ORIGINAL ARTICLE: Monoclonal autoantibodies to the TSH receptor, one with stimulating activity and one with blocking activity, obtained from the same blood sample

Evans, Michele K.; Sanders, Jane; Tagami, Tetsuya; Sanders, Paul G.; Young, Stuart; Roberts, Emma; Wilmot, Jane; Hu, Xiaoling; Kabelis, Katarzyna; Clark, J. C. D.; Holl, Sabrina; Richards, Tonya; Collyer, Alastair; Furmaniak, Jadwiga; Smith, Bernard Rees

doi:10.1111/j.1365-2265.2010.03831.x

Cited by 103 publications

(138 citation statements)

References 35 publications

(150 reference statements)

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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: 71%

“…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%

“…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).…”

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confidence: 88%

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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: 71%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 88%

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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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“…2,[6][7][8] A evolução de tirotoxicose/hipertiroidismo subclínico para hipotiroidismo clínico pode enquadrar-se simplesmente na história natural da TL, cujo processo destrutivo autoimune condiciona libertação das hormonas tiroideias (tirotoxicose transitória), e posterior hipotiroidismo inerente à destruição glandular e consequente diminuição da reserva funcional da tiróide. A este processo, no entanto, pode-se ter associado a ação bloqueadora dos TRAbs.…”

Section: Discussionunclassified

Hipotiroidismo Associado a Anticorpos Anti-Receptor da Hormona TSH com Ação Bloqueadora Determinada In Vitro

Marques¹,

Chikh

Charrié

et al. 2015

Acta Med Port

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RESUMOOs anticorpos anti-receptor da hormona estimulante da tiróide causam habitualmente hipertiroidismo. No entanto, a sua atividade pode ser bloqueadora, condicionando o hipotiroidismo. Apresenta-se o caso de uma doente do sexo feminino, 11 anos, com diabetes mellitus tipo 1, doença celíaca e tiroidite linfocítica em eutiroidismo ao diagnóstico. Cerca de dois anos após a avaliação inicial, a hormona estimulante da tiróide apresentava-se suprimida com T4 livre normal. Nove meses depois, a evolução foi para hipotiroidismo notandose concomitantemente elevação dos anticorpos anti-receptor da hormona estimulante da tiróide, mantendo-se a doente sempre assintomática. Células chinese hamster ovary foram transfetadas com o receptor de hormona estimulante da tiróide, e após incubação com o soro da doente, verificou-se uma atividade bloqueadora 'moderada' dos anticorpos anti-receptor da hormona estimulante da tiróide, excluindo-se ação estimuladora concomitante. Neste caso, o reconhecimento da ação bloqueadora dos anticorpos anti-receptor da hormona estimulante da tiróide detetados no soro suporta a hipótese de uma etiologia multifatorial para o hipotiroidismo que, na ausência dos testes in vitro, tenderíamos a interpretar unicamente como sequela do processo destrutivo associado à tiroidite linfocítica. Palavras-chave: Doença de Graves; Hipotiroidismo; Receptores da Tireotropina; Tireoidite Autoimune. ABSTRACTThyroid-stimulating hormone-receptor autoantibodies normally causes hyperthyroidism. However, they might have blocking activity causing hypothyroidism. A 11-year-old girl followed due to type 1 diabetes mellitus, celiac disease and euthyroid lymphocytic thyroiditis at diagnosis. Two years after the initial evaluation, thyroid-stimulating hormone was suppressed with normal free T4; nine months later, a biochemical evolution to hypothyroidism with thyroid-stimulating hormone-receptor autoantibodies elevation was seen; the patient remained always asymptomatic. Chinese hamster ovary cells were transfected with the recombinant human thyroid-stimulating hormone -receptor, and then exposed to the patient´s serum; it was estimated a 'moderate' blocking activity of these thyroid-stimulating hormone-receptor autoantibodies, and concomitantly excluded stimulating action. In this case, the acknowledgment of the blocking activity of the serum thyroid-stimulating hormone-receptor autoantibodies, supported the hypothesis of a multifactorial aetiology of the hypothyroidism, which in the absence of the in vitro tests, we would consider only as a consequence of the destructive process associated to lymphocytic thyroiditis. Keywords: Graves Disease; Hypothyroidism; Receptors, Thyrotropin; Thyroiditis, Autoimmune. INTRODUÇÃOOs anticorpos anti-receptor da hormona estimulante da tiróide (TRAbs) ao ligarem-se a este receptor têm, habitualmente, uma ação similar à da hormona estimulante da tirói-de (TSH) conduzindo à produção de hormonas tiroideias. Os TRAbs são causa direta da doença de Graves (DG), a principal forma de hipertiroidismo.1...

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“…K1-18 is a TSH receptor (TSHR) human monoclonal autoantibody (MAb; IgG1/kappa) with the ability to stimulate cAMP production in TSHR-transfected CHO cells and to inhibit TSH binding to the receptor at nanogram per millilitre concentrations , Evans et al 2010. K1-18 has high binding affinity for the TSHR of w6 .…”

Section: Introductionmentioning

confidence: 99%

Similarities and differences in interactions of thyroid stimulating and blocking autoantibodies with the TSH receptor

Miguel

Sanders

et al. 2012

Journal of Molecular Endocrinology

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Binding of a new thyroid-stimulating human monoclonal autoantibody (MAb) K1-18 to the TSH receptor (TSHR) leucinerich domain (LRD) was predicted using charge-charge interaction mapping based on unique complementarities between the TSHR in interactions with the thyroid-stimulating human MAb M22 or the thyroid-blocking human MAb K1-70. The interactions of K1-18 with the TSHR LRD were compared with the interactions in the crystal structures of the M22-TSHR LRD and K1-70-TSHR LRD complexes. Furthermore, the predicted position of K1-18 on the TSHR was validated by the effects of TSHR mutations on the stimulating activity of K1-18. A similar approach was adopted for predicting binding of a mouse thyroid-blocking MAb RSR-B2 to the TSHR. K1-18 is predicted to bind to the TSHR LRD in a similar way as TSH and M22. The binding analysis suggests that K1-18 light chain (LC) mimics binding of the TSH-a chain and the heavy chain (HC) mimics binding of the TSH-b chain. By contrast, M22 HC mimics the interactions of TSH-a while M22 LC mimics TSH-b in interactions with the TSHR. The observed interactions in the M22-TSHR LRD and K1-70-TSHR LRD complexes (crystal structures) with TSH-TSHR LRD (comparative model) and K1-18-TSHR LRD (predictive binding) suggest that K1-18 and M22 interactions with the receptor may reflect interaction of thyroid-stimulating autoantibodies in general. Furthermore, K1-70 and RSR-B2 interactions with the TSHR LRD may reflect binding of TSHR-blocking autoantibodies in general.

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ORIGINAL ARTICLE: Monoclonal autoantibodies to the TSH receptor, one with stimulating activity and one with blocking activity, obtained from the same blood sample

Abstract: This study provides proof that a patient can produce a mixture of blocking and stimulating TSHR autoantibodies at the same time.

Cited by 103 publications

References 35 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

Hipotiroidismo Associado a Anticorpos Anti-Receptor da Hormona TSH com Ação Bloqueadora Determinada In Vitro

Similarities and differences in interactions of thyroid stimulating and blocking autoantibodies with the TSH receptor

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