Rabphilin-3A as a targeted autoantigen in lymphocytic infundibulo-neurohypophysitis

Shintaro Iwama, Yoshihisa Sugimura, Atsushi Kiyota, Takuya Kato, Atsushi Enomoto, Haruyuki Suzuki, Naoko Iwata, Seiji Takeuchi, Kohtaro Nakashima, Hiroshi Takagi, Hisakazu Izumida, Hiroshi Ochiai, Haruki Fujisawa, Hidetaka Suga, Hiroshi Arima, Yoshie Shimoyama, Masahide Takahashi, Hiroshi Nishioka, San E. Ishikawa, Akira Shimatsu & 2 others Patrizio Caturegli, Yutaka Oiso

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Context: Central diabetes insipidus (CDI) can be caused by several diseases, but in about half of the patients the etiological diagnosis remains unknown. Lymphocytic infundibulo-neurohypophysitis (LINH) is an increasingly recognized entity among cases of idiopathic CDI; however, the differential diagnosis from other pituitary diseases including tumors can be difficult because of similar clinical and radiological manifestations. The definite diagnosis of LINH requires invasive pituitary biopsy. Objective: The study was designed to identify the autoantigen(s) in LINH and thus develop a diagnostic test based on serum autoantibodies. Design: Rat posterior pituitary lysate was immunoprecipitated with IgGs purified from the sera of patients with LINH or control subjects. The immunoprecipitates were subjected to liquid chromatographytandem mass spectrometry to screen for pituitary autoantigens of LINH. Subsequently, we made recombinant proteins of candidate autoantigens and analyzed autoantibodies in serum by Western blotting. Results: Rabphilin-3A proved to be the most diagnostically useful autoantigen. Anti-rabphilin-3A antibodies were detected in 22 of the 29 (76%) patients (including 4 of the 4 biopsy-proven samples) with LINH and 2 of 18 (11.1%) patients with biopsy-proven lymphocytic adeno-hypophysitis. In contrast, these antibodies were absent in patients with biopsy-proven sellar/suprasellar masses without lymphocytic hypophysitis (n=34), including 18 patients with CDI. Rabphilin-3Awas expressed in posterior pituitary and hypothalamic vasopressin neurons but not anterior pituitary. Conclusions: These results suggest that rabphilin-3A is a major autoantigen in LINH. Autoantibodies to rabphilin-3A may serve as a biomarker for the diagnosis of LINH and be useful for the differential diagnosis in patients with CDI.

Original languageEnglish
Pages (from-to)E946-E954
JournalJournal of Clinical Endocrinology and Metabolism
Volume100
Issue number7
DOIs
Publication statusPublished - 01-07-2015

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Autoantigens
Biopsy
Medical problems
Neurogenic Diabetes Insipidus
Autoantibodies
Antibodies
Differential Diagnosis
Serum
Biomarkers
Pituitary Diseases
Vasopressins
Recombinant Proteins
Neurons
Mass spectrometry
Rats
Tumors
rabphilin-3A
Routine Diagnostic Tests
Mass Spectrometry
Liquids

