A novel model for treatment of hypertrophic pachymeningitis

• Published in: Annals of clinical and translational neurology Vol. 6; no. 3; pp. 431 - 444
• Main Authors: 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, Junichi
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.03.2019; Wiley; John Wiley and Sons Inc
• Subjects: Adaptor Proteins, Signal Transducing - deficiency; Animals; Cytokines; Disease; Dura Mater - drug effects; Dura Mater - immunology; Dura Mater - pathology; Fibrosis; Grants; Human subjects; Humans; Hypertrophy; Immunoglobulins; Immunology; Inflammation; Irbesartan - pharmacology; Laboratory animals; Life Sciences; Lymphocytes; Medical research; Membrane Proteins - deficiency; Meningitis - drug therapy; Meningitis - metabolism; Meningitis - physiopathology; Mice; Mice, Transgenic; Models, Animal; Pharmaceuticals; Phosphorylation; Rodents; Science; Signal Transduction; Smad2 Protein - metabolism; Smad3 Protein - metabolism; Spinal cord; Transforming Growth Factor beta1 - metabolism; Japan
• ISSN: 2328-9503; 2328-9503
• DOI: 10.1002/acn3.715

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.