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The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 2 514-518
Copyright © 1998 by The Endocrine Society

Original Studies

A Change from Stimulatory to Blocking Antibody Activity in Graves’ Disease during Pregnancy1

A. W. C. Kung and B. M. Jones

Departments of Medicine (A.W.C.K.) and Pathology (B.M.J.), University of Hong Kong, Queen Mary Hospital, Hong Kong, Republic of China

Address all correspondence and requests for reprints to: Dr. Annie W. C. Kung, Department of Medicine, University of Hong Kong, Queen Mary Hospital, 102 Pokfulam Road, Hong Kong, Republic of China.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Remission of Graves’ disease (GD) during pregnancy with recrudescence after delivery is commonly observed. However, as pregnancy is associated with type 2 rather than type 1 cytokine production, a decrease in thyroid-stimulating antibody (TSAb) activity alone is unlikely to account for the remission during pregnancy. We hypothesized that a change in the antibody characteristics may occur as pregnancy advances. Fifteen women were studied in the first, second, and third trimesters of pregnancy and 4 months postpartum. TSH receptor antibodies were determined using human thyroid cell cultures, and lymphocyte subsets were measured by flow cytometry.

Median TSAb (determined by cAMP release) decreased from 280% (96–3200) to 130% (range, 35–350; P < 0.05) during pregnancy, but no significant change was noted with the TSH binding inhibitory antibody (TBII; determined by RRA). Thyroid stimulation-blocking antibody (TSBAb; inhibition of TSH-stimulated cAMP release) increased from 16 ± 9% to 43 ± 16% (mean ± SD; P < 0.005). The increase in TSBAb was observed even among those patients who were in clinical remission before pregnancy. Overall, a negative correlation was observed between TSBAb activities and free T4 levels during pregnancy (r = -0.279; P < 0.05). Reciprocal changes in TSAb, TBII, and TSBAb levels were observed in the seven patients who relapsed during the postpartum period. In comparison, the healthy pregnant women (n = 14) were all negative for TSAb, TBII, and TSBAb throughout pregnancy.

The absolute number of T lymphocytes, T helper cells, and natural killer cells, but not B cells, decreased significantly during pregnancy in both healthy women and GD patients. GD patients had significantly more CD5+ B cells at all stages of pregnancy compared to controls. In conclusion, a change in specificity from stimulatory to blocking antibodies was observed in GD patients during pregnancy and may contribute to the remission of GD during pregnancy.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
IT HAS LONG been known that there is a close association between the neuroendocrine system and the immune system. During pregnancy, the maternal immune response is suppressed to prevent rejection of the fetus (1). Early pregnancy is associated with increases in several cytokines, but as pregnancy progresses, the type 1 cytokines {gamma}-interferon and interleukin-2 decline, and type 2 cytokines, particularly interleukin-4, increase (2, 3, 4). This shift permits the histoincompatible fetal-placental unit to avoid rejection by a maternal cell-mediated immune attack. Suppression of the potent abortant interferon-{gamma} is essential for fetal survival. Immune deviation, the switching from type 1 to type 2 cytokine predominance, ameliorates the course of many autoimmune diseases. If this mechanism is also operative in Graves’ disease (GD) it will be necessary to understand why thyroid-stimulating antibody (TSAb) levels fall as gestation progresses despite increased production of B cell stimulatory type 2 cytokines.

Limited and conflicting data on lymphocyte subsets in pregnant women with GD have been obtained. T helper cells, natural killer (NK) cells, as well as B cells decrease during late pregnancy in healthy women (5). In GD pregnant women, Amino et al. found a significant increase in T helper cells and an increased T helper/suppressor cell ratio in the third trimester (6). An increase in total B lymphocytes and a decrease in NK cells were found in those subjects with postpartum relapse of GD. However, Bizzarro et al. found that T helper cells decreased significantly throughout pregnancy, with no changes in the number of T suppressor cells, in both GD patients and normal subjects (7).

The aim of this study was to evaluate the clinical course of pregnant women with GD, their TSH receptor antibody activity, and their lymphocyte subset populations to determine the possible cause of the amelioration of the disease during pregnancy.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Patients

Fifteen women with GD were studied prospectively as soon as pregnancy was confirmed. To avoid possible immunomodulatory action of anti-thyroid drugs, only patients with mild disease on no medications or those taking less than 10 mg carbimazole or 100 mg propylthiouracil daily for the preceding 6 months were recruited. Treatment was stopped in the 7 patients who were taking antithyroid drugs in the second trimester. Fasting blood samples were obtained in the first trimester (10–12 weeks), the second trimester (24th week), and the third trimester (34th week) and 4 months postpartum. For comparison, 14 healthy pregnant women were studied at the same stages of pregnancy, and 10 nonpregnant female GD patients were studied during antithyroid drug treatment. Informed consent was obtained from all subjects, and the protocol was approved by the ethics committee of the University of Hong Kong.

