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Clinical Studies |
Department of Internal Medicine, Seoul National University College of Medicine (W.B.K., H.K.C., H.K.L., B.Y.C.), Seoul, Korea; Section on Cell Regulation, Metabolic Diseases Branch, National Institute of Diabetes, Digestive, and Kidney Disease, National Institutes of Health (L.D.K.), Bethesda, Maryland 20892; and Second Department of Internal Medicine, Chiba University School of Medicine (K.T.), Chiba 260, Japan
Address all correspondence and requests for reprints to: Bo Youn Cho, Department of Internal Medicine, Seoul National University Hospital, 28 Yungondong, Chongno-gu, Seoul 110–744, Korea.
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Abstract |
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Introduction |
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Despite these data, minor epitopes appear to exist outside of the N-terminal region of the TSHR extracellular domain and can be detected using human TSHR (hTSHR)-LH/CGR chimeras that substitute the N-terminal region of the TSHR extracellular domain between residues 8–165 (Mc1 + 2) or 90–165 (Mc2) with equivalent LH/CGR residues. Further, the presence of TSHRAbs directed at these minor epitopes within a patient’s stimulating TSHRAb population appears to have clinical significance (9, 10). Thus, in a study of 66 patients using the TSHR-LH/CGR chimeras (9), patients with stimulating TSHRAbs reactive with minor determinants involving residues other than 25–165, as well as the major epitopes within residues 25–165, were more likely to become euthyroid during antithyroid drug therapy than those with a homogenous epitope distribution, i.e. those with autoantibodies involving only residues 25–165. The location of these minor epitopes remains unclear, although studies with synthetic peptides have identified many potential epitopes sites: residues 172–202, 309–337, 341–358, 353–364, 352–366, or 372–397 (1, 2, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22). These epitopes appear, however, to be related to the major N-terminal epitopes in studies using combinatorial mixtures of peptides (19, 23) and may reflect the nonlinear, conformational nature of epitope (1, 2, 8, 9, 10, 24, 25, 26) or the phenomenon termed epitope spreading. Thus, it has recently been documented that epitopes for the T cell repertoire are not fixed but rather evolve during the course of disease in experimental autoimmune encephalitis, a model of T cell-mediated autoimmunity (27, 28). It is largely unknown whether epitopes change during the course of anti-TSHR autoimmune thyroid disease or whether such changes have any clinical relevance in human autoimmune disease, including autoimmune thyroid disease.
To determine whether stimulating TSHRAb epitopes would change during the course of Graves’ disease, and whether this might have clinical implications, we serially measured stimulating TSHRAb activities of IgGs from 39 patients with Graves’ disease using Chinese hamster ovary (CHO) cells transfected with wild-type hTSHR (CHO-hTSHR) or two chimeric receptors (Mc1 + 2 and Mc2) before and during treatment for 8 months.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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cAMP RIA kits were obtained from Incstar (Minneapolis, MN) and protein A-Sepharose CL-4B columns were from Pharmacia Fine Chemicals (Uppsala, Sweden). The source of all other materials was the same as reported previously (7, 9).
Subjects and sera
Sera were obtained from 33 normal individuals who had no history, clinical, or chemical evidence (abnormal thyroid hormone and TSH levels) of thyroid disease. The diagnosis of the 39 patients with Graves’ disease was based on conventional clinical and laboratory criteria, including elevated serum thyroid hormone levels, undetectable TSH by a sensitive RIA, and diffuse goiter with increased 99mTcO4- uptake at scintiscan. Thirty-one patients were treated with antithyroid drug alone throughout the study and eight were treated with radioactive iodine in addition to an antithyroid drug. The protocol for methimazole therapy was 30 mg/day for 1 month, 10–20 mg/day from the second month to the time of normalization of the serum free T4 level, and a maintenance dose (5–10 mg/day) thereafter. Propylthiouracil treatment was similar, except that the dose was 10-fold higher. All patients were enrolled in the study under institution guidelines and appropriate approval and consent; they were followed up by a single physician who, throughout the study, had no information on the results of stimulating TSHRAb activities measured in wild-type or chimeric receptor assays.
Sera were obtained before the start of treatment and every 2 months during treatment for 8 months; they were stored at -70 C until IgG preparation. IgGs were extracted by affinity chromatography using protein A-Sepharose CL-4B columns (9); IgG was lyophilized and stored at -20 C until assay.