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical

Cite this

Iwama, Shintaro ; Sugimura, Yoshihisa ; Kiyota, Atsushi ; Kato, Takuya ; Enomoto, Atsushi ; Suzuki, Haruyuki ; Iwata, Naoko ; Takeuchi, Seiji ; Nakashima, Kohtaro ; Takagi, Hiroshi ; Izumida, Hisakazu ; Ochiai, Hiroshi ; Fujisawa, Haruki ; Suga, Hidetaka ; Arima, Hiroshi ; Shimoyama, Yoshie ; Takahashi, Masahide ; Nishioka, Hiroshi ; Ishikawa, San E. ; Shimatsu, Akira ; Caturegli, Patrizio ; Oiso, Yutaka. / Rabphilin-3A as a targeted autoantigen in lymphocytic infundibulo-neurohypophysitis. In: Journal of Clinical Endocrinology and Metabolism. 2015 ; Vol. 100, No. 7. pp. E946-E954.
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abstract = "Context: Central diabetes insipidus (CDI) can be caused by several diseases, but in about half of the patients the etiological diagnosis remains unknown. Lymphocytic infundibulo-neurohypophysitis (LINH) is an increasingly recognized entity among cases of idiopathic CDI; however, the differential diagnosis from other pituitary diseases including tumors can be difficult because of similar clinical and radiological manifestations. The definite diagnosis of LINH requires invasive pituitary biopsy. Objective: The study was designed to identify the autoantigen(s) in LINH and thus develop a diagnostic test based on serum autoantibodies. Design: Rat posterior pituitary lysate was immunoprecipitated with IgGs purified from the sera of patients with LINH or control subjects. The immunoprecipitates were subjected to liquid chromatographytandem mass spectrometry to screen for pituitary autoantigens of LINH. Subsequently, we made recombinant proteins of candidate autoantigens and analyzed autoantibodies in serum by Western blotting. Results: Rabphilin-3A proved to be the most diagnostically useful autoantigen. Anti-rabphilin-3A antibodies were detected in 22 of the 29 (76{\%}) patients (including 4 of the 4 biopsy-proven samples) with LINH and 2 of 18 (11.1{\%}) patients with biopsy-proven lymphocytic adeno-hypophysitis. In contrast, these antibodies were absent in patients with biopsy-proven sellar/suprasellar masses without lymphocytic hypophysitis (n=34), including 18 patients with CDI. Rabphilin-3Awas expressed in posterior pituitary and hypothalamic vasopressin neurons but not anterior pituitary. Conclusions: These results suggest that rabphilin-3A is a major autoantigen in LINH. Autoantibodies to rabphilin-3A may serve as a biomarker for the diagnosis of LINH and be useful for the differential diagnosis in patients with CDI.",
author = "Shintaro Iwama and Yoshihisa Sugimura and Atsushi Kiyota and Takuya Kato and Atsushi Enomoto and Haruyuki Suzuki and Naoko Iwata and Seiji Takeuchi and Kohtaro Nakashima and Hiroshi Takagi and Hisakazu Izumida and Hiroshi Ochiai and Haruki Fujisawa and Hidetaka Suga and Hiroshi Arima and Yoshie Shimoyama and Masahide Takahashi and Hiroshi Nishioka and Ishikawa, {San E.} and Akira Shimatsu and Patrizio Caturegli and Yutaka Oiso",
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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', Journal of Clinical Endocrinology and Metabolism, vol. 100, no. 7, pp. E946-E954. https://doi.org/10.1210/jc.2014-4209

Rabphilin-3A as a targeted autoantigen in lymphocytic infundibulo-neurohypophysitis. / Iwama, Shintaro; Sugimura, Yoshihisa; Kiyota, Atsushi; Kato, Takuya; Enomoto, Atsushi; Suzuki, Haruyuki; Iwata, Naoko; Takeuchi, Seiji; Nakashima, Kohtaro; Takagi, Hiroshi; Izumida, Hisakazu; Ochiai, Hiroshi; Fujisawa, Haruki; Suga, Hidetaka; Arima, Hiroshi; Shimoyama, Yoshie; Takahashi, Masahide; Nishioka, Hiroshi; Ishikawa, San E.; Shimatsu, Akira; Caturegli, Patrizio; Oiso, Yutaka.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 100, No. 7, 01.07.2015, p. E946-E954.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Rabphilin-3A as a targeted autoantigen in lymphocytic infundibulo-neurohypophysitis

AU - Iwama, Shintaro

AU - Sugimura, Yoshihisa

AU - Kiyota, Atsushi

AU - Kato, Takuya

AU - Enomoto, Atsushi

AU - Suzuki, Haruyuki

AU - Iwata, Naoko

AU - Takeuchi, Seiji

AU - Nakashima, Kohtaro

AU - Takagi, Hiroshi

AU - Izumida, Hisakazu

AU - Ochiai, Hiroshi

AU - Fujisawa, Haruki

AU - Suga, Hidetaka

AU - Arima, Hiroshi

AU - Shimoyama, Yoshie

AU - Takahashi, Masahide

AU - Nishioka, Hiroshi

AU - Ishikawa, San E.

