Human monoclonal thyroid stimulating autoantibody

Sanders, Jane; Evans, Michele K.; Premawardhana, Lakdasa; Depraetere, Hilde; Jeffreys, Jennifer; Richards, Tonya; Furmaniak, Jadwiga; Smith, Bernard Rees

doi:10.1016/s0140-6736(03)13866-4

Cited by 156 publications

(148 citation statements)

References 5 publications

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“…This finding of restricted L chain usage for TSAb activity after SHM events suggests that agonistic activity to the TSHR is mediated by a particular conformation of Ab that can perhaps be attained by a few combinations of IGH and IGK rearrangements. These observations are in line with tentative findings on the common usage of certain gene rearrangements in monoclonal TSAbs from experimental Graves' disease (7,8,30) and the human monoclonal TSAbs from patients with autoimmune hyperthyroidism (11,12). Although limited information is available, there appears to be notable similarity in the gene usage by mouse and human monoclonal TSAbs (Supplemental Table I).…”

Section: Discussionsupporting

confidence: 84%

“…The monoclonal TSAbs derived from experimental models of Graves' disease have been shown to be pathogenic in vivo, confirming their role in disease pathogenesis (8)(9)(10). Importantly, human monoclonal TSAbs from patients with Graves' disease have also been derived, providing detail into their molecular and biochemical properties, and pathogenicity in vivo (11)(12)(13). A major advance has been the delineation of the atomic structures of immune complex of human monoclonal TSAb, M22 and human monoclonal TSBAb, and K1-70 with human TSHR A-subunit (14)(15)(16).…”

mentioning

confidence: 70%

“…KSAb1 and KSAb2 are thus equivalent to the TSAbs present in Graves' disease patients (11,12). Importantly, both KSAb1 and KSAb2 are derived from the same original precursor B cell as they use identical germline gene rearrangements, thus giving an opportunity to evaluate the Ag specificity of their germline precursor (30).…”

Section: Discussionmentioning

confidence: 99%

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Yersinia enterocolitica Provides the Link between Thyroid-Stimulating Antibodies and Their Germline Counterparts in Graves’ Disease

Hargreaves

Grasso

Hampe

et al. 2013

The Journal of Immunology

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Graves’ disease results from thyroid-stimulating Abs (TSAbs) activating the thyrotropin receptor (TSHR). How TSAbs arise from early precursor B cells has not been established. Genetic and environmental factors may contribute to pathogenesis, including the bacterium Yersinia enterocolitica. We developed two pathogenic monoclonal TSAbs from a single experimental mouse undergoing Graves’ disease, which shared the same H and L chain germline gene rearrangements and then diversified by numerous somatic hypermutations. To address the Ag specificity of the shared germline precursor of the monoclonal TSAbs, we prepared rFab germline, which showed negligible binding to TSHR, indicating importance of somatic hypermutation in acquiring TSAb activity. Using rFab chimeras, we demonstrate the dominant role of the H chain V region in TSHR recognition. The role of microbial Ags was tested with Y. enterocolitica proteins. The monoclonal TSAbs recognize 37-kDa envelope proteins, also recognized by rFab germline. MALDI-TOF identified the proteins as outer membrane porin (Omp) A and OmpC. Using recombinant OmpA, OmpC, and related OmpF, we demonstrate cross-reactivity of monoclonal TSAbs with the heterogeneous porins. Importantly, rFab germline binds recombinant OmpA, OmpC, and OmpF confirming reactivity with Y. enterocolitica. A human monoclonal TSAb, M22 with similar properties to murine TSAbs, also binds recombinant porins, showing cross-reactivity of a spontaneously arising pathogenic Ab with Y. enterocolitica. The data provide a mechanistic framework for molecular mimicry in Graves’ disease, where early precursor B cells are expanded by Y. enterocolitica porins to undergo somatic hypermutation to acquire a cross-reactive pathogenic response to TSHR.

