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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 3 1280-1284
Copyright © 2003 by The Endocrine Society

Postpartum Thyroiditis Is Associated with Fluctuations in Transforming Growth Factor-ß1 Serum Levels

A. Olivieri, S. De Angelis, V. Vaccari, H. Valensise, F. Magnani, M. A. Stazi, R. Cotichini, E. Gilardi, V. Cordeddu, M. Sorcini and M. Boirivant

Metabolism and Pathological Biochemistry Laboratory (A.O., S.D.A., E.G., V.C., M.S.), Immunology Laboratory (V.V., M.B.), and Epidemiology and Biostatistic Laboratory (M.A.S., R.C.), Italian National Institute of Health, 00161 Rome Italy; and Obstetric and Gynecologic Department, Tor Vergata University (H.V., F.M.), 00186 Rome, Italy

Address all correspondence and requests for reprints to: Dr. Antonella Olivieri, Laboratorio di Metabolismo e Biochimica Patologica, Istituto Superiore di Sanità, V.le Regina Elena 299, 00161 Rome, Italy. E-mail: olivieri{at}iss.it.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Postpartum thyroiditis (PPT) is characterized by a rapid evolution and recovery of euthyroidism. Therefore, it can represent a good model to study early cytokine fluctuations in autoimmune thyroid diseases. TGFß1 is an immunosuppressive cytokine, as it inhibits T and B cell proliferation, natural killer cell cytotoxic activity, and the generation of T cell cytotoxicity.

The aim of this study was to assess serum concentrations of TGFß1 during pregnancy and to study possible serum fluctuations of this cytokine during the different phases of PPT. Thyroid biochemical pattern, antithyroid autoantibodies (ATA), and total and active TGFß1 (aTGFß1) serum concentrations were evaluated in 63 pregnant women. Thirty-four of them were ATA+, and 29 were ATA-. Twenty of the 34 ATA+ women were followed in the postpartum year. Nine of these 20 women developed PPT; 11 remained euthyroid. All of the PPT women became euthyroid during the follow-up. Our results showed 1) detectable serum levels of aTGFß1 in 50% of ATA+ pregnant women, suggesting that the presence of autoantibodies may characterize a favorable condition for TGFß1 activation; and 2) decreased total TGFß1 and increased aTGFß1 serum levels during the active phase of PPT in ATA+ women. This seems to suggest that inflammation may be responsible for TGFß1 activation and autoantibody increase because of antigen release. Although further studies of women with persistent hypothyroidism after the postpartum year are needed, the possibility that the enhanced activation of TGFß1 may contribute to resolution of thyroid inflammation postpartum cannot be excluded.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
TGFß1 BELONGS TO A family of multifunctional polypeptides and is produced by a wide variety of lymphoid and nonlymphoid cells. The TGFßs are involved in a variety of different biological processes, including embryonic development, tumorigenesis, fibrosis, wound healing, hemopoiesis, and immunoregulation (1, 2). Lymphoid cells mostly produce TGFß1, an isoform that is also found in large amounts in bones and platelets and in the serum (3). TGFß1 is secreted as an inert precursor molecule and is converted to its biologically active form extracellulary (4). The active TGFß1 25-kDa homodimer is noncovalently associated with a precursor molecule [latency-associated peptide (LAP)] to form a 75-kDa inactive complex. Total TGFß1 (tTGFß1) must be cleaved from the latent complex to become biologically active. Although several mechanisms of activation have been proposed, the precise in vivo process is not completely understood. However, proteolytic cleavage of LAP can release active TGFß1 (aTGFß1) from the latent complex, and this activation may be mediated by macrophages in inflammatory sites (5). In blood, both aTGFß1 and inactive TGFß1-LAP complex are present (6).

