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Chapter 7 Thyroid Dysfunction and the Immune System
Handbook of Systemic Autoimmune Diseases, Volume 9 Endocrine Manifestations of Systemic Autoimmune Diseases Sara E. Walker and Luis J. Jara, editors
CHAPTER 7
Thyroid Dysfunction and the Immune System Alejandro Ruiz-Argu¨ellesa,, Mario Garcı´ a-Carrascob a
b
Laboratorios Clı´nicos de Puebla, Me´xico Beneme´rita Universidad Auto´noma de Puebla, Me´xico
It is now accepted that the neuroendocrine system can influence the development and function of the immune system. Conversely, the information regarding how the immune system participates in the regulation of endocrine activity is rather scant, particularly for immune–endocrine interactions of the hypothalamus–pituitary–thyroid axis. It is known that thyroid-stimulating hormone (TSH) may be produced by many types of extra-pituitary cells such as T and B lymphocytes, splenic dendritic cells, bone marrow hematopoietic cells, and intestinal epithelial cells; however, little is known regarding the physiological role of these TSH pathways. Recent evidence suggests the existence of complex regulatory functions mediated by intra-thyroid bone marrow–derived cells that affect thyroid function in both physiological and pathological conditions.
1. Physiological interactions of thyroid function and the immune system That TSH is produced by cells of the immune has been known for decades (Smith et al., 1982; Kruger and Blalock, 1986). Leukocytes produce TSH when stimulated by TSH-releasing hormone or with staphylococcus enterotoxin A (Smith et al., 1982; Kruger and Blalock, 1986; Kruger et al., 1989). Additionally, thyroid hormones also may Corresponding author.
Tel.: (+52222) 2438100; Fax: (+52222) 2438428 E-mail address: [email protected] r 2008 Published by Elsevier B.V. DOI: 10.1016/S1571-5078(07)00207-3
serve as negative feedback regulators of hematopoietic TSH production, as they do in the hypothalamus–pituitary–thyroid axis (Harbour et al., 1989). Splenic dendritic cells (DCs) have also been shown to be an important source of TSH production. When stimulated in vitro, DCs produce threefold to sixfold more TSH than B or T lymphocytes (Bagriacik et al., 2001). Within the bone marrow, TSH is produced by a sub-population of hematopoietic precursor cells bearing the CD45+/CD11b+ phenotype (Zhou et al., 2002; Klein and Wang, 2004). TSH synthesis also takes place in intestinal epithelial cells and intestinal T cells (Wang et al., 1997). TSH production seems to be restricted in sub-villus crypt regions (Scofield et al., 2005)—a site where local T-cell development occurs (Saito et al., 1998)—as well as in certain focal areas of the epithelium (Scofield et al., 2005). In at least two examples, it has been shown that viral infections in the intestine result in an increased local synthesis of TSH (Scofield et al., 2005), which suggests a paracrine action of TSH, which might operate elsewhere in the organism, including the thyroid gland itself. Although it is known that TSH is produced by cells of the immune system, it is not clear how immune-cell–derived TSH participates in the immunoregulatory circuits in health and disease. There are two possible venues through which immunederived TSH could modify the immune response: one would be the direct effect of TSH on immune cells, while the other could operate in an indirect fashion through TSH-induced thyroid hormone. Both these possibilities are not mutually exclusive.
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A. Ruiz-Argu¨elles, M. Garcı´a-Carrasco
Since TSH is produced by leukocytes, it is possible that TSH acts as a biological response modifier within the immune system, as a cytokine-like molecule. Consonant with this hypothesis is the demonstration of the presence of TSH receptors on lymphoid and myeloid cells (Coutelier et al., 1990; Bagriacik and Klein, 2000) and the proven ability of TSH to induce several immune response-related functions (Fabris et al., 1995, p. 14; Kruger, 1996). TSH alone increases the in vitro production and secretion of antibodies (Blalock et al., 1984; Kruger and Blalock, 1986; Kruger et al., 1989) as well as the in vitro proliferative response of lymphocytes to mitogens (Provinciali et al., 1992). When combined with interleukin-2, TSH increases the potential of this cytokine to induce natural killer cell activity (IL-2) (Provinciali et al., 1992), and stimulation of splenic DCs by TSH increases the activity of interleukin-1b and interleukin-12 in the presence of phagocytic stimuli (Bagriacik and Klein, 2000). In the hematopoietic milieu, TSH increases the synthesis and secretion of TNFa (Whetsell et al., 1999; Klein and Wang, 2004), and triggers phosphorylation of the Jak2 kinase (Whetsell et al., 1999). Inasmuch as these functions are exerted on cells expressing TSH receptors, it is very likely that they are mediated by direct interaction of TSH with its corresponding receptor. Consonant with the second alternative, that is TSH acting through thyroid hormone release, are several reports of impaired immune function in hypothyroidism. In TSH receptor defective (C.RF-hyt/hyt) mice, there is impairment of B-cell development (Foster et al., 1999; Dorshkind and Horseman, 2005), which can be corrected by exogenous administration of T4 (Foster et al., 1999). Additionally, mice that are genetically unable to express T3 receptor show reduced numbers of T and B lymphocytes, as well as myeloid cells in the bone marrow, thymus, and spleen (Beigneux et al., 2003). A very attractive possibility is that another role of ‘‘immune’’ TSH would be the micro regulation of thyroid function. This would mainly participate in the communication between the immune system and the thyroid, rather than in the overall regulation of thyroid function which remains the responsibility of the hypothalamus and pituitary. For this to occur, it must be accepted that immune cells that are capable
