{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T00:36:43Z","timestamp":1773275803250,"version":"3.50.1"},"reference-count":44,"publisher":"Oxford University Press (OUP)","issue":"9","license":[{"start":{"date-parts":[[2019,5,1]],"date-time":"2019-05-01T00:00:00Z","timestamp":1556668800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,5,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Transgenic NOD.H2h4 mice that express the human (h) TSHR A-subunit in the thyroid gland spontaneously develop pathogenic TSHR autoantibodies resembling those in patients with Graves disease. Nanoparticles coupled to recombinant hTSHR A-subunit protein and a tolerogenic molecule (ligand for the endogenous aryl-hydrocarbon receptor; ITE) were injected i.p. four times at weekly intervals into hTSHR\/NOD.H2h4 mice with the goal of blocking TSHR Ab development. Unexpectedly, in transgenic mice, injecting TSHR A-subunit\u2013ITE nanoparticles (not ITE-nanoparticles or buffer) accelerated and enhanced the development of pathogenic TSHR Abs measured by inhibition of TSH binding to the TSHR. Nonpathogenic TSHR Abs (ELISA) were enhanced in transgenics and induced in wild-type littermates. Serendipitously, these findings have important implications for disease pathogenesis: development of Graves TSHR Abs is limited by the availability of A-subunit protein, which is shed from membrane bound TSHR, expressed at low levels in the thyroid. The enhanced TSHR Ab response following injected TSHR A-subunit protein-nanoparticles is reminiscent of the transient increase in pathogenic TSHR Abs following the release of thyroid autoantigens after radio-iodine therapy in Graves patients. However, in the hTSHR\/NOD.H2h4 model, enhancement is specific for TSHR Abs, with Abs to thyroglobulin and thyroid peroxidase remaining unchanged. In conclusion, despite the inclusion of a tolerogenic molecule, injected nanoparticles coated with TSHR A-subunit protein enhanced and accelerated development of pathogenic TSHR Abs in hTSHR\/NOD. NOD.H2h4. These findings emphasize the need for sufficient TSHR A-subunit protein to activate the immune system and the generation of stimulatory TSHR Abs in genetically predisposed individuals.<\/jats:p>","DOI":"10.4049\/jimmunol.1900038","type":"journal-article","created":{"date-parts":[[2019,4,3]],"date-time":"2019-04-03T21:58:31Z","timestamp":1554328711000},"page":"2570-2577","source":"Crossref","is-referenced-by-count":4,"title":["Nanoparticles Bearing TSH Receptor Protein and a Tolerogenic Molecule Do Not Induce Immune Tolerance but Exacerbate Thyroid Autoimmunity in hTSHR\/NOD.<i>H2h4<\/i> Mice"],"prefix":"10.1093","volume":"202","author":[{"given":"Sandra M","family":"McLachlan","sequence":"first","affiliation":[{"name":"Cedars-Sinai Medical Center , Los Angeles, CA 90048"},{"name":"David Geffen School of Medicine, University of California , Los Angeles, Los Angeles, CA 90095"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Holly A","family":"Aliesky","sequence":"additional","affiliation":[{"name":"Cedars-Sinai Medical Center , Los Angeles, CA 90048"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Basil","family":"Rapoport","sequence":"additional","affiliation":[{"name":"Cedars-Sinai Medical Center , Los Angeles, CA 90048"},{"name":"David Geffen School of Medicine, University of California , Los Angeles, Los Angeles, CA 90095"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2019,5,1]]},"reference":[{"key":"2025030417561725400_r1","doi-asserted-by":"crossref","first-page":"686","DOI":"10.1016\/j.tibtech.2018.02.008","article-title":"Antigen-specific tolerization and targeted delivery as therapeutic strategies for autoimmune diseases","volume":"36","author":"Shakya","year":"2018","journal-title":"Trends Biotechnol."},{"key":"2025030417561725400_r2","doi-asserted-by":"crossref","first-page":"4048","DOI":"10.1016\/j.vaccine.2017.05.009","article-title":"An epitope-specific DerG-PG70 LEAPS vaccine modulates T cell responses and suppresses arthritis progression in two related murine models of rheumatoid arthritis","volume":"35","author":"Mikecz","year":"2017","journal-title":"Vaccine"},{"key":"2025030417561725400_r3","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1055\/s-0035-1548872","article-title":"The essential role of circulating thyroglobulin in maintaining dominance of natural regulatory T cell function to prevent autoimmune thyroiditis","volume":"47","author":"Kong","year":"2015","journal-title":"Horm. 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Immunol. Immunopathol."},{"key":"2025030417561725400_r13","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1006\/jaut.1999.0272","article-title":"Spontaneous autoimmune thyroiditis in NOD.H-2h4 mice","volume":"12","author":"Braley-Mullen","year":"1999","journal-title":"J. Autoimmun."},{"key":"2025030417561725400_r14","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1006\/cimm.1998.1446","article-title":"Both CD4(+) T cells and CD8(+) T cells are required for iodine accelerated thyroiditis in NOD mice","volume":"192","author":"Hutchings","year":"1999","journal-title":"Cell. 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Metab."},{"key":"2025030417561725400_r18","doi-asserted-by":"crossref","first-page":"e43517","DOI":"10.1371\/journal.pone.0043517","article-title":"Breaking tolerance in transgenic mice expressing the human TSH receptor A-subunit: thyroiditis, epitope spreading and adjuvant as a \u2018double edged sword\u2019","volume":"7","author":"McLachlan","year":"2012","journal-title":"PLoS One"},{"key":"2025030417561725400_r19","doi-asserted-by":"crossref","DOI":"10.1111\/cei.13249","article-title":"To reflect human autoimmune thyroiditis, thyroid peroxidase (not thyroglobulin) antibodies should be measured in female (not sex-independent) NOD.H2h4 mice","author":"McLachlan","year":"2019","journal-title":"Clin. Exp. 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Immunol."},{"key":"2025030417561725400_r22","doi-asserted-by":"crossref","first-page":"5724","DOI":"10.1210\/en.2007-1024","article-title":"The link between Graves\u2019 disease and Hashimoto\u2019s thyroiditis: a role for regulatory T cells","volume":"148","author":"McLachlan","year":"2007","journal-title":"Endocrinology"},{"key":"2025030417561725400_r23","doi-asserted-by":"crossref","first-page":"1458","DOI":"10.4049\/jimmunol.160.3.1458","article-title":"Genetic immunization against the human thyrotropin receptor causes thyroiditis and allows production of monoclonal antibodies recognizing the native receptor","volume":"160","author":"Costagliola","year":"1998","journal-title":"J. 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Immunol."},{"key":"2025030417561725400_r30","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1084\/jem.178.3.793","article-title":"I-E+ nonobese diabetic mice develop insulitis and diabetes","volume":"178","author":"Podolin","year":"1993","journal-title":"J. Exp. Med."},{"key":"2025030417561725400_r31","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1210\/en.2016-1875","article-title":"Genes outside the major histocompatibility complex locus are linked to the development of thyroid autoantibodies and thyroiditis in NOD.H2h4 mice","volume":"158","author":"McLachlan","year":"2017","journal-title":"Endocrinology"},{"key":"2025030417561725400_r32","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1084\/jem.149.3.758","article-title":"The induction of cell-mediated immunity and tolerance with protein antigens coupled to syngeneic lymphoid cells","volume":"149","author":"Miller","year":"1979","journal-title":"J. Exp. 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