Chronic exposure in vivo to thyrotropin receptor stimulating monoclonal antibodies sustains high thyroxine levels and thyroid hyperplasia in thyroid autoimmunity‐prone HLA‐DRB1*0301 transgenic mice

Abstract

Summary We have examined the induction of autoimmunity and the maintenance of sustained hyperthyroidism in autoimmunity‐prone human leucocyte antigen (HLA) DR3 transgenic non‐obese diabetic (NOD) mice following chronic stimulation of the thyrotropin receptor (TSHR) by monoclonal thyroid‐stimulating autoantibodies (TSAbs). Animals received weekly injections over the course of 9 weeks of monoclonal antibodies (mAbs) with strong thyroid‐stimulating properties. Administration of the mAbs KSAb1 (IgG2b) or KSAb2 (IgG2a), which have similar stimulating properties but different TSH‐binding blocking activity, resulted in significantly elevated serum thyroxine (T4) levels and thyroid hyperplasia. After the first injection, an initial surge then fall in serum T4 levels was followed by sustained elevated levels with subsequent injections for at least 63 days. Examination of KSAb1 and KSAb2 serum bioactivity showed that the accumulation of the TSAbs in serum was related to their subclass half‐lives. The thyroid glands were enlarged and histological examination showed hyperplastic follicles, with minimal accompanying thyroid inflammation. Our results show that chronic in vivo administration of mAbs with strong thyroid‐stimulating activity resulted in elevated T4 levels, suggesting persistent stimulation without receptor desensitization, giving a potential explanation for the sustained hyperthyroid status in patients with Graves' disease. Moreover, despite the presence of HLA disease susceptibility alleles and the autoimmune prone NOD background genes, chronic stimulation of the thyroid gland did not lead to immune cell‐mediated follicular destruction, suggesting the persistence of immunoregulatory influences to suppress autoimmunity.

Increased risk of thyroid pathology in patients with thyroid hemiagenesis: results of a large cohort case–control study

“…It is uncertain whether sustained overstimulation of the hemiagenetic gland in patients with THA might promote an autoimmune reaction targeted at thyroid autoantigens, and as a result, increase the risk of autoimmune thyroid disease development in genetically susceptible individuals (29,30). Before 1997, when a mandatory model of iodine prophylaxis, based on household salt iodization, was implemented, the region of Poland was classified as a moderate iodine-deficient area (31).…”

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

“…Monoclonal TSAbs with powerful agonist activity have been characterized from mice undergoing experimental Graves' disease following immunization by genetic delivery of plasmid or adenovirus encoding TSHR or the extracellular region of the receptor, known as TSHR A-subunit (7)(8)(9). 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).…”

“…With the development of monoclonal TSAbs with pathogenic properties in vivo, their relationship with Y. enterocolitica and Graves' disease remains to be elucidated. We have previously described two monoclonal TSAbs, KSAb1 (IgG 2b /k) and KSAb2 (IgG 2a /k), with strong agonist activity in the low nanogram range, developed from a single animal undergoing experimental Graves' disease (9,10). Detailed genetic analysis revealed both TSAbs to have undergone numerous somatic hypermutations (SHM) and to be clonally related, because they use the same germline Ig V region gene rearrangements (30).…”

Noninflammatory Diffuse Follicular Hypertrophy/Hyperplasia of Graves Disease: Morphometric Evaluation in an Experimental Mouse Model

“…The histological finding of an increase in the follicle/stroma ratio would support an increase in follicular volume that, without evidence of deficient cell function, correlates with hyperthyroidism. In this scenario, persistent stimulation without receptor desensitization provides a potential explanation for the sustained hyperthyroid status as reported in our earlier study on an induced model of GD in humanized nonobese diabetic mice [30]. …”