of producing TSH, are also capable of trafficking to the thyroid and exerting paracrine regulation. Two clinical conditions seem to support this hypothesis: the first of them is the Euthyroid Sick Syndrome (ESS); a hypothyroidic condition of humans that occurs in the absence of thyroid disease, where conversion of T4 to T3 is impaired in mild forms, but the output of T4 itself may be found decreased in severe forms. ESS can present as a complication of a variety of infectious and non-infectious inflammatory diseases or after prolonged fasting (De Groot, 1999; Papanicolaou, 2000; Klemperer, 2002; Inan et al., 2003; Brierre et al., 2004). Although the true significance of ESS is not known, it may represent a physiological mechanism aimed at conserving energy during periods of stress (De groot, 1999; Larsen et al., 2002; Fakete et al., 2004). The detailed mechanisms of how the different conditions can trigger ESS have been described elsewhere (Klein, 2006), but it has been forwarded that the immune system, rather than the endocrine axis, is responsible for the recovery of euthyroid function after the underlying pathological condition is resolved. This assumes the existence of an inherent ability of the immune system to continually assess the status of the infectious condition and thus to determine whether it is safe for the host to return to a state of normal metabolic activity. The second is the ESS-like condition that follows hematopoietic stem cell transplantation, which can be due to total body irradiation (Wehmann et al., 1985; Hershman et al., 1990; Vexiau et al., 1993; Kauppilla et al., 1998; Ishiguro et al., 2004; Carlson et al., 1992; Lio et al., 1988; Matsumoto et al., 2004) or chemotherapy in the absence of irradiation (Toubert et al., 1997; Slatter et al., 2004). In this condition, T3 and occasionally T4 levels are diminished in the presence of normal TSH output. Inasmuch as the thyroid is resistant to clinical radiation, the reason for the impairment of thyroid function is unknown but it is not secondary to the thyroid gland damage by the immunosuppressive treatment itself. Moreover, thyroid hormone levels in bone marrow graft recipients remain suppressed in the face of otherwise normal circulating TSH levels. As in ESS, it seems that pituitary TSH has a minimal, if any, influence on thyroid function in these patients. Again, intra-thyroid TSH production by immune system cells is a novel and very interesting explanation.
Thyroid Dysfunction and the Immune System
A simple interpretation of these observations is that inflammatory stress might act through the hypothalamus–pituitary–thyroid axis to initiate and maintain an overall condition of decreased metabolic activity, basically aimed to energy conservation by the host during the period of infection or fasting. Once the infection is eliminated or controlled by the innate and adaptive immune responses, the immune system would provide the initial signal that would trigger an adjustment in thyroid hormone function and the resultant recovery of metabolism. The relationship between thyroid dysfunction and autoimmunity can be analyzed in pathological conditions, but also from a physiological state that has shed important clues to the understanding of this interaction. In recent years, there has been an increasing interest in disturbances of thyroid function that occur in mothers after delivery, a prevalence that seems to be higher than previously thought. Additionally, it has been proven that patients with previous thyroid dysfunction before pregnancy may have recurrences. In particular, a transient destructive type of postpartum hyperthyroidism has been recognized which may be silent. Preliminary studies on the prevalence of this particular disorder have shown that it is far more common that postpartum Graves’ hyperthyroidism (Amino et al., 1976, 1982). For the survival of the foreign fetus to occur, modulation of the maternal immune system to prevent its rejection seems mandatory. Accordingly, the maternal immune response becomes suppressed during pregnancy by a variety of mechanisms, which can also affect the clinical behavior and fate of a variety of autoimmune diseases, resulting in a transient amelioration of their activity during pregnancy, which is followed by a postpartum relapse. Hence, postpartum exacerbation may occur for autoimmune thyroid diseases as Hashimoto’s thyroiditis and Graves’ disease, as it does for non-thyroid autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus (Ginsburg and Walfish, 1977; Walfish and Chan, 1985). The high frequency of these syndromes likely reflects changes in peripartum immune network regulation; however, the preferential involvement of thyroid in these pregnancy-associated autoimmune disorders remains a conundrum. The
77
most plausible explanation might reside in the bidirectional complex interactions between thyroid function and the immune system.
