TY - JOUR
T1 - A novel model for treatment of hypertrophic pachymeningitis
AU - Cui, Yiwen
AU - Masaki, Katsuhisa
AU - Zhang, Xu
AU - Yamasaki, Ryo
AU - Fujii, Takayuki
AU - Ogata, Hidenori
AU - Hayashida, Shotaro
AU - Yamaguchi, Hiroo
AU - Hyodo, Fuminori
AU - Eto, Hinako
AU - Koyama, Sachiko
AU - Iinuma, Kyoko
AU - Yonekawa, Tomomi
AU - Matsushita, Takuya
AU - Yoshida, Mari
AU - Yamada, Kazunori
AU - Kawano, Mitsuhiro
AU - Malissen, Marie
AU - Malissen, Bernard
AU - Kira, Junichi
N1 - Funding Information:
We thank Mr. Takaaki Kanemaru, Department of Morphology Core Unit, Kyushu University, for his technical assistance. We thank J. Ludovic Croxford, PhD, from Edanz Group (www.edanzediting.com/ac) for editing a draft of this manuscript. This study was supported in part by a Health and Labour Sciences Research Grant on Intractable Diseases (H26-Nanchitou (Nan)-Ippan-074) from the Ministry of Health, Labour and Welfare, Japan (J.K.); the Practical Research Project for Rare/Intractable Diseases from the Japan Agency for Medical Research and Development (AMED) (J.K.); a “Glial assembly” Grant-in-Aid for Scientific Research on Innovative Areas (MEXT KAKENHI Grant Numbers 25117001 and 25117012) from the Ministry of Education, Culture, Sports, Science and Technology of Japan (J.K.); JSPS KAKENHI Grants-in-Aid for Scientific Research (A) (Grant Number 16H02657) (J.K.), (C) (Grant Number 16K09694) (R.Y.), and (C) (Grant Number 26461295) (K.M.) from the Japan Society for the Promotion of Science, and CNRS and INSERM (B.M. and M.M.).
Funding Information:
This study was supported in part by a Health and Labour Sciences Research Grant on Intractable Diseases (H26-Nanchitou (Nan)-Ippan-074) from the Ministry of Health, Labour and Welfare, Japan (J.K.); the Practical Research Project for Rare/Intractable Diseases from the Japan Agency for Medical Research and Development (AMED) (J.K.); a “Glial assembly” Grant-in-Aid for Scientific Research on Innovative Areas (MEXT KAKENHI Grant Numbers 25117001 and 25117012) from the Ministry of Education, Culture, Sports, Science and Technology of Japan (J.K.); JSPS KAKENHI Grants-in-Aid for Scientific Research (A) (Grant Number 16H02657) (J.K.), (C) (Grant Number 16K09694) (R.Y.), and (C) (Grant Number 26461295) (K.M.) from the Japan Society for the Promotion of Science, and CNRS and INSERM (B.M. and M.M.).
Publisher Copyright:
© 2019 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.
PY - 2019/3
Y1 - 2019/3
N2 - Objective: Immunoglobulin (Ig)G4-related disease is a major cause of hypertrophic pachymeningitis (HP), presenting as a progressive thickening of the dura mater. HP lacks an animal model to determine its underlying mechanisms. We developed a suitable animal model for the treatment of HP. Methods: We longitudinally evaluated dura in mice with a mutation (Y136F) in the linker for activation of T cells (LAT), which induced type 2 T helper (Th2) cell proliferation and IgG1 (IgG4 human equivalent) overexpression. Mice were therapeutically administered daily oral irbesartan from 3 to 6 weeks of age. Human IgG4-related, anti-neutrophil cytoplasmic antibody-related, and idiopathic HP dura were also immunohistochemically examined. Results: LATY136F mice showing dural gadolinium enhancement on magnetic resonance imaging had massive infiltration of B220+ B cells, IgG1+ cells, CD138+ plasma cells, CD3+ T cells, F4/80+ macrophages, and polymorphonuclear leukocytes in the dura at 3 weeks of age, followed by marked fibrotic thickening. In dural lesions, transforming growth factor (TGF)-β1 was produced preferentially in B cells and macrophages while TGF-β receptor I (TGF-βRI) was markedly upregulated on fibroblasts. Quantitative western blotting revealed significant upregulation of TGF-β1, TGF-βRI, and phosphorylated SMAD2/SMAD3 in dura of LATY136F mice aged 13 weeks. A similar upregulation of TGF-βRI, SMAD2/SMAD3, and phosphorylated SMAD2/SMAD3 was present in autopsied dura of all three types of human HP. Irbesartan abolished dural inflammatory cell infiltration and fibrotic thickening in all treated LATY136F mice with reduced TGF-β1 and nonphosphorylated and phosphorylated SMAD2/SMAD3. Interpretation: TGF-β1/SMAD2/SMAD3 pathway is critical in HP and is a potential novel therapeutic target.
AB - Objective: Immunoglobulin (Ig)G4-related disease is a major cause of hypertrophic pachymeningitis (HP), presenting as a progressive thickening of the dura mater. HP lacks an animal model to determine its underlying mechanisms. We developed a suitable animal model for the treatment of HP. Methods: We longitudinally evaluated dura in mice with a mutation (Y136F) in the linker for activation of T cells (LAT), which induced type 2 T helper (Th2) cell proliferation and IgG1 (IgG4 human equivalent) overexpression. Mice were therapeutically administered daily oral irbesartan from 3 to 6 weeks of age. Human IgG4-related, anti-neutrophil cytoplasmic antibody-related, and idiopathic HP dura were also immunohistochemically examined. Results: LATY136F mice showing dural gadolinium enhancement on magnetic resonance imaging had massive infiltration of B220+ B cells, IgG1+ cells, CD138+ plasma cells, CD3+ T cells, F4/80+ macrophages, and polymorphonuclear leukocytes in the dura at 3 weeks of age, followed by marked fibrotic thickening. In dural lesions, transforming growth factor (TGF)-β1 was produced preferentially in B cells and macrophages while TGF-β receptor I (TGF-βRI) was markedly upregulated on fibroblasts. Quantitative western blotting revealed significant upregulation of TGF-β1, TGF-βRI, and phosphorylated SMAD2/SMAD3 in dura of LATY136F mice aged 13 weeks. A similar upregulation of TGF-βRI, SMAD2/SMAD3, and phosphorylated SMAD2/SMAD3 was present in autopsied dura of all three types of human HP. Irbesartan abolished dural inflammatory cell infiltration and fibrotic thickening in all treated LATY136F mice with reduced TGF-β1 and nonphosphorylated and phosphorylated SMAD2/SMAD3. Interpretation: TGF-β1/SMAD2/SMAD3 pathway is critical in HP and is a potential novel therapeutic target.
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U2 - 10.1002/acn3.715
DO - 10.1002/acn3.715
M3 - Article
AN - SCOPUS:85061673286
SN - 2328-9503
VL - 6
SP - 431
EP - 444
JO - Annals of Clinical and Translational Neurology
JF - Annals of Clinical and Translational Neurology
IS - 3
ER -
