12 results on '"Keishi Mizuguchi"'
Search Results
2. Case report: Navigating treatment pathways for cardiac intimal sarcoma with PDGFRβ N666K mutation
- Author
-
Akihiro Nishiyama, Shigeki Sato, Hiroyuki Sakaguchi, Hiroshi Kotani, Kaname Yamashita, Koushiro Ohtsubo, Keishi Mizuguchi, Hiroko Ikeda, Kenji Iino, Hirofumi Takemura, and Shinji Takeuchi
- Subjects
intimal sarcoma ,PDGFRβ N666K mutation ,precision oncology ,MDM2 amplification ,CDK4 amplification ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
In the realm of rare cardiac tumors, intimal sarcoma presents a formidable challenge, often requiring innovative treatment approaches. This case report presents a unique instance of primary intimal sarcoma in the left atrium, underscoring the critical role of genomic profiling in guiding treatment. Initial genomic testing unveiled a somatic, active mutation in PDGFRβ (PDGFRβ N666K), accompanied by MDM2 and CDK4 amplifications. This discovery directed the treatment course toward pazopanib, a PDGFRβ inhibitor, following irradiation. The patient’s response was remarkable, with the therapeutic efficacy of pazopanib lasting for 16.3 months. However, the patient experienced a recurrence in the left atrium, where subsequent genomic analysis revealed the absence of the PDGFRβ N666K mutation and a significant reduction in PDGFRβ expression. This case report illustrates the complexities and evolving nature of cardiac intimal sarcoma treatment, emphasizing the potential of PDGFRβ signaling as a strategic target and highlighting the importance of adapting treatment pathways in response to genetic shifts.
- Published
- 2024
- Full Text
- View/download PDF
3. BMP signaling alters aquaporin-4 expression in the mouse cerebral cortex
- Author
-
Kazuya Morita, Naoyuki Matsumoto, Kengo Saito, Toshihide Hamabe-Horiike, Keishi Mizuguchi, Yohei Shinmyo, and Hiroshi Kawasaki
- Subjects
Medicine ,Science - Abstract
Abstract Aquaporin-4 (AQP4) is a predominant water channel expressed in astrocytes in the mammalian brain. AQP4 is crucial for the regulation of homeostatic water movement across the blood–brain barrier (BBB). Although the molecular mechanisms regulating AQP4 levels in the cerebral cortex under pathological conditions have been intensively investigated, those under normal physiological conditions are not fully understood. Here we demonstrate that AQP4 is selectively expressed in astrocytes in the mouse cerebral cortex during development. BMP signaling was preferentially activated in AQP4-positive astrocytes. Furthermore, activation of BMP signaling by in utero electroporation markedly increased AQP4 levels in the cerebral cortex, and inhibition of BMP signaling strongly suppressed them. These results indicate that BMP signaling alters AQP4 levels in the mouse cerebral cortex during development.
- Published
- 2021
- Full Text
- View/download PDF
4. Tertiary lymphoid tissue in early‐stage IgG4-related tubulointerstitial nephritis incidentally detected with a tumor lesion of the ureteropelvic junction: a case report
- Author
-
Tatsuhito Miyanaga, Keishi Mizuguchi, Satoshi Hara, Takeshi Zoshima, Dai Inoue, Ryo Nishioka, Ichiro Mizushima, Kiyoaki Ito, Hiroshi Fuji, Kazunori Yamada, Yuki Sato, Motoko Yanagita, and Mitsuhiro Kawano
- Subjects
IgG4-related kidney disease ,IgG4-related tubulointerstitial nephritis ,Tertiary lymphoid tissue ,Diseases of the genitourinary system. Urology ,RC870-923 - Abstract
Abstract Background IgG4-related kidney disease causes renal impairment of unknown pathogenesis that may progress to kidney failure. Although ectopic germinