A novel model for treatment of hypertrophic pachymeningitis

Cui, Yiwen; Kitajima, Masaki; Zhang, Xu; Yamasaki, Ryo; Fujii, Takayuki; Ogata, Hidenori; Hayashida, Shinsaku; Yamaguchi, Hideyo; Hyodo, Fuminori; Eto, Hiroyuki; Koyama, Sachiko; Iinuma, K.; Yonekawa, Tomomi; Matsushita, Takuya; Yoshida, Mari; Yamada, Kazunori; Kawano, Mitsuhiro; Malissen, Bernard; Kira, Jun‐ichi

doi:10.1002/acn3.715

Cited by 14 publications

(8 citation statements)

References 39 publications

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“…Overall, IgG4-related hypertrophic pachymeningitis is a rare disorder that has been diagnosed more frequently in Japan [ 12 , 14 ]. Differential diagnoses, in particular in cases with tumor-like intracranial manifestations, include lymphoma, sarcoidosis, and other immunological or infectious granulomatous diseases [ 3 , 20 ]. From a clinical point of view, the diagnosis should be based on radiological and laboratory findings as well as on the effectiveness of corticosteroid or immunosuppressive therapy [ 2 , 12 ].…”

Section: Discussionmentioning

confidence: 99%

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IgG4-related hypertrophic pachymeningitis with tumor-like intracranial and intracerebral lesions

et al. 2022

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Objective IgG4-related hypertrophic pachymeningitis is a rare fibroinflammatory disorder that may cause localized or diffused thickening of the dura mater. Misinterpretations of the clinical and imaging findings are common. Clinical manifestations depend on the location of the inflammatory lesion and on compression of neural structures leading to functional deficits. A dural biopsy is commonly needed for a definitive diagnosis. Immunomodulatory therapy is considered the therapy of choice. Methods Four patients with IgG4-related hypertrophic pachymeningitis were identified over a 5-year period. Patient-related characteristics including age, preoperative workup, signs and symptoms of patients, and diagnostic procedures were evaluated. Furthermore, the surgical treatment and 5-year follow-up outcomes were analyzed. Results There were two adults and two adolescents (mean age 32 years; range 15 to 67 years). Two patients were male, and two were female. No history of disease was known in any of the patients. Clinical symptoms were epilepsy (n = 2), ataxia and nausea (n = 1), and facial nerve palsy (n = 1). MR imaging studies showed contrast enhancing lesions in the temporal region in two patients, and in the cerebellar region in the other two patients. Subtotal resection was performed in two instances and a biopsy via a suboccipital retrosigmoid approach was obtained in the other two patients. Histochemical and immunohistochemical investigations revealed an IgG 4 disease in all of these patients. Immunomodulatorry therapy led to clinical stability during follow-up of 5 years in all four cases. Conclusion The diagnosis of IgG4-related hypertrophic pachymeningitis is challenging, but is of great relevance as treatment differs significantly from other forms of pachymeningitis and a specific therapeutic approach may avoid long-term neurological complications. Our series contributes to a better clinical characterization of this rare disease.

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Section: Discussionmentioning

confidence: 99%

“…It manifests as localized or diffused thickening of the dura mater [ 23 , 27 ]. Clinical manifestations depend on the location of the inflammatory lesion and on compression of neural structures leading to functional deficits [ 3 , 5 ]. A dural biopsy is commonly needed to establish a definite diagnosis [ 2 , 30 ].…”

Section: Introductionmentioning

confidence: 99%

IgG4-related hypertrophic pachymeningitis with tumor-like intracranial and intracerebral lesions

et al. 2022

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“…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%

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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“…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 [ 11 ]. In recent years, some reports showed that the LAT mouse could be an animal model of IgG4-RD [ 12 , 13 ]. LAT mice showed IgG1-positive plasmacyte infiltration and fibrosis in some organs, including the SGs, as well as elevated Th2 cytokine and serum IgG1 [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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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), suggesting 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 (analog 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/3 T3) 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/3 T3. 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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A novel model for treatment of hypertrophic pachymeningitis

Cited by 14 publications

References 39 publications

IgG4-related hypertrophic pachymeningitis with tumor-like intracranial and intracerebral lesions

IgG4-related hypertrophic pachymeningitis with tumor-like intracranial and intracerebral lesions

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

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