AU - Shimatsu, Akira

AU - Caturegli, Patrizio

AU - Oiso, Yutaka

PY - 2015/7/1

Y1 - 2015/7/1

N2 - Context: Central diabetes insipidus (CDI) can be caused by several diseases, but in about half of the patients the etiological diagnosis remains unknown. Lymphocytic infundibulo-neurohypophysitis (LINH) is an increasingly recognized entity among cases of idiopathic CDI; however, the differential diagnosis from other pituitary diseases including tumors can be difficult because of similar clinical and radiological manifestations. The definite diagnosis of LINH requires invasive pituitary biopsy. Objective: The study was designed to identify the autoantigen(s) in LINH and thus develop a diagnostic test based on serum autoantibodies. Design: Rat posterior pituitary lysate was immunoprecipitated with IgGs purified from the sera of patients with LINH or control subjects. The immunoprecipitates were subjected to liquid chromatographytandem mass spectrometry to screen for pituitary autoantigens of LINH. Subsequently, we made recombinant proteins of candidate autoantigens and analyzed autoantibodies in serum by Western blotting. Results: Rabphilin-3A proved to be the most diagnostically useful autoantigen. Anti-rabphilin-3A antibodies were detected in 22 of the 29 (76%) patients (including 4 of the 4 biopsy-proven samples) with LINH and 2 of 18 (11.1%) patients with biopsy-proven lymphocytic adeno-hypophysitis. In contrast, these antibodies were absent in patients with biopsy-proven sellar/suprasellar masses without lymphocytic hypophysitis (n=34), including 18 patients with CDI. Rabphilin-3Awas expressed in posterior pituitary and hypothalamic vasopressin neurons but not anterior pituitary. Conclusions: These results suggest that rabphilin-3A is a major autoantigen in LINH. Autoantibodies to rabphilin-3A may serve as a biomarker for the diagnosis of LINH and be useful for the differential diagnosis in patients with CDI.

AB - Context: Central diabetes insipidus (CDI) can be caused by several diseases, but in about half of the patients the etiological diagnosis remains unknown. Lymphocytic infundibulo-neurohypophysitis (LINH) is an increasingly recognized entity among cases of idiopathic CDI; however, the differential diagnosis from other pituitary diseases including tumors can be difficult because of similar clinical and radiological manifestations. The definite diagnosis of LINH requires invasive pituitary biopsy. Objective: The study was designed to identify the autoantigen(s) in LINH and thus develop a diagnostic test based on serum autoantibodies. Design: Rat posterior pituitary lysate was immunoprecipitated with IgGs purified from the sera of patients with LINH or control subjects. The immunoprecipitates were subjected to liquid chromatographytandem mass spectrometry to screen for pituitary autoantigens of LINH. Subsequently, we made recombinant proteins of candidate autoantigens and analyzed autoantibodies in serum by Western blotting. Results: Rabphilin-3A proved to be the most diagnostically useful autoantigen. Anti-rabphilin-3A antibodies were detected in 22 of the 29 (76%) patients (including 4 of the 4 biopsy-proven samples) with LINH and 2 of 18 (11.1%) patients with biopsy-proven lymphocytic adeno-hypophysitis. In contrast, these antibodies were absent in patients with biopsy-proven sellar/suprasellar masses without lymphocytic hypophysitis (n=34), including 18 patients with CDI. Rabphilin-3Awas expressed in posterior pituitary and hypothalamic vasopressin neurons but not anterior pituitary. Conclusions: These results suggest that rabphilin-3A is a major autoantigen in LINH. Autoantibodies to rabphilin-3A may serve as a biomarker for the diagnosis of LINH and be useful for the differential diagnosis in patients with CDI.

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U2 - 10.1210/jc.2014-4209

DO - 10.1210/jc.2014-4209

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