Handbook of Clinical Neurology, Vol. 124 (3rd series) Clinical Neuroendocrinology E. Fliers, M. Korbonits, and J.A. Romijn, Editors © 2014 Elsevier B.V. All rights reserved
Chapter 29
Autoimmune hypophysitis: new developments YUTAKA TAKAHASHI* Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
INTRODUCTION Autoimmune hypophysitis (AH), often referred to as lymphocytic hypophysitis, is defined as an inflammatory condition of the pituitary gland of autoimmune etiology that leads to pituitary dysfunction (Caturegli et al., 2005; Hamnvik et al., 2010); however, its pathogenesis is still incompletely defined. It is classified into three subtypes based on the affected anatomic region: lymphocytic adenohypophysitis (LAH), lymphocytic infundibuloneurophypophysitis (LINH), and lymphocytic panhypophysitis (LPH) (Caturegli et al., 2005). Although AH is a rare disease, its incidence has increased as physicians become increasingly aware of the entity. As the prevalence, five cases of AH were detected in 619 consecutive pituitary surgeries (0.8%) (Buxton and Robertson, 2001), and Leung et al. reported 13 cases among 2000 patients who underwent transsphenoidal surgery (0.65%) (Leung et al., 2004). LAH is the most common subtype, with clinical and histologic involvement primarily of the anterior pituitary. LAH was first described in 1962 by Goudie and Pinkerton (Goudie and Pinkerton, 1962). They reported a 22-year-old woman who died 14 months after her second delivery, presumably because of adrenal insufficiency. LAH primarily affects women between 30 and 40 years of age and is associated with pregnancy. In 20–50% of patients, LAH is associated with other autoimmune disorders, such as Hashimoto’s thyroiditis, Graves’ disease, autoimmune adrenalitis, and pernicious anemia, as well as type 1 diabetes, in which it is associated with autoimmune polyglandular syndrome (APS). The pathologic and serologic features of LAH are consistent with an autoimmune etiology. Lymphocytic infiltrate is observed in the pituitary, and several autoantibodies directed against
pituitary antigens, e.g., growth hormone (GH) (Tanaka et al., 2002), a-enolase (Crock, 1998), and secretogranin-2 (Bensing et al., 2007b) have been detected. LINH was first described in 1970 by Saito et al., who observed a 66-year-old woman with a 1 month history of central diabetes insipidus (Saito et al., 1970). LINH affects the posterior pituitary and the pituitary stalk, with diabetes insipidus as its main clinical feature. LPH was first reported in 1991 in a 40-year-old male with a 3 month history of headaches, impotence, polyuria, and polydipsia. A histologic examination revealed extensive infiltration of the adenohypophysis and neurohypophysis by lymphocytes, plasma cells, and histiocytes (Nussbaum et al., 1991). While the etiology of AH is unknown, it exhibits several epidemiologic features of autoimmune mechanisms. Moreover, few triggers of AH – apart from pregnancy – have been described. One intriguing exception, which also suggests an autoimmune etiology, is exposure to the cytotoxic T lymphocyte protein 4 (CTLA4)-blocker tremelimumab (Shaw et al., 2007). CTLA4 blockade – used in the treatment of malignant melanoma – has also been implicated in the development of several other tissue-specific autoimmune endocrinopathies. Although the mechanisms underlying this association have not yet been elucidated, given that single nucleotide polymorphisms in the CTLA4 locus are associated with Graves’ disease and type 1 diabetes (Ueda et al., 2003), CTLA4 may be closely related to the tissue-specific autoimmunity, including the pituitary. The definition and precise mechanisms of AH have not yet been clarified; however, novel clinical entities (IgG4-related hypophysitis and anti-PIT1 antibody syndrome) related to the unique autoantibodies found in AH have recently been reported. Therefore, these
*Correspondence to: Dr Yutaka Takahashi, Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan. Tel: þ81-78-382-5861, Fax: þ81-78-3822080, E-mail: [email protected]
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clinical entities will be instrumental in understanding the pathophysiology of AH.
PITUITARY AUTOANTIBODIES Although T lymphocytes are more likely to be critical for the development of AH because of the predominant infiltrate of CD4 þ T cells, only the function of B lymphocytes has been assessed by measuring autoantibodies against the pituitary, due to the technical limitations. Antibodies against pituitary antigens have been mainly detected by indirect immunofluorescence or immunoblotting (Caturegli et al., 2005). Depending on the specific method used for screening, 6–57% of patients with confirmed hypophysitis have positive autoantibodies (Hamnvik et al., 2010). The specificity of pituitary antibodies is low, as they have also been found in various nonautoimmune pituitary diseases, including pituitary adenomas, empty sella syndrome, and Sheehan syndrome, as well as in other autoimmune diseases, such as type 1 diabetes and autoimmune thyroid diseases. The pituitary antigens reported include GH1 or placental GH2 (Takao et al., 2001), a-enolase (Crock, 1998), pituitary gland-specific factors 1a and 2 (PGSF1a, 2) (Tanaka et al., 2002), secretogranin-2 (Bensing et al., 2007b), CGI99, chorionic somatomammotropin (Lupi et al., 2008), and TDRD6 (Bensing et al., 2007a). In general, these autoantibodies are used as a marker with limitations because of the specificity and unclarified pathophysiologic significance in hypophysitis. In fact, many autoantigens are located within the cytosol, sequestered from the blood; thus it is unlikely that their function is directly affected by antibodies. Although pathogenic autoantibodies in AH have not yet been reported, it has been suggested that some antibodies may be closely related to pathogenesis, e.g., antipituitary antibodies against gonadotropin-secreting cells in adult male patients with idiopathic hypogonadotropic hypogonadism (De Bellis et al., 2007). Furthermore, De Bellis et al. reported that antipituitary antibodies were present at high titers in 4 of 27 patients with ACTH deficiency (15%), 4 of 20 patients with GH deficiency (20%), and 5 of 19 with hypogonadotropic hypogonadism (21%), and that these antibodies targeted corticotrophs, somatotrophs, and gonadotrophs, respectively (De Bellis et al., 2011). Recently, Smith et al. screened a pituitary cDNA expression library by using sera from patients with lymphocytic hypophysitis and identified an autoantigen, Tpit, as well as PGSF1a, PGSF2, and neuron-specific enolase (NSE), which were reported previously (Smith et al., 2012). Significantly positive autoantibody reactivity against Tpit was found in 9 of 86 hypophysitis patients (11%) compared with 1 of 90 control subjects. Autoantibodies were also detected against chromodomain
helicase DNA-binding protein 8 (CHD8), presynaptic cytomatrix protein (piccolo), Ca2 þ -dependent secretion activator (CADPS), PGSF2, and NSE; however, such antibodies were detected at a frequency that did not differ from that of the healthy controls. Intriguingly, Tpit is a transcription factor that is essential for the differentiation of corticotrophs and mutations in the TPIT gene cause congenital isolated ACTH deficiency (Lamolet et al., 2001; Pulichino et al., 2003a, b). Given that corticotrophs are often the first cell type to be affected in lymphocytic hypophysitis and that some cases of isolated ACTH deficiency are related to autoimmune diseases including APS (Crock, 1998; Kasperlik-Zaluska et al., 2003), a causal involvement of anti-Tpit antibody in the development of lymphocytic hypophysitis has been speculated. However, this antibody is not specific to lymphocytic hypophysitis, as it has also been detected in other autoimmune endocrine diseases. Further investigation is necessary to elucidate the significance of anti-Tpit antibody. Molecular mimicry has been proposed to mediate the underlying mechanism responsible for pathogenesis in AH, which is often associated with pregnancy. GH2, chorionic somatomammotropin, and g-enolase proteins are expressed in the placenta, and it is possible that immune recognition of these proteins spreads during pregnancy to GH1 and a-enolase (O’Dwyer et al., 2002; Wegner et al., 2009). A number of studies have investigated the significance of pituitary antibodies. In the patients with APS, organ-specific antibodies are frequently observed (Michels and Gottlieb, 2010). These autoantibodies are usually detected in more than 90% of affected patients at the onset of the clinical phase, but they may sometimes also be detected in the preclinical phase of the disease (Falorni et al., 2004; Maghnie et al., 2006). Bellastella et al. conducted a longitudinal study for 5 years observing 149 antipituitary antibody (APA)-positive and 50 APA-negative patients with APS and normal pituitary function (Bellastella et al., 2010). APA was evaluated in this study by an indirect immunofluorescence method using prepubertal baboon pituitary glands. During the 5 years of the study, hypopituitarism occurred in 28 of 149 (19%) APA-positive patients, but in none of the 50 APA-negative patients. All patients that developed pituitary dysfunction throughout the study span exhibited a characteristic immunostaining pattern, in which a part of pituitary cells was positive for the immunofluorescence. These data suggest that measurement of APA may help to predict the occurrence of hypopituitarism.
