Shintaro Iwama1, Yoshihisa Sugimura1, Atsushi Kiyota1, Takuya Kato1, Atsushi Enomoto1, Haruyuki Suzuki1, Naoko Iwata1, Seiji Takeuchi1, Kohtaro Nakashima1, Hiroshi Takagi1, Hisakazu Izumida1, Hiroshi Ochiai1, Haruki Fujisawa1, Hidetaka Suga1, Hiroshi Arima1, Yoshie Shimoyama1, Masahide Takahashi1, Hiroshi Nishioka1, San-e Ishikawa1, Akira Shimatsu1, Patrizio Caturegli1, Yutaka Oiso1. 1. Department of Endocrinology and Diabetes (S.Iw., Y.Su., A.K., H.S., N.I., S.T., K.N., H.T., H.I., H.O., H.F., H.S., H.A., Y.O.) and Department of Pathology (T.K., A.E., M.T.), Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan; Research Center of Health, Physical Fitness and Sports (S.Iw.), Nagoya University, Nagoya 464-8601, Japan; Department of Pathology and Clinical Laboratory (Y.Sh.), Nagoya University Hospital, Nagoya 466-8560, Japan; Department of Hypothalamic and Pituitary Surgery (H.N.), Toranomon Hospital, Tokyo 105-0001, Japan; Department of Medicine (S.Is.), Jichi Medical University Saitama Medical Center, Saitama, 330-8503, Japan; Clinical Research Institute (A.S.), National Hospital Organization Kyoto Medical Center, Kyoto 612-8555, Japan; Department of Pathology (P.C.), Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Feinstone Department of Molecular Microbiology and Immunology (P.C.), Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21205; and Japan Hypophysitis Research Group (S.Iw., Y.Su., H.N., S.Is., A.S., Y.O.), Nagoya 466-8550, Japan.
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 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.
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.
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