2. The thyroid gland as a target of autoimmune disease Cell-mediated as well as antibody-mediated immunity and genetic predisposition all play a role in autoimmune thyroid disease (Weetman, 1992). Multigenic predisposition (Davies, 1998) plus environmental stress is apparently necessary for activation of the autoimmune process. As with other autoimmue diseases, thyroid autoimmunity is more common in women than in men most likely because of both, genetic as well as hormonal factors (Chiovato et al., 1993). Among environmental factors, it is known that excessive dietary iodine intake (Laurberg et al., 1998) and smoking increase the risk of hypothyroidism in Hashimoto’s thyroiditis (Fukata et al., 1996) and the risk of ophthalmopathy in Graves’ disease. Several cytokines are involved in the pathophysiology of autoimmune thyroid disease: interferon a, interleukin-2, and macrophage colony-stimulating factor may induce autoimmune thyroiditis (Volpe, 1993). Patients with autoimmune thyroid disease may have a variety of thyroid-specific antibodies, including thyroid-stimulating thyrotropin receptor antibodies, TSH receptor-blocking and inhibitory antibodies, anti-thyroglobulin antibodies, antithyroidperoxidase (TPO) antibodies, anti-sodiumiodide symporter, and, possibly, growth-stimulating antibodies (Endo et al., 1996). Cell-mediated autoimmunity and apoptosis are factors in the destruction of thyroid cells and the development of hypothyroidism in Hashimoto’s thyroiditis (McLachlan et al., 1990). Goiter results from lymphocytic infiltration, fibrosis, and, possibly, thyroid stimulation by TSH. In Graves’ disease, hyperthyroidism and goiter are caused by autoantibodies against the TSH receptor that mimic the effect of TSH on thyroid follicular cells. The cause of extra-thyroidal manifestations, such as ophthalmopathy and thyroid dermopathy, is less clear. The autoimmune process in the affected tissues may be
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due to an antigenic determinant common to both thyroid cells and these tissues (Bahn and Heufelder, 1993; Arscott and Baker, 1998). Sub-clinical hypothyroidism is defined as mild elevation of serum TSH levels and normal circulating thyroid hormone levels. Anti-thyroid antibodies are positive in 95% of affected patients. Silent thyroiditis is a similar condition that may have autoimmune origin. It is associated with transient excessive thyroid hormone release and low radioiodine uptake. Silent thyroiditis can occur in both men and women, unrelated to pregnancy. In most affected patients, the hypothyroidism is not permanent. The mechanisms underlying the autoimmune process that leads to thyroid disease must be more complex than those involved in other ‘‘organspecific’’ autoimmune diseases. Autoimmune thyroid diseases can be found in association with a wide variety of other overt autoimmune diseases or conditions that have been related to autoimmune phenomena. The following is an alphabetical list of such conditions:
Alopecia areata Autoimmune liver Autoimmune polyglandular syndromes (e.g., Addison’s disease, hypoparathyroidism, type 1 diabetes, ovarian failure) Celiac disease Chronic ulcerative colitis Crohn’s disease Down syndrome Hepatitis C infection Idiopathic thrombocythemia Idiopathic thrombocytopenic purpura Klinefelter’s syndrome Mixed connective tissue disease Myasthenia gravis Polymyalgia rheumatica Primary biliary cirrhosis Rheumatoid arthritis Scleredema Sjo¨gren’s syndrome Systemic lupus erythematosus Turner’s syndrome Vitiligo
When analyzing this variety of conditions, it is clear that mechanisms other than antigenic mimicry or cross reactivity of autoantibodies, or selfreacting cells, are operating in patients with such combinations of clinical manifestations. The more is learned about the complex interactions of neuroendocrine regulation and the immune system, specifically about the role of extra-pituitary TSH on several cells and tissues, our understanding of the disease pathophysiology will become clearer. Acceptance that immune TSH might be a ubiquitous regulatory molecule of other physiological processes is, doubtlessly, a most interesting explanation.
Key points Cells of the immune system are capable to secrete thyroid-stimulating hormone. Immune TSH as well as pituitary may participate in immunoregulatory circuits. Physiologic neuro–immune–endrocine interactions are manifold and bidirectional.
References Amino, N., Miyai, K., Onishi, T., et al. 1976. Transient hypothyroidism after delivery in autoimmune thyroiditis. J. Clin. Endocrinol. Metab. 42, 296–301. Amino, N., Mori, H., Iwatani, Y., et al. 1982. High prevalence of transient post-partum thyrotoxicosis and hypothyroidism. N. Engl. J. Med. 306, 849–852. Arscott, P., Baker, J.J. 1998. Apoptosis and thyroiditis. Clin. Immunol. Immunopathol. 87, 207–217. Bagriacik, E.U., Klein, J.R. 2000. The thyrotropin (thyroid stimulating hormone) receptor is expressed on murine dendritic cells and on a subset of CD43RBhigh lymph node T cells: functional role of thyroid stimulating hormone during immune activation. J. Immunol. 164, 6158–6165. Bagriacik, E.U., Zhou, Q., Wang, H.-C., Klein, J. 2001. Rapid and transient reduction in circulating thyroid hormones following systemic antigen priming: implications for functional collaboration between dendritic cells and thyroid. Cell. Immunol. 212, 92–100. Bahn, R.S., Heufelder, A.E. 1993. Pathogenesis of Graves’ ophthalmopathy. N. Engl. J. Med. 329, 1468–1475.