Stable transfectants containing CHO-hTSHR and CHO-hTSHR-LH/CGR chimeras
hTSHR cloning, amplification of complementary LH/CGR DNA fragments, and construction of chimeric receptors in a pSG5 expression vector has been described (7, 9, 10). Numbering from the methionine start site, residues 8–165 of the hTSHR were replaced by residues 10–166 of the rat LH/CGR in Mc1 + 2 chimeras; in Mc2, residues 90–165 of the hTSHR were replaced by residues 91–166 of the rat LH/CGR. Stable CHO clones expressing wild-type hTSHR (CHO-hTSHR) or chimeric receptors Mc1 + 2 or Mc2 were obtained as previously described after transfection with lipofectin and selection by limiting dilution (9, 10). They were maintained in Ham’s F-12 media containing 10% FCS and 1 g/L geneticin (9). For stimulating TSHRAb assays, cells were plated in 24-well plates (3–4 x 104 cells/well), fed fresh medium 48 h later, and used 12–24 h later at 100% confluency (5–6 x 105 cells/well). The cAMP response to bovine TSH or Graves’ disease IgG was stable for over 3 months of continuous culture.
Stimulating TSHRAb assays
Assays were performed in NaCl-free HBSS containing 20 mmol/L HEPES (pH 7.4), 1% BSA, 0.5 mmol/L 3-isobutyl-1-methylxanthine, and 222 mmol/L sucrose to make it isotonic (9, 10). Bovine TSH (0.1U/L) or the purified IgGs (10 g/L), dissolved in 300 µl incubation media, was incubated with cells for 2 h at 37 C; supernatants were aspirated, stored at -20 C, and cAMP released into the medium measured by RIA (9, 10). Stimulating TSHRAb activity, the percent increase in cAMP production by comparison with assays with equivalent amounts of pooled normal IgG, was defined as positive when the value was greater than 2 SD above the mean value of normal IgG: >145% in wild-type TSHR- or Mc1 + 2 chimera-transfected cells; >110% in assays using Mc2 chimera-transfected cells. Serial samples from each patient were run in a same batch of assays; all samples were run in duplicate or triplicate and on at least three separate occasions. Intra- and interassay variations in stimulating TSHRAb activity were 3.9% to 9.0% and 12.7% to 16.6%, respectively.
Measurements of thyroid hormones and autoantibodies
All assays used commercially available kits as previously described (9). Normal ranges for serum free T4 and total T3 concentrations were 0.93–2.13 ng/dL and 85–178 ng/dL, respectively; the normal TSH range was 0.38–4.1 mU/L. A titer of greater than 0.3 U/mL was considered positive for thyroglobulin and thyroid peroxidase antibodies. Thyrotropin binding inhibitor immunoglobulin (TBII) activity, measured with a radioreceptor assay as the percent inhibition of [125I]TSH binding, was positive when it exceeded 15%, which is 2 SD above the mean value of 64 normal samples; intra- and interassay variances of TBII activity were 1.7–8.0% and 3.7–10.5%, respectively.
Statistical analysis of data
To determine significance, we used Kruskal-Wallis one-way ANOVA.
Duncan’s multiple range test was performed when the ANOVA indicated a
significant difference. Differences in categorical data between
subgroups were analyzed by a 
-square test with Yates’ correction
(two-tailed). P < 0.05 was considered statistically
significant.
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Results |
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The 39 patients who were enrolled in this study were a subgroup of
the patients we characterized in our original report (9). Similar to
the original group of 66, 95% of the patients (37 of 39) had IgG that
exhibited stimulating TSHRAb activity in assays using CHO cells
transfected with the wild-type hTSHR (Fig. 1
).
Twenty-four of the 37 (65%) had antibodies whose activity completely
depended on the N-terminal region of the extracellular domain,
i.e. exhibited no activity in assays using CHO
cells transfected with the Mc1 + 2 or Mc2 chimeras (Fig. 1). Three of
the 37 had IgG that also exhibited activity in assays using the Mc1 + 2
TSHR-LH/CGR-transfected cells; 7 of 37 were positive in assays using
Mc2-chimera-transfected cells; and 3 were positive in both (Fig. 1). In
all but two of the IgGs that exhibited activity in the chimera assays,
there was a major decrease in stimulating TSHRAb activities in chimera
assays by comparison to assays with wild-type TSHR-transfected cells,
similar to the total population of 66 as originally reported (9).