Regarding the immunoregulating role of TGFß1, this is an immunosuppressive cytokine, as it inhibits T and B cell proliferation, natural killer cell cytotoxic activity, and the generation of T cell cytotoxicity (7, 8). Furthermore, TGFß1 is able to inhibit both T helper type 1 and T helper type 2 cytokine production and decreases the interferon-{gamma}-induced expression of HLA class II antigens (9). Recently much attention has been focused on the role of TGFß1 in promoting tolerance and, consequently, on its antiinflammatory and immunosuppressive roles in the pathophysiology of autoimmune diseases (1, 10). Numerous studies have revealed protection from autoimmunity, documenting TGFß1-mediated effects in several experimental models of autoimmune diseases, including colitis, autoimmune diabetes, collagen-induced arthritis, and thyroiditis (11, 12, 13, 14, 15).

It is well known that the course of autoimmune thyroiditis is regulated by the interplay of several cytokines (16). As the pathogenesis of postpartum thyroiditis (PPT) involves humoral and cellular immune mechanisms and shows a rapid evolution and recovery of euthyroidism, this condition could represent a useful model to study cytokine fluctuations in thyroid autoimmune diseases. In particular, it could be a powerful model to study regulatory mechanisms counteracting inflammation. PPT is usually painless and transient. It is characterized by the development of transient thyrotoxicosis and/or hypothyroidism, generally during the first 6 months of the postpartum period. The immunological features of PPT include the presence of thyroid peroxidase (TPOAb) and, less commonly, thyroglobulin (TgAb) autoantibodies, abnormalities in circulating T cell population, and goiter with lymphocytic infiltration (17, 18). Although the thyroid autoimmune response is dramatic in PPT, the major role of antithyroid autoantibodies (ATA) in the immunopathogenesis of this condition, as in other autoimmune thyroid diseases, remains to be determined. Cell-mediated factors, such as cytotoxicity, cytokine production, and complement-associated mechanisms, play a major role in the genesis of thyroid cell destruction, whereas the ATA titer is generally considered a marker of the disease. However, it is unknown how the subset of ATA-positive pregnant women who develop PPT differs from the ATA-positive women remaining euthyroid in the postpartum.

As only a few studies have been undertaken to assess circulating TGFß1 concentrations in human autoimmune diseases, the aim of this study was to assess serum concentrations of TGFß1 (total and active form) during pregnancy in ATA-positive (ATA+) and ATA-negative (ATA-) pregnant women and 2) to study possible serum fluctuations of the cytokine during the different phases of PPT.


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

Thyroid biochemical pattern, ATA, and serum tTGFß1 and aTGFß1 concentrations were evaluated in 63 pregnant women. These were out-patients of the Obstetric and Gynecology Clinic of Tor Vergata University (Rome, Italy). Twenty-nine of the 63 pregnant women were ATA-, and 34 were ATA+ (22 with TPOAb, 6 with TgAb, 6 with TPOAb and TgAb). Twenty of the 34 ATA+ women consented to be followed in the postpartum year. In these women the thyroid hormone profile and serum TGFß1 levels (total and active forms) were assessed at 3, 6, 9, and 12 months after parturition. PPT was diagnosed when two or more consecutive free T4 (FT4), free T3 (FT3), or TSH concentrations were outside the normal reference ranges. Hypothyroidism was defined as increased TSH serum concentrations with or without decreased FT4 concentrations; thyrotoxicosis was defined as increased serum concentrations of FT4, FT3, or both, with suppressed TSH values. None of the women had a personal history of thyroid disease, and none was receiving any medication that could influence thyroid function. All pregnant women taking part in the study gave their written consent to be included. Sera used for this study were collected in polypropylene tubes and stored at -80 C for detection of thyroid pattern and ATA and TGFß1 concentrations.

Radioimmunological and enzyme immunological assays

Radioimmunological kits for detection of serum T3, T4, thyroglobulin, and TSH were purchased from Radim (Pomezia, Italy). BRAHMS RIA kits (Berlin, Germany) were used for detection of FT3, FT4, TgAb, and TPOAb. The intraassay variability for RIA assay was less than 7%.