IGG4-RELATED HYPOPHYSITIS Immunoglobulin G4 (IgG4)-related disease is a newly recognized clinical entity that was proposed following
AUTOIMMUNE HYPOPHYSITIS: NEW DEVELOPMENTS the close observation of patients with autoimmune pancreatitis (Hamano et al., 2001). It is characterized by elevated serum IgG4 concentration and tumefaction or tissue infiltration by IgG4-positive plasma cells. IgG4related disease involves many tissues and is associated with Mikulicz’s disease, autoimmune pancreatitis, hypophysitis, Riedel’s thyroiditis, interstitial nephritis, prostatitis, lymphadenopathy, retroperitoneal fibrosis, inflammatory aortic aneurysm, and inflammatory pseudotumor (Umehara et al., 2012). IgG4-related hypophysitis has been reported during the last few years; it was initially diagnosed on clinical grounds in 2004 (van der Vliet and Perenboom, 2004), and then by pathology in 2007 (Wong et al., 2007). The first case reported was a 66-year-old woman with multiple pseudotumors in the salivary glands, pancreas, and retroperineum. The first pathologically proven case presented pituitary expansion with blurred vision and hypogonadism and a history of autoimmune pancreatitis. Histopathology of the pituitary mass showed a dense lymphoplasmacytic infiltrate among residual nests of adenohypophysial cells and fibrosis. Immunohistochemical staining for IgG4 and k/llight chains highlighted the presence of numerous polyclonal plasma cells in pituitary, pancreas, and gall bladder specimens. Shimatsu et al. reviewed 22 Japanese patients with IgG4-related hypophysitis (Shimatsu et al., 2009). The majority of cases involved middle-aged to elderly men presenting various degrees of hypopituitarism and diabetes insipidus who also demonstrated a thickened pituitary stalk and/or pituitary mass. These structures shrank significantly in response to glucocorticoid therapy, even in low doses. The presence of IgG4-related systemic disease and an elevated level of IgG4 before glucocorticoid therapy were the main clues that led to correct diagnosis. Leporati et al. reported the first Caucasian patient with IgG4-related hypophysitis, who manifested severe headache with panhypopituitarism and symmetric enlargement of pituitary and thickened stalk shown by magnetic resonance imaging (MRI), reviewed the published literature, and proposed diagnostic criteria (Leporati et al., 2011). These criteria are as follows: pituitary histopathology of mononuclear infiltration of the pituitary gland, rich in lymphocytes and plasma cells, with IgG4-positive cells; sellar mass and/or thickened pituitary stalk; biopsy-proven involvement of other organs; increased serum IgG4 concentrations of more than 140 mg/dL; and shrinkage of the pituitary mass and symptom improvement with steroids. At present, the pathogenic mechanism and the underlying immunologic abnormalities of IgG4-related disease remain unclear. IgG4 is thought to protect against type I allergy (IgE-mediated type I hypersensitivity) by inhibiting the functions of IgE, and it may also prevent type II (cytotoxic and antibody-dependent hypersensitivity)
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and III (immune complex disease) allergy by blocking the Fc-mediated effector functions of IgG1 and by inhibiting the formation of large immune complexes. Moreover, IgG4 is predominantly expressed under conditions of chronic antigen exposure, which may be related to the chronic features of IgG4-related disease (Umehara et al., 2012). Aberrant immunologic findings have been observed in patients with IgG4-related disease. The numbers of regulatory T cells (Treg) expressing CD4 þ CD25 þ Foxp3 are significantly higher in the affected tissues and peripheral blood of patients (Zen and Nakanuma, 2011). Furthermore, a Th2-dominant immune response and increased production of Th2-type cytokines such as IL-4, IL-5, IL-10, and IL-13 are observed (Akitake et al., 2010; Suzuki et al., 2010). Indeed, overexpression of the regulatory cytokines, namely IL-10 and transforming growth factor (TGF-b), has been reported in patients with IgG4-related disease (Nakashima et al., 2010). IL-10 and TGF-b have potent activities in directing B cells to produce IgG4 or to induce fibroplasias, respectively. IL-4, IL-5, and IL-13 are important for class switching to IgE production and eosinophil migration. Thus, the data suggest that abnormalities in the production of these cytokines may be involved in the pathogenesis of IgG4-related disease.
ANTI-PIT-1 ANTIBODY SYNDROME The pituitary-specific transcriptional factor 1 (PIT-1; also known as POU1F1) plays a crucial role in regulating the expression of GH, prolactin (PRL), and TSH-b in the anterior pituitary. PIT-1 is essential for the differentiation, proliferation, and maintenance of somatotrophs, lactotrophs, and thyrotrophs in the pituitary (Ingraham et al., 1988; Cohen et al., 1996). As a result, abnormalities in the PIT-1 gene result in short stature and congenital combined pituitary hormone deficiency (CPHD), which is characterized by GH, PRL, and TSH deficiencies (Pfaffle et al., 1992; Tatsumi et al., 1992). In contrast, acquired CPHD is generally caused by various types of damage to the hypothalamic–pituitary region, resulting in impaired hormone secretion in a nonspecific pattern. Recently, Yamamoto et al. reported three patients with acquired deficiency of GH, PRL, and TSH (Yamamoto et al., 2011). Mutations previously associated with CPHD were excluded in these patients, who otherwise exhibited relatively normal ACTH and gonadotropin function. Moreover, all three patients showed normal growth and displayed no signs of pituitary deficiencies earlier in life. Intriguingly, anti-PIT-1 antibody and various other autoantibodies were detected in the patients’ sera. An ELISA-based screening revealed that anti-PIT-1 antibody was highly specific to the disease and
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Fig. 29.1. In a normal condition, the transcriptional factor PIT-1 maintains the GH-, PRL-, and TSH-secreting cells (A); however, autoimmunity against PIT-1 impaired these cells and caused a specific defect in these hormones (B).