Methods

Thyroid function test. Serum free T4 (fT4) was determined by a competitive chemiluminometric immunoassay, and TSH was determined by a two-site immunochemiluminometric assay using an Automated Chemiluminescence System (ACS 180, Ciba Corning Diagnostic Corp., Medfield, MA). The normal range of fT4 was 10–19 pmol/L. The inter- and intraassay coefficients of variance for fT4 and TSH were 4.9% and 3.6%, and 4.8% and 3.6%, respectively. As fT4 assays may give spuriously low results during pregnancy, an abnormal fT4 reading was confirmed with a free T4 index (FTI) measurement (Abbott Laboratory, North Chicago, IL). The normal range of FTI was 76–154.

Antithyroid antibodies. TSH binding inhibitory Ig (TBII) was determined by inhibition of specific [125I]bovine TSH binding to porcine thyroid membranes with a RRA (RSR, Cardiff, UK). Assay results were expressed in terms of inhibition of TSH binding, calculated as follows: 100% x [1 - (labeled TSH specifically bound in the presence of test serum/labeled TSH specifically bound in the presence of normal serum)].

TSAb was determined in purified IgG by measuring cAMP release from human thyroid cell cultures using the method described by Rapoport et al. (8). IgG was prepared by passing serum through a diethylaminoethyl column followed by dialysis.

Thyroid stimulation blocking antibody (TSBAb) was determined by inhibition of the TSH-stimulated cAMP response by IgG samples as reported previously (8, 9): TSBAb = 100% x {1 - [(cAMP accumulation in the presence of TSH and test Ig)/cAMP accumulation in the presence of TSH (1 mIU/L) and normal Ig)]}.

Triplicate assays were performed on all samples for antibody assays. cAMP assays were performed in duplicate by RIA (Incstar Corp., Stillwater, MN). The normal ranges in 20 healthy subjects for TBII, TSAb, and TSBAb were +15% to -15%, 60–160%, and -28% to +24%, respectively. The determination of TSAB and TSBAb in the same sera was performed in the same assay. The intra- and interassay coefficients of variance for TSII, TSAb, and TSBAb were 5.0% and 8.6%, 10.6% and 18.6%, and 10.7% and 15.6%, respectively.

Antithyroglobulin (anti-Tg) and antimicrosomal (anti-Tm) Ab were determined by particle gel agglutination (Serodia, Fujirebio, Japan). Normal subjects have an antibody titer of less than 100 for both assays.

Lymphocyte subsets. Lymphocyte subset determination was only performed for the pregnant GD patients and their controls, not for the nonpregnant GD subjects, as this had been reported previously (10). Whole blood was collected into ethylenediamine tetraacetate and stained with pairs of monoclonal antibodies labeled with fluorescein isothiocyanate or phycoerythrin (Simultest, Beckon Dickinson, San Jose, CA). Subset proportions were determined after red cell lysis with the Profile II flow cytometer (Coulter, Hialeah, FL). The subsets evaluated were CD3+ T cells, CD19+ B cells, CD3+4+ T helper cells, CD3+8+ T suppressors/cytotoxic cells, CD3-16/56+ NK cells, and CD5+19+ B-la cells. Gated cells were more than 95% CD45+14- and less than 2% positive when stained with isotype-matched control monoclonal antibodies.

Statistics

Comparisons between patients and between patients and controls were performed using two-way ANOVA. Comparison within groups were performed using two-sample t tests or Wilcoxon ranks test depending on the distribution of the data.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Thyroid function tests

Seven patients took antithyroid drugs during pregnancy, and four were biochemically toxic in the first trimester. In the second trimester, all patients were biochemically euthyroid, and all antithyroid drugs were stopped (Fig. 1Go). As a group, fT4 levels were significantly lowered by the second (P < 0.05) and third (P < 0.005) trimesters. During the third trimester, three subjects had subnormal fT4 levels (7, 8, and 9 pmol/L) as well as FTI (62, 68, and 72), but normal TSH levels. Eight patients relapsed during the postpartum period. For the nonpregnant GD patients, fT4 levels fell progressively and returned to the euthyroid range at 3 months of treatment (Fig. 1Go). All healthy pregnant controls had normal fT4 levels throughout pregnancy.