TGFß1 was measured in duplicate by a solid phase ELISA purchased from Genzyme (Cambridge, MA). The detection level of the method was 0.03 ng/ml. The variability of the duplicates was less than 10% of the mean value. For the detection of tTGFß1 (circulating active plus inactive TGFß1), serum samples were acidified with 1 N HCl for 1 h. This activation procedure allows the biologically active form of TGFß1 to be released from the biological inactive complex formed by a noncovalent association of mature TGFß1 dimer with LAP. The activation procedure was avoided for the detection of serum aTGFß1. As recommended by the manufacturer, acidifications and dilutions were performed in polypropylene tubes.

Statistical analysis

Log transformation of the not normally distributed ATA titer and TSH concentration was performed before comparing data between groups. Comparisons between ATA+ and ATA- pregnant women were performed using a t test for unpaired data. During the postpartum, follow-up data were analyzed using a t test for paired data. Data are presented in the text as the mean ± SEM to immediately compare the groups.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
Pregnancy

The mean age was similar in ATA- and ATA+ pregnant women (31.9 ± 0.7 and 32.1 ± 0.7 yr, respectively), as was the mean gestational age (27.1 ± 0.8 and 25.5 ± 0.9 wk, respectively). The biochemical thyroid patterns in the ATA+ and ATA- pregnant women are shown in Table 1Go. No significant differences were observed in total and free thyroid hormone levels or in TSH and T4-binding globulin serum concentrations. A significantly higher mean value of thyroglobulin was found in ATA- compared with ATA+ women (P = 0.01).


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  		Table 1. Biochemical thyroid pattern in the ATA+ and ATA- pregnant women

 
Distributions of tTGFß1 and aTGFß1 assessed in the two groups of pregnant women are presented in Fig. 1Go. Comparison of mean values of serum tTGFß1 did not show any significant difference between the groups of ATA- and ATA+ women (37.3 ± 3.1 and 40.7 ± 2.3 ng/ml, respectively). Nevertheless, detectable levels of aTGFß1 were observed in 50% of the ATA+ pregnant women (range, 0.4–7.1 ng/ml), but not in the ATA- group. Moreover, the pregnant women with detectable levels of aTGFß1 showed a higher mean ATA titer than that found in the women with undetectable concentrations of this cytokine [TPOAb, 543 ± 143 vs. 180 ± 65 U/ml (P = 0.03); TgAb, 64 ± 31 vs. 39 ± 13 U/ml (P = NS)].



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  		Figure 1. Distribution of individual serum concentrations of tTGFß1 and aTGFß1 in ATA- (n = 29) and ATA+ (n = 34) women during pregnancy.

 
Postpartum follow-up

Nine (45%) of the 20 women followed in the postpartum year developed PPT (ATA+/PPT+), 11 remained euthyroid (ATA+/PPT-). All of the women with PPT became euthyroid during the follow-up.

No significant differences between ATA+/PPT+ and ATA+/PPT- groups were observed in the mean values of ATA during pregnancy (TPOAb, 418 ± 164 and 324 ± 125 U/ml; TgAb, 21 ± 15 and 47 ± 18 U/ml). This is probably because these values were taken at about 26 wk rather than earlier when TPOAbs represent a condition at risk for the development of PPT (19). Again, no significant differences were found between the groups in the mean values of tTGFß1 (45.5 ± 8.9 and 39.5 ± 12.5 ng/ml) and aTGFß1 (0.67 ± 0.3 and 0.71 ± 0.4 ng/ml, respectively) detected during pregnancy. Four of 9 ATA+/PPT+ and 3 of 11 ATA+/PPT- women had detectable serum levels of aTGFß1 during pregnancy (range, 0.4–4.5 and 0.9–2.5 ng/ml, respectively). Among the 11 euthyroid ATA+/PPT- women, 8 remained ATA+ in the postpartum, and 3 women, who had low ATA titers during pregnancy (1 woman with TPOAb of 191 U/ml; 2 women with TgAb of 69 and 145 U/ml), became ATA- during the first 3 months of the postpartum follow-up. All of them had undetectable aTGFß1 levels during pregnancy. As expected (20), the ATA titer dramatically rose after delivery in all of the ATA+ women who were followed. Although not significantly different, a higher median peak postpartum TPOAb level was observed during the follow-up in the ATA+/PPT+ (4696 U/ml; range, 390-6854) than in the ATA+/PPT- group (710 U/ml; range, 293-5271).

