Critical role of rabphilin-3A in the pathophysiology of experimental lymphocytic neurohypophysitis

Yoshinori Yasuda, Shintaro Iwama, Atsushi Kiyota, Hisakazu Izumida, Kohtaro Nakashima, Naoko Iwata, Yoshihiro Ito, Yoshiaki Morishita, Motomitsu Goto, Hidetaka Suga, Ryoichi Banno, Atsushi Enomoto, Masahide Takahashi, Hiroshi Arima, Yoshihisa Sugimura

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Abstract

Autoimmune hypophysitis (AH) is thought to be an autoimmune disease characterized by lymphocytic infiltration of the pituitary gland. Among AH pathologies, lymphocytic infundibulo-neurohypophysitis (LINH) involves infiltration of the neurohypophysis and/or the hypothalamic infundibulum, causing central diabetes insipidus resulting from insufficiency of arginine vasopressin secretion. The pathophysiological and pathogenetic mechanisms underlying LINH are largely unknown. Clinically, differentiating LINH from other pituitary diseases accompanied by mass lesions, including tumours, has often been difficult, because of similar clinical manifestations. We recently reported that rabphilin-3A is an autoantigen and that anti-rabphilin-3A antibodies constitute a possible diagnostic marker for LINH. However, the involvement of rabphilin-3A in the pathogenesis of LINH remains to be elucidated. This study was undertaken to explore the role of rabphilin-3A in lymphocytic neurohypophysitis and to investigate the mechanism. We found that immunization of mice with rabphilin-3A led to neurohypophysitis. Lymphocytic infiltration was observed in the neurohypophysis and supraoptic nucleus 1 month after the first immunization. Mice immunized with rabphilin-3A showed an increase in the volume of urine that was hypotonic as compared with control mice. Administration of a cocktail of monoclonal anti-rabphilin-3A antibodies did not induce neurohypophysitis. However, abatacept, which is a chimeric protein that suppresses T-cell activation, decreased the number of T cells specific for rabphilin-3A in peripheral blood mononuclear cells (PBMCs). It ameliorated lymphocytic infiltration of CD3+ T cells in the neurohypophysis of mice that had been immunized with rabphilin-3A. Additionally, there was a linear association between the number of T cells specific for rabphilin-3A in PBMCs and the number of CD3+ T cells infiltrating the neurohypophysis. In conclusion, we suggest that rabphilin-3A is a pathogenic antigen, and that T cells specific for rabphilin-3A are involved in the pathogenesis of neurohypophysitis in mice.

Original languageEnglish
Pages (from-to)469-478
Number of pages10
JournalJournal of Pathology
Volume244
Issue number4
DOIs
Publication statusPublished - 01-04-2018

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Posterior Pituitary Gland
T-Lymphocytes
Pituitary Gland
rabphilin-3A
Immunization
Neurogenic Diabetes Insipidus
Pituitary Diseases
Supraoptic Nucleus
Blood Cell Count
Antibodies
Arginine Vasopressin
Autoantigens
Autoimmune Diseases
Blood Cells
Urine
Pathology
Antigens
Neoplasms
Proteins
Autoimmune Hypophysitis

