Characterization of Monoclonal Antibodies Derived from Lymphocytes from Graves' Disease Patients in a Cytochemical Bioassay for Thyroid Stimulators*

Ealey, P. A.; Kohn, Leonard D.; Ekins, Roger; Marshall, Nicholas J.

doi:10.1210/jcem-58-5-909

Cited by 40 publications

(19 citation statements)

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“…4B, column b as well as a), a feature of TBIIs in Graves patients (11)(12)(13). The ability to inhibit TSH-induced increases in cAMP levels correlated with TBII rather than stimulating TSHRAb activity-i.e., TSHRAb with thyroid-stimulating and TBII activities are functionally distinct, consistent with studies of monoclonal TSHRAbs from Graves patients (28,29).…”

Section: Resultsmentioning

confidence: 96%

“…However, in no case did the immunization produce thyroid-stimulating TSHR antibodies (TSHRAbs), which increase thyroid hormone levels, the hallmark of Graves, nor were the morphologic or histologic features of the disease induced: glandular enlargement, thyrocyte hypercellularity, and thyrocyte intrusion into the follicular lumen. Further, in most studies (1)(2)(3)(4)(5)(6)(7)(8)(9)(10), the antibodies that inhibited TSH binding were not shown to inhibit TSH activity mediated specifically by the TSH receptor, a feature characteristic of TSH binding inhibitory immunoglobulins (TBIIs) in GD (11)(12)(13).…”

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confidence: 99%

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Induction of Graves-like disease in mice by immunization with fibroblasts transfected with the thyrotropin receptor and a class II molecule.

Shimojo

Kohno

Yamaguchi

et al. 1996

Proc. Natl. Acad. Sci. U.S.A.

214

132

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Graves disease is an autoimmune thyroid disease characterized by the presence of antibodies against the thyrotropin receptor (TSHR), which stimulate the thyroid to cause hyperthyroidism and/or goiter. By immunizing mice with fibroblasts transfected with both the human TSHR and a major histocompatibility complex class II molecule, but not by either alone, we have induced immune hyperthyroidism that has the major humoral and histological features of Graves disease: stimulating TSHR antibodies, thyrotropin binding inhibiting immunoglobulins, which are different from the stimulating TSHR antibodies, increased thyroid hormone levels, thyroid enlargement, thyrocyte hypercellularity, and thyrocyte intrusion into the follicular lumen. The results suggest that the aberrant expression of major histocompatibility complex class II molecules on cells that express a native form of the TSHR can result in the induction of functional anti-TSHR antibodies that stimulate the thyroid. They additionally suggest that the acquisition of antigen-presenting ability on a target cell containing the TSHR can activate T and B cells normally present in an animal and induce a disease with the major features of autoimmune Graves.Numerous attempts (1-10) to develop a Graves disease (GD) model by immunizing animals with the extracellular domain of the thyrotropin receptor (TSHR) have largely failed. In most cases, antibodies to the TSHR that could inhibit thyrotropin (TSH) binding and, in some cases, thyroiditis with a large lymphocytic infiltration were produced (1-10). However, in no case did the immunization produce thyroid-stimulating TSHR antibodies (TSHRAbs), which increase thyroid hormone levels, the hallmark of Graves, nor were the morphologic or histologic features of the disease induced: glandular enlargement, thyrocyte hypercellularity, and thyrocyte intrusion into the follicular lumen. Further, in most studies (1-10), the antibodies that inhibited TSH binding were not shown to inhibit TSH activity mediated specifically by the TSH receptor, a feature characteristic of TSH binding inhibitory immunoglobulins (TBIIs) in GD (11-13).These studies depended on the ability of the animal to process the TSHR as an extracellular antigen, rather than as a receptor in a functional state on a cell. They did not take into account the possibility that the TSHR might be presented to the immune system as a result of abnormal major histocompatibility complex (MHC) class I or class II expression on thyrocytes, thereby allowing normal immune tolerance to be broken. Thus, several studies have implicated class I as an important component in the development of autoimmune thyroid disease and in the action of methimazole, a drug used to treat GD (14-18). In addition, aberrant class II expression, as well as abnormal expression of class I molecules, is evident on thyrocytes in autoimmune thyroid diseases (19-21), although the cause and role of aberrant class II in disease expression remains controversial (22). The sum of these observations (1-22) raised...

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Section: Resultsmentioning

confidence: 96%

mentioning

confidence: 99%

Induction of Graves-like disease in mice by immunization with fibroblasts transfected with the thyrotropin receptor and a class II molecule.