Mean serum profiles of tTGFß1, aTGFß1, and TPOAb from pregnancy throughout the postpartum follow-up are shown in Fig. 2Go. In the ATA+/PPT+ women (Fig. 2AGo), a significantly lower mean value of serum tTGFß1 was observed during the hypothyroid phase of PPT compared with that found during pregnancy (28.7 ± 1.2 vs. 45.5 ± 2.9 ng/ml; P = 0.02). Nevertheless, serum tTGFß1 levels gradually rose to pregnancy values during the euthyroid phase (46.2 ± 7.7 ng/ml). In the same group of women a significantly higher mean aTGFß1 level was found during the toxic phase of PPT (six women) compared with the mean level of this cytokine observed during pregnancy (5.0 ± 1.4 vs. 0.7 ± 0.4 ng/ml; P = 0.03). No significant difference was found between mean values of aTGFß1 during pregnancy and at the end of follow-up (euthyroid phase, 1.4 ± 0.9 ng/ml). The mean TPOAb level was significantly higher during the hypothyroid phase of PPT compared with the pregnancy mean level (3003 ± 1458 vs. 418 ± 164 U/ml; P < 0.01).



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  		Figure 2. Mean serum profiles of tTGFß1, aTGFß1, and TPOAb in ATA+/PPT+ (A) and ATA+/PPT- women (B). A, The following significant differences were observed: *, aTGFß1: pregnancy vs. toxic phase (P = 0.03); **, tTGFß1: pregnancy vs. hypothyroid phase (P = 0.02); °, TPOAb: pregnancy vs. hypothyroid phase (P < 0.01). B, Significant differences were observed only in TPOAb levels: °°, pregnancy vs. 6 months postpartum (P = 0.01).

 
As distinct from that found in the women developing PPT, in the ATA+/PPT- group (Fig. 2BGo) no significant differences in the mean values of tTGFß1 and aTGFß1 were observed at any time of follow-up. On the other hand, the mean profile of TPOAb showed a significantly higher value at 6 months postpartum than that found during pregnancy (2061 ± 1013 vs. 411 ± 187 U/ml; P = 0.01).


   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
Several immunological changes occur during pregnancy to maintain maternal immune system tolerant of paternal major histocompatibility antigens expressed by the fetus. A reduced B cell reactivity, at least in part due to placental steroids, has been hypothesized during pregnancy (21). As sex steroids are negative regulators of B cell activity, the high concentration of estrogens produced during pregnancy can contribute to the fall in autoantibody secretion generally occurring during gestation. With regard to T cells, during pregnancy the immune response undergoes a major shift in T cell control to reduce inflammatory T cells (T helper type 1 cells), in favor of less damaging immune cells (T helper type 2 cells) (22). A reduction of the interferon-{gamma}/IL-4 ratio, which may be a useful measure of the CD4+ T helper type 1/T helper type 2 ratio, has been reported during pregnancy and in the early postpartum (23). Also, apoptosis, which is a well recognized mechanism of immune control, is increased during pregnancy and in the first days postpartum (23). TGFß1 has been suggested to have importance for the immune suppression occurring in pregnancy (24). This cytokine has an important role in the promotion of Th2 differentiation (1). Moreover, it is released by apoptotic lymphocytes and actively secreted by macrophages during the phagocytosis of apoptotic bodies (6, 25). Taken as a whole this information may explain our observation that during pregnancy the concentrations of serum tTGFß1 are similarly distributed in ATA+ and ATA- women, indicating the importance of TGFß1 production to immune T cell control during pregnancy. The fact that 50% of the ATA+ pregnant women (but none of the ATA- group) experienced detectable levels of aTGFß1 and that women with aTGFß1 had higher ATA levels than pregnant women with undetectable concentrations of this cytokine might suggest that conditions triggering autoantibody production may also bring about TGFß1 activation. Actually, the results obtained in the present study showed that aTGFß1 is increased during the toxic phase of PPT. This finding suggests that inflammation could be responsible for both TGFß1 activation and the increase in autoantibody titer because of antigen release.