absent in control subjects. Immunohistochemical analysis demonstrated that PIT-1-, GH-, PRL-, and TSHpositive cells were absent in the pituitary of patient, who exhibited a range of autoimmune endocrinopathies. These clinical manifestations were compatible with the definition of APS. However, the main manifestations of APS-1 – hypoparathyroidism and Candida infection – were not observed. Moreover, the pituitary abnormalities clearly differed from those of common hypophysitis associated with APS, in which pituitary hormone secretion is impaired nonspecifically. Therefore, a novel clinical entity termed “anti-PIT-1 antibody syndrome” was proposed, which is related to APS. Anti-PIT-1 antibodies were present in these patients’ sera but not in the sera of control subjects or patients with various other autoimmune-related diseases, indicating that the anti-PIT-1 antibody is highly specific to the disease. Furthermore, other autoantibodies previously reported in common hypophysitis, such as anti-GH, -a-enolase, or -TDRD6 antibodies, were not detected by immunoblotting. In addition, any obvious pituitary abnormalities such as an enlargement, which is frequently observed in hypophysitis, were not detected by MRI, demonstrating the difference of anti-PIT-1 antibody syndrome from common hypophysitis. Pathogenic autoantibodies such as anti-TSH receptor antibody in Graves’ disease and antiacetylcholine receptor antibody in myasthenia gravis are generally directed against cell surface antigens. Thus, it is unlikely that PIT-1 protein – a nuclear transcription factor – is a direct target for anti-PIT-1 antibodies. It is possible that immune intolerance to PIT-1 occurred by an as yet unknown mechanism, thereby provoking the attack of PIT-1-expressing cells by cytotoxic T cells through recognition of PIT-1 epitopes exposed with MHC (HLA) antigen on the cell surface. As a result, anti-PIT-1 antibodies would be produced. Regarding abnormal T cell function,
lymphocytic infiltration of the pituitary, thyroid, adrenal gland, liver, and pancreas was observed (Yamamoto et al., 2011). The combination of the impaired GH, PRL, and TSH hormones; the antigen, PIT-1; and the specificity of the autoantibody to this disease strongly suggest that the anti-PIT-1 antibody is closely related to pathogenesis (Fig. 29.1). However, further investigation is required in order to elucidate the underlying mechanisms by transferring of antibody or T cells from the patients to animals to reconstitute the disease. There are several interesting implications of this novel syndrome. It demonstrated a new cause of cell-restricted pituitary hormone deficiencies that is very similar to PIT-1-dependent congenital CPHD. The striking specificity of the pituitary cell death observed in the patient may warrant the re-evaluation of patients with CPHD without detectable mutations for the presence of autoimmune antibodies against the specific transcriptional factors (Drouin and Takayasu, 2011). Indeed, most patients with CPHD do not display the gene abnormalities in the expected transcription factors. Another interesting hypothesis raised by this syndrome is that if autoimmunity to nuclear proteins – particularly transcription factors – is related to their functional impairment, various acquired diseases may be caused by autoimmunity to transcription factors. Although few cases demonstrating the presence of autoantibody against transcription factors have been reported thus far (Hedstrand et al., 2001), this concept may apply to various acquired conditions.
AUTOIMMUNITYAND METABOLIC DISEASE Recently, Winer et al. reported that B cells promote insulin resistance through modulation of T cells and production of pathogenic IgG antibodies (Winer et al., 2011).
AUTOIMMUNE HYPOPHYSITIS: NEW DEVELOPMENTS They demonstrated that B cells play a pivotal role in inducing insulin resistance in diet-induced obese (DIO) mice. The transfer of IgG from DIO mice rapidly induced insulin resistance and glucose intolerance, indicating that pathogenic IgG was produced in DIO mice. IgG autoantibodies that segregate with insulin sensitivity were also detected in insulin-resistant human subjects. Moreover, the antigens targeted by such IgG autoantibodies are mostly intracellular proteins, many of which are expressed in tissues including immune cells, the pancreas, nervous tissue, muscle, or fat. Taken together, these results imply that the pathologic relevance of autoantibodies needs to be re-evaluated in order to understand the pathogenesis of endocrine and metabolic diseases with unknown etiology.
CONCLUSION Novel clinical entities associated with hypophysitis that have recently been reported demonstrate the heterogeneity of this disease and provide an important clues for understanding pathogenesis and definition of hypophysitis, as well as the significance of antipituitary antibodies.
ABBREVIATIONS AH, autoimmune hypophysitis; LAH, lymphocytic adenohypophysitis; LINH, lymphocytic infundibuloneurophypophysitis; LPH, lymphocytic panhypophysitis; APS, autoimmune polyglandular syndrome; GH, growth hormone; CTLA4, cytotoxic T-lymphocyte protein 4; PGSF1a, 2, pituitary gland specific factors 1a and 2; NSE, neuron-specific enolase; CHD8, chromodomain helicase DNA-binding protein 8; CADPS, Ca2 þ dependent secretion activator; APA, antipituitary antibody; IgG4, immunoglobulin G4; PIT-1, POU1F1, pituitary-specific transcriptional factor-1; CPHD, combined pituitary hormone deficiency; DIO, diet-induced obese.
REFERENCES Akitake R, Watanabe T, Zaima C et al. (2010). Possible involvement of T helper type 2 responses to Toll-like receptor ligands in IgG4-related sclerosing disease. Gut 59: 542–545. Bellastella G, Rotondi M, Pane E et al. (2010). Predictive role of the immunostaining pattern of immunofluorescence and the titers of antipituitary antibodies at presentation for the occurrence of autoimmune hypopituitarism in patients with autoimmune polyendocrine syndromes over a five-year follow-up. J Clin Endocrinol Metab 95: 3750–3757. Bensing S, Fetissov SO, Mulder J et al. (2007a). Pituitary autoantibodies in autoimmune polyendocrine syndrome type 1. Proc Natl Acad Sci U S A 104: 949–954.
