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Growth hormone and proopiomelanocortin are targeted by autoantibodies in a patient with biopsy-proven IgG4-related hypophysitis

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Abstract

Hypophysitis is a chronic inflammation of the pituitary gland often caused by autoimmunity. Among the autoimmune diseases it is one of the few where the autoantigens remain to be identified. The goal of the paper was to characterize the antigenic profile in a previously reported patient with IgG4-related hypophysitis. Immunofluorescence and immunoblotting were performed to detect antibodies to human pituitary proteins. The proteins recognized by western blotting were then submitted to mass spectrometry for sequencing. The patient’s autoantibodies recognized two unique bands around 40 and 30 kDa on immunoblotting. Sequencing revealed one peptide from proopiomelanocortin in the 40 kDa band and four peptides from growth hormone in the 30 kDa band. This work represents the first antigenic profile in IgG4-related hypophysitis, and the first recognition of proopiomelanocortin as a possible pituitary autoantigen. In addition, the work supports previous suggestions of growth hormone as a pituitary autoantigen. Further studies are needed to prove the pathogenicity and diagnostic utility of these two pituitary proteins.

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References

  1. Caturegli P, Lupi I, Landek-Salgado M, Kimura H, Rose NR (2008) Pituitary autoimmunity: 30 years later. Autoimmun Rev 7:631–637

    Article  PubMed  CAS  Google Scholar 

  2. Caturegli P, Newschaffer C, Olivi A, Pomper MG, Burger PC, Rose NR (2005) Autoimmune hypophysitis. Endocr Rev 26:599–614

    Article  PubMed  CAS  Google Scholar 

  3. Aste L, Bellinzona M, Meleddu V, Farci G, Manieli C, Godano U (2010) Xanthomatous hypophysitis mimicking a pituitary adenoma: case report and review of the literature. J Oncol 2010:195323. doi:10.1155/2010/195323

    Article  PubMed  Google Scholar 

  4. Gutenberg A, Caturegli P, Metz I, Martinez R, Mohr A, Bruck W, Rohde V (2011) Necrotizing infundibulo-hypophysitis: an entity too rare to be true? Pituitary. doi:10.1007/s11102-011-0307-2

  5. Leporati P, Landek-Salgado M, Lupi I, Chiovato L, Caturegli P (2011) IgG4-related autoimmune hypophysitis: an emerging clinicopathological entity. J Clin Endocrinol Metab 96(7):1971–1980

    Article  Google Scholar 

  6. Shimatsu A, Oki Y, Fujisawa I, Sano T (2009) Pituitary and stalk lesions (infundibulo-hypophysitis) associated with immunoglobulin G4-related systemic disease: an emerging clinical entity. Endocr J 56(9):1033–1041

    Article  PubMed  Google Scholar 

  7. Khosroshahi A, Stone JH (2011) A clinical overview of IgG4-related systemic disease. Curr Opin Rheumatol 23(1):57–66. doi:10.1097/BOR.0b013e3283418057

    Article  PubMed  CAS  Google Scholar 

  8. Frulloni L, Lunardi C, Simone R, Dolcino M, Scattolini C, Falconi M, Benini L, Vantini I, Corrocher R, Puccetti A (2009) Identification of a novel antibody associated with autoimmune pancreatitis. N Engl J Med 361(22):2135–2142. doi:10.1056/NEJMoa0903068

    Article  PubMed  CAS  Google Scholar 

  9. Caturegli P (2007) Autoimmune hypophysitis: an underestimated disease in search of its autoantigen(s). J Clin Endocrinol Metab 92(6):2038–2040

    Article  PubMed  CAS  Google Scholar 

  10. Lupi I, Broman KW, Tzou SC, Gutenberg A, Martino E, Caturegli P (2008) Novel autoantigens in autoimmune hypophysitis. Clin Endocrinol 69:269–278

    Article  CAS  Google Scholar 

  11. Crock PA (1998) Cytosolic autoantigens in lymphocytic hypophysitis. J Clin Endocrinol Metab 83(2):609–618

    Article  PubMed  CAS  Google Scholar 

  12. Takao T, Nanamiya W, Matsumoto R, Asaba K, Okabayashi T, Hashimoto K (2001) Antipituitary antibodies in patients with lymphocytic hypophysitis. Horm Res 55:288–292

    Article  PubMed  CAS  Google Scholar 

  13. Tanaka S, Tatsumi KI, Kimura M, Takano T, Murakami Y, Takao T, Hashimoto K, Kato Y, Amino N (2002) Detection of autoantibodies against the pituitary-specific proteins in patients with lymphocytic hypophysitis. Eur J Endocrinol 147:767–775

    Article  PubMed  CAS  Google Scholar 

  14. Bensing S, Hulting AL, Hoog A, Ericson K, Kampe O (2007) Lymphocytic hypophysitis: report of two biopsy-proven cases and one suspected case with pituitary autoantibodies. J Endocrinol Invest 30(2):153–162

    PubMed  CAS  Google Scholar 

  15. 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

    Article  PubMed  CAS  Google Scholar 

  16. Crock P, Salvi M, Miller A, Wall J, Guyda H (1993) Detection of anti-pituitary autoantibodies by immunoblotting. J Immunol Methods 162:31–40

    Article  PubMed  CAS  Google Scholar 

  17. Glück M, Scherbaum WA (1990) Substrate specificity for the detection of autoantibodies to anterior pituitary cells in human sera. Horm Metab Res 22:541–545

    Article  PubMed  Google Scholar 

  18. Pouplard A, Bottazzo GF, Doniach D, Roitt IM (1976) Binding of human immunoglobulins to pituitary ACTH cells. Nature 261(5556):142–144