In the postpartum year approximately 4–6% of women develop PPT as a transient form of thyroiditis (26, 27), and the occurrence of permanent hypothyroidism is observed in approximately a quarter of women followed for several years after apparent resolution of PPT (28). PPT proceeds in a sequence from a widespread thyroid cell lysis causing release of excessive amounts of thyroid hormone (toxic phase), followed by a resulting thyroid cell loss (hypothyroid phase), thyroid cell regrowth, and thyroid function recovery. How the immune system is able to regain its equilibrium and allow the thyroid gland to recover from postpartum thyroid disease remains unclear. Among possible mechanisms explaining the transience of PPT, the clonal suicide (via programmed cell death) of thyroid-specific T cells following thyroid cell destruction and the induction of antigen-specific regulatory (suppressor) T cells have been suggested (29). These two apparently distinct mechanisms are at least in part connected, because, as alluded to above, recent evidence has indicated that apoptotic cells may be actively involved in suppressing the inflammatory response by inducing/releasing antiinflammatory cytokines such as TGFß1 (6) and IL-10 (30, 31). Generally, in autoimmune diseases TGFß1 expression correlates with recovery/remission of the disease, whereas its production appears to be absent during active phases of inflammation (32, 33). In our study a reduction of serum tTGFß1 levels was observed from the toxic phase to the hypothyroid phase of PPT, whereas increasing values up to pregnancy levels were found at the end of follow-up. This finding may suggest that during active inflammation TGFß1 is greatly used and consumed at the site of inflammation. This is supported by the presence of high serum levels of aTGFß1 during the toxic phase of PPT in the same women. Probably a major amount of TGFß1 undergoes the activation process in the inflammation site, with a spillover of aTGFß1 from thyroid tissue into serum. Although it is not possible to assess the relative contribution of lymphoid and nonlymphoid cells to TGFß1 production, it is interesting to consider the fact that the activation process of TGFß1 is enhanced during the active phase of PPT, and some of the aTGFß1 may result from the damage and repair of thyroid cells. In fact, it is known that the thyrocyte itself can produce TGFß1 (34). In the present study all of the women with PPT became euthyroid during the postpartum year. Therefore, we do not know what serum TGFß1 levels would be in women whose PPT persists. However, increased circulating tTGFß1 levels have been reported to be associated with the remission phase of the disease in a series of patients with multiple sclerosis (35, 36).

Finally, whether TGFß1 can be considered a cytokine with an exclusive antiinflammatory role is still controversial. In fact, a recent study has suggested apparent proinflammatory effects of physiological amounts of TGFß1 produced during the development of spontaneous autoimmune thyroiditis in NOD.H-2h4 mice (34). Nevertheless, as all of the women observed in this study experienced transient thyroiditis, and given the antiinflammatory role of TGFß1, we favor the hypothesis that the increased serum concentrations of the aTGFß1 may contribute to a complex endogenous, but still unknown, antiinflammatory mechanism aimed at protecting the thyroid gland from permanent immunological damage during the year postpartum. Further studies of serum TGFß1 levels in women with persistent hypothyroidism after the postpartum year are needed to support this hypothesis.


   Acknowledgments
 
The skillful technical assistance of F. Latini is gratefully acknowledged.


   Footnotes
 
This work was supported by Health Ministry Project 1999 99/F (Inflammatory Bowel Diseases and Autoimmune Diseases–Mucosal Immunoregulation in Pathogenesis and Prevention).

Abbreviations: ATA, Antithyroid autoantibodies; aTGFß1, active TGFß1; FT3, free T3; FT4, free T4; PPT, postpartum thyroiditis; LAP, latency-associated peptide; TgAb, thyroglobulin autoantibodies; TPOAb, thyroid peroxidase autoantibodies; tTGFß1, total TGFß1.

Received June 25, 2002.

Accepted December 13, 2002.


   References
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 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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