EVOLVING CONCEPTS ARTICLE
Thyroid autoimmunity may manifest clinically as chronic autoimmune or Hashimoto’s thyroiditis (HT) and its variants (postpartum/sporadic thyroiditis) or as Graves’ disease (GD) and atrophic thyroiditis. These autoimmune thyroid diseases (AITD) occur as a result of aberrant immune response against thyroid antigens due to breakdown of self-tolerance . Although HT and GD share a common genetic background and may occur in the same family or the same individual, they have different pathophysiology and clinical presentation.
Evidence suggests that the phenotypic presentation of AITD as GD or HT largely depends on the predominant pattern of immune response during the development of autoimmunity. This is likely determined by environmental factors, through epigenetic effects, among which stress appears to play an important role [2,3]. Stress affects the immune system through activation of neuroendocrine pathways. During a stress response the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS) are activated, resulting in systemic elevations of glucocorticoids and catecholamines. These neuroendocrine responses are essential for the organism in maintaining homeostasis .
It has long been thought that stress hormones, glucocorticoids in particular, exert a generalized immune suppressive effect. However, accumulating evidence suggests that stress, through its effector neuroendocrine pathways, has a differential effect on the immune response, suppressing cellular and potentiating humoral immunity [5,6]. This review supports the hypothesis that stress, by affecting the balance of immune response, may influence the clinical expression of thyroid autoimmunity.
Regulation of Th1 and Th2 immune responses
The pattern of immune response (cellular vs. humoral) is largely regulated by antigen-presenting cells (APCs) such as dendritic cells (DCs), macrophages and natural killer (NK) cells, which are components of innate immunity. APCs’ major function is to present non-self antigens in conjunction with major histocompatibility complex (MHC) molecules and co-stimulatory signals to CD4+ T helper (Th) cells. Depending on the signal they receive from APCs, naive CD4+ Th cells are further differentiated into Th1 or Th2 cells that are components of adaptive immunity. In turn, Th1 cells secrete pro-inflammatory (type 1) cytokines, including interferon (INF)-gamma, interleukin (IL)-2 and tumor necrosis factor (TNF)-alpha, which are responsible for cell-mediated immune responses. On the other hand, Th2 cells produce anti-inflammatory (type 2) cytokines, primarily IL-4, IL-5, IL-10 and IL-13, which provide help to antigen specific B lymphocytes to produce antibodies involved in humoral immunity [7,8]. A third member of the T helper cell class, IL-17 producing CD4+ T cells, called Th17 cells has been recently recognized as a distinct Th subset, and has been linked to autoimmune inflammatory disorders.
Recent studies on the Th1/Th2 paradigm helped in better understanding of the mechanisms of differentiation of each subset as well as the transcription factors involved in their regulation. Thus, evidence suggests that IL-12 is important for Th1-cell differentiation, through STAT4 (signal transducer and activator of transcription 4) and the activation of the transcription factor T-bet (T-box expressed T cells), which upregulates INF-gamma and other type 1 cytokines and downregulate the expression of type 2 cytokines. Conversely, IL-4 induces Th2-cell differentiation through STAT6 and activation of GATA3 transcription factor, which upregulates IL-4 and IL-5 and downregulates INF-gamma expression [9,10], (Figure 1).
Figure 1. Interleukin (IL)-12 and IL-4 direct the differentiation of naïve CD4+ T cells towards Th1 or Th2 subtypes producing type 1 or type 2 cytokines, respectively. Th2 cells express the transcription factor GATA-3 that induces expression of Th2- specific cytokines and inhibits IFN-gamma production in developing Th1 cells. T-bet, a Th1-speciffic T-box transcription factor, induces IFN-gamma and represses IL-4 and IL-5 production in Th2 cells.