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Section: Discussionsupporting

confidence: 84%

mentioning

confidence: 70%

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Yersinia enterocolitica Provides the Link between Thyroid-Stimulating Antibodies and Their Germline Counterparts in Graves’ Disease

Hargreaves

Grasso

Hampe

et al. 2013

The Journal of Immunology

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“…[6][7][8] Classical TBII assays are limited by their inability to discriminate between thyroid-stimulating antibodies (TSAbs) and thyroid-blocking antibodies (TBAbs). However, the most newly developed thirdgeneration TBII assay inhibits binding of a labeled TSAb (monoclonal Ab clone #M22) rather than labeled TSH to the TSH receptor 9,10 This results in enhanced sensitivity and specificity vs earlier assays using radiolabeled TSH. 6,8,11,12 The TSI bioassay measures cyclic adenosine monophosphate production after TSAb binds to TSH receptor.…”

Section: Introductionmentioning

confidence: 99%

Relevance of TSH-receptor antibody levels in predicting disease course in Graves’ orbitopathy: comparison of the third-generation TBII assay and Mc4-TSI bioassay

Jang

Shin

Lee

et al. 2013

Eye

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Aims To investigate if TSH-receptor antibody (TRAb) levels measured in early Graves' orbitopathy (GO) stages are predictive of clinical disease course beyond 1 year after initial GO diagnosis and to compare performance of two newly developed TRAb assays (third-generation thyrotropin-binding inhibitor immunoglobulin (TBII) assay vs Mc4-thyroid-stimulating immunoglobulin (TSI) bioassay) in predicting disease course. Methods Newly diagnosed, untreated GO patients whose duration of ocular symptoms was less than 6 months were included. One year after initial diagnosis, all patients were classified as presenting either a mild (Group 1) or severe course (Group 2) according to their clinical manifestations. The measurements of two TRAb assays at initial GO diagnosis were used for analysis. Results Data from 112 patients were available for analysis. Seventy-three patients (65.2%) were designated as Group 1, and 39 patients (34.8%) as Group 2. Patients with higher initial TRAb levels demonstrated a higher risk of severe disease course upon multiple regression analysis (Po0.01). The cutoff values for the prediction of severe course of the third-generation TBII and Mc4-TSI assays were 10.67 IU/l and 555.10%, respectively, with assay specificities of 84.9 and 89.0%. The TBII assay predictive power

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“…M22 is a human monoclonal autoantibody to the TSHR prepared using lymphocytes from a patient with Graves' disease. It has powerful thyroid stimulating and TSH binding inhibiting activity and binds to the TSHR with high affinity (5!10 10 l/mol; Sanders et al 2003Sanders et al , 2004. The unbound M22 Fab crystal structure, solved at 1 .…”

Section: Introductionmentioning

confidence: 99%

Thyroid stimulating autoantibody M22 mimics TSH binding to the TSH receptor leucine rich domain: a comparative structural study of protein–protein interactions

Miguel¹,

Sanders²,

Chirgadze³

et al. 2009

Journal of Molecular Endocrinology

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The TSH receptor (TSHR) ligands M22 (a thyroid stimulating human monoclonal antibody) and TSH, bind to the concave surface of the leucine rich repeats domain (LRD) of the TSHR and here, we show that M22 mimics closely the binding of TSH. We compared interactions produced by M22 with the TSHR in the M22-TSHR crystal structure (2 . 55 Å resolution) and produced by TSH with the TSHR in a TSH-TSHR comparative model. The crystal structure of the TSHR and a comparative model of TSH based on the crystal structure of FSH were used as components to build the TSH-TSHR model. This model was built based on the FSH-FSH receptor structure (2 . 9 Å ) and then the structure of the TSHR in the model was replaced by the TSHR crystal structure. The analysis shows that M22 light chain mimics the TSHb chain in its interaction with TSHR LRD, while M22 heavy chain mimics the interactions of the TSHa chain. The M22-TSHR complex contains a greater number of hydrogen bonds and salt bridges and fewer hydrophobic interactions than the TSH-TSHR complex, consistent with a higher M22 binding affinity. Furthermore, the surface area formed by TSHR residues N208, Q235, R255, and N256 has been identified as a candidate target region for small molecules which might selectively block binding of autoantibodies to the TSHR.

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Human monoclonal thyroid stimulating autoantibody

Cited by 156 publications

References 5 publications

Yersinia enterocolitica Provides the Link between Thyroid-Stimulating Antibodies and Their Germline Counterparts in Graves’ Disease

Yersinia enterocolitica Provides the Link between Thyroid-Stimulating Antibodies and Their Germline Counterparts in Graves’ Disease

Relevance of TSH-receptor antibody levels in predicting disease course in Graves’ orbitopathy: comparison of the third-generation TBII assay and Mc4-TSI bioassay

Thyroid stimulating autoantibody M22 mimics TSH binding to the TSH receptor leucine rich domain: a comparative structural study of protein–protein interactions

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