Thyrotropin-blocking autoantibodies and thyroid-stimulating autoantibodies: potential mechanisms involved in the pendulum swinging from hypothyroidism to hyperthyroidism or vice versa

Abstract

Background: Thyrotropin receptor (TSHR) antibodies that stimulate the thyroid (TSAb) cause Graves' hyperthyroidism and TSHR antibodies which block thyrotropin action (TBAb) are occasionally responsible for hypothyroidism. Unusual patients switch from TSAb to TBAb (or vice versa) with concomitant thyroid function changes. We have examined case reports to obtain insight into the basis for "switching."

Summary: TBAb to TSAb switching occurs in patients treated with levothyroxine (LT4); the reverse switch (TBAb to TSAb) occurs after anti-thyroid drug therapy; TSAb/TBAb alterations may occur during pregnancy and are well recognized in transient neonatal thyroid dysfunction. Factors that may impact the shift include: (i) LT4 treatment, usually associated with decreased thyroid autoantibodies, in unusual patients induces or enhances thyroid autoantibody levels; (ii) antithyroid drug treatment decreases thyroid autoantibody levels; (iii) hyperthyroidism can polarize antigen-presenting cells, leading to impaired development of regulatory T cells, thereby compromising control of autoimmunity; (iv) immune-suppression/hemodilution reduces thyroid autoantibodies during pregnancy and rebounds postpartum; (v) maternally transferred IgG transiently impacts thyroid function in neonates until metabolized; (vi) a Graves' disease model involving immunizing TSHR-knockout mice with mouse TSHR-adenovirus and transfer of TSHR antibody-secreting splenocytes to athymic mice demonstrates the TSAb to TBAb shift, paralleling the outcome of maternally transferred "term limited" TSHR antibodies in neonates. Finally, perhaps most important, as illustrated by dilution analyses of patients' sera in vitro, TSHR antibody concentrations and affinities play a critical role in switching TSAb and TBAb functional activities in vivo.

Conclusions: Switching between TBAb and TSAb (or vice versa) occurs in unusual patients after LT4 therapy for hypothyroidism or anti-thyroid drug treatment for Graves' disease. These changes involve differences in TSAb versus TBAb concentrations, affinities and/or potencies in individual patients. Thus, anti-thyroid drugs or suppression/hemodilution in pregnancy reduce initially low TSAb levels even further, leading to TBAb dominance. In contrast, TSAb emergence after LT4 administration may be sufficient to counteract TBAb inhibition. The occurrence of "switching" emphasizes the need for careful patient monitoring and management. Finally, whole genome screening of relatively rare "switch" patients and appropriate Graves' and Hashimoto's controls could provide unexpected and valuable information regarding the basis for thyroid autoimmunity.

FIG. 1.

Two types of thyrotropin receptor (TSHR) antibody assays. (A) Assays employing competition by TSHR autoantibodies for ligand (TSH or monoclonal antibody) binding to the TSHR. The ligand may be radio-labeled or tagged with an enzyme or fluorescent dye. The three generations of such assays are described in the text. (B) Bioassays involving cultured thyroid cells or nonthyroidal cells expressing the recombinant human TSHR.

FIG. 2.

Difficulty in measuring TSH-blocking autoantibodies (TBAb) in the presence of thyroid-stimulating autoantibodies (TSAb). (A) Schematic depiction of a range of agonists of increasing potency. The TSHR, similar to many receptors, has a degree of ligand-independent or constitutive activity (27,28), as shown by the horizontal line through the wedge. TSHR ligands (TSH or TSAb) further increase receptor activity (not shown to scale). An inverse agonist suppresses constitutive activity, whereas a full agonist maximally activates the receptor. Ligands of intermediate activity are either neutral agonists (no activation of the receptor or suppression of constitutive activity) or partial agonists or inverse agonists. Ligands can also be an antagonist for another ligand depending on their relative affinities and binding sites. Therefore, a TSAb that is a partial (not a full) agonist can also be an antagonist for TSH. If a serum displays both TSAb and TBAb activity, unless the former is very weak and the latter is very strong, it cannot be assumed that there are two separate antibodies. (B) Difficulty in quantifying TBAb activity in the presence of TSAb. All TBAb bioassay data are expressed as the percent decrease in TSHR activation induced by TBAb relative to a baseline denominator, the latter being the activity of a standard, constant, and low TSH concentration. However, if TSAb activity is also present, different reports in the literature either do, or do not, subtract this TSAb value from the baseline denominator. This variation can have a major effect on deciding whether a TBAb is positive. For example, in a serum lacking TSAb activity (i), a patient's IgG or serum may inhibit TSH activity by 30%. Since many reports require 30%–40% inhibition of TSH activity to establish TBAb positivity, this serum would be regarded as TBAb negative. However, if weak intrinsic TSAb activity (ii) is present in the same serum and is subtracted to establish the “100%” TSH denominator, a 30% suppression of TSH activity represents a calculated TBAb activity of 50%, which is now positive. In an extreme example (iii), a stronger TSAb serum occupying most TSHR on the cell surface is a partial agonist, generating a 70% signal of that for TSH. This serum suppresses TSH activity by the same 30% but has a calculated TBAb of 100% after TSAb subtraction despite the absence of TBAb. In our view, therefore, it is preferable not to subtract TSAb activity in calculating the TBAb assay data.

FIG. 3.

(A) TSAb and (B) TBAb at different dilutions in the TBAb-positive hypothyroid patient from whom monoclonal TSAb and TBAb were isolated (5). Data from Table 1 are plotted.