subunit transgenic mice were resistant to immunization with low-dose A-subunit-Ad, although high-dose A-subunit or holoreceptor adenovirus immunization elicited low-level immune responses 5. In the present report, using immunohistochemistry and analysis of thyroid extracts, we categorized the extent of intrathyroidal A-subunit expression in progeny from the five founders and have studied one Lo-expressor and two Hi-expressor transgenic lines.
The data obtained provide novel insight into tolerance and the role of Treg in the pathogenesis of thyroid autoimmune disease. Immunization of the transgenic lines with TSHR-Ad indicated that Hi-expressor mice had a suppressed or absent immune response compared with Lo-expressors. These data are consistent with the Hi-expressors having a greater degree of central tolerance, a process in which self-reactive T cells, which bind with high affinity to peptides from self-antigens expressed in the thymus, are deleted.
Intrathymic expression of the TSHR has been reported for humans 24 , 25 and rats 26 , but A-subunit mRNA was undetectable in thymic tissue from Hi-expressor mice not shown. Although some self-antigens, for example Tg 27 , can be studied in thymic tissue predominantly nonexpressing thymocytes , others are studied in thymic medullary epithelial cells We cannot, therefore, exclude a role for peripheral tolerance in the A-subunit transgenics.
However, as in mice transgenic for hen egg lysozyme 29 , it is likely that high peripheral expression of the human A-subunit correlates with increased central tolerance and low peripheral expression with decreased tolerance to the TSHR. It has recently been recognized that thymic expression of several tissue-restricted antigens varies considerably between individuals Therefore, breaking tolerance is inversely related to the extent of A-subunit transgene expressed in the thyroid, and Treg do not appear to play an important role in this process.
A clinical relationship between these two diseases has long been recognized. With minimal or no lymphocytic infiltration, it is self-evident that there are no reports of progression of hyperthyroidism to hypothyroidism in these mice. Lymphocytic thyroiditis is readily induced using adjuvant combined with self protein, murine Tg 31 or mTPO Despite extensive lymphocytic infiltration, in most studies, the animals remain euthyroid. Indeed, transgenic mice with thyroid-restricted expression of the chemokine CCL21 develop massive lymphocytic B and T cell thyroid infiltration without thyroid autoantibodies, and thyroid function remains unaffected However, until the present report, no animal model has included all the pathological features of human autoimmune thyroid disease, namely hyperthyroidism, massive lymphocytic infiltration leading to hypothyroidism, and autoantibody spreading from the TSHR to TPO and Tg, the other major thyroid-specific autoantigens.
However, it should be emphasized that none of these studies involving Treg depletion led to severe thyroiditis or to hypothyroidism. In contrast, after CD25 Treg depletion, all Lo-expressor mice studied developed hypothyroidism after the second immunization Fig.
Besides inducing extensive thyroid lymphocytic infiltration and hypothyroidism in Lo-expressor A-subunit transgenics, immunization had another unexpected result that mimics human thyroid autoimmune disease, namely spreading of the humoral autoantibody response from the TSHR to other thyroid-specific autoantigens. We provide a hypothesis to explain these intriguing findings Fig. Presumably, cross-reactivity to mouse TSHR peptides is limited or absent.
The immune response is also restrained by Treg. In transgenics but not wild-type mice , lymphocytes home to the thyroid, the source of their target peptides, the human A-subunit. The infiltrating lymphocytes likely including cytotoxic cells and generating cytokines cause thyrocyte damage that can lead to overt hypothyroidism.
Release of thyroid antigens in this inflammatory milieu breaks tolerance to other thyroid antigens. Consequently, our findings provide the first unequivocal evidence for intermolecular autoantibody spreading in thyroid autoimmunity. Schematic representation of the hypothesis whereby Treg depletion in TSHR-immunized Lo-expressor transgenics leads to hypothyroidism and spreading of the immune response to other thyroid self antigens.