    Article  PubMed  CAS  Google Scholar 

  19. Lewis UJ (1992) Growth hormone what is it and what does it do? Trends Endocrinol Metab 3(4):117–121. doi:1043-2760(92)90099-M

    Article  PubMed  CAS  Google Scholar 

  20. Caturegli P, Rose NR, Kimura M, Kimura H, Tzou SC (2003) Studies on murine thyroiditis: new insights from organ flow cytometry. Thyroid 13(5):419–426. doi:10.1089/105072503322021070

    Article  PubMed  Google Scholar 

  21. Charrier J, Martal J (1988) Growth hormones. 1. Polymorphism (minireview). Reprod Nutr Dev 28(4A):857–887

  22. Baumann GP (2009) Growth hormone isoforms. Growth Horm IGF Res 19(4):333–340. doi:10.1016/j.ghir.2009.04.011

    Article  PubMed  CAS  Google Scholar 

  23. Bellastella G, Rotondi M, Pane E, Dello IA, Pirali B, Dalla Mora L, Falorni A, Sinisi AA, Bizzarro A, Colao A, Chiovato L, De Bellis A (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. doi:10.1210/jc.2010-0551

  24. 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

    Article  PubMed  Google Scholar 

  25. Tzou SC, Lupi I, Landek M, Gutenberg A, Tzou YM, Kimura H, Pinna G, Rose NR, Caturegli P (2008) Autoimmune hypophysitis of SJL mice: clinical insights from a new animal model. Endocrinology 49(7):3461–3469

    Article  Google Scholar 

  26. Raffin-Sanson ML, de Keyzer Y, Bertagna X (2003) Proopiomelanocortin, a polypeptide precursor with multiple functions: from physiology to pathological conditions. Eur J Endocrinol 149(2):79–90

    Article  PubMed  CAS  Google Scholar 

  27. Grigorakis SI, Anastasiou E, Dai K, Souvatzoglou A, Alevizaki M (2000) Three mRNA transcripts of the proopiomelanocortin gene in human placenta at term. Eur J Endocrinol 142(5):533–536

    Article  PubMed  CAS  Google Scholar 

  28. Raffin-Sanson ML, Massias JF, Ankotche A, Coste J, de Keyzer Y, Oliver C, Dumont C, Cabrol D, Ferre F, Bertagna X (1999) High precursor level in maternal blood results from the alternate mode of proopiomelanocortin processing in human placenta. Clin Endocrinol (Oxf) 50(1):85–94

    Article  CAS  Google Scholar 

  29. Raffin-Sanson ML, Ferre F, Coste J, Oliver C, Cabrol D, Bertagna X (2000) Pro-opiomelanocortin in human pregnancy: evolution of maternal plasma levels, concentrations in cord blood, amniotic fluid and at the feto-maternal interface. Eur J Endocrinol 142(1):53–59

    Article  PubMed  CAS  Google Scholar 

  30. Bourdelle-Hego MF, Dewailly D, Cappoen JP, Lingard-Leroy C, Fossati P (1985) Hypophysite du post partum, une ètiologie très souvent mécounnue d’hypopituitarism antérieur; à propos de 2 obsevations. Rev Franc Endocrinol Clin 26:99–104

    Google Scholar 

  31. Sauter NP, Toni R, McLaughlin CD, Dyess EM, Kritzman J, Lechan RM (1990) Isolated adrenocorticotropin deficiency associated with an autoantibody to a corticotroph antigen that is not adrenocorticotropin or other proopiomelanocortin-derived peptides. J Clin Endocrinol Metab 70(5):1391–1397

    Article  PubMed  CAS  Google Scholar 

  32. Bensing S, Kasperlik-Zaluska AA, Czarnocka B, Crock PA, Hulting A (2005) Autoantibodies against pituitary proteins in patients with adrenocorticotropin-deficiency. Eur J Clin Invest 35:126–132

    Article  PubMed  CAS  Google Scholar 

  33. De Bellis A, Pane E, Bellastella G, Sinisi AA, Colella C, Giordano R, Giavoli C, Lania A, Ambrosio MR, Di Somma C, Zatelli MC, Arvat E, Colao A, Bizzarro A, Bellastella A (2011) Detection of anti-pituitary and anti-hypothalamus antibodies to investigate the role of pituitary or hypothalamic autoimmunity in patients with selective idiopathy hypopituitarism. Clin Endocrinol (Oxf). doi:10.1111/j.1365-2265.2011.04056.x

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Acknowledgments

This work was supported by NIH grant DK080351 to PC. The authors are grateful to Drs. Cristina Cupini, Rodolfo Fonte and Enio Martino for the care of the patient.

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Authors and Affiliations

  1. Department of Pathology, The Johns Hopkins University School of Medicine, Ross 656, 720 Rutland Avenue, Baltimore, MD, 21205, USA

    M. A. Landek-Salgado, P. Leporati, A. Geis & P. Caturegli

  2. Unit of Internal Medicine and Endocrinology, Fondazione Salvatore Maugeri IRCCS, University of Pavia, Pavia, Italy

    P. Leporati

  3. Department of Endocrinology and Metabolism, University of Pisa, Pisa, Italy

    I. Lupi

  4. Feinstone Department of Molecular Microbiology and Immunology, The Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA

    P. Caturegli

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  1. M. A. Landek-Salgado
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  2. P. Leporati
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  3. I. Lupi
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Correspondence to P. Caturegli.

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Landek-Salgado, M.A., Leporati, P., Lupi, I. et al. Growth hormone and proopiomelanocortin are targeted by autoantibodies in a patient with biopsy-proven IgG4-related hypophysitis. Pituitary 15, 412–419 (2012). https://doi.org/10.1007/s11102-011-0338-8

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