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  		Figure 1. Serial changes (mean ± SD) in serum fT4 in pregnant GD patients ({diamondsuit}), nonpregnant GD patients ({blacksquare}), and healthy pregnant controls ({blacktriangleup}). Times 1, 2, 3, and 4 represent the first, second, and third trimesters and 4 months postpartum for the pregnant subjects and 0, 3, 6, and 9 months for the nonpregnant subjects.

 
Antithyroid antibodies

Two patients were in remission for more than 2 yr before pregnancy. They did not have any detectable antibodies during or after pregnancy and remained euthyroid throughout. The remaining 13 patients all had circulating TSAb and/or TBII in the first trimester. Three subjects had TSBAb in the first trimester. By the third trimester, TSBAb were detectable in 10 subjects (Fig. 2Go). As a group, TSBAb levels were significantly higher (P < 0.001) as pregnancy advanced (16 ± 9%, 32 ± 16%, and 43 ± 16% in the first, second, and third trimesters, respectively). The 3 subjects with low fT4 levels in the third trimester had the highest TSBAb activities (Fig. 2Go). Overall, a negative correlation was observed between TSBAb activities and fT4 levels during pregnancy (r = -0.279; P < 0.05). In comparison, TSAb activity, but not TBII, fell progressively as pregnancy advanced (Fig. 2Go). The median TSAb levels in the first, second, and third trimesters were 280% (range, 96–3200%), 200% (range, 100-1700%), and 130% (range, 35–350%), respectively (P < 0.05). TBII activity did not correlate with TSAb or TSBAb at any time during pregnancy. However, after delivery, TBII was significantly correlated with TSAb (r = 0.53; P < 0.05), but not with TSBAb. Seven patients relapsed after delivery, and all but 1 had detectable TBII and TSAb activities. A reciprocal decrease in TSBAb activity was noted after delivery.



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  		Figure 2. Serial changes in TSBAb in pregnant GD patients, nonpregnant GD patients, and healthy pregnant controls. pp, Postpartum.

 
All of the nonpregnant GD patients were positive for TSAb (Fig. 3Go) and TBII (Fig. 4Go). Only one patient had detectable TSBAb activity at presentation (Fig. 2Go). TSAb and TBII activities decreased significantly after 9 months of treatment (both P < 0.005). There was a significant positive correlation between fT4 and TSAb (r = 0.39; P < 0.05) as well as with TBII (r = 0.48; P < 0.01) over time in these nonpregnant patients. In comparison, none of the healthy pregnant women had detectable TSAb, TBII, or TSBAb activity at any time during pregnancy.



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  		Figure 3. Serial changes in TSAb in pregnant GD patients, nonpregnant GD patients, and healthy pregnant controls. pp, Postpartum.

 


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  		Figure 4. Serial changes in TBII in pregnant GD patients, nonpregnant GD patients, and healthy pregnant controls. pp, Postpartum.

 
The anti-Tm Ab titer decreased slightly as pregnancy advanced [median, 400 (range, <100 to 25,600), 400 (range, <100 to 25,600), and 400 (range, <100 to 6,400) in first, second, and third trimesters, respectively; P < 0.05], but no significant change was detected in the anti-Tg antibody level (data not shown). For the nonpregnant GD patients, anti-Tm Ab decreased significantly after 9 months of treatment [median, 1,600 (range, 1,600–25,600) vs. 6,400 (range, 1,600–25,600); P < 0.02]. The anti-Tg antibody titer also decreased with treatment, but the change was not statistically significant (data not shown). None of the healthy pregnant woman had detectable anti-Tg or anti-Tm Ab.

Lymphocyte subpopulations

Both GD patients and normal pregnant controls showed significant decreases in the absolute number of total T lymphocytes, T helper cells, and T suppressor/cytotoxic cells by the third trimester (Table 1Go). The CD4/CD8 ratios remained the same throughout pregnancy and during the postpartum period in both GD patients and controls. The percentage and number of B cells did not change throughout pregnancy. However, the percentages and numbers of NK cells and CD5+ B cells decreased during the second and third trimesters in both GD patients and normal controls and increased again during the postpartum period. Compared to normal pregnant women, GD patients had significantly higher CD5+ B cells and lower NK cells at all stages of pregnancy as well as during the postpartum period (Table 1Go).