Additional details of this hypothesis are described in the text Discussion. Incidentally, it should be noted that hyperthyroidism developed only in wild-type littermates immunized with TSHR-Ad and not in Lo-expressor transgenics. The relatively low proportion of hyperthyroid wild-type mice is anticipated; to break tolerance in A-subunit transgenic animals, immunizations required high-dose adenovirus immunizations, which generate fewer hyperthyroid animals than low-dose immunizations Extensive thyroiditis explains why Lo-expressor transgenics depleted of CD25 Treg became hypothyroid.
However, it is less clear why Lo-expressor transgenics that were not Treg depleted remained euthyroid. It is possible that sufficient A-subunit protein is generated in the thyroid to neutralize thyroid-stimulating antibodies. What evidence is available of a role for Treg in human thyroid autoimmunity?
In humans, the number and function of Treg are still unclear, depending on the Treg markers and assays employed as well as the disease. In another study, intrathyroidal Treg were reduced compared with those in peripheral blood, possibly because of increased apoptosis Despite the limited number of studies and in some cases the limited number of patients investigated , these data are consistent with our findings for the association between thyroiditis and Treg in mice and incidentally with the early studies of Volpe and Iitaka 44 concerning a suppressor T cell defect.
In summary, the present study provides the first description of a complete animal model of autoimmune thyroid disease mimicking all the clinical and pathological features of human disease. This finding has two important clinical implications. We thank our colleagues for generously providing us with reagents: Dr.
We are also grateful for contributions by Dr. Boris Catz, Los Angeles. Am J Hum Genet 73 : — Google Scholar. Endocr Rev 19 : — J Clin Invest : — J Immunol : — Cell 49 : — Trends Mol Med 13 : — J Exp Med : — Endocrinology : — J Clin Endocrinol Metab 84 : — Bradford MM A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding.
Anal Biochem 72 : — Thyroid 16 : — J Virol 70 : — Characterization of receptor expression in normal lymphoid cells and EL-4 cells. Thyroid 9 : — Gene : — The immune system works by recognizing threats such as bacteria and viruses and then mobilizing antibodies to attack and eliminate the offenders — learn more about the inner workings of the immune system here.
This prompts the release of thyroid antibodies in the form of thyroid peroxidase TPO and antithyroglobulin. These militants attack the thyroid, which causes irreparable damage and inhibits thyroid functionality. As the assault progresses, symptoms of hypothyroidism including fatigue, weight gain, hair loss, constipation, cognitive difficulties, and memory loss, may develop and continually increase in severity.
When thyroid antibodies attack the thyroid tissue, the damaged cells release stored thyroid hormone into the bloodstream. Such events cause abrupt hormone spikes that produce symptoms similar to those seen in hyperthyroidism.
This is known as Hashitoxicosis and is often accompanied by symptoms such as panic attacks, anxiety, racing heartbeat, sweating, jitteriness, diarrhea, and sudden weight loss. The condition is caused by an overproduction of thyroid antibodies, specifically thyrotropin receptor antibody TRAb and thyroid-stimulating immunoglobulin TSI. These substances mimic thyroid-stimulating hormone TSH , thereby accelerating thyroid activity and increasing the level of circulating thyroid hormone in the blood.
This triggers an unsustainable hastening of virtually every bodily process that ultimately results in a system-wide crash. Excessive thyroid activity triggered by Graves causes symptoms such as irritability, anxiety, insomnia, weight loss, heat intolerance, diarrhea, and erectile dysfunction.
The result is significant discomfort, an inability to move or close the eyes, inhibited visual capacity, and bulging eyes. However, due to the increased prevalence of certain thyroid antibodies, one may be diagnosed with both conditions. The occurrence of symptoms and their impact on thyroid function depends on the balance of different antibodies promoted by each condition. Although they may not be present at the same time, the effects of these conditions may cause a patient to alternate between symptoms of hypothyroidism and hyperthyroidism.
It is common for individuals to develop additional autoimmune conditions following the first. Thyroid autoimmune disorders are no different.
Regardless of the specific autoimmune condition, treatment of thyroid and autoimmune disease must be tuned and optimized for each patient.
In treating any form of autoimmune thyroid disease, natural treatments typically provide the best results. This is because such approaches often attend to a greater selection of contributing factors.
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