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Bensing S, Hulting AL, Hoog A et al. (2007b). Lymphocytic hypophysitis: report of two biopsy-proven cases and one suspected case with pituitary autoantibodies. J Endocrinol Invest 30: 153–162. Buxton N, Robertson I (2001). Lymphocytic and granulocytic hypophysitis: a single centre experience. Br J Neurosurg 15: 242–245, discussion 245–246. Caturegli P, Newschaffer C, Olivi A et al. (2005). Autoimmune hypophysitis. Endocr Rev 26: 599–614. Cohen LE, Wondisford FE, Radovick S (1996). Role of Pit-1 in the gene expression of growth hormone, prolactin, and thyrotropin. Endocrinol Metab Clin North Am 25: 523–540. Crock PA (1998). Cytosolic autoantigens in lymphocytic hypophysitis. J Clin Endocrinol Metab 83: 609–618. De Bellis A, Sinisi AA, Conte M et al. (2007). Antipituitary antibodies against gonadotropin-secreting cells in adult male patients with apparently idiopathic hypogonadotropic hypogonadism. J Clin Endocrinol Metab 92: 604–607. De Bellis A, Pane E, Bellastella G et al. (2011). Detection of antipituitary and antihypothalamus antibodies to investigate the role of pituitary or hypothalamic autoimmunity in patients with selective idiopathic hypopituitarism. Clin Endocrinol (Oxf) 75: 361–366. Drouin J, Takayasu S (2011). Autoimmunity: acquired versus inherited pituitary deficiency – same difference? Nat Rev Endocrinol 7: 255–256. Falorni A, Laureti S, De Bellis A et al. (2004). Italian addison network study: update of diagnostic criteria for the etiological classification of primary adrenal insufficiency. J Clin Endocrinol Metab 89: 1598–1604. Goudie RB, Pinkerton PH (1962). Anterior hypophysitis and Hashimoto’s disease in a young woman. J Pathol Bacteriol 83: 584–585. Hamano H, Kawa S, Horiuchi A et al. (2001). High serum IgG4 concentrations in patients with sclerosing pancreatitis. N Engl J Med 344: 732–738. Hamnvik OP, Laury AR, Laws Jr ER et al. (2010). Lymphocytic hypophysitis with diabetes insipidus in a young man. Nat Rev Endocrinol 6: 464–470. Hedstrand H, Ekwall O, Olsson MJ et al. (2001). The transcription factors SOX9 and SOX10 are vitiligo autoantigens in autoimmune polyendocrine syndrome type I. J Biol Chem 276: 35390–35395. Ingraham HA, Chen RP, Mangalam HJ et al. (1988). A tissuespecific transcription factor containing a homeodomain specifies a pituitary phenotype. Cell 55: 519–529. Kasperlik-Zaluska AA, Czarnocka B, Czech W (2003). Autoimmunity as the most frequent cause of idiopathic secondary adrenal insufficiency: report of 111 cases. Autoimmunity 36: 155–159. Lamolet B, Pulichino AM, Lamonerie T et al. (2001). A pituitary cell-restricted T box factor, Tpit, activates POMC transcription in cooperation with Pitx homeoproteins. Cell 104: 849–859. Leporati P, Landek-Salgado MA, Lupi I et al. (2011). IgG4related hypophysitis: a new addition to the hypophysitis spectrum. J Clin Endocrinol Metab 96: 1971–1980.
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Y. TAKAHASHI
Leung GK, Lopes MB, Thorner MO et al. (2004). Primary hypophysitis: a single-center experience in 16 cases. J Neurosurg 101: 262–271. Lupi I, Broman KW, Tzou SC et al. (2008). Novel autoantigens in autoimmune hypophysitis. Clin Endocrinol (Oxf) 69: 269–278. Maghnie M, Ghirardello S, De Bellis A et al. (2006). Idiopathic central diabetes insipidus in children and young adults is commonly associated with vasopressin-cell antibodies and markers of autoimmunity. Clin Endocrinol (Oxf) 65: 470–478. Michels AW, Gottlieb PA (2010). Autoimmune polyglandular syndromes. Nat Rev Endocrinol 6: 270–277. Nakashima H, Miyake K, Moriyama M et al. (2010). An amplification of IL-10 and TGF-beta in patients with IgG4related tubulointerstitial nephritis. Clin Nephrol 73: 385–391. Nussbaum CE, Okawara SH, Jacobs LS (1991). Lymphocytic hypophysitis with involvement of the cavernous sinus and hypothalamus. Neurosurgery 28: 440–444. O’Dwyer DT, Clifton V, Hall A et al. (2002). Pituitary autoantibodies in lymphocytic hypophysitis target both gammaand alpha-Enolase – a link with pregnancy? Arch Physiol Biochem 110: 94–98. Pfaffle RW, DiMattia GE, Parks JS et al. (1992). Mutation of the POU-specific domain of Pit-1 and hypopituitarism without pituitary hypoplasia. Science 257: 1118–1121. Pulichino AM, Vallette-Kasic S, Couture C et al. (2003a). Human and mouse TPIT gene mutations cause early onset pituitary ACTH deficiency. Genes Dev 17: 711–716. Pulichino AM, Vallette-Kasic S, Tsai JP et al. (2003b). Tpit determines alternate fates during pituitary cell differentiation. Genes Dev 17: 738–747. Saito T, Yoshida S, Nakao K et al. (1970). Chronic hypernatremia associated with inflammation of the neurohypophysis. J Clin Endocrinol Metab 31: 391–396. Shaw SA, Camacho LH, McCutcheon IE et al. (2007). Transient hypophysitis after cytotoxic T lymphocyteassociated antigen 4 (CTLA4) blockade. J Clin Endocrinol Metab 92: 1201–1202. Shimatsu A, Oki Y, Fujisawa I et al. (2009). Pituitary and stalk lesions (infundibulo-hypophysitis) associated with immunoglobulin G4-related systemic disease: an emerging clinical entity. Endocr J 56: 1033–1041.
Smith CJ, Bensing S, Burns C et al. (2012). Identification of Tpit and other novel autoantigens in lymphocytic hypophysitis; immunoscreening of a pituitary cDNA library and development of immunoprecipitation assays. Eur J Endocrinol 166: 391–398. Suzuki K, Tamaru J, Okuyama A et al. (2010). IgG4-positive multi-organ lymphoproliferative syndrome manifesting as chronic symmetrical sclerosing dacryo-sialadenitis with subsequent secondary portal hypertension and remarkable IgG4-linked IL-4 elevation. Rheumatology (Oxford) 49: 1789–1791. Takao T, Nanamiya W, Matsumoto R et al. (2001). Antipituitary antibodies in patients with lymphocytic hypophysitis. Horm Res 55: 288–292. Tanaka S, Tatsumi KI, Kimura M et al. (2002). Detection of autoantibodies against the pituitary-specific proteins in patients with lymphocytic hypophysitis. Eur J Endocrinol 147: 767–775. Tatsumi K, Miyai K, Notomi T et al. (1992). Cretinism with combined hormone deficiency caused by a mutation in the PIT1 gene. Nat Genet 1: 56–58. Ueda H, Howson JM, Esposito L et al. (2003). Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature 423: 506–511. Umehara H, Okazaki K, Masaki Y et al. (2012). A novel clinical entity, IgG4-related disease (IgG4RD): general concept and details. Mod Rheumatol 22: 1–14. van der Vliet HJ, Perenboom RM (2004). Multiple pseudotumors in IgG4-associated multifocal systemic fibrosis. Ann Intern Med 141: 896–897. Wegner N, Wait R, Venables PJ (2009). Evolutionarily conserved antigens in autoimmune disease: implications for an infective aetiology. Int J Biochem Cell Biol 41: 390–397. Winer DA, Winer S, Shen L et al. (2011). B cells promote insulin resistance through modulation of T cells and production of pathogenic IgG antibodies. Nat Med 17: 610–617. Wong S, Lam WY, Wong WK et al. (2007). Hypophysitis presented as inflammatory pseudotumor in immunoglobulin G4-related systemic disease. Hum Pathol 38: 1720–1723. Yamamoto M, Iguchi G, Takeno R et al. (2011). Adult combined GH, prolactin, and TSH deficiency associated with circulating PIT-1 antibody in humans. J Clin Invest 121: 113–119. Zen Y, Nakanuma Y (2011). Pathogenesis of IgG4-related disease. Curr Opin Rheumatol 23: 114–118.