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine

Cite this

Yasuda, Yoshinori ; Iwama, Shintaro ; Kiyota, Atsushi ; Izumida, Hisakazu ; Nakashima, Kohtaro ; Iwata, Naoko ; Ito, Yoshihiro ; Morishita, Yoshiaki ; Goto, Motomitsu ; Suga, Hidetaka ; Banno, Ryoichi ; Enomoto, Atsushi ; Takahashi, Masahide ; Arima, Hiroshi ; Sugimura, Yoshihisa. / Critical role of rabphilin-3A in the pathophysiology of experimental lymphocytic neurohypophysitis. In: Journal of Pathology. 2018 ; Vol. 244, No. 4. pp. 469-478.
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abstract = "Autoimmune hypophysitis (AH) is thought to be an autoimmune disease characterized by lymphocytic infiltration of the pituitary gland. Among AH pathologies, lymphocytic infundibulo-neurohypophysitis (LINH) involves infiltration of the neurohypophysis and/or the hypothalamic infundibulum, causing central diabetes insipidus resulting from insufficiency of arginine vasopressin secretion. The pathophysiological and pathogenetic mechanisms underlying LINH are largely unknown. Clinically, differentiating LINH from other pituitary diseases accompanied by mass lesions, including tumours, has often been difficult, because of similar clinical manifestations. We recently reported that rabphilin-3A is an autoantigen and that anti-rabphilin-3A antibodies constitute a possible diagnostic marker for LINH. However, the involvement of rabphilin-3A in the pathogenesis of LINH remains to be elucidated. This study was undertaken to explore the role of rabphilin-3A in lymphocytic neurohypophysitis and to investigate the mechanism. We found that immunization of mice with rabphilin-3A led to neurohypophysitis. Lymphocytic infiltration was observed in the neurohypophysis and supraoptic nucleus 1 month after the first immunization. Mice immunized with rabphilin-3A showed an increase in the volume of urine that was hypotonic as compared with control mice. Administration of a cocktail of monoclonal anti-rabphilin-3A antibodies did not induce neurohypophysitis. However, abatacept, which is a chimeric protein that suppresses T-cell activation, decreased the number of T cells specific for rabphilin-3A in peripheral blood mononuclear cells (PBMCs). It ameliorated lymphocytic infiltration of CD3+ T cells in the neurohypophysis of mice that had been immunized with rabphilin-3A. Additionally, there was a linear association between the number of T cells specific for rabphilin-3A in PBMCs and the number of CD3+ T cells infiltrating the neurohypophysis. In conclusion, we suggest that rabphilin-3A is a pathogenic antigen, and that T cells specific for rabphilin-3A are involved in the pathogenesis of neurohypophysitis in mice.",
author = "Yoshinori Yasuda and Shintaro Iwama and Atsushi Kiyota and Hisakazu Izumida and Kohtaro Nakashima and Naoko Iwata and Yoshihiro Ito and Yoshiaki Morishita and Motomitsu Goto and Hidetaka Suga and Ryoichi Banno and Atsushi Enomoto and Masahide Takahashi and Hiroshi Arima and Yoshihisa Sugimura",
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Yasuda, Y, Iwama, S, Kiyota, A, Izumida, H, Nakashima, K, Iwata, N, Ito, Y, Morishita, Y, Goto, M, Suga, H, Banno, R, Enomoto, A, Takahashi, M, Arima, H & Sugimura, Y 2018, 'Critical role of rabphilin-3A in the pathophysiology of experimental lymphocytic neurohypophysitis', Journal of Pathology, vol. 244, no. 4, pp. 469-478. https://doi.org/10.1002/path.5046

Critical role of rabphilin-3A in the pathophysiology of experimental lymphocytic neurohypophysitis. / Yasuda, Yoshinori; Iwama, Shintaro; Kiyota, Atsushi; Izumida, Hisakazu; Nakashima, Kohtaro; Iwata, Naoko; Ito, Yoshihiro; Morishita, Yoshiaki; Goto, Motomitsu; Suga, Hidetaka; Banno, Ryoichi; Enomoto, Atsushi; Takahashi, Masahide; Arima, Hiroshi; Sugimura, Yoshihisa.

In: Journal of Pathology, Vol. 244, No. 4, 01.04.2018, p. 469-478.

Research output: Contribution to journalArticle

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T1 - Critical role of rabphilin-3A in the pathophysiology of experimental lymphocytic neurohypophysitis

