3 years ago

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

Yoshihisa Sugimura, Masahide Takahashi, Hidetaka Suga, Shintaro Iwama, Yoshinori Yasuda, Hisakazu Izumida, Atsushi Kiyota, Hiroshi Arima, Atsushi Enomoto, Ryoichi Banno, Motomitsu Goto, Naoko Iwata, Kohtaro Nakashima, Yoshiaki Morishita, Yoshihiro Ito
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) represents infiltration of the neurohypophysis and/or the hypothalamic infundibulum, causing central diabetes insipidus due to insufficiency of arginine vasopressin (AVP) secretion. The pathophysiological and pathogenetic mechanisms underlying LINH are largely unknown. Clinically, differentiating LINH from other pituitary diseases accompanied by mass lesions, including tumors, has been often difficult because of similar clinical manifestations. We recently reported that rabphilin-3A is an autoantigen and that anti-rabphilin-3A antibodies are 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 further to investigate the mechanism. We found that immunization of mice with rabphilin-3A led to neurohypophysitis. The lymphocytic infiltration was observed in the neurohypophysis and supraoptic nucleus (SON) one month after the first immunization. Mice immunized with rabphilin-3A showed an increase in the volume of urine that was hypotonic 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 into 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.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1002/path.5046

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