Rabphilin-3A as a Targeted Autoantigen in Lymphocytic Infundibulo-neurohypophysitis

• Published in: The journal of clinical endocrinology and metabolism Vol. 100; no. 7; pp. E946 - E954
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States Endocrine Society 01-07-2015; Copyright by The Endocrine Society
• Subjects: Adaptor Proteins, Signal Transducing - immunology; Adaptor Proteins, Signal Transducing - metabolism; Adult; Animals; Autoantibodies - blood; Autoantigens - immunology; Autoimmune Diseases - blood; Autoimmune Diseases - immunology; Autoimmune Diseases - metabolism; Diabetes Insipidus, Neurogenic - blood; Diabetes Insipidus, Neurogenic - diagnosis; Diabetes Insipidus, Neurogenic - immunology; Diabetes Insipidus, Neurogenic - metabolism; Diagnosis, Differential; Female; HEK293 Cells; Hot Topics in Translational Endocrinology; Humans; Lymphocytes - immunology; Male; Nerve Tissue Proteins - immunology; Nerve Tissue Proteins - metabolism; Pituitary Gland, Posterior - immunology; Pituitary Gland, Posterior - metabolism; Rabphilin-3A; Rats; Rats, Sprague-Dawley; Vesicular Transport Proteins - immunology; Vesicular Transport Proteins - metabolism; Young Adult
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.2014-4209

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 chromatography-tandem 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-3A was 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.