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Anti-pituitary antibodies against corticotrophs in IgG4-related hypophysitis

Abstract

Purpose

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.

Methods

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.

Results

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.

Conclusions

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.

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Acknowledgements

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).

Author contributions

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.

Funding

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).

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Correspondence to Shintaro Iwama.

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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.

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Supplementary material 1 (DOCX 32 KB)

11102_2016_780_MOESM2_ESM.docx

Supplementary Figure 1. MRI findings in patients with IgG4-RH. MRI images showed both pituitary gland enlargement and stalk thickening (A) (B) or stalk thickening only (C) (D) in patients with IgG4-RH. Representative images from Pt 3 (A), Pt 11 (B), Pt 2 (C), and Pt 8 (D) (DOCX 1017 KB)

11102_2016_780_MOESM3_ESM.docx

Supplementary Figure 2. Evaluation of pituitary functions in patients with IgG4-RH. Testing of pituitary function included stimulation tests with corticotropin-releasing hormone (CRH), thyrotropin-releasing hormone (TRH), growth hormone-releasing hormone (GRH) or growth hormone-releasing peptide 2 (GHRP2), or luteinizing hormone-releasing hormone (LH-RH). The gonadal axis was impaired in Pt 8 (A). The GH axis and gonadal axis were impaired in Pt 1 (B). The TSH axis and gonadal axis were impaired in Pt 3 (C) (DOCX 510 KB)

11102_2016_780_MOESM4_ESM.tif

Supplementary Figure 3. Double indirect immunofluorescence (IIF) analysis using rat pituitary gland (A), human posterior pituitary gland (B), rat hypothalamus (C), and monkey hypothalamus (D) as substrate. A. Anti-pituitary antibodies (APA) did not bind to anterior or posterior pituitary tissue from rat (center panel). The posterior pituitary is labeled red using anti-arginine vasopressin (AVP) antibody (left panel). B. Posterior pituitary, labeled by anti-AVP antibody (left panel). Serum from a patient with IgG4-RH does not contain antibodies to the posterior pituitary (center panel). C. Rat hypothalamic supraoptic nucleus (SON), labeled by anti-AVP antibody (left panel). Serum from a patient with IgG4-RH does not contain antibodies to the rat SON (center panel). D. Monkey hypothalamus section including SON or paraventricular nucleus (PVN), labeled by anti-AVP antibody (left panel). Serum from a patient with IgG4-RH does not contain antibodies to the monkey SON or PVN (center panel). Representative images from Pt 1 (A), Pt 2 (B), Pt 4 (C) and Pt 14 (D) (TIF 20083 KB)

11102_2016_780_MOESM5_ESM.tif

Supplementary Figure 4. Western blot of GH protein in the serum of a healthy control. GH protein was detected around 20kD using anti-GH antibody as a positive control (second lane) and in the serum from healthy control (third lane) (TIF 5704 KB)

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Iwata, N., Iwama, S., Sugimura, Y. et al. Anti-pituitary antibodies against corticotrophs in IgG4-related hypophysitis. Pituitary 20, 301–310 (2017). https://doi.org/10.1007/s11102-016-0780-8

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Keywords

  • IgG4
  • Hypophysitis
  • Autoantibody
  • Autoantigen
  • Corticotroph
  • POMC