Chapter 29
Autoimmune hypophysitis: new developments YUTAKA TAKAHASHI* Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
INTRODUCTION Autoimmune hypophysitis (AH), often referred to as lymphocytic hypophysitis, is defined as an inflammatory condition of the pituitary gland of autoimmune etiology that leads to pituitary dysfunction (Caturegli et al., 2005; Hamnvik et al., 2010); however, its pathogenesis is still incompletely defined. It is classified into three subtypes based on the affected anatomic region: lymphocytic adenohypophysitis (LAH), lymphocytic infundibuloneurophypophysitis (LINH), and lymphocytic panhypophysitis (LPH) (Caturegli et al., 2005). Although AH is a rare disease, its incidence has increased as physicians become increasingly aware of the entity. As the prevalence, five cases of AH were detected in 619 consecutive pituitary surgeries (0.8%) (Buxton and Robertson, 2001), and Leung et al. reported 13 cases among 2000 patients who underwent transsphenoidal surgery (0.65%) (Leung et al., 2004). LAH is the most common subtype, with clinical and histologic involvement primarily of the anterior pituitary. LAH was first described in 1962 by Goudie and Pinkerton (Goudie and Pinkerton, 1962). They reported a 22-year-old woman who died 14 months after her second delivery, presumably because of adrenal insufficiency. LAH primarily affects women between 30 and 40 years of age and is associated with pregnancy. In 20–50% of patients, LAH is associated with other autoimmune disorders, such as Hashimoto’s thyroiditis, Graves’ disease, autoimmune adrenalitis, and pernicious anemia, as well as type 1 diabetes, in which it is associated with autoimmune polyglandular syndrome (APS). The pathologic and serologic features of LAH are consistent with an autoimmune etiology. Lymphocytic infiltrate is observed in the pituitary, and several autoantibodies directed against
pituitary antigens, e.g., growth hormone (GH) (Tanaka et al., 2002), a-enolase (Crock, 1998), and secretogranin-2 (Bensing et al., 2007b) have been detected. LINH was first described in 1970 by Saito et al., who observed a 66-year-old woman with a 1 month history of central diabetes insipidus (Saito et al., 1970). LINH affects the posterior pituitary and the pituitary stalk, with diabetes insipidus as its main clinical feature. LPH was first reported in 1991 in a 40-year-old male with a 3 month history of headaches, impotence, polyuria, and polydipsia. A histologic examination revealed extensive infiltration of the adenohypophysis and neurohypophysis by lymphocytes, plasma cells, and histiocytes (Nussbaum et al., 1991). While the etiology of AH is unknown, it exhibits several epidemiologic features of autoimmune mechanisms. Moreover, few triggers of AH – apart from pregnancy – have been described. One intriguing exception, which also suggests an autoimmune etiology, is exposure to the cytotoxic T lymphocyte protein 4 (CTLA4)-blocker tremelimumab (Shaw et al., 2007). CTLA4 blockade – used in the treatment of malignant melanoma – has also been implicated in the development of several other tissue-specific autoimmune endocrinopathies. Although the mechanisms underlying this association have not yet been elucidated, given that single nucleotide polymorphisms in the CTLA4 locus are associated with Graves’ disease and type 1 diabetes (Ueda et al., 2003), CTLA4 may be closely related to the tissue-specific autoimmunity, including the pituitary. The definition and precise mechanisms of AH have not yet been clarified; however, novel clinical entities (IgG4-related hypophysitis and anti-PIT1 antibody syndrome) related to the unique autoantibodies found in AH have recently been reported. Therefore, these
*Correspondence to: Dr Yutaka Takahashi, Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan. Tel: þ81-78-382-5861, Fax: þ81-78-3822080, E-mail: [email protected]
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clinical entities will be instrumental in understanding the pathophysiology of AH.
PITUITARY AUTOANTIBODIES Although T lymphocytes are more likely to be critical for the development of AH because of the predominant infiltrate of CD4 þ T cells, only the function of B lymphocytes has been assessed by measuring autoantibodies against the pituitary, due to the technical limitations. Antibodies against pituitary antigens have been mainly detected by indirect immunofluorescence or immunoblotting (Caturegli et al., 2005). Depending on the specific method used for screening, 6–57% of patients with confirmed hypophysitis have positive autoantibodies (Hamnvik et al., 2010). The specificity of pituitary antibodies is low, as they have also been found in various nonautoimmune pituitary diseases, including pituitary adenomas, empty sella syndrome, and Sheehan syndrome, as well as in other autoimmune diseases, such as type 1 diabetes and autoimmune thyroid diseases. The pituitary antigens reported include GH1 or placental GH2 (Takao et al., 2001), a-enolase (Crock, 1998), pituitary gland-specific factors 1a and 2 (PGSF1a, 2) (Tanaka et al., 2002), secretogranin-2 (Bensing et al., 2007b), CGI99, chorionic somatomammotropin (Lupi et al., 2008), and TDRD6 (Bensing et al., 2007a). In general, these autoantibodies are used as a marker with limitations because of the specificity and unclarified pathophysiologic significance in hypophysitis. In fact, many autoantigens are located within the cytosol, sequestered from the blood; thus it is unlikely that their function is directly affected by antibodies. Although pathogenic autoantibodies in AH have not yet been reported, it has been suggested that some antibodies may be closely related to pathogenesis, e.g., antipituitary antibodies against gonadotropin-secreting cells in adult male patients with idiopathic hypogonadotropic hypogonadism (De Bellis et al., 2007). Furthermore, De Bellis et al. reported that antipituitary antibodies were present at high titers in 4 of 27 patients with ACTH deficiency (15%), 4 of 20 patients with GH deficiency (20%), and 5 of 19 with hypogonadotropic hypogonadism (21%), and that these antibodies targeted corticotrophs, somatotrophs, and gonadotrophs, respectively (De Bellis et al., 2011). Recently, Smith et al. screened a pituitary cDNA expression library by using sera from patients with lymphocytic hypophysitis and identified an autoantigen, Tpit, as well as PGSF1a, PGSF2, and neuron-specific enolase (NSE), which were reported previously (Smith et al., 2012). Significantly positive autoantibody reactivity against Tpit was found in 9 of 86 hypophysitis patients (11%) compared with 1 of 90 control subjects. Autoantibodies were also detected against chromodomain
helicase DNA-binding protein 8 (CHD8), presynaptic cytomatrix protein (piccolo), Ca2 þ -dependent secretion activator (CADPS), PGSF2, and NSE; however, such antibodies were detected at a frequency that did not differ from that of the healthy controls. Intriguingly, Tpit is a transcription factor that is essential for the differentiation of corticotrophs and mutations in the TPIT gene cause congenital isolated ACTH deficiency (Lamolet et al., 2001; Pulichino et al., 2003a, b). Given that corticotrophs are often the first cell type to be affected in lymphocytic hypophysitis and that some cases of isolated ACTH deficiency are related to autoimmune diseases including APS (Crock, 1998; Kasperlik-Zaluska et al., 2003), a causal involvement of anti-Tpit antibody in the development of lymphocytic hypophysitis has been speculated. However, this antibody is not specific to lymphocytic hypophysitis, as it has also been detected in other autoimmune endocrine diseases. Further investigation is necessary to elucidate the significance of anti-Tpit antibody. Molecular mimicry has been proposed to mediate the underlying mechanism responsible for pathogenesis in AH, which is often associated with pregnancy. GH2, chorionic somatomammotropin, and g-enolase proteins are expressed in the placenta, and it is possible that immune recognition of these proteins spreads during pregnancy to GH1 and a-enolase (O’Dwyer et al., 2002; Wegner et al., 2009). A number of studies have investigated the significance of pituitary antibodies. In the patients with APS, organ-specific antibodies are frequently observed (Michels and Gottlieb, 2010). These autoantibodies are usually detected in more than 90% of affected patients at the onset of the clinical phase, but they may sometimes also be detected in the preclinical phase of the disease (Falorni et al., 2004; Maghnie et al., 2006). Bellastella et al. conducted a longitudinal study for 5 years observing 149 antipituitary antibody (APA)-positive and 50 APA-negative patients with APS and normal pituitary function (Bellastella et al., 2010). APA was evaluated in this study by an indirect immunofluorescence method using prepubertal baboon pituitary glands. During the 5 years of the study, hypopituitarism occurred in 28 of 149 (19%) APA-positive patients, but in none of the 50 APA-negative patients. All patients that developed pituitary dysfunction throughout the study span exhibited a characteristic immunostaining pattern, in which a part of pituitary cells was positive for the immunofluorescence. These data suggest that measurement of APA may help to predict the occurrence of hypopituitarism.
