Anti-pituitary antibodies against corticotrophs in IgG4-related hypophysitis
- 427 Downloads
IgG4-related disease is a systemic inflammatory disease characterized by infiltration of IgG4-positive plasma cells into multiple organs, including the pituitary gland. Autoimmunity is thought to be involved in the pathogenesis of IgG4-related disease. The diagnosis of IgG4-related hypophysitis (IgG4-RH) is difficult because its clinical features, such as pituitary swelling and hypopituitarism, are similar to those of other pituitary diseases, including lymphocytic hypophysitis and sellar/suprasellar tumors. The presence and significance of anti-pituitary antibodies (APA) in IgG4-RH is unclear.
In this case-control study, we used single indirect immunofluorescence on human pituitary substrates to assess the prevalence of serum APA in 17 patients with IgG4-RH, 8 control patients with other pituitary diseases (lymphocytic infundibulo-neurohypophysitis, 3; craniopharyngioma, 2; germinoma, 3), and 9 healthy subjects. We further analyzed the endocrine cells targeted by the antibodies using double indirect immunofluorescence.
APA were found in 5 of 17 patients with IgG4-RH (29%), and in none of the pituitary controls or healthy subjects. The endocrine cells targeted by the antibodies in the 5 IgG4-RH cases were exclusively corticotrophs. Antibodies were of the IgG1 subclass, rather than IgG4, in all 5 cases, suggesting that IgG4 is not directly involved in the pathogenesis. Finally, antibodies recognized pro-opiomelanocortin in 2 of the cases.
Our study suggests that autoimmunity is involved in the pathogenesis of IgG4-RH and that corticotrophs are the main antigenic target, highlighting a possible new diagnostic marker for this condition.
KeywordsIgG4 Hypophysitis Autoantibody Autoantigen Corticotroph POMC
Institutions providing sera were as follows: Nagoya University, Toranomon Hospital (Dr Hiroshi Nishioka, Dr Shozo Yamada), Tokyo Women’s Medical University (Professor Naomi Hizuka, Dr Izumi Fukuda), National Hospital Organization Kyoto Medical Center (Dr Akira Shimatsu), Aichi Medical University (Professor Hirokazu Imai), Japanese Red Cross Nagoya Daiichi Hospital (Dr Atsushi Kiyota), Anjo Kosei Hospital (Dr Kunikazu Kondo), Yokohama City University Medical Center (Dr Hiromi Watanabe), Toyohashi Municipal Hospital (Dr Ikuo Yamamori), Tosei General Hospital (Dr Kimiko Akahane), Gifu Prefectural Tajimi Hospital (Dr Tetuji Okawa).
NI performed most of the experiments and contributed to manuscript writing. SI designed and performed some of the experiments and contributed to manuscript writing. YY, KN, and ST performed a part of the experiments. PC evaluated a part of the results. HD, YI, HS, MG, and RB discussed the results. SI, YS, and HA discussed the results, sponsored the study and wrote the manuscript.
This work was supported in part by a Grant-in-Aid for Scientific Research from the Japanese Society for the Promotion of Science 26893106 (to S. Iwama) and 24591360 (to Y. Sugimura), by Grants-in-Aid for Scientific Research (Research on Hypothalamo-hypophyseal Disorders) from the Ministry of Health, Labor and Welfare, Japan. P. Caturegli was supported by the National Institutes of Health (Grant DK080351).
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
All procedures involving human participants were performed in accordance with the ethical standards of our institutional research committee and with the 1964 Helsinki declaration and its later amendments. All animal studies were performed in accordance with the institutional guidelines for animal care at Nagoya University, which conform to National Institutes of Health animal care guidelines.
Informed consent was obtained from all individuals included in the study.