Thyroid Dysfunction and the Immune System Beigneux, A.P., Moser, A.H., Shigenaga, J.K., Grunfeld, C., Feingold, K.R. 2003. Sick euthyroid syndrome is associated with decreased, TR expression and DNA binding in mouse liver. Am. J. Physiol. Endocrinol. Metab. 284, E228–E236. Blalock, J.E., Johnson, H.M., Smith, E.M., Torres, B.A. 1984. Enhancement of the in vitro antibody response by thyrotropin. Biochem. Biophys. Res. Comm. 25, 30–34. Brierre, S., Kumari, R., Deboisblanc, B.P. 2004. The endocrine system during sepsis. Am. J. Med. Sci. 328, 238–247. Carlson, K., Lonnerholm, G., Smedmyr, B., Oberg, G., Simonsson, B. 1992. Thyroid function after autologous bone marrow transplantation. Bone Marrow Transplant. 10, 123–127. Chiovato, L., Lapi, P., Fiore, E., et al. 1993. Thyroid autoimmunity and female gender. J. Endocrinol. Invest. 16, 384–391. Coutelier, J.P., Kehrl, J.H., Bellur, S.S., Kohn, L.D., Notkins, A.L., Prabhakar, B.S. 1990. Binding and functional effects of thyroid stimulating hormone to human immune cells. J. Clin. Immunol. 10, 204–210. Davies, T.F. 1998. Autoimmune thyroid disease genes come in many styles and colors (Editorial). J. Clin. Endocrinol. Metab 83 (10), 3391–3393. De Groot, L.J. 1999. Dangerous dogmas in medicine: the nonthyrodial illness syndrome. J. Clin. Endocrinol. Metab. 84, 151–164. Dorshkind, K., Horseman, N.D. 2005. The roles of prolactin, growth hormone, insulin-like growth factor-I, and thyroid hormones in lymphocyte development and function: insights from genetic models of hormone and hormone receptor deficiency. Endocr. Rev. 21, 292–312. Endo, T., Kaneshige, M., Nakazto, M., et al. 1996. Autoantibody against thyroid iodide transporter in the sera from patients with Hashimoto’s thyroiditis possesses iodide transport inhibitory activity. Biochem. Biophys. Res. Commun. 228, 199–202. Fabris, N., Mochegiani, E., Provinciali, M. 1995. Pituitarythyroid axis and immune system: a reciprocal neuroendocrine-immune interaction. Horm. Res. 43, 29–38. Fakete, C., Gereben, B., Doleschall, M., Harney, J.W., Dora, J.M., Bianco, A.C., Sarkar, S., Liposits, Z., Rand, W., Emerson, C., Kacskovics, I., Larsen, P.R., Lechan, R.M. 2004. Lipopolysaccharide induces type 2 iodothyronine deiodinase in the mediobasal hypothalamus: implications for the nonthyroidal illness syndrome. Endocrinology 145, 1649–1655. Foster, M.P., Montecino-Rodriguez, E., Dorshkind, K. 1999. Proliferation of bone marrow pro-B cells is dependent on stimulation by the pituitary/thyroid axis. J. Immunol. 163, 5883–5889. Fukata, S., Kuma, K., Sugawara, M. 1996. Relationship between cigarette smoking and hypothyroidism in patients with Hashimoto’s thyroiditis. J. Endocrinol. Invest. 19, 607–612. Ginsburg, J., Walfish, P.G. 1977. Post-partum transient thyrotoxicosis with painless thyroiditis. Lancet 1, 1125–1128. Harbour, D.V., Kruger, T.E., Coppenhaver, D., Smith, E.M., Meyer, W.J., III 1989. Differential expression and regu-
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lation of thyrotropin (TSH) in T cell lines. Mol. Cell. Endocrinol. 64, 229–241. Hershman, J.M., Eriksen, E., Kaufman, N., Chaplin, R.E. 1990. Thyroid function tests in patients undergoing bone marrow transplantation. Bone Marrow Transplant. 6, 49–51. Inan, M., Koyuncu, A., Aydin, C., Turan, M., Gokgoz, S., Sen, M. 2003. Thyroid hormone supplementation in sepsis: an experimental study. Surg. Today 33, 24–29. Ishiguro, H., Yasuda, Y., Omita, Y., Shinagawa, T., Shimizu, T., Morimoto, T., Hattori, K., Matsumoto, M., Inoue, H., Yabe, H., Yabe, M., Shinohara, O., Kato, S. 2004. Longterm follow-up of thyroid function in patients who received bone marrow transplantation during childhood and adolescences. J. Clin. Endocrinol. Metab. 89, 5981–5986. Kauppilla, M., Koskinen, P., Irjala, K., Remes, K., Viikari, J. 1998. Long-term effects of allogeneic bone marrow transplantation (BMT) on pituitary, gonad, thyroid and adrenal function in adults. Bone Marrow Transplant. 22, 331–337. Klein, J.R. 2006. The immune system as a regulator of thyroid hormona activity. Exp. Biol. Med. 231, 229–236. Klein, J.R., Wang, H.-C. 2004. Characterization of a novel set of resident intrathyroidal bone marrow-derived hematopoietic cells: potential for immune-endocrine interactions in thyroid homeostasis. J. Exp. Biol. 207, 55–65. Klemperer, J.D. 2002. Thyroid hormone and cardiac surgery. Thyroid 12, 517–521. Kruger, T.E. 1996. Immunomodulation of peripheral lymphocytes by hormones of the hypothalamus–pituitary–thyroid axis. Adv. Neuroimmunol. 