Department of Neurology Neurological Institute Graduate School of Medical Sciences Kyushu University Fukuoka Japan.
Innovation Center for Medical Redox Navigation Kyushu University Fukuoka Japan.
Ann Clin Transl Neurol. 2019 Jan 15;6(3):431-444. doi: 10.1002/acn3.715. eCollection 2019 Mar.
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.
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.
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)-1 was produced preferentially in B cells and macrophages while TGF-β receptor I (TGF- RI) was markedly upregulated on fibroblasts. Quantitative western blotting revealed significant upregulation of TGF-1, TGF- RI, and phosphorylated SMAD2/SMAD3 in dura of LATY136F mice aged 13 weeks. A similar upregulation of TGF- 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-β1 and nonphosphorylated and phosphorylated SMAD2/SMAD3.
TGF-1/SMAD2/SMAD3 pathway is critical in HP and is a potential novel therapeutic target.
免疫球蛋白（Ig）G4 相关疾病是肥厚性脑脊膜炎（HP）的主要病因，表现为硬脑膜进行性增厚。目前缺乏用于确定其潜在机制的 HP 动物模型。我们为此开发了一种适合治疗 HP 的动物模型。
我们对 T 细胞激活连接蛋白（LAT）中的 Y136F 突变（Y136F）小鼠进行了纵向评估，该突变诱导 2 型辅助性 T 细胞（Th2）增殖和 IgG1（IgG4 人等效物）过度表达。从小鼠 3 周到 6 周龄时，每天给予口服厄贝沙坦治疗。我们还对人类 IgG4 相关、抗中性粒细胞胞质抗体相关和特发性 HP 硬脑膜进行了免疫组织化学检查。
在磁共振成像上显示硬脑膜钆增强的 LATY136F 小鼠在 3 周龄时硬脑膜中就有大量 B220+B 细胞、IgG1 细胞、CD138 浆细胞、CD3 T 细胞、F4/80 巨噬细胞和多形核白细胞浸润，随后出现明显的纤维化增厚。在硬脑膜病变中，转化生长因子（TGF）-1 优先在 B 细胞和巨噬细胞中产生，而 TGF-β 受体 I（TGF-RI）在成纤维细胞中显著上调。定量 Western 印迹显示，13 周龄 LATY136F 小鼠硬脑膜中 TGF-1、TGF-RI 和磷酸化 SMAD2/SMAD3 显著上调。所有三种类型的人类 HP 尸检硬脑膜中均存在 TGF-RI、SMAD2/SMAD3 和磷酸化 SMAD2/SMAD3 的类似上调。厄贝沙坦消除了所有经治疗的 LATY136F 小鼠的硬脑膜炎症细胞浸润和纤维化增厚，同时降低了 TGF-β1 和非磷酸化及磷酸化 SMAD2/SMAD3。
TGF-1/SMAD2/SMAD3 通路在 HP 中至关重要，是一种潜在的新型治疗靶点。