Shimojo

Kohno

Yamaguchi

et al. 1996

Proc. Natl. Acad. Sci. U.S.A.

214

132

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“…Contradictory data exist for and against this hypothesis. Evidence and TSH binding-inhibitory activities (22)(23)(24), but none of these antibodies have been proven to be against the TSH receptor. The reported ability of IgG from patients with autoimmune thyroid disease to immunoprecipitate TSH -TSH receptor complexes (25)(26)(27)(28) would also support the existence of separate binding sites for TSH receptor antibodies and TSH.…”

Section: Discussionmentioning

confidence: 99%

Binding domains of stimulatory and inhibitory thyrotropin (TSH) receptor autoantibodies determined with chimeric TSH-lutropin/chorionic gonadotropin receptors.

Nagayama

Wadsworth²,

Russo³

et al. 1991

J. Clin. Invest.

152

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“…Autoantibodies against various thyroid antigens such as thyroid peroxidase (TPO), thyroglobulin (Tg), sodium iodide symporter (SLC5A5: NIS), and Pendred syndrome gene (SLC26A4: Pendrin) are present in the sera of patients with Hashimoto's thyroiditis (3,4). Furthermore, Graves' hyperthyroidism is caused by production of thyroid-stimulating antibodies (TSAbs) against the thyroid-stimulating hormone receptor (TSHR) (5). Although the production of autoantibodies requires disruption of self-tolerance and activation of an adaptive immune response, the underlying molecular mechanisms that trigger such changes are still unknown.…”

Section: Introductionmentioning

confidence: 99%

Demonstration of Innate Immune Responses in the Thyroid Gland: Potential to Sense Danger and a Possible Trigger for Autoimmune Reactions

Kawashima

Yamazaki²,

Hara

et al. 2013

Thyroid

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Background: Autoimmune thyroid disease is an archetypal organ-specific autoimmune disorder that is characterized by the production of thyroid autoantibodies and lymphocytic infiltration into the thyroid. However, the underlying mechanisms by which specific thyroid antibodies are produced are largely unknown. Recent studies have shown that innate immune responses affect both the phenotype and the severity of autoimmune reactions. Moreover, it appears that even non-immune cells, including thyroid cells, have an ability to launch such responses. The aim of this study was to conduct a more detailed analysis of innate immune responses of the thyroid upon stimulation with various ''non-self'' and ''self'' factors that might contribute to the initiation of autoimmune reactions. Methods: We used rat thyroid FRTL-5 cells, human thyroid cells, and mice to investigate the effects of various pathogen-associated molecular patterns (PAMPs), danger-associated molecular patterns (DAMPs), and iodide on gene expression and function that were related to innate immune responses. Results: RT-PCR analysis showed that both rat and human thyroid cells expressed mRNAs for Toll-like receptors (TLRs) that sense PAMPs. Stimulation of thyrocytes with TLR ligands resulted in activation of the interferon-beta (IFN-b) promoter and the nuclear factor kappa-light-chain-enhancer of activated B cells (NFjB)-dependent promoter. As a result, pro-inflammatory cytokines, chemokines, and type I interferons were produced. Similar activation was observed when thyroid cells were stimulated with double-stranded DNA, one of the typical DAMPs. In addition to these PAMPs and DAMPs, treatment of thyroid cells with high concentrations of iodide increased mRNA expression of various cytokines. Conclusion: We show that thyroid cells express functional sensors for exogenous and endogenous dangers, and that they are capable of launching innate immune responses without the assistance of immune cells. Such responses may relate to the development of thyroiditis, which in turn may trigger autoimmune reactions.

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Characterization of Monoclonal Antibodies Derived from Lymphocytes from Graves' Disease Patients in a Cytochemical Bioassay for Thyroid Stimulators*

Cited by 40 publications

References 0 publications

Induction of Graves-like disease in mice by immunization with fibroblasts transfected with the thyrotropin receptor and a class II molecule.

Induction of Graves-like disease in mice by immunization with fibroblasts transfected with the thyrotropin receptor and a class II molecule.

Binding domains of stimulatory and inhibitory thyrotropin (TSH) receptor autoantibodies determined with chimeric TSH-lutropin/chorionic gonadotropin receptors.

Demonstration of Innate Immune Responses in the Thyroid Gland: Potential to Sense Danger and a Possible Trigger for Autoimmune Reactions

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