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Changes in stimulating TSHRAb activities during treatment measured with CHO-hTSHR/chimera assay system
With the exception of the 2 patients who were negative at the start of the follow period, stimulating TSHRAb activities measured using wild-type CHO-hTSHR cells tended to decrease during 8 months of treatment in the 39 patients under study, whether they were treated with antithyroid drugs alone (n = 31) or antithyroid drugs plus radioactive iodine (n = 8). The degree of the decrease in stimulating TSHRAb activity measured in the cells transfected with wild-type hTSHR was, however, variable, as will be evident below.
When changes in stimulating TSHRAb activity were measured using Mc2
assays, the results were more revealing (Fig. 2; Table 1). Thus, of the 10 patients who had positive
stimulating TSHRAb activities measured in Mc2-transfected cells before
treatment, 7 exhibited a decrease in Mc2 activity, and 3 had persistent
activity during treatment (Fig. 2A; Table 1). Within the 27 patients
who had negative stimulating TSHRAb activity in Mc2 assays before
treatment, stimulating TSHRAb activity measured in Mc2 assays were
persistently negative before and during treatment in 10 (Fig. 2, B-I;
Table 1). Unexpectedly, IgG from 19 of 29 patients who had no
stimulating TSHRAb activity in Mc2-transfected cells before treatment,
exhibited significant (P < 0.05) stimulating TSHRAb
activity in the Mc2 chimera assays either transiently or persistently
during the 8-month treatment period (Fig. 2, B-II; Tables 1 and 2).
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The first was the heterogeneous epitope group, whose IgG had positive
Mc2 stimulating TSHRAb initially and, therefore, a heterogeneous
epitope distribution with some stimulating TSHRAb activity toward an
atypical epitope before the start of treatment. In this group, we
cannot be sure whether the stimulating TSHRAb epitope changed during
treatment, because most of these patients had IgG exhibiting a
coincident decrease in Mc2 stimulating TSHRAb activity measured in CHO
cells with wild-type TSHR or the Mc2 chimera during the 8-month period.
The second is the persistently homogeneous epitope group, whose Mc2
stimulating TSHRAb activity remained persistently negative. Thus, these
patients maintained a population of stimulating TSHRAbs whose
functional epitope remained residues 90–165 on the N-terminus of the
TSHR extracellular domain (Fig. 2, B-I).
The third and most interesting group was the changing epitope group,
whose stimulating TSHRAb epitope shifted from residues 90–165 and
included minor epitope(s) outside of this region (Fig. 2, B-II; Table 1). Stimulating TSHRAbs measurable in the Mc2 chimera assays appeared
despite a simultaneous and significant decrease in stimulating TSHRAb
activity measured using wild-type CHO-hTSHR cells (Table 2). In some of
these patients, the stimulating TSHRAbs reactive with residues other
than 90–165 developed early and persisted during treatment; others
developed early but then disappeared (Fig. 2, B-II; Table 1). In some
of these patients, the stimulating TSHRAbs reactive with residues other
than 90–165 developed only late in treatment (Fig. 2, B-II; Table 1).
Of the changing epitope group patients, all except 4 were treated with
antithyroid drug only and 4 with radioactive iodine plus antithyroid
drugs; relatively more patients with radioiodine were in the group with
a poor response to antithyroid drug therapy (4 of 10 vs. 4
of 19). Radioiodine treatment did not alter results nor did there
appear to be a correlation with any affect of radioiodine.
In most cases (5 of 6), stimulating TSHRAbs activities measured with Mc1 + 2 chimeric receptor at the start of treatment became negative during treatment. Negative to positive conversion occurred in 7 cases, all of whom belonged to the changing epitope group (data not shown). The Mc1 + 2 data were, therefore, consistent with the Mc2 data suggesting that the stimulating TSHRAb epitope changes during the course of the 8-month treatment period. However, Mc1 + 2 assays were a less sensitive index of the changing epitope than Mc2 assays.
Clinical characteristics, responses to treatment, and changes in stimulating TSHRAbs in three subgroups of patients with Graves’ disease
There were no significance differences in age, sex
ratio, positive family history, duration of symptoms of thyrotoxicosis,
mean goiter size, frequency of ophthalmopathy, or initial thyroid
hormone levels in the three groups (Table 3). There is a
tendency for larger goiters in the heterogeneous epitope group,
however, no statistically significant difference could be found.
