1. A novel model for treatment of hypertrophic pachymeningitis
- Author
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Takayuki Fujii, Yiwen Cui, Sachiko Koyama, Mitsuhiro Kawano, Xu Zhang, Ryo Yamasaki, Takuya Matsushita, Hinako Eto, Hiroo Yamaguchi, Hidenori Ogata, Kazunori Yamada, Marie Malissen, Mari Yoshida, Jun Ichi Kira, Fuminori Hyodo, Bernard Malissen, Shotaro Hayashida, Kyoko Iinuma, Katsuhisa Masaki, Tomomi Yonekawa, Sichuan University [Chengdu] (SCU), institute for pheromone research, Indiana University [Bloomington], Indiana University System-Indiana University System, Department of Molecular Biosciences [Lawrence], University of Kansas [Lawrence] (KU), Kanazawa University (KU), Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)
- Subjects
0301 basic medicine ,Pathology ,medicine.medical_specialty ,CD3 ,Dura mater ,Linker for Activation of T cells ,Inflammation ,Mice, Transgenic ,Smad2 Protein ,Transforming Growth Factor beta1 ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Downregulation and upregulation ,Fibrosis ,Medicine ,Animals ,Humans ,Meningitis ,Smad3 Protein ,Phosphorylation ,Receptor ,Research Articles ,Adaptor Proteins, Signal Transducing ,biology ,integumentary system ,business.industry ,General Neuroscience ,Membrane Proteins ,Hypertrophy ,Irbesartan ,medicine.disease ,3. Good health ,030104 developmental biology ,medicine.anatomical_structure ,Models, Animal ,biology.protein ,[SDV.IMM]Life Sciences [q-bio]/Immunology ,Neurology (clinical) ,Dura Mater ,Antibody ,medicine.symptom ,business ,030217 neurology & neurosurgery ,Signal Transduction ,Research Article - 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)-beta 1 was produced preferentially in B cells and macrophages while TGF-beta receptor I (TGF-beta RI) was markedly upregulated on fibroblasts. Quantitative western blotting revealed significant upregulation of TGF-beta 1, TGF-beta RI, and phosphorylated SMAD2/SMAD3 in dura of LATY136F mice aged 13 weeks. A similar upregulation of TGF-beta RI, 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-beta 1 and nonphosphorylated and phosphorylated SMAD2/SMAD3. Interpretation TGF-beta 1/SMAD2/SMAD3 pathway is critical in HP and is a potential novel therapeutic target.
- Published
- 2019
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