- 6.Bando H, Iguchi G, Fukuoka H, Taniguchi M, Yamamoto M, Matsumoto R, Suda K, Nishizawa H, Takahashi M, Kohmura E, Takahashi Y (2014) The prevalence of IgG4-related hypophysitis in 170 consecutive patients with hypopituitarism and/or central diabetes insipidus and review of the literature. Eur J Endocrinol 170(2):161–172. doi: 10.1530/EJE-13-0642 CrossRefPubMedGoogle Scholar
- 8.Aparisi L, Farre A, Gomez-Cambronero L, Martinez J, De Las Heras G, Corts J, Navarro S, Mora J, Lopez-Hoyos M, Sabater L, Ferrandez A, Bautista D, Perez-Mateo M, Mery S, Sastre, J (2005) Antibodies to carbonic anhydrase and IgG4 levels in idiopathic chronic pancreatitis: relevance for diagnosis of autoimmune pancreatitis. Gut 54(5):703–709. doi: 10.1136/gut.2004.047142 CrossRefPubMedPubMedCentralGoogle Scholar
- 10.Asada M, Nishio A, Uchida K, Kido M, Ueno S, Uza N, Kiriya K, Inoue S, Kitamura H, Ohashi S, Tamaki H, Fukui T, Matsuura M, Kawasaki K, Nishi T, Watanabe N, Nakase H, Chiba T, Okazaki K (2006) Identification of a novel autoantibody against pancreatic secretory trypsin inhibitor in patients with autoimmune pancreatitis. Pancreas 33(1):20–26. doi: 10.1097/01.mpa.0000226881.48204.fd CrossRefPubMedGoogle Scholar
- 12.Ricciuti A, De Remigis A, Landek-Salgado MA, De Vincentiis L, Guaraldi F, Lupi I, Iwama S, Wand GS, Salvatori R, Caturegli, P (2014) Detection of pituitary antibodies by immunofluorescence: approach and results in patients with pituitary diseases. J Clin Endocrinol Metab 99(5):1758–1766. doi: 10.1210/jc.2014-1049 CrossRefPubMedPubMedCentralGoogle Scholar
- 13.Iwama S, Sugimura Y, Kiyota A, Kato T, Enomoto A, Suzuki H, Iwata N, Takeuchi S, Nakashima K, Takagi H, Izumida H, Ochiai H, Fujisawa H, Suga H, Arima H, Shimoyama Y, Takahashi M, Nishioka H, Ishikawa SE, Shimatsu A, Caturegli P, Oiso Y (2015) Rabphilin-3A as a targeted autoantigen in lymphocytic infundibulo-neurohypophysitis. J Clin Endocrinol Metab 100(7):E946–E954. doi: 10.1210/jc.2014-4209 CrossRefPubMedPubMedCentralGoogle Scholar
- 14.Iwama S, Sugimura Y, Suzuki H, Murase T, Ozaki N, Nagasaki H, Arima H, Murata Y, Sawada M, Oiso Y (2011) Time-dependent changes in proinflammatory and neurotrophic responses of microglia and astrocytes in a rat model of osmotic demyelination syndrome. Glia 59(3):452–462. doi: 10.1002/glia.21114 CrossRefPubMedGoogle Scholar
- 17.Kiyota A, Iwama S, Sugimura Y, Takeuchi S, Takagi H, Iwata N, Nakashima K, Suzuki H, Nishioka T, Kato T, Enomoto A, Arima H, Kaibuchi K, Oiso Y (2015) Identification of the novel autoantigen candidate Rab GDP dissociation inhibitor alpha in isolated adrenocorticotropin deficiency. Endocr J 62(2):153–160. doi: 10.1507/endocrj.EJ14-0369 CrossRefPubMedGoogle Scholar
- 22.Tatsumi KI, Tanaka S, Takano T, Tahara S, Murakami Y, Takao T, Hashimoto K, Kato Y, Teramoto A, Amino N (2003) Frequent appearance of autoantibodies against prohormone convertase 1/3 and neuroendocrine protein 7B2 in patients with nonfunctioning pituitary macroadenoma. Endocr 22(3):335–340. doi: 10.1385/endo:22:3:335 CrossRefGoogle Scholar
