LatY136F knock-in mouse model for human IgG4-related disease

Yamada, Kazunori; Zuka, Masahiko; Ito, Kiyoaki; Mizuguchi, Keishi; Kakuchi, Yasushi; Onoe, Tamehito; Suzuki, Yasunori; Yamagishi, Masakazu; Izui, Shozo; Malissen, Bernard; Kawano, Mitsuhiro

doi:10.1371/journal.pone.0198417

Cited by 20 publications

(20 citation statements)

References 38 publications

(47 reference statements)

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“…Lung lesions of LAT Y136F knock-in mice also had characteristic pathological findings of IgG4-RLD. This was similar to the findings previously described in other organs such as salivary glands, pancreas, and kidney in LAT Y136F knock-in mice [ 23 ], indicating that lung lesions in LAT Y136F knock-in mice are also very similar to IgG4-RD.…”

Section: Discussionsupporting

confidence: 91%

“…Several animal models of IgG4-RD have been reported [ 19 – 22 ]. Our previous study using LAT Y136F knock-in mice examined lesions in the pancreas, salivary glands, and kidneys, as well as dural lesions [ 23 ]. Here, we further investigated whether these mice could also constitute appropriate models of lung lesions in IgG4-RD.…”

Section: Discussionmentioning

confidence: 99%

“…Several animal models of IgG4-RD have been established [ 19 – 22 ]. We first reported that LAT Y136F knock-in mice display several immunopathological features characteristic of IgG4-RD in organs such as salivary glands, pancreas, and kidney, as well as dural lesions in which many IgG1-positive cells and fibrosis are present [ 23 , 24 ].…”

Section: Introductionmentioning

confidence: 99%

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The pronounced lung lesions developing in LATY136F knock-in mice mimic human IgG4-related lung disease

Waseda¹,

Yamada²,

Mizuguchi³

et al. 2021

PLoS ONE

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Rationale Immunoglobulin (Ig) G4-related disease (IgG4-RD) is a novel clinical disease entity characterized by an elevated serum IgG4 concentration and tumefaction or tissue infiltration by IgG4-positive plasma cells. Pathological changes are most frequently seen in the pancreas, lacrimal glands, and salivary glands, but pathological changes in the lung also exist. Linker for activation of T cell (LAT)Y136F knock-in mice show Th2-dominant immunoreactions with elevated serum IgG1 levels, corresponding to human IgG4. We have reported that LATY136F knock-in mice display several characteristic features of IgG4-RD and concluded that they constitute an appropriate model of human IgG4-RD in salivary glands, pancreas, and kidney lesions. Objectives The aim of this study is to evaluate whether lung lesions in LATY136F knock-in mice can be a model of IgG4-related lung disease. Methods Lung tissue samples from LATY136F knock-in mice (LAT) and wild-type mice (WT) were immunostained for IgG1 and obtained for pathological evaluation, and cell fractions and cytokine levels in broncho-alveolar lavage fluid (BALF) were analyzed. Results In the LAT group, IgG1-positive inflammatory cells increased starting at 4 weeks of age and peaked at 10 weeks of age. The total cell count and percentage of lymphocytes increased significantly in BALF in the LAT group compared to the WT group. In BALF, Th2-dominant cytokines and transforming growth factor-β were also increased. In the LAT group, marked inflammation around broncho-vascular bundles peaked at 10 weeks of age. After 10 weeks, fibrosis around broncho-vascular bundles and bronchiectasis were observed in LATY136F knock-in mice but not WT mice. Conclusions LATY136F knock-in mice constitute an appropriate model of lung lesions in IgG4-RD.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The pronounced lung lesions developing in LATY136F knock-in mice mimic human IgG4-related lung disease

Waseda¹,

Yamada²,

Mizuguchi³

et al. 2021

PLoS ONE

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“…The linker for activation of T cells (LAT) Y136F knockin mouse (LAT mouse) has been reported as a mouse with elevated type-2 T-helper (Th2) cytokine and serum IgG1 (human IgG4-equivalent) levels [10]. In recent years, some reports showed that the LAT mouse could be an animal model of IgG4-RD [11,12]. LAT mice showed IgG1-positive plasmacyte in ltration and brosis in some organs, including the SGs, as well as elevated Th2 cytokine and serum IgG1 [11].…”

Section: Introductionmentioning

confidence: 99%

Pathogenic roles and therapeutic potential of the CCL8–CCR8 axis in a murine model of IgG4-related sialadenitis

Honda

Tsuboi

Ono

et al. 2021

Preprint

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Background Our previous studies reveal that CCL18-CCR8 chemokine axis is upregulated in patients of immunoglobulin G4-related disease (IgG4-RD), suggest that the CCL18–CCR8 axis is implicated in the etiology of IgG4-RD. Although, whether this axis has a potential as a therapeutic target remains unclear. Our purpose was to clarify the pathogenic roles and therapeutic potential of the murine CCL8 (analogue of human CCL18)–CCR8 axis by using an animal model of IgG4-RD (LAT Y136F knockin mice; LAT mice).Methods We compared the infiltration of inflammatory cells and the fibrosis of the salivary glands of 6-week-old LAT mice and littermate mice. The expressions of Ccl8 and Ccr8 were also compared. Next, we investigated the therapeutic effects of intravenous administration of anti-CCL8 neutralizing antibody in LAT mice against inflammation and fibrosis of the salivary glands. We also investigated the effects of stimulation with recombinant mouse CCL8 on the collagen production in a mouse fibroblast cell line (NIH/3T3) in vitro.Results When compared with the littermates, the LAT mice showed apparent infiltration of inflammatory cells, and fibrosis in the salivary glands. The focus and fibrosis score in the salivary glands were significantly higher in the LAT mice than in the littermates. The expression levels of Ccl8 in the spleen and of Ccr8 in the salivary glands were significantly higher in the LAT mice than in the littermates. Anti-CCL8 antibody significantly improved the focus and fibrosis score in the salivary glands of the LAT mice. In vitro, stimulation with recombinant mouse CCL8 significantly increased the expression of collagen and ERK1/2 phosphorylation in NIH/3T3.Conclusion We clarified the overexpression and therapeutic potential of the mouse CCL8–CCR8 axis in LAT mice, which could play a crucial role in fibrosis via ERK1/2 phosphorylation, as well as the chemotaxis of inflammatory cells. The human CCL18–CCR8 axis might be a novel therapeutic target for IgG4-RD.

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“…In the present study, we established a novel animal model of HP using IgG4‐related disease model mice with a mutation (Y136F) in the linker for activation of T cells (LAT) to investigate therapeutic targets . LAT controls the development and function of T cells by assembling a multiprotein complex following tyrosine phosphorylation .…”

Section: Introductionmentioning

confidence: 99%

A novel model for treatment of hypertrophic pachymeningitis

Cui

Kitajima

Zhang

et al. 2019

Ann Clin Transl Neurol

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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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LatY136F knock-in mouse model for human IgG4-related disease

Cited by 20 publications

References 38 publications

The pronounced lung lesions developing in LATY136F knock-in mice mimic human IgG4-related lung disease

The pronounced lung lesions developing in LATY136F knock-in mice mimic human IgG4-related lung disease

Pathogenic roles and therapeutic potential of the CCL8–CCR8 axis in a murine model of IgG4-related sialadenitis

A novel model for treatment of hypertrophic pachymeningitis

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