6, 387–395. Kruger, T.E., Blalock, J.E. 1986. Cellular requirements for thyrotropin enhancement of in vitro antibody production. J. Immunol. 137, 197–200. Kruger, T.E., Smith, E.M., Harbour, D.V., Blalock, J.E. 1989. Thyrotropin: an endogenous regulator of the in vitro immune response. J. Immunol. 142, 744–747. Larsen, P.R., Davies, T.F., Schumberger, M.J., Hay, I.D. 2002. Thyroid physiology and diagnostic evaluation of patients with thyroid disorders. In: K.S. Plonsky (Ed.), Williams Textbook of Endocrinology, 10th ed., WB Saunders, Philadelphia, p. 350. Laurberg, P., Pedersen, K.M., Hreidarsson, A., et al. 1998. Iodine intake and the pattern of thyroid disorders: a comparative epidemiological study of thyroid abnormalities in the elderly in Iceland and in Jutland, Denmark. J. Clin. Endocrinol. Metab. 83 (3), 765–769. Lio, S., Arcese, W., Papa, G., D’Armiento, M. 1988. Thyroid and pituitary function following bone marrow transplantation. Arch. Intern. Med. 148, 1066–1077. Matsumoto, M., Ishiguro, H., Tomita, Y., Inoue, H., Yasuda, Y., Shimizu, T., Shinagawa, T., Hattori, K., Yabe, H., Kubota, C., Yabe, M., Kato, S., Shinohara, O. 2004. Changes in thyroid function after bone marrow transplant in young patients. Pediatr. Int. 46, 291–295. McLachlan, S., Atherton, M., Nakajima, Y., et al. 1990. Thyroid peroxidase and the induction of autoimmune thyroid disease. Clin. Exp. Immunol. 79, 182–188. Papanicolaou, D.A. 2000. Euthyroid sick syndrome and the role of cytokines. Rev. Endocr. Metab. Disord. 1, 43–48.
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Provinciali, M., Di Stefano, G., Fabris, N. 1992. Improvement in the proliferative capacity and natural killer cell activity of murine spleen lymphocytes by thyrotropin. Int. J. Immunopharmacol. 14, 865–870. Saito, H., Kanamori, Y., Takemori, T., Nariuchi, H., Kubota, E., Takahashi-Iwanga, H., Iwanga, T., Ishikawa, H. 1998. Generation of intestinal T cells from progenitors residing in gut cryptopatches. Science 280, 275–278. Scofield, V.L., Montufar-Solis, D., Cheng, E., Estes, M.K., Klein, J.R. 2005. Intestinal TSH production is localized in villus ‘‘hotblocks’’ and is coupled to IL-7 production: evidence for involvement of TSH during acute virus infection. Immunol. Lett. 99, 36–44. Slatter, M.A., Gennery, A.R., Cheetham, T.D., Bhattacherya, A., Crooks, B.N., Flood, T.J., Cant, A.J., Abinun, M. 2004. Thyroid dysfunction after bone marrow transplantation for primary immunodeficiency without the use of total body irradiation in conditioning. Bone Marrow Transplant. 33, 949–953. Smith, E.M., Phan, M., Kruger, T.E., Coppenhaver, D.H., Blalock, J.E. 1982. Human lymphocyte production of immunoreactive thyrotropin. Proc. Natl. Acad. Sci. USA 80, 6010–6013. Toubert, M.E., Socie, G., Gluckman, E., Aractingi, S., Esperou, H., Devergie, A., Ribaud, P., Parquet, N., Schlageter, M.H., Beressi, J.P., Rain, J.D., Vexiau, P. 1997. Short- and longterm follow-up of thyroid dysfunction after allogeneic bone
marrow transplantation without the use of preparative total body irradiation. Br. J. Haematol. 98, 453–457. Vexiau, P., Perez-Castiglioni, P., Socie, G., Devergie, A., Toubert, M.E., Aractingi, S., Gluckman, E. 1993. The ‘‘euthyroid sick syndrome’’: incidence, risk factors and prognostic value soon after allogeneic bone marrow transplantation. Br. J. Haematol. 85, 778–782. Volpe, R. 1993. The role of cytokines in the development of autoimmune thyroid disease. Thyroid 3, 177–178. Walfish, P.G., Chan, J.Y.C. 1985. Post-partum hyperthyroidism. Clin. Endocrinol. Metab. 14, 417–447. Wang, H.-C., Whetsell, M., Klein, J.R. 1997. Local hormone networks and intestinal T cell homeostasis. Science 275, 1937–1939. Weetman, A. 1992. Autoimmune thyroiditis: predisposition and pathogenesis. Clin. Endocrinol. 36, 307–323. Wehmann, R.E., Gregerman, R.I., Burns, W.H., Saral, R., Santos, G.W. 1985. Suppression of thyrotropin in the lowthyroxine state of severe nonthyroidal illness. N. Engl. J. Med. 312, 546–552. Whetsell, M., Bagriacik, E.U., Seetharamaiah, G.S., Prabhakar, B.S., Klein, J.R. 1999. Neuroendocrine-induced synthesis of bone marrow-derived cytokines with inflammatory immunomodulating properties. Cell. Immunol. 192, 159–166. Zhou, Q., Wang, H.-C., Klein, J.R. 2002. Characterization of a novel anti-mouse thyrotropin monoclonal antibody. Hybrid. Hybridomics 21, 75–79.