- 24.Smith CJ, Oscarson M, Ronnblom L, Alimohammadi M, Perheentupa J, Husebye ES, Gustafsson J, Nordmark G, Meloni A, Crock PA, Kampe O, Bensing S (2011) TSGA10—a target for autoantibodies in autoimmune polyendocrine syndrome type 1 and systemic lupus erythematosus. Scand J Immunol 73(2):147–153. doi: 10.1111/j.1365-3083.2010.02486.x CrossRefPubMedGoogle Scholar
- 25.Smith CJ, Bensing S, Burns C, Robinson PJ, Kasperlik-Zaluska AA, Scott RJ, Kampe O, Crock PA (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(3):391–398. doi: 10.1530/eje-11-1015 CrossRefPubMedPubMedCentralGoogle Scholar
- 27.Yamamoto M, Iguchi G, Takeno R, Okimura Y, Sano T, Takahashi M, Nishizawa H, Handayaningshi AE, Fukuoka H, Tobita M, Saitoh T, Tojo K, Mokubo A, Morinobu A, Iida K, Kaji H, Seino S, Chihara K, Takahashi Y (2011) Adult combined GH, prolactin, and TSH deficiency associated with circulating PIT-1 antibody in humans. J Clin Invest 121(1):113–119. doi: 10.1172/jci44073 CrossRefPubMedGoogle Scholar
- 28.Bando H, Iguchi G, Fukuoka H, Yamamoto M, Hidaka-Takeno R, Okimura Y, Matsumoto R, Suda K, Nishizawa H, Takahashi M, Tojo K, Takahashi Y (2014) Involvement of PIT-1-reactive cytotoxic T lymphocytes in anti-PIT-1 antibody syndrome. J Clin Endocrinol Metab 99(9):E1744–E1749. doi: 10.1210/jc.2014-1769 CrossRefPubMedGoogle Scholar
- 32.Pivonello R, De Bellis A, Faggiano A, Di Salle F, Petretta M, Di Somma C, Perrino S, Altucci P, Bizzarro A, Bellastella A, Lombardi G, Colao, A (2003) Central diabetes insipidus and autoimmunity: relationship between the occurrence of antibodies to arginine vasopressin-secreting cells and clinical, immunological, and radiological features in a large cohort of patients with central diabetes insipidus of known and unknown etiology. J Clin Endocrinol Metab 88(4):1629–1636. doi: 10.1210/jc.2002-020791 CrossRefPubMedGoogle Scholar
- 33.De Bellis A, Colao A, Di Salle F, Muccitelli VI, Iorio S, Perrino S, Pivonello R, Coronella C, Bizzarro A, Lombardi G, Bellastella, A (1999) A longitudinal study of vasopressin cell antibodies, posterior pituitary function, and magnetic resonance imaging evaluations in subclinical autoimmune central diabetes insipidus. J Clin Endocrinol Metab 84(9):3047–3051. doi: 10.1210/jcem.84.9.5945 CrossRefPubMedGoogle Scholar
- 34.Bellastella G, Bizzarro A, Aitella E, Barrasso M, Cozzolino D, Di Martino S, Esposito K, De Bellis A (2015) Pregnancy may favour the development of severe autoimmune central diabetes insipidus in women with vasopressin cell antibodies: description of two cases. Eur J Endocrinol 172(3):K11–K17. doi: 10.1530/EJE-14-0762 CrossRefPubMedGoogle Scholar
- 35.De Bellis A, Sinisi AA, Pane E, Dello Iacovo A, Bellastella G, Di Scala G, Falorni A, Giavoli C, Gasco V, Giordano R, Ambrosio MR, Colao A, Bizzarro A, Bellastella A, Italian Autoimmune Hypophysitis Network, G (2012) Involvement of hypothalamus autoimmunity in patients with autoimmune hypopituitarism: role of antibodies to hypothalamic cells. J Clin Endocrinol Metab 97(10):3684–3690. doi: 10.1210/jc.2012-2269 CrossRefPubMedGoogle Scholar
- 36.De Bellis A, Bizzarro A, Conte M, Perrino S, Coronella C, Solimeno S, Sinisi AM, Stile LA, Pisano G, Bellastella A (2003) Antipituitary antibodies in adults with apparently idiopathic growth hormone deficiency and in adults with autoimmune endocrine diseases. J Clin Endocrinol Metab 88(2):650–654. doi: 10.1210/jc.2002-021054 CrossRefPubMedGoogle Scholar