IGG4-RELATED HYPOPHYSITIS Immunoglobulin G4 (IgG4)-related disease is a newly recognized clinical entity that was proposed following
AUTOIMMUNE HYPOPHYSITIS: NEW DEVELOPMENTS the close observation of patients with autoimmune pancreatitis (Hamano et al., 2001). It is characterized by elevated serum IgG4 concentration and tumefaction or tissue infiltration by IgG4-positive plasma cells. IgG4related disease involves many tissues and is associated with Mikulicz’s disease, autoimmune pancreatitis, hypophysitis, Riedel’s thyroiditis, interstitial nephritis, prostatitis, lymphadenopathy, retroperitoneal fibrosis, inflammatory aortic aneurysm, and inflammatory pseudotumor (Umehara et al., 2012). IgG4-related hypophysitis has been reported during the last few years; it was initially diagnosed on clinical grounds in 2004 (van der Vliet and Perenboom, 2004), and then by pathology in 2007 (Wong et al., 2007). The first case reported was a 66-year-old woman with multiple pseudotumors in the salivary glands, pancreas, and retroperineum. The first pathologically proven case presented pituitary expansion with blurred vision and hypogonadism and a history of autoimmune pancreatitis. Histopathology of the pituitary mass showed a dense lymphoplasmacytic infiltrate among residual nests of adenohypophysial cells and fibrosis. Immunohistochemical staining for IgG4 and k/llight chains highlighted the presence of numerous polyclonal plasma cells in pituitary, pancreas, and gall bladder specimens. Shimatsu et al. reviewed 22 Japanese patients with IgG4-related hypophysitis (Shimatsu et al., 2009). The majority of cases involved middle-aged to elderly men presenting various degrees of hypopituitarism and diabetes insipidus who also demonstrated a thickened pituitary stalk and/or pituitary mass. These structures shrank significantly in response to glucocorticoid therapy, even in low doses. The presence of IgG4-related systemic disease and an elevated level of IgG4 before glucocorticoid therapy were the main clues that led to correct diagnosis. Leporati et al. reported the first Caucasian patient with IgG4-related hypophysitis, who manifested severe headache with panhypopituitarism and symmetric enlargement of pituitary and thickened stalk shown by magnetic resonance imaging (MRI), reviewed the published literature, and proposed diagnostic criteria (Leporati et al., 2011). These criteria are as follows: pituitary histopathology of mononuclear infiltration of the pituitary gland, rich in lymphocytes and plasma cells, with IgG4-positive cells; sellar mass and/or thickened pituitary stalk; biopsy-proven involvement of other organs; increased serum IgG4 concentrations of more than 140 mg/dL; and shrinkage of the pituitary mass and symptom improvement with steroids. At present, the pathogenic mechanism and the underlying immunologic abnormalities of IgG4-related disease remain unclear. IgG4 is thought to protect against type I allergy (IgE-mediated type I hypersensitivity) by inhibiting the functions of IgE, and it may also prevent type II (cytotoxic and antibody-dependent hypersensitivity)
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and III (immune complex disease) allergy by blocking the Fc-mediated effector functions of IgG1 and by inhibiting the formation of large immune complexes. Moreover, IgG4 is predominantly expressed under conditions of chronic antigen exposure, which may be related to the chronic features of IgG4-related disease (Umehara et al., 2012). Aberrant immunologic findings have been observed in patients with IgG4-related disease. The numbers of regulatory T cells (Treg) expressing CD4 þ CD25 þ Foxp3 are significantly higher in the affected tissues and peripheral blood of patients (Zen and Nakanuma, 2011). Furthermore, a Th2-dominant immune response and increased production of Th2-type cytokines such as IL-4, IL-5, IL-10, and IL-13 are observed (Akitake et al., 2010; Suzuki et al., 2010). Indeed, overexpression of the regulatory cytokines, namely IL-10 and transforming growth factor (TGF-b), has been reported in patients with IgG4-related disease (Nakashima et al., 2010). IL-10 and TGF-b have potent activities in directing B cells to produce IgG4 or to induce fibroplasias, respectively. IL-4, IL-5, and IL-13 are important for class switching to IgE production and eosinophil migration. Thus, the data suggest that abnormalities in the production of these cytokines may be involved in the pathogenesis of IgG4-related disease.
ANTI-PIT-1 ANTIBODY SYNDROME The pituitary-specific transcriptional factor 1 (PIT-1; also known as POU1F1) plays a crucial role in regulating the expression of GH, prolactin (PRL), and TSH-b in the anterior pituitary. PIT-1 is essential for the differentiation, proliferation, and maintenance of somatotrophs, lactotrophs, and thyrotrophs in the pituitary (Ingraham et al., 1988; Cohen et al., 1996). As a result, abnormalities in the PIT-1 gene result in short stature and congenital combined pituitary hormone deficiency (CPHD), which is characterized by GH, PRL, and TSH deficiencies (Pfaffle et al., 1992; Tatsumi et al., 1992). In contrast, acquired CPHD is generally caused by various types of damage to the hypothalamic–pituitary region, resulting in impaired hormone secretion in a nonspecific pattern. Recently, Yamamoto et al. reported three patients with acquired deficiency of GH, PRL, and TSH (Yamamoto et al., 2011). Mutations previously associated with CPHD were excluded in these patients, who otherwise exhibited relatively normal ACTH and gonadotropin function. Moreover, all three patients showed normal growth and displayed no signs of pituitary deficiencies earlier in life. Intriguingly, anti-PIT-1 antibody and various other autoantibodies were detected in the patients’ sera. An ELISA-based screening revealed that anti-PIT-1 antibody was highly specific to the disease and
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Fig. 29.1. In a normal condition, the transcriptional factor PIT-1 maintains the GH-, PRL-, and TSH-secreting cells (A); however, autoimmunity against PIT-1 impaired these cells and caused a specific defect in these hormones (B).