CHAPTER 7
Thyroid Dysfunction and the Immune System Alejandro Ruiz-Argu¨ellesa,, Mario Garcı´ a-Carrascob a
b
Laboratorios Clı´nicos de Puebla, Me´xico Beneme´rita Universidad Auto´noma de Puebla, Me´xico
It is now accepted that the neuroendocrine system can influence the development and function of the immune system. Conversely, the information regarding how the immune system participates in the regulation of endocrine activity is rather scant, particularly for immune–endocrine interactions of the hypothalamus–pituitary–thyroid axis. It is known that thyroid-stimulating hormone (TSH) may be produced by many types of extra-pituitary cells such as T and B lymphocytes, splenic dendritic cells, bone marrow hematopoietic cells, and intestinal epithelial cells; however, little is known regarding the physiological role of these TSH pathways. Recent evidence suggests the existence of complex regulatory functions mediated by intra-thyroid bone marrow–derived cells that affect thyroid function in both physiological and pathological conditions.
1. Physiological interactions of thyroid function and the immune system That TSH is produced by cells of the immune has been known for decades (Smith et al., 1982; Kruger and Blalock, 1986). Leukocytes produce TSH when stimulated by TSH-releasing hormone or with staphylococcus enterotoxin A (Smith et al., 1982; Kruger and Blalock, 1986; Kruger et al., 1989). Additionally, thyroid hormones also may Corresponding author.
Tel.: (+52222) 2438100; Fax: (+52222) 2438428 E-mail address: [email protected] r 2008 Published by Elsevier B.V. DOI: 10.1016/S1571-5078(07)00207-3
serve as negative feedback regulators of hematopoietic TSH production, as they do in the hypothalamus–pituitary–thyroid axis (Harbour et al., 1989). Splenic dendritic cells (DCs) have also been shown to be an important source of TSH production. When stimulated in vitro, DCs produce threefold to sixfold more TSH than B or T lymphocytes (Bagriacik et al., 2001). Within the bone marrow, TSH is produced by a sub-population of hematopoietic precursor cells bearing the CD45+/CD11b+ phenotype (Zhou et al., 2002; Klein and Wang, 2004). TSH synthesis also takes place in intestinal epithelial cells and intestinal T cells (Wang et al., 1997). TSH production seems to be restricted in sub-villus crypt regions (Scofield et al., 2005)—a site where local T-cell development occurs (Saito et al., 1998)—as well as in certain focal areas of the epithelium (Scofield et al., 2005). In at least two examples, it has been shown that viral infections in the intestine result in an increased local synthesis of TSH (Scofield et al., 2005), which suggests a paracrine action of TSH, which might operate elsewhere in the organism, including the thyroid gland itself. Although it is known that TSH is produced by cells of the immune system, it is not clear how immune-cell–derived TSH participates in the immunoregulatory circuits in health and disease. There are two possible venues through which immunederived TSH could modify the immune response: one would be the direct effect of TSH on immune cells, while the other could operate in an indirect fashion through TSH-induced thyroid hormone. Both these possibilities are not mutually exclusive.