Stress hormones and the Th1/Th2 balance
Effect of glucocorticoids and catecholamines
Evidence suggests that glucocorticoids, at levels achieved during stress, suppress cell-mediated and potentiate humoral immunity. Glucocorticoids, acting through their cytoplasmic/nuclear receptors on APCs, suppress the production of IL-12, the main cytokine inducer of Th1 responses, and downregulate the expression of IL-12 receptors on T cells and natural killer cells, thus inhibiting INF-gamma production. On the other hand, glucocorticoids promote the production of IL-4 and IL-10 by the Th2 cells. The latter could be the result of diminishing the restraining effect of IL-12 and INF-gamma on Th2 cells [11 – 14]. Additional evidence suggests that glucocorticoids may also block the transcriptional activity of T-bet, the key transcription factor in Th1-mediated cellular immunity .
In a similar way, catecholamines, acting on APCs through beta2-adrenergic receptors (ARs) suppress the production of IL-12, thus inhibiting the differentiation of Th1 cells, while enhancing Th2 cell differentiation . Furthermore, catecholamines appear to inhibit the production of TNF-alpha and potentiate the production of IL-10 by APCs [17,18]. Notably, beta2-ARs are expressed only on Th1 and not on Th2 cells, and this may provide an additional explanation for the differential effect of catecholamines on Th1/Th2 balance. Thus, beta2-AR agonists inhibit INF-gamma production by Th1 cells but do not affect IL-4 production by Th2 cells . Furthermore, glucocorticoids can enhance the sensitivity of peripheral mononuclear cells to the immunomodulatory effects of catecholamines, indicating cooperative effects of the stress hormones on the immune deviation of the type1/type2 cytokine balance in favor of type 2 expression . In conclusion, main stress hormones, glucocorticoids and catecholamines appear to cause selective suppression of cellular immunity and enhance humoral immunity by down-regulating type-1 and up-regulating type-2 cytokine expression.
Epigenetic regulation of T cell differentiation and stress hormones
Epigenetic regulation of gene expression is an important mechanism that controls transcriptional activation or repression of specific gene loci. Methylation of CpGs DNA is generally associated with transcriptional inactivity within a gene locus, whereas removal of the methyl group from cytosine signals a shift from inert chromatin to active or open loci .
Recent studies have examined and implicated DNA methylation as a significant regulator of lineage commitment and specific cytokine production during Th cell differentiation . Mice deficient of a maintenance methyltransferase (Dnmt 1) experience ectopic cytokine production in T cells, where aberrant expression of IL-4 is attributed to inappropriate demethylation and depressed silencing of the IL-4 gene .
The differentiation of naive CD4+ T lymphocytes along the Th1 or Th2 differentiation pathway is thought to be regulated by epigenetic mechanisms leading to activation or silencing of the locus encoding type 2 cytokines (IL-4, IL-13) or the locus encoding IFN-gamma, respectively . A general model proposes that naive T cells have the potential to differentiate into either Th1 or Th2 cells. Following induction of the differentiation program, the transcriptional rate of IL-4 and IFN-gamma genes diverge. The Th1 differentiation program leads to increase in the transcriptional activity of IFN-gamma gene and the silencing of the genes for IL-4, IL-5 and IL-13. The opposite is true for the Th2 differentiation program, which leads to increased transcriptional activity of IL-4, IL-5 and IL-13 genes and silencing of the INF-gamma gene. Key stimulators of the Th1 differentiation program include IL-12 and the transcription factor STAT4 and the IFN-gamma/STAT1-transcription factor T-bet signaling pathways, whereas stimulators of the Th2 differentiation program includes the IL-4/STAT6 and the transcription factor GATA-3 signaling pathway .