absent in control subjects. Immunohistochemical analysis demonstrated that PIT-1-, GH-, PRL-, and TSHpositive cells were absent in the pituitary of patient, who exhibited a range of autoimmune endocrinopathies. These clinical manifestations were compatible with the definition of APS. However, the main manifestations of APS-1 – hypoparathyroidism and Candida infection – were not observed. Moreover, the pituitary abnormalities clearly differed from those of common hypophysitis associated with APS, in which pituitary hormone secretion is impaired nonspecifically. Therefore, a novel clinical entity termed “anti-PIT-1 antibody syndrome” was proposed, which is related to APS. Anti-PIT-1 antibodies were present in these patients’ sera but not in the sera of control subjects or patients with various other autoimmune-related diseases, indicating that the anti-PIT-1 antibody is highly specific to the disease. Furthermore, other autoantibodies previously reported in common hypophysitis, such as anti-GH, -a-enolase, or -TDRD6 antibodies, were not detected by immunoblotting. In addition, any obvious pituitary abnormalities such as an enlargement, which is frequently observed in hypophysitis, were not detected by MRI, demonstrating the difference of anti-PIT-1 antibody syndrome from common hypophysitis. Pathogenic autoantibodies such as anti-TSH receptor antibody in Graves’ disease and antiacetylcholine receptor antibody in myasthenia gravis are generally directed against cell surface antigens. Thus, it is unlikely that PIT-1 protein – a nuclear transcription factor – is a direct target for anti-PIT-1 antibodies. It is possible that immune intolerance to PIT-1 occurred by an as yet unknown mechanism, thereby provoking the attack of PIT-1-expressing cells by cytotoxic T cells through recognition of PIT-1 epitopes exposed with MHC (HLA) antigen on the cell surface. As a result, anti-PIT-1 antibodies would be produced. Regarding abnormal T cell function,
lymphocytic infiltration of the pituitary, thyroid, adrenal gland, liver, and pancreas was observed (Yamamoto et al., 2011). The combination of the impaired GH, PRL, and TSH hormones; the antigen, PIT-1; and the specificity of the autoantibody to this disease strongly suggest that the anti-PIT-1 antibody is closely related to pathogenesis (Fig. 29.1). However, further investigation is required in order to elucidate the underlying mechanisms by transferring of antibody or T cells from the patients to animals to reconstitute the disease. There are several interesting implications of this novel syndrome. It demonstrated a new cause of cell-restricted pituitary hormone deficiencies that is very similar to PIT-1-dependent congenital CPHD. The striking specificity of the pituitary cell death observed in the patient may warrant the re-evaluation of patients with CPHD without detectable mutations for the presence of autoimmune antibodies against the specific transcriptional factors (Drouin and Takayasu, 2011). Indeed, most patients with CPHD do not display the gene abnormalities in the expected transcription factors. Another interesting hypothesis raised by this syndrome is that if autoimmunity to nuclear proteins – particularly transcription factors – is related to their functional impairment, various acquired diseases may be caused by autoimmunity to transcription factors. Although few cases demonstrating the presence of autoantibody against transcription factors have been reported thus far (Hedstrand et al., 2001), this concept may apply to various acquired conditions.
AUTOIMMUNITYAND METABOLIC DISEASE Recently, Winer et al. reported that B cells promote insulin resistance through modulation of T cells and production of pathogenic IgG antibodies (Winer et al., 2011).
AUTOIMMUNE HYPOPHYSITIS: NEW DEVELOPMENTS They demonstrated that B cells play a pivotal role in inducing insulin resistance in diet-induced obese (DIO) mice. The transfer of IgG from DIO mice rapidly induced insulin resistance and glucose intolerance, indicating that pathogenic IgG was produced in DIO mice. IgG autoantibodies that segregate with insulin sensitivity were also detected in insulin-resistant human subjects. Moreover, the antigens targeted by such IgG autoantibodies are mostly intracellular proteins, many of which are expressed in tissues including immune cells, the pancreas, nervous tissue, muscle, or fat. Taken together, these results imply that the pathologic relevance of autoantibodies needs to be re-evaluated in order to understand the pathogenesis of endocrine and metabolic diseases with unknown etiology.
CONCLUSION Novel clinical entities associated with hypophysitis that have recently been reported demonstrate the heterogeneity of this disease and provide an important clues for understanding pathogenesis and definition of hypophysitis, as well as the significance of antipituitary antibodies.
ABBREVIATIONS AH, autoimmune hypophysitis; LAH, lymphocytic adenohypophysitis; LINH, lymphocytic infundibuloneurophypophysitis; LPH, lymphocytic panhypophysitis; APS, autoimmune polyglandular syndrome; GH, growth hormone; CTLA4, cytotoxic T-lymphocyte protein 4; PGSF1a, 2, pituitary gland specific factors 1a and 2; NSE, neuron-specific enolase; CHD8, chromodomain helicase DNA-binding protein 8; CADPS, Ca2 þ dependent secretion activator; APA, antipituitary antibody; IgG4, immunoglobulin G4; PIT-1, POU1F1, pituitary-specific transcriptional factor-1; CPHD, combined pituitary hormone deficiency; DIO, diet-induced obese.
REFERENCES Akitake R, Watanabe T, Zaima C et al. (2010). Possible involvement of T helper type 2 responses to Toll-like receptor ligands in IgG4-related sclerosing disease. Gut 59: 542–545. Bellastella G, Rotondi M, Pane E et al. (2010). Predictive role of the immunostaining pattern of immunofluorescence and the titers of antipituitary antibodies at presentation for the occurrence of autoimmune hypopituitarism in patients with autoimmune polyendocrine syndromes over a five-year follow-up. J Clin Endocrinol Metab 95: 3750–3757. Bensing S, Fetissov SO, Mulder J et al. (2007a). Pituitary autoantibodies in autoimmune polyendocrine syndrome type 1. Proc Natl Acad Sci U S A 104: 949–954.