76
A. Ruiz-Argu¨elles, M. Garcı´a-Carrasco
Since TSH is produced by leukocytes, it is possible that TSH acts as a biological response modifier within the immune system, as a cytokine-like molecule. Consonant with this hypothesis is the demonstration of the presence of TSH receptors on lymphoid and myeloid cells (Coutelier et al., 1990; Bagriacik and Klein, 2000) and the proven ability of TSH to induce several immune response-related functions (Fabris et al., 1995, p. 14; Kruger, 1996). TSH alone increases the in vitro production and secretion of antibodies (Blalock et al., 1984; Kruger and Blalock, 1986; Kruger et al., 1989) as well as the in vitro proliferative response of lymphocytes to mitogens (Provinciali et al., 1992). When combined with interleukin-2, TSH increases the potential of this cytokine to induce natural killer cell activity (IL-2) (Provinciali et al., 1992), and stimulation of splenic DCs by TSH increases the activity of interleukin-1b and interleukin-12 in the presence of phagocytic stimuli (Bagriacik and Klein, 2000). In the hematopoietic milieu, TSH increases the synthesis and secretion of TNFa (Whetsell et al., 1999; Klein and Wang, 2004), and triggers phosphorylation of the Jak2 kinase (Whetsell et al., 1999). Inasmuch as these functions are exerted on cells expressing TSH receptors, it is very likely that they are mediated by direct interaction of TSH with its corresponding receptor. Consonant with the second alternative, that is TSH acting through thyroid hormone release, are several reports of impaired immune function in hypothyroidism. In TSH receptor defective (C.RF-hyt/hyt) mice, there is impairment of B-cell development (Foster et al., 1999; Dorshkind and Horseman, 2005), which can be corrected by exogenous administration of T4 (Foster et al., 1999). Additionally, mice that are genetically unable to express T3 receptor show reduced numbers of T and B lymphocytes, as well as myeloid cells in the bone marrow, thymus, and spleen (Beigneux et al., 2003). A very attractive possibility is that another role of ‘‘immune’’ TSH would be the micro regulation of thyroid function. This would mainly participate in the communication between the immune system and the thyroid, rather than in the overall regulation of thyroid function which remains the responsibility of the hypothalamus and pituitary. For this to occur, it must be accepted that immune cells that are capable
of producing TSH, are also capable of trafficking to the thyroid and exerting paracrine regulation. Two clinical conditions seem to support this hypothesis: the first of them is the Euthyroid Sick Syndrome (ESS); a hypothyroidic condition of humans that occurs in the absence of thyroid disease, where conversion of T4 to T3 is impaired in mild forms, but the output of T4 itself may be found decreased in severe forms. ESS can present as a complication of a variety of infectious and non-infectious inflammatory diseases or after prolonged fasting (De Groot, 1999; Papanicolaou, 2000; Klemperer, 2002; Inan et al., 2003; Brierre et al., 2004). Although the true significance of ESS is not known, it may represent a physiological mechanism aimed at conserving energy during periods of stress (De groot, 1999; Larsen et al., 2002; Fakete et al., 2004). The detailed mechanisms of how the different conditions can trigger ESS have been described elsewhere (Klein, 2006), but it has been forwarded that the immune system, rather than the endocrine axis, is responsible for the recovery of euthyroid function after the underlying pathological condition is resolved. This assumes the existence of an inherent ability of the immune system to continually assess the status of the infectious condition and thus to determine whether it is safe for the host to return to a state of normal metabolic activity. The second is the ESS-like condition that follows hematopoietic stem cell transplantation, which can be due to total body irradiation (Wehmann et al., 1985; Hershman et al., 1990; Vexiau et al., 1993; Kauppilla et al., 1998; Ishiguro et al., 2004; Carlson et al., 1992; Lio et al., 1988; Matsumoto et al., 2004) or chemotherapy in the absence of irradiation (Toubert et al., 1997; Slatter et al., 2004). In this condition, T3 and occasionally T4 levels are diminished in the presence of normal TSH output. Inasmuch as the thyroid is resistant to clinical radiation, the reason for the impairment of thyroid function is unknown but it is not secondary to the thyroid gland damage by the immunosuppressive treatment itself. Moreover, thyroid hormone levels in bone marrow graft recipients remain suppressed in the face of otherwise normal circulating TSH levels. As in ESS, it seems that pituitary TSH has a minimal, if any, influence on thyroid function in these patients. Again, intra-thyroid TSH production by immune system cells is a novel and very interesting explanation.
Thyroid Dysfunction and the Immune System
A simple interpretation of these observations is that inflammatory stress might act through the hypothalamus–pituitary–thyroid axis to initiate and maintain an overall condition of decreased metabolic activity, basically aimed to energy conservation by the host during the period of infection or fasting. Once the infection is eliminated or controlled by the innate and adaptive immune responses, the immune system would provide the initial signal that would trigger an adjustment in thyroid hormone function and the resultant recovery of metabolism. The relationship between thyroid dysfunction and autoimmunity can be analyzed in pathological conditions, but also from a physiological state that has shed important clues to the understanding of this interaction. In recent years, there has been an increasing interest in disturbances of thyroid function that occur in mothers after delivery, a prevalence that seems to be higher than previously thought. Additionally, it has been proven that patients with previous thyroid dysfunction before pregnancy may have recurrences. In particular, a transient destructive type of postpartum hyperthyroidism has been recognized which may be silent. Preliminary studies on the prevalence of this particular disorder have shown that it is far more common that postpartum Graves’ hyperthyroidism (Amino et al., 1976, 1982). For the survival of the foreign fetus to occur, modulation of the maternal immune system to prevent its rejection seems mandatory. Accordingly, the maternal immune response becomes suppressed during pregnancy by a variety of mechanisms, which can also affect the clinical behavior and fate of a variety of autoimmune diseases, resulting in a transient amelioration of their activity during pregnancy, which is followed by a postpartum relapse. Hence, postpartum exacerbation may occur for autoimmune thyroid diseases as Hashimoto’s thyroiditis and Graves’ disease, as it does for non-thyroid autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus (Ginsburg and Walfish, 1977; Walfish and Chan, 1985). The high frequency of these syndromes likely reflects changes in peripartum immune network regulation; however, the preferential involvement of thyroid in these pregnancy-associated autoimmune disorders remains a conundrum. The
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most plausible explanation might reside in the bidirectional complex interactions between thyroid function and the immune system.