It appears that specific epigenetic changes regulate the activation of INF-gamma gene during the process of differentiation of CD4+ T cells into Th1 cells and also the silencing of the same gene in differentiating Th2 cells . Recent evidence suggests that specific histone-methylation patterns of chromatin surrounding INF-gamma gene could explain the permissive chromatin environment for INF-gamma gene expression in differentiated Th1 cells, relative to the non-permissive chromatin environment for IFN-gamma gene expression in Th2 cells . The dynamic nature of the epigenetic changes that drive the silencing of IFN-gamma gene is dependent on two transcriptional activators of Th2 cell differentiation: GATA3 and STAT 6. In Th1 cells, the histone-acetylation across the INF-gamma gene locus is dependent on STAT 4 and T-bet . Glucocorticoid hormones bind to glucocorticoid receptors, which act as transcription regulators of many genes. Among these genes, of particular interest is DNA (cytokine-5)-methytransferase 1 (Dnmt1). Dnmt1 is involved in preservation of DNA methylation pattern as well as in de novo DNA methylation, and is important in epigenetic transcription repression . Recent reports suggest that glucocorticoids can modulate Dnmt 1 expression . There is also experimental evidence suggesting that the activated glucocorticoid receptor inhibits T-bet by direct protein-protein interaction and that glucocorticoid treatment reduces T-bet and STAT1 expression in mononuclear cells [15,30].
It is likely, therefore, that stress hormones, glucocorticoids in particular may influence T cell differentiation towards a Th2-type response, through epigenetic modification. The exact mechanism involved in this process awaits further elucidation.
The Th1/Th2 balance in thyroid autoimmunity
AITD, the most common-organ-specific autoimmune condition, may present clinically either as HT and its variants (postpartum or sporadic thyroiditis), or as GD, and atrophic thyroiditis . The main autoantigens in AITD are thyroglobulin (TG), thyroid peroxidase (TPO) and the TSH receptor (TSHr). HT is characterized by lymphocytic infiltration of the thyroid parenchyma causing a diffuse or micronodular goitre in association with positive serum anti-TPO and/or anti-TG antibodies, and varying degrees of thyroid dysfunction. The intra-thyroidal immune cells are T and B lymphocytes with CD4+ Th1–subtype predominating, although Th2 cells are also present . Thyroid follicular cells in close proximity to the infiltrating lymphocytes appear apoptotic, suggesting immune-mediated apoptotic destruction of these cells .
On the other hand, in GD, there is a follicular cell hypertrophy and hyperplasia along with hyperfunction, manifesting as a diffuse goitre and hyperthyroidism. The lymphocytic infiltration of the thyroid is patchy and not as massive as in HT and the majority of T lymphocytes are CD4+ Th2 cells, although Th1 cell are also present. TSHr-stimulating antibodies are the hallmark of Graves disease, and are responsible for the thyroid follicular growth and hyperfunction [32,34]. On the other hand, atrophic thyroiditis is rare and is characterized by a small (atrophic) thyroid gland and clinical hypothyroidism. TSHr-blocking antibodies are present in up to 50% of patients with atrophic thyroiditis and may be responsible for thyroid atrophy and hypofunction .
Studies in animal models suggest that thyroid autoimmunity is a three-stage process . In the first stage, there is an increase of intra-thyroidal APC’s which take up and present thyroid auto-antigens together with MHC class II antigens plus co-stimulatory molecules to the CD4+T cells. The second stage involves the interaction of the Th lymphocytes with the presented autoantigen. If immune tolerance and its regulation by co-stimulatory signals are lost, then inappropriate activation of antigen-specific T-lymphocytes takes place, leading to differentiation and clonal expansion of autoreactive CD4+ Th cells, and antibody-producing B lymphocytes. In the final stage, the generated autoreactive T and B lymphocytes accumulate in large numbers within the thyroid parenchyma, which becomes “a battlefield” with infiltrating lymphocytes and defending thyreocytes. The outcome of this interaction is largely dependent on the Th1/Th2 balance and the pattern of cytokines released in the local microenvironment [1,2], and determines the clinical phenotypes of thyroid autoimmunity.