AU - Yasuda, Yoshinori

AU - Iwama, Shintaro

AU - Kiyota, Atsushi

AU - Izumida, Hisakazu

AU - Nakashima, Kohtaro

AU - Iwata, Naoko

AU - Ito, Yoshihiro

AU - Morishita, Yoshiaki

AU - Goto, Motomitsu

AU - Suga, Hidetaka

AU - Banno, Ryoichi

AU - Enomoto, Atsushi

AU - Takahashi, Masahide

AU - Arima, Hiroshi

AU - Sugimura, Yoshihisa

PY - 2018/4/1

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N2 - Autoimmune hypophysitis (AH) is thought to be an autoimmune disease characterized by lymphocytic infiltration of the pituitary gland. Among AH pathologies, lymphocytic infundibulo-neurohypophysitis (LINH) involves infiltration of the neurohypophysis and/or the hypothalamic infundibulum, causing central diabetes insipidus resulting from insufficiency of arginine vasopressin secretion. The pathophysiological and pathogenetic mechanisms underlying LINH are largely unknown. Clinically, differentiating LINH from other pituitary diseases accompanied by mass lesions, including tumours, has often been difficult, because of similar clinical manifestations. We recently reported that rabphilin-3A is an autoantigen and that anti-rabphilin-3A antibodies constitute a possible diagnostic marker for LINH. However, the involvement of rabphilin-3A in the pathogenesis of LINH remains to be elucidated. This study was undertaken to explore the role of rabphilin-3A in lymphocytic neurohypophysitis and to investigate the mechanism. We found that immunization of mice with rabphilin-3A led to neurohypophysitis. Lymphocytic infiltration was observed in the neurohypophysis and supraoptic nucleus 1 month after the first immunization. Mice immunized with rabphilin-3A showed an increase in the volume of urine that was hypotonic as compared with control mice. Administration of a cocktail of monoclonal anti-rabphilin-3A antibodies did not induce neurohypophysitis. However, abatacept, which is a chimeric protein that suppresses T-cell activation, decreased the number of T cells specific for rabphilin-3A in peripheral blood mononuclear cells (PBMCs). It ameliorated lymphocytic infiltration of CD3+ T cells in the neurohypophysis of mice that had been immunized with rabphilin-3A. Additionally, there was a linear association between the number of T cells specific for rabphilin-3A in PBMCs and the number of CD3+ T cells infiltrating the neurohypophysis. In conclusion, we suggest that rabphilin-3A is a pathogenic antigen, and that T cells specific for rabphilin-3A are involved in the pathogenesis of neurohypophysitis in mice.

AB - Autoimmune hypophysitis (AH) is thought to be an autoimmune disease characterized by lymphocytic infiltration of the pituitary gland. Among AH pathologies, lymphocytic infundibulo-neurohypophysitis (LINH) involves infiltration of the neurohypophysis and/or the hypothalamic infundibulum, causing central diabetes insipidus resulting from insufficiency of arginine vasopressin secretion. The pathophysiological and pathogenetic mechanisms underlying LINH are largely unknown. Clinically, differentiating LINH from other pituitary diseases accompanied by mass lesions, including tumours, has often been difficult, because of similar clinical manifestations. We recently reported that rabphilin-3A is an autoantigen and that anti-rabphilin-3A antibodies constitute a possible diagnostic marker for LINH. However, the involvement of rabphilin-3A in the pathogenesis of LINH remains to be elucidated. This study was undertaken to explore the role of rabphilin-3A in lymphocytic neurohypophysitis and to investigate the mechanism. We found that immunization of mice with rabphilin-3A led to neurohypophysitis. Lymphocytic infiltration was observed in the neurohypophysis and supraoptic nucleus 1 month after the first immunization. Mice immunized with rabphilin-3A showed an increase in the volume of urine that was hypotonic as compared with control mice. Administration of a cocktail of monoclonal anti-rabphilin-3A antibodies did not induce neurohypophysitis. However, abatacept, which is a chimeric protein that suppresses T-cell activation, decreased the number of T cells specific for rabphilin-3A in peripheral blood mononuclear cells (PBMCs). It ameliorated lymphocytic infiltration of CD3+ T cells in the neurohypophysis of mice that had been immunized with rabphilin-3A. Additionally, there was a linear association between the number of T cells specific for rabphilin-3A in PBMCs and the number of CD3+ T cells infiltrating the neurohypophysis. In conclusion, we suggest that rabphilin-3A is a pathogenic antigen, and that T cells specific for rabphilin-3A are involved in the pathogenesis of neurohypophysitis in mice.

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