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). Patients in the changing epitope group responded very well to therapy, as did patients within the heterogeneous epitope group. In contrast, patients in the persistently homogeneous epitope group, who never had stimulating TSHRAbs directed at the heterogeneous epitope, had a poor response to antithyroid drugs. Thus, the total cumulative dose of antithyroid drug (propylthiouracil equivalent) to render the patient euthyroid was lower in the heterogeneous epitope group and the changing epitope group than in the persistently homogeneous epitope group (58 ± 13 g, 85 ± 45 g, and 47 ± 13 g in the heterogeneous epitope group, the persistently homogeneous epitope group, or the changing epitope group, respectively, P < 0.05), and the duration of antithyroid drug treatment needed to achieve the euthyroid state was shorter in the heterogeneous epitope group and the changing epitope group than in the persistently homogeneous epitope group (2.5 ± 0.9, 3.7 ± 1.9, and 2.5 ± 0.6 months in the heterogeneous epitope group, the persistently homogeneous epitope group, or the changing epitope group, respectively, P < 0.05). In summation, patients with stimulating TSHRAbs having a heterogeneous epitope at the start of the disease, or who develop stimulating TSHRAbs having a heterogeneous epitope during the course of the disease (changing epitope group) are good responders to antithyroid drug therapy.
Changes in stimulating TSHRAb activity measured in wild-type
CHO-hTSHR assays and in TBII activity measured in a standard commercial
assay additionally distinguished the three different groups during the
8-month treatment period (Fig. 3). Thus, when compared with
pretreatment activities, the percentage decrease in stimulating TSHRAb
activities was better in the heterogeneous epitope group than in the
persistently homogeneous epitope group or the changing epitope group
(Fig. 3). This was evident despite the much higher stimulating TSHRAb
values in the patients of the heterogeneous epitope group. Further,
TBII activity changes were different in the three groups. Thus, TBII
activity decreased in parallel with stimulating TSHRAb activity in the
heterogeneous epitope group (Fig. 3A). The decrease in TBII activity
was slightly delayed in time in the persistent homogeneous epitope
group but then changed in parallel to the change in stimulating TSHRAb
activity (Fig. 3B). In contrast, however, the decrease in TBII activity
was significantly less (P > 0.05 in ANOVA) than the
decrease in stimulating TSHRAb activity in the changing epitope group
(Fig. 3C; changing epitope group vs. other two groups at 6
and 8 months). The different pattern of the decreases in stimulating
TSHRAb and TBII activities among the three groups further suggests that
there are shifts in epitope reactivity among the three groups, and
supports conclusions that there are differences in epitopes for the two
different types of TSHR autoantibodies in studies using membrane
preparations from CHO cells transfected with wild-type hTSHR and the
Mc2 chimera (10).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The Mc1 + 2 and Mc2 chimera-transfected cells used in this study and in our previous study (9) are useful cell lines to detect stimulating TSHRAbs involving epitopes on the N-terminal portion of the TSHR extracellular domain (9, 10). Using these chimeras, we can show that the major epitopes for stimulating TSHRAbs exist on the N-terminal portion of the TSHR extracellular domain in 95% of patients (9). We can also detect the minority of stimulating TSHRAbs whose epitopes are elsewhere in the TSHR and detect the changes in these with time during treatment. The Mc2 chimera is particularly sensitive in detecting the heterogeneous stimulating TSHRAb epitope in most of these patients (9, 10); thus, residues 90–165 contain a critical epitope whose presence is required for the activity of most TSHRAbs (1, 2, 3, 4, 5, 6, 7, 8, 9, 10).
Wild-type hTSHR- and Mc2 chimera- transfected cell have comparable and
stable cAMP responses to TSH over extended time periods. It is,
therefore, easy to verify the adequacy of functional receptor
expression in each assay, and easy to show that variability in
different assays cannot explain changes in reactivity of the IgGs to
chimeric receptors (9). Moreover, interassay variance is eliminated by
measuring stimulating TSHRAb activities of serial samples from one
patient in the same assay batch. Thus, the fact that stimulating TSHRAb
activity measured with chimeric receptor assays developed in 19
patients who had no activity before treatment, despite a decrease in
stimulating TSHRAb activity in wild-type receptor assays measured in
the same IgGs at the same time, means that epitopes for stimulating
TSHRAbs are not fixed but may change within a given patient with
Graves’ disease. The data additionally suggest that changes in the
stimulating TSHRAb epitope from the region within residues 90–165 to
outside of the region by determinant spreading result in the production
of stimulating TSHRAbs that not only have an atypical epitope but also
may be less potent stimulator, since stimulating TSHRAb activity in
wild-type TSHR assays simultaneously decreases (Table 2).