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  		Table 1. Lymphocyte subsets in patients with Graves’ disease and normal controls during pregnancy

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
This study is the first demonstration of a change in the TSH receptor antibody characteristic in GD patients during pregnancy. The conversion from stimulating to blocking antibodies was associated with the clinical remission of thyrotoxicosis. We observed that although the titer of TSAb decreased as pregnancy advanced, TSBAb increased in the second and third trimesters of pregnancy, and TBII activity remained unchanged. There was a significant negative correlation between TSBAb and fT4 during pregnancy. Furthermore, reciprocal changes were observed in TSAb, TBII, and TSBAb in the patients who relapsed during the postpartum period. This suggests that a change in the activity of the various B cells specific for different TSH receptor epitopes plays an important role in the remission of GD during pregnancy.

Changes in thyroid antibody characteristics occurring naturally or during treatment of autoimmune thyroid disease had been observed (11, 12). A change in antibody activity is usually associated with clinical remission of the hyperthyroidism or development of hypothyroidism. The exact mechanism of these changes remains unknown, but it is now well accepted that TSH receptor antibodies are heterogeneous, the products of different clones of T and B cells responding to different epitopes of the TSH receptor, and are not due to formation of antiidiotype antibodies (13, 14).

The present study used human thyroid tissue for the detection of TSH receptor antibody activities, as human thyrocytes contain all of the functional epitopes for antibody determination and behave as a natural in vivo assay. One limitation to our present study is that the sera of these pregnant women had not been pretreated with anti-hCG antibody to reduce the possible stimulatory action of hCG. However, as healthy pregnant women did not demonstrate any TSAb, TSBAb, or TBII activity, this suggests that the results obtained from the various assays truly reflect the activity arising from the TSH receptor antibodies and not from hCG. Indeed, using a highly sensitive bioassay system with human thyroid follicles, Yamazaki et al. (15) could only demonstrate thyrotropic activity from hCG variants, not from native human hCG preparations from normal pregnant women. Furthermore, it could be argued that as the level of TSAb decreased during treatment, an apparent increase in TSBAb activity could occur as a result of a reduced stimulation of the receptor by the mixture of TSH and TSAb during incubation of the thyrocytes. To explore this possibility, nonpregnant GD patients were studied serially. The results revealed that despite a drop in the TSAb level, there was no increase in TSBAb activity as the patients underwent clinical remission.

During pregnancy there is suppression of cell-mediated immune function, but preservation or enhancement of humoral immunity (2). In the present study we observed a reduction in the absolute number of total T lymphocytes and NK cells in both GD patients and normal controls, which was consistent with a reduction in cell-mediated immune function (3). In contrast to a previous report of suppressed B cells during pregnancy (16), our study noted that the absolute numbers and percentages of B cells did not change. Anti-Tg and anti-Tm Ab persisted in these patients, suggesting the maintenance of humoral immune function. Although the number of CD5+ B cells diminished as pregnancy progressed, their level was still significantly higher than that in controls. Higher than normal numbers of B-la cells have been reported previously in untreated GD (10, 17), with the numbers returning to normal after treatment. Pregnancy, therefore, appears to delay the normalization of this B cell subset in GD. Furthermore, it appears that the behaviors of the distinct B cells specific for TSAB and TSBAb are different with respect to the modulatory effects of various neuroendocrine hormones associated with pregnancy (18). It would be interesting to determine whether these antibodies are produced by distinct subsets of B lymphocytes with different responses to pregnancy hormones. Discordant changes in antithyroid antibodies were reported by Tamaki et al. (19). Although anti-Tm Ab decreased during pregnancy, TBII either increased or decreased. In an experimental model of autoimmune thyroiditis in severe combined immunodeficient mice, the intrathyroidal B cells specific for TSAB and TSBAb behaved differently with respect to the timing of production as well as the pattern of secretion of TSAb and TSBAb (20).

The exact mechanism accounting for the change from stimulating to blocking antibodies during pregnancy in patients with autoimmune thyroid disease is unknown. Studies of antibody isotype and cytokine production may shed further light on this phenomenon and enable the development of immunotherapy to induce natural remission of GD.


   Acknowledgments
 
The authors thank Miss Shirley Yeung, Ms. Kannie Chan, Ms. Sally Wong, and Mr. K. S. Lau for technical assistance; Mr. Stanley Yeung for analyzing the data, and Miss Carlina Ng for typing the manuscript.


   Footnotes
 
1 Presented in part at the 10th International Congress of Endocrinology, San Francisco, CA, 1996. Back

Received July 21, 1997.

Revised September 29, 1997.