Predominance of a Th1-type immune response, favoring cell-mediated immunity, may create a pro-apoptotic milieu for the thyroid cells. Fas and/or TNF-related apoptosis-inducing ligand (TRAIL)-dependent apoptotic pathways are activated by type-1 proinflammatory cytokines such as TNF-alpha, INF-gamma and IL-2, and the thyroid cells undergo apoptosis, leading to HT or its variants [37,38]. A predominant Th2–type immune response, favoring humoral immunity, may induce antigen-specific B lymphocytes to produce anti-TSHr antibodies. If the prevailing type of anti-TSHr antibodies is stimulatory, thyroid cell hyperplasia and hyperfunction ensue, leading to Graves’ hyperthyroidism. If, on the other hand, TSHr blocking antibodies predominate, then thyroid cell atrophy and hypofunction occur, leading to atrophic thyroiditis (Figure 2).
Thus, the phenotypic expression of thyroid autoimmunity towards GD or HT is dependent on the balance of Th1 vs. Th2 immune responses regulated by APCs and the type of cytokines predominating in the thyroid parenchyma. The fact that both conditions may develop in the same individual at different time points, suggests that the Th1/Th2 balance is a dynamic process that may be influenced by exogenous factors acting on APCs.
Association of stress with thyroid autoimmunity
The first clinical observation of an association between stressful life events and hyperthyroidism was made by Parry in 1825 along with the description of the disease, and subsequently by Graves, von Basedow and others . Both physical stress, such as trauma or major illness, and psychological stress such as bereavement have been implicated. These early reports were followed by epidemiological observations of an increased incidence of hyperthyroidism during major wars, a condition named “kriegsbasedow” . Thus, the incidence of hyperthyroidism in the Danish population increased significantly during the 1941-1945 German occupation. Also, Hospital admissions for thyrotoxicosis in occupied Scandinavian countries increased five- to six-fold during the 1939-1945 war and returned to normal rates after the war .
More recent evidence for such an association was the five-fold increase in GD compared to toxic nodular goitre (TNG) observed during the civil war in former Yugoslavia . Other studies failed to show an increase in antithyroid drug use during the civil unrest in Northern Ireland  or an increase in preceding stressful life events in thyrotoxic patients attending an outpatient’s clinic . However, the latter reports failed to distinguish between GD and other causes of thyrotoxicosis. In an earlier study, Forteza found that most of his 115 patients experienced stressful events just before the first signs of GD .
Following these early clinical observations, a number of case-control studies and population-based surveys using self-rated questionnaires have examined the effect of stress on the onset or the clinical course of Graves’ thyrotoxicosis.
Stress and the onset of Graves’ disease
The first large population-based clinical study that established an association between stressful life events and the onset of GD was from Sweden. Using a self-rated questionnaire, 208 patients with newly diagnosed GD were found to have more negative life events and higher negative life event scores in the year preceding the diagnosis, compared to 372 controls . Subsequent case-control studies in different ethnic populations, confirmed the association of stressful life events with the onset of GD [46-48]. One of these studies from Japan reported an association of stress with GD in women but not in men .
The above studies have been criticized because of their retrospective nature, the influence of recall bias, and the fact that thyrotoxicosis itself might also manifest with anxiety symptoms and negative emotional events, raising the question of distinguishing between cause and effect [50,51]. This problem was partially addressed by a more recent study that compared patients with GD to patients with TNG and healthy controls, in order to correct for the effect of thyrotoxicosis. A significant increase in the number of negative life events was found in the GD patients compared to those with TNG and normal controls . This finding supports the notion that stress may precipitate autoimmune as opposed to non-autoimmune hyperthyroidism. A recent nested case-control study in a cohort of 790 euthyroid women, who were first and second degree relatives of AITD patients, examined prospectively the relationship between stress and the de novo occurrence of thyroid antibodies or the development of clinical autoimmune hyper-/hypothyroidism. The authors reported that exposure to stress was not different between subjects who developed TPO-Abs and those who did not. Also no differences were observed in stress exposure between hyper-/hypothyroid cases and controls. Based on these findings, the authors concluded that, stress is not involved in the pathogenesis of AITD .
