A novel model for treatment of hypertrophic pachymeningitis

Yiwen Cui, Katsuhisa Masaki, Xu Zhang, Ryo Yamasaki, Takayuki Fujii, Hidenori Ogata, Shotaro Hayashida, Hiroo Yamaguchi, Fuminori Hyodo, Hinako Eto, Sachiko Koyama, Kyoko Iinuma, Tomomi Yonekawa, Takuya Matsushita, Mari Yoshida, Kazunori Yamada, Mitsuhiro Kawano, Marie Malissen, Bernard Malissen, Jun-Ichi Kira

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Abstract

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.

Original languageEnglish
Pages (from-to)431-444
Number of pages14
JournalAnnals of Clinical and Translational Neurology
Volume6
Issue number3
DOIs
Publication statusPublished - Mar 1 2019

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Transforming Growth Factors
Meningitis
irbesartan
Immunoglobulin G
B-Lymphocytes
Up-Regulation
Animal Models
Macrophages
T-Lymphocytes
Dura Mater
Antineutrophil Cytoplasmic Antibodies
Th2 Cells
Critical Pathways
Growth Factor Receptors
Gadolinium
Helper-Inducer T-Lymphocytes
Plasma Cells
Immunoglobulins
Neutrophils
Fibroblasts

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Clinical Neurology

Cite this

A novel model for treatment of hypertrophic pachymeningitis. / Cui, Yiwen; Masaki, Katsuhisa; Zhang, Xu; Yamasaki, Ryo; Fujii, Takayuki; Ogata, Hidenori; Hayashida, Shotaro; Yamaguchi, Hiroo; Hyodo, Fuminori; Eto, Hinako; Koyama, Sachiko; Iinuma, Kyoko; Yonekawa, Tomomi; Matsushita, Takuya; Yoshida, Mari; Yamada, Kazunori; Kawano, Mitsuhiro; Malissen, Marie; Malissen, Bernard; Kira, Jun-Ichi.

In: Annals of Clinical and Translational Neurology, Vol. 6, No. 3, 01.03.2019, p. 431-444.

Research output: Contribution to journalArticle

Cui, Y, Masaki, K, Zhang, X, Yamasaki, R, Fujii, T, Ogata, H, Hayashida, S, Yamaguchi, H, Hyodo, F, Eto, H, Koyama, S, Iinuma, K, Yonekawa, T, Matsushita, T, Yoshida, M, Yamada, K, Kawano, M, Malissen, M, Malissen, B & Kira, J-I 2019, 'A novel model for treatment of hypertrophic pachymeningitis', Annals of Clinical and Translational Neurology, vol. 6, no. 3, pp. 431-444. https://doi.org/10.1002/acn3.715
Cui, Yiwen ; Masaki, Katsuhisa ; Zhang, Xu ; Yamasaki, Ryo ; Fujii, Takayuki ; Ogata, Hidenori ; Hayashida, Shotaro ; Yamaguchi, Hiroo ; Hyodo, Fuminori ; Eto, Hinako ; Koyama, Sachiko ; Iinuma, Kyoko ; Yonekawa, Tomomi ; Matsushita, Takuya ; Yoshida, Mari ; Yamada, Kazunori ; Kawano, Mitsuhiro ; Malissen, Marie ; Malissen, Bernard ; Kira, Jun-Ichi. / A novel model for treatment of hypertrophic pachymeningitis. In: Annals of Clinical and Translational Neurology. 2019 ; Vol. 6, No. 3. pp. 431-444.
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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, Jun-Ichi

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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.

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