Accepted November 5, 1997.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Vander beeken Y, Vlieghe MP, Delespesse G, Duchateau I. 1982 Characterization of immunoregulatory T cells during pregnancy by monoclonal antibodies. Clin Exp Immunol. 48:118–120.[Medline]
  2. Wegmann TG, Lin H, Guilbert L, Mosmann TR. 1993 Bidirectional cytokine interactions in the maternal-fetal relationship: is successful pregnancy a TH2 phenomenon? Immunol Today. 14:353–356.[CrossRef][Medline]
  3. Lin H, Mosmann TR, Guilbert L, Tuntipopipat S, Wegmann TG. 1993 Synthesis of T helper type-2 cytokines at the maternal-fetal interface. J Immunol. 151:4562–4573.[Abstract]
  4. Delassus S, Cutinho GC, Saucier C, Darche S, Kourilsky P. 1994 Differential cytokine expression in maternal blood and placenta during murine gestation. J Immunol. 152:2411–2420.[Abstract]
  5. Watanabe M, Iwatani Y, Kaneda T, et al. 1997 Changes in T, B, and NK lymphocyte subsets during and after normal pregnancy. Am J Reprod Immunol. 37:368–377.
  6. Amino N, Iwatani Y, Tamaki H, Mori H, Aozasa M, Miyai K. 1985 Postpartum autoimmune thyroid syndromes. In: Walfish PG, Wall JR, Volpe, Volpe R, eds. Autoimmunity and the thyroid. London: Academic Press; 289–314.
  7. Bizzarro A, Fontana A, De Bellis A, Daponte A, Iacono G, Peluso G. 1987 T-Lymphocyte subsets in pregnant women with Graves’ disease. Acta Endocrinol (Copenh). 114:218–227.[Medline]
  8. Rapoport B, Greenspan FS, Filetti S, Pepitone M. 1984 Clinical experience with a human thyroid cell bioassay for thyroid-stimulating immunoglobulin. J Clin Endocrinol Metab. 58:332–338.[Abstract]
  9. Konishi J, Iida Y, Endo K, et al. 1983 Inhibition of thyrotropin-induced adenosine 3',5'-monophosphate increase by immunoglobulins from patients with primary myxedema. J Clin Endocrinol Metab. 57:544–549.[Abstract]
  10. Jones BM, Cheng IKP, Wong RWS, Kung AWC. 1993 CD5-positive and CD5-negative rheumatoid factor-secreting B cells in IgA nephropathy, rheu-matoid arthritis and Graves’ disease. Scand J Immunol. 38:575–580.[Medline]
  11. Kraiem Z, Baron E, Kahana L, Sadeh O, Sheinfeld M. 1992 Changes in stimulating and blocking TSH receptor antibodies in a patient undergoing three cycles of transition from hypo to hyperthyroidism and back to hypothyroidism. Clin Endocrinol (Oxf). 36:211–216.[Medline]
  12. Weetman AP, McGregor AM. 1994 Autoimmune thyroid disease: further developments in our understanding. Endocr Rev. 15:788–830.[Abstract]
  13. DeGroot LJ, Quintans J. 1989 The causes of autoimmune thyroid disease. Endocr Rev. 10:537–562.[Medline]
  14. Weetman AP, McGregor AM. 1984 Autoimmune thyroid disease. Developments in our understanding. Endocr Rev. 5:309–355.[Medline]
  15. Yamazaki K, Sato K, Shizume K, et al. 1995 Potent thyrotropic activity of human chorionic gonadotropin variants in terms of 125I incorporation and de novo synthesized thyroid hormone release in human thyroid follicles. J Clin Endocrinol Metab. 80:473–479.[Abstract]
  16. Iwatani Y, Amino N, Tachi J, et al. 1989 Changes of lymphocyte subsets in normal pregnant and postpartum women: postpartum increase in NK/K (Leu 7) cells. Am J Reprod Immunol Microbiol. 18:52–55.
  17. Iwatani Y, Amino N, Kaneda T, et al. 1989 Marked increase of CD5+ B-cells in hyperthyroid Graves’ disease. Clin Exp Immunol. 78:196–200.[Medline]
  18. Wilder RL. 1995 Neuroendocrine-immune system interactions and autoimmunity. Annu Rev Immunol. 13:307–338.[CrossRef][Medline]
  19. Tamaki H, Amino N, Iwatani Y, Tachi J, Mitsuda N, Tanizawa O, Miyai K. 1989 Discordant changes in serum anti-TSH receptor antibody and antithyroid microsomal antibody during pregnancy in antoimmune thyroid diseases. Thyroidology. 1:73–77.[Medline]
  20. Yoshikawa N, Arreaza G, Mukuta T, et al. 1994 Studies of human thyroid xenografts from Hashimoto’s thyroiditis in severe combined immunodeficient (SCID) mice: detection of thyroid stimulation-blocking antibody. Thyroid. 4:13–18.[Medline]



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