421
Bensing S, Hulting AL, Hoog A et al. (2007b). Lymphocytic hypophysitis: report of two biopsy-proven cases and one suspected case with pituitary autoantibodies. J Endocrinol Invest 30: 153–162. Buxton N, Robertson I (2001). Lymphocytic and granulocytic hypophysitis: a single centre experience. Br J Neurosurg 15: 242–245, discussion 245–246. Caturegli P, Newschaffer C, Olivi A et al. (2005). Autoimmune hypophysitis. Endocr Rev 26: 599–614. Cohen LE, Wondisford FE, Radovick S (1996). Role of Pit-1 in the gene expression of growth hormone, prolactin, and thyrotropin. Endocrinol Metab Clin North Am 25: 523–540. Crock PA (1998). Cytosolic autoantigens in lymphocytic hypophysitis. J Clin Endocrinol Metab 83: 609–618. De Bellis A, Sinisi AA, Conte M et al. (2007). Antipituitary antibodies against gonadotropin-secreting cells in adult male patients with apparently idiopathic hypogonadotropic hypogonadism. J Clin Endocrinol Metab 92: 604–607. De Bellis A, Pane E, Bellastella G et al. (2011). Detection of antipituitary and antihypothalamus antibodies to investigate the role of pituitary or hypothalamic autoimmunity in patients with selective idiopathic hypopituitarism. Clin Endocrinol (Oxf) 75: 361–366. Drouin J, Takayasu S (2011). Autoimmunity: acquired versus inherited pituitary deficiency – same difference? Nat Rev Endocrinol 7: 255–256. Falorni A, Laureti S, De Bellis A et al. (2004). Italian addison network study: update of diagnostic criteria for the etiological classification of primary adrenal insufficiency. J Clin Endocrinol Metab 89: 1598–1604. Goudie RB, Pinkerton PH (1962). Anterior hypophysitis and Hashimoto’s disease in a young woman. J Pathol Bacteriol 83: 584–585. Hamano H, Kawa S, Horiuchi A et al. (2001). High serum IgG4 concentrations in patients with sclerosing pancreatitis. N Engl J Med 344: 732–738. Hamnvik OP, Laury AR, Laws Jr ER et al. (2010). Lymphocytic hypophysitis with diabetes insipidus in a young man. Nat Rev Endocrinol 6: 464–470. Hedstrand H, Ekwall O, Olsson MJ et al. (2001). The transcription factors SOX9 and SOX10 are vitiligo autoantigens in autoimmune polyendocrine syndrome type I. J Biol Chem 276: 35390–35395. Ingraham HA, Chen RP, Mangalam HJ et al. (1988). A tissuespecific transcription factor containing a homeodomain specifies a pituitary phenotype. Cell 55: 519–529. Kasperlik-Zaluska AA, Czarnocka B, Czech W (2003). Autoimmunity as the most frequent cause of idiopathic secondary adrenal insufficiency: report of 111 cases. Autoimmunity 36: 155–159. Lamolet B, Pulichino AM, Lamonerie T et al. (2001). A pituitary cell-restricted T box factor, Tpit, activates POMC transcription in cooperation with Pitx homeoproteins. Cell 104: 849–859. Leporati P, Landek-Salgado MA, Lupi I et al. (2011). IgG4related hypophysitis: a new addition to the hypophysitis spectrum. J Clin Endocrinol Metab 96: 1971–1980.
422
Y. TAKAHASHI
Leung GK, Lopes MB, Thorner MO et al. (2004). Primary hypophysitis: a single-center experience in 16 cases. J Neurosurg 101: 262–271. Lupi I, Broman KW, Tzou SC et al. (2008). Novel autoantigens in autoimmune hypophysitis. Clin Endocrinol (Oxf) 69: 269–278. Maghnie M, Ghirardello S, De Bellis A et al. (2006). Idiopathic central diabetes insipidus in children and young adults is commonly associated with vasopressin-cell antibodies and markers of autoimmunity. Clin Endocrinol (Oxf) 65: 470–478. Michels AW, Gottlieb PA (2010). Autoimmune polyglandular syndromes. Nat Rev Endocrinol 6: 270–277. Nakashima H, Miyake K, Moriyama M et al. (2010). An amplification of IL-10 and TGF-beta in patients with IgG4related tubulointerstitial nephritis. Clin Nephrol 73: 385–391. Nussbaum CE, Okawara SH, Jacobs LS (1991). Lymphocytic hypophysitis with involvement of the cavernous sinus and hypothalamus. Neurosurgery 28: 440–444. O’Dwyer DT, Clifton V, Hall A et al. (2002). Pituitary autoantibodies in lymphocytic hypophysitis target both gammaand alpha-Enolase – a link with pregnancy? Arch Physiol Biochem 110: 94–98. Pfaffle RW, DiMattia GE, Parks JS et al. (1992). Mutation of the POU-specific domain of Pit-1 and hypopituitarism without pituitary hypoplasia. Science 257: 1118–1121. Pulichino AM, Vallette-Kasic S, Couture C et al. (2003a). Human and mouse TPIT gene mutations cause early onset pituitary ACTH deficiency. Genes Dev 17: 711–716. Pulichino AM, Vallette-Kasic S, Tsai JP et al. (2003b). Tpit determines alternate fates during pituitary cell differentiation. Genes Dev 17: 738–747. Saito T, Yoshida S, Nakao K et al. (1970). Chronic hypernatremia associated with inflammation of the neurohypophysis. J Clin Endocrinol Metab 31: 391–396. Shaw SA, Camacho LH, McCutcheon IE et al. (2007). Transient hypophysitis after cytotoxic T lymphocyteassociated antigen 4 (CTLA4) blockade. J Clin Endocrinol Metab 92: 1201–1202. Shimatsu A, Oki Y, Fujisawa I et al. (2009). Pituitary and stalk lesions (infundibulo-hypophysitis) associated with immunoglobulin G4-related systemic disease: an emerging clinical entity. Endocr J 56: 1033–1041.
Smith CJ, Bensing S, Burns C et al. (2012). Identification of Tpit and other novel autoantigens in lymphocytic hypophysitis; immunoscreening of a pituitary cDNA library and development of immunoprecipitation assays. Eur J Endocrinol 166: 391–398. Suzuki K, Tamaru J, Okuyama A et al. (2010). IgG4-positive multi-organ lymphoproliferative syndrome manifesting as chronic symmetrical sclerosing dacryo-sialadenitis with subsequent secondary portal hypertension and remarkable IgG4-linked IL-4 elevation. Rheumatology (Oxford) 49: 1789–1791. Takao T, Nanamiya W, Matsumoto R et al. (2001). Antipituitary antibodies in patients with lymphocytic hypophysitis. Horm Res 55: 288–292. Tanaka S, Tatsumi KI, Kimura M et al. (2002). Detection of autoantibodies against the pituitary-specific proteins in patients with lymphocytic hypophysitis. Eur J Endocrinol 147: 767–775. Tatsumi K, Miyai K, Notomi T et al. (1992). Cretinism with combined hormone deficiency caused by a mutation in the PIT1 gene. Nat Genet 1: 56–58. Ueda H, Howson JM, Esposito L et al. (2003). Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature 423: 506–511. Umehara H, Okazaki K, Masaki Y et al. (2012). A novel clinical entity, IgG4-related disease (IgG4RD): general concept and details. Mod Rheumatol 22: 1–14. van der Vliet HJ, Perenboom RM (2004). Multiple pseudotumors in IgG4-associated multifocal systemic fibrosis. Ann Intern Med 141: 896–897. Wegner N, Wait R, Venables PJ (2009). Evolutionarily conserved antigens in autoimmune disease: implications for an infective aetiology. Int J Biochem Cell Biol 41: 390–397. Winer DA, Winer S, Shen L et al. (2011). B cells promote insulin resistance through modulation of T cells and production of pathogenic IgG antibodies. Nat Med 17: 610–617. Wong S, Lam WY, Wong WK et al. (2007). Hypophysitis presented as inflammatory pseudotumor in immunoglobulin G4-related systemic disease. Hum Pathol 38: 1720–1723. Yamamoto M, Iguchi G, Takeno R et al. (2011). Adult combined GH, prolactin, and TSH deficiency associated with circulating PIT-1 antibody in humans. J Clin Invest 121: 113–119. Zen Y, Nakanuma Y (2011). Pathogenesis of IgG4-related disease. Curr Opin Rheumatol 23: 114–118.