Stress and the clinical course of Graves’ disease
Few studies have examined the effect of stress on the clinical course of GD. In a retrospective study, treatment with a benzodiazepine, in addition to routine antithyroid drug therapy, reduced the relapse rate of thyrotoxicosis from 74% in patients not treated with benzodiazeoine to 29% in those treated with benzodiazepine, suggesting that stress management was effective in improving the prognosis of GD . Two prospective case-control studies also suggest that stress may have a negative impact on the outcome of GD. The first study from Japan investigated the outcome of patients with newly diagnosed GD after 12 months antithyroid drug therapy in relation to stressful life events. The authors reported that “daily stresses “at 6 months after starting therapy were associated with continued hyperthyroid state 12 months later . This effect was seen only in women, however, as the number of males in the study was too small to reach a significant effect. In a more recent study, it was shown that the relapse rate after antithyroid drug treatment for GD was related to daily stresses and some personality traits, and that stress scores correlated with the level of anti-TSHr antibodies after cessation of antithyroid drugs . The findings from these studies, although limited in number, indicate that stress may affect the clinical course of GD.
Several case reports also support a relationship between stress and the onset or outcome of GD. Misaki et al. reported three cases of Graves’ hyperthyroidism occurring after partial thyroidectomy for papillary carcinoma . The authors suggested that surgical stress might alter immune homeostasis converting preclinical into clinical Graves’ hyperthyroidism. An association of stress with the onset and clinical course of GD has also been reported in children. Mortillo and Gardner describe four children in whom a “separation” event was related to the onset or relapse of GD . We have reported five patients who developed mild autoimmune hyperthyroidism following a major stressful life event such as bereavement, job loss, stress at work, and major surgery. In all cases, the hyperthyroidism went into a remission following a short course (up to 6 months) of a low dose antithyroid drug treatment, and resolution of the stress situation .
Stress and Hashimoto’s thyroiditis
In contrast to GD, few studies have examined the association between stress and HT. Two case-control studies evaluated the role of stressful events in HT or postpartum thyroiditis. They concluded that stress was not the trigger in either condition [60,61]. A recent population study also did not find a relationship between stressful life events and the presence of anti-TPO antibodies among euthyroid women .The onset and clinical course of HT are often insidious and the diagnosis may be delayed until the patient develop overt hypothyroidism, making it difficult to assess the role of stress in the onset and natural history of the disease.
In summary, the evidence from the available epidemiological observations and clinical studies suggests a possible association between stress and GD but not with HT. The biological mechanisms underlying the association of stress with GD are not known, but a possible explanation is given below.
Stress in the clinical expression of thyroid autoimmunity: a unifying hypothesis
Evidence from animal studies and clinical observations suggests that a hyperactive or hypoactive stress response may be associated with decreased or increased vulnerability to different types of autoimmune diseases . For example, Fisher rats, that have hyperactive stress system, are resistant to experimentally induced Th1-mediated autoimmune diseases, such as rheumatoid arthritis, uveitis, and experimental allergic encephalomyelitis. Conversely, Lewis rats, which have hypoactive HPA axis, are prone to develop Th1-mediated autoimmune conditions .
A physiological condition with changing in the Th1/Th2 balance is pregnancy and the postpartum period. Pregnancy causes suppression of Th1-mediated cellular immune activity and preservation or enhancement of Th2-mediated humoral immunity. In the third trimester, Th1-type cytokines such as INF-gamma and IL-2 decline and Th2 cytokines, in particular IL-4, increase. This shift may permit the histoincompatible fetal-placental unit to avoid rejection by a cell-mediated maternal immune attack [64,65]. These immune changes in pregnancy develop in parallel with a marked increase in glucocorticoids along with increases in estrogen and progesterone. Progesterone appears to cause a shift in the Th1/Th2 balance similar to that described for glucocorticoids . Indeed, the changes in the hormonal milieu may explain why pregnant women experience remission of Th1-mediated autoimmune disease such as rheumatoid arthritis, multiple sclerosis, and autoimmune thyroiditis, and aggravation of Th2-mediated autoimmune conditions such as lupus erythematosus [67-69].
