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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