2. The thyroid gland as a target of autoimmune disease Cell-mediated as well as antibody-mediated immunity and genetic predisposition all play a role in autoimmune thyroid disease (Weetman, 1992). Multigenic predisposition (Davies, 1998) plus environmental stress is apparently necessary for activation of the autoimmune process. As with other autoimmue diseases, thyroid autoimmunity is more common in women than in men most likely because of both, genetic as well as hormonal factors (Chiovato et al., 1993). Among environmental factors, it is known that excessive dietary iodine intake (Laurberg et al., 1998) and smoking increase the risk of hypothyroidism in Hashimoto’s thyroiditis (Fukata et al., 1996) and the risk of ophthalmopathy in Graves’ disease. Several cytokines are involved in the pathophysiology of autoimmune thyroid disease: interferon a, interleukin-2, and macrophage colony-stimulating factor may induce autoimmune thyroiditis (Volpe, 1993). Patients with autoimmune thyroid disease may have a variety of thyroid-specific antibodies, including thyroid-stimulating thyrotropin receptor antibodies, TSH receptor-blocking and inhibitory antibodies, anti-thyroglobulin antibodies, antithyroidperoxidase (TPO) antibodies, anti-sodiumiodide symporter, and, possibly, growth-stimulating antibodies (Endo et al., 1996). Cell-mediated autoimmunity and apoptosis are factors in the destruction of thyroid cells and the development of hypothyroidism in Hashimoto’s thyroiditis (McLachlan et al., 1990). Goiter results from lymphocytic infiltration, fibrosis, and, possibly, thyroid stimulation by TSH. In Graves’ disease, hyperthyroidism and goiter are caused by autoantibodies against the TSH receptor that mimic the effect of TSH on thyroid follicular cells. The cause of extra-thyroidal manifestations, such as ophthalmopathy and thyroid dermopathy, is less clear. The autoimmune process in the affected tissues may be
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due to an antigenic determinant common to both thyroid cells and these tissues (Bahn and Heufelder, 1993; Arscott and Baker, 1998). Sub-clinical hypothyroidism is defined as mild elevation of serum TSH levels and normal circulating thyroid hormone levels. Anti-thyroid antibodies are positive in 95% of affected patients. Silent thyroiditis is a similar condition that may have autoimmune origin. It is associated with transient excessive thyroid hormone release and low radioiodine uptake. Silent thyroiditis can occur in both men and women, unrelated to pregnancy. In most affected patients, the hypothyroidism is not permanent. The mechanisms underlying the autoimmune process that leads to thyroid disease must be more complex than those involved in other ‘‘organspecific’’ autoimmune diseases. Autoimmune thyroid diseases can be found in association with a wide variety of other overt autoimmune diseases or conditions that have been related to autoimmune phenomena. The following is an alphabetical list of such conditions:
Alopecia areata Autoimmune liver Autoimmune polyglandular syndromes (e.g., Addison’s disease, hypoparathyroidism, type 1 diabetes, ovarian failure) Celiac disease Chronic ulcerative colitis Crohn’s disease Down syndrome Hepatitis C infection Idiopathic thrombocythemia Idiopathic thrombocytopenic purpura Klinefelter’s syndrome Mixed connective tissue disease Myasthenia gravis Polymyalgia rheumatica Primary biliary cirrhosis Rheumatoid arthritis Scleredema Sjo¨gren’s syndrome Systemic lupus erythematosus Turner’s syndrome Vitiligo
When analyzing this variety of conditions, it is clear that mechanisms other than antigenic mimicry or cross reactivity of autoantibodies, or selfreacting cells, are operating in patients with such combinations of clinical manifestations. The more is learned about the complex interactions of neuroendocrine regulation and the immune system, specifically about the role of extra-pituitary TSH on several cells and tissues, our understanding of the disease pathophysiology will become clearer. Acceptance that immune TSH might be a ubiquitous regulatory molecule of other physiological processes is, doubtlessly, a most interesting explanation.
Key points Cells of the immune system are capable to secrete thyroid-stimulating hormone. Immune TSH as well as pituitary may participate in immunoregulatory circuits. Physiologic neuro–immune–endrocine interactions are manifold and bidirectional.
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