- 37.De Bellis A, Salerno M, Conte M, Coronella C, Tirelli G, Battaglia M, Esposito V, Ruocco G, Bellastella G, Bizzarro A, Bellastella A (2006) Antipituitary antibodies recognizing growth hormone (GH)-producing cells in children with idiopathic GH deficiency and in children with idiopathic short stature. J Clin Endocrinol Metab 91(7):2484–2489. doi: 10.1210/jc.2006-0040 CrossRefPubMedGoogle Scholar
- 38.De Bellis A, Bizzarro A, Perrino S, Coronella C, Conte M, Pasquali D, Sinisi AA, Betterle C, Bellastella A (2005) Characterization of antipituitary antibodies targeting pituitary hormone-secreting cells in idiopathic growth hormone deficiency and autoimmune endocrine diseases. Clin Endocrinol (Oxf) 63(1):45–49. doi: 10.1111/j.1365-2265.2005.02296.x CrossRefGoogle Scholar
- 39.De Bellis A, Bellastella G, Maiorino MI, Aitella E, Lucci E, Cozzolino D, Bellastella A, Bizzarro A, Giugliano D, Esposito K, Italian Autoimmune Hypophysitis Network, G (2016) Longitudinal behavior of autoimmune GH deficiency: from childhood to transition age. Eur J Endocrinol 174(3):381–387. doi: 10.1530/EJE-15-0766 CrossRefPubMedGoogle Scholar
- 40.De Bellis A, Sinisi AA, Conte M, Coronella C, Bellastella G, Esposito D, Pasquali D, Ruocco G, Bizzarro A, Bellastella A (2007) Antipituitary antibodies against gonadotropin-secreting cells in adult male patients with apparently idiopathic hypogonadotropic hypogonadism. J Clin Endocrinol Metab 92(2):604–607. doi: 10.1210/jc.2006-1216 CrossRefPubMedGoogle Scholar
- 41.De Bellis A, Colella C, Bellastella G, Lucci E, Sinisi AA, Bizzarro A, Holdaway I (2013) Late primary autoimmune hypothyroidism in a patient with postdelivery autoimmune hypopituitarism associated with antibodies to growth hormone and prolactin-secreting cells. Thyroid 23(8):1037–1041. doi: 10.1089/thy.2012.0482 CrossRefPubMedGoogle Scholar
- 42.Delvecchio M, De Bellis A, Francavilla R, Rutigliano V, Predieri B, Indrio F, De Venuto D, Sinisi AA, Bizzarro A, Bellastella A, Iughetti L, Cavallo L, Italian Autoimmune Hypophysitis Network, S (2010) Anti-pituitary antibodies in children with newly diagnosed celiac disease: a novel finding contributing to linear-growth impairment. Am J Gastroenterol 105(3):691–696. doi: 10.1038/ajg.2009.642 CrossRefPubMedGoogle Scholar
- 43.Bellastella G, Rotondi M, Pane E, Dello Iacovo A, Pirali B, Dalla Mora L, Falorni A, Sinisi AA, Bizzarro A, Colao A, Chiovato L, De Bellis A, Italian Autoimmune Hypophysitis Network, S (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(8):3750–3757. doi: 10.1210/jc.2010-0551 CrossRefPubMedGoogle Scholar
- 44.De Bellis A, Dello Iacovo A, Bellastella G, Savoia A, Cozzolino D, Sinisi AA, Bizzarro A, Bellastella A, Giugliano D (2014) Characterization of pituitary cells targeted by antipituitary antibodies in patients with isolated autoimmune diseases without pituitary insufficiency may help to foresee the kind of future hypopituitarism. Pituitary 17(5):457–463. doi: 10.1007/s11102-013-0526-9 CrossRefPubMedGoogle Scholar