In the postpartum period, the hormonal milieu changes abruptly, with glucocorticoids, estrogens and progesterone decreasing to subnormal levels, allowing a prompt recovery of cell-mediated immune function . This Th2 to Th1 “return shift” might explain the increase in the incidence of postpartum thyroiditis and other Th1-mediated autoimmune conditions. Analogous clinical situations associated with a decreased stress system activity are seen during the period that follows cure from Cushing’s syndrome or discontinuation of glucocorticoid therapy [70-71]. These situations have been associated with increased susceptibility to Th1-mediated immune disorders. A similar rebound reaction may occur in periods that follow cessation of chronic stress. Conversely, GD and other Th2-predominant conditions are frequently associated with allergic diseases . Further support for the importance of the Th2 pathway in GD comes from observations that recurrence after anti-thyroid drug therapy is more likely following an attack of allergic rhinitis with elevated lgE levels, which is a marker of Th2 activity . Interestingly, in this regard, humanized anti-CD52 monoclonal antibody therapy for multiple sclerosis, that causes change in the immune response from Th1 to Th2 phenotype, was reported to trigger the development of GD .
On the basis of these observations and the information cited above, a unifying hypothesis for the role of stress in the clinical expression of AITD can be formulated. Environmental factors, interacting with genetic factors, may induce an aberrant immune response against thyroid autoantigens and render an individual susceptible to develop thyroid autoimmunity. The potential of precursor CD4+T lymphocytes to differentiate toward Th1 or Th2 type activity following interaction with APCs is an important switching point for the development of cell-mediated versus humoral autoimmunity. If a susceptible individual is under severe stress, the stress hormones may steer the balance toward a Th2 phenotype. Effector Th2 cells and type 2 cytokines will then induce antigen-specific B lymphocytes to produce anti-TSHr antibodies. The concomitant suppression of Th1-effector pathway will protect thyroid cells from a cell-mediated immune attack. Under these circumstances, the clinical outcome will be GD. Conversely, if a susceptible person is recovering from a stress response (when the stress axis is hypoactive) or postpartum, when the immune suppressive effect of pregnancy is gone, a rebound reaction may reactivate the Th1-mediated branch pathway, leading to cellular immune response and apoptotic destruction of thyroid follicular cells by the proinflammatory cytokines. The likely outcome will then be autoimmune (sporadic) or postpartum thyroiditis, respectively (Figure 3).
Circumstantial evidence suggests that HT and GD, the two opposite clinical entities of AITD, manifest different immune phenotypes. HT is predominately a Th1-mediated autoimmune disease, whereas GD has a predominant Th2 phenotype. There is convincing evidence from epidemiological and clinical studies supporting the hypothesis that stress may favor the development of GD, but there is limited information on the role of stress in HT. However, whether stress plays a causative role in the development of GD is not yet clear. It is likely, that in susceptible individuals, stress hormones may influence the clinical expression of thyroid autoimmunity towards the development of GD by suppressing cellular immunity and potentiating humoral immunity. Epigenetic mechanisms may be involved in this process. On the other hand, recovery from stress, though a rebound effect of cellular immunity, may favor the development of autoimmune thyroiditis. This is a working hypothesis based on circumstantial evidence and needs further substantiation. Future studies also need to focus on identifying agents that can restore the type1/type2 cytokine balance, in the presence of stress hormones, and serve as a basis for the interventions to prevent the stress-associated immune conditions in humans.
A Tsatsoulis, C Limniati – Department of Endocrinology, University of Ioannina
45110, Ioannina Greece
Corresponding author: Agathocles Tsatsoulis, MD, PhD, FRCP; Professor of Medicine-Endocrinology, Department of Endocrinology, University of Ioannina, 45110, Ioannina, Greece; Email: firstname.lastname@example.org
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