Anti-pituitary antibodies against corticotrophs in IgG4-related hypophysitis
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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.
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