We previously showed (9) that patients with Graves’ disease who have a heterogeneous stimulating TSHRAb epitope distribution when first seen, as evidenced by positive activity in Mc1 + 2 and Mc2 chimera assays, have a good response to antithyroid drug therapy (9). In the present study, we found that not only do patients having a heterogeneous stimulating TSHRAb population initially, but also those whose stimulating TSHRAb population becomes heterogeneous during treatment, have good responses to antithyroid drug therapy. Thus, those patients whose stimulating TSHRAb activity converted from negative to positive in Mc2 chimera assays responded as well to antithyroid drugs as those who had the atypical epitope at the start of treatment. In contrast, patients whose stimulating TSHRAb totally depends on the N-terminus of the extracellular domain throughout the course of their disease, particularly residues 90–165 in the Mc2 region, i.e. having no stimulating TSHRAb activity in Mc2 assays, are more resistant to antithyroid drug treatment. Persistent homogeneity of epitopes for stimulating TSHRAb within the major epitope of the extracellular domain of TSHR is, therefore, characteristic of antithyroid drug resistant
The exact pathophysiological basis for this phenomenon is not clear; however, the findings of this study reinforce our view that stimulating TSHRAb epitope heterogeneity has clinical relevance in Graves’ disease as previously described (9). Placed in clinical perspective, this is an important finding, because we can now identify about 75% of patients who are likely to have a good response to antithyroid drugs by simply measuring stimulating TSHRAb activity with Mc2-transfected cells before or during treatment of hyperthyroidism. Long-term remission rates in these patients are not yet known, but the ability to prospectively identify groups with different antibody populations and different responses to antithyroid drug therapy opens the door to evaluate this point.
The discrepancy between the changes in TBII and stimulating TSHRAb activities suggests that stimulating TSHRAb and TBII epitopes in Graves’ disease are different, and that each activity is exerted by a different population of TSHRAbs, consistent with both early and recent (32, 33, 34) studies of monoclonal antibodies to TSHR. In recent work (10) using the Mc2 chimera in newly developed TBII assays, three different TBIIs were identified. Two were in Graves’ patients. One was absolutely dependent on residues 90–165 for activity, like many stimulating TSHRAbs. The other may be associated with epitopes involving residues 30–75 and can be distinguished by its close association with conversion activity in Mc2 assays, the phenomenon of recovering stimulating TSHRAb activity in vitro by the addition of anti-human IgG (10). The third type of TBII has its epitope on the C-terminal portion of the extracellular domain of the TSHR (1, 2, 3, 4, 5, 7, 10) and is seen in patients with the triad of idiopathic myxedema or Hashimoto’s disease, blocking TSHRAb activity, and hypothyroidism.
TBII values fell more slowly than stimulating TSHRAb activity in the changing epitope group. Because the hyperthyroidism of this group patients is more responsive to antithyroid drug, it is conceivable that the TBII epitope changed from residues 90–165 to residues 30–61 or the C-terminal region, and that this contributes to the more rapid therapeutic response. Characterization of the TBII epitope in these patients, using chimera assays as described (10), should resolve this issue. It will be interesting to determine whether there is a correlation between the TBII epitope, stimulating TSHRAb heterogeneity, and/or the clinical response to antithyroid drug, i.e. whether changes in the TBII epitope are also associated with the decrease in disease activity in Graves’ disease during treatment.
It is not clear whether the changes in the epitope for stimulating TSHRAbs would have occurred spontaneously or are induced by treatment of hyperthyroidism because all patients were treated in this study. Observation of serial changes in epitopes for stimulating TSHRAb in the natural course of Graves’ disease without treatment may, therefore, be rewarding, especially if epitope changes are associated with the spontaneous remission of Graves’ disease.
In conclusion, using TSHR-LH/CGR chimeric receptor transfected cell lines, we have documented changes in B cell epitopes for stimulating TSHRAbs in half of the patients with Graves’ disease during treatment of hyperthyroidism, and found that changes in epitopes for stimulating TSHRAb in those patients are clinically relevant.
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Footnotes |
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Received January 16, 1997.
Revised February 16, 1997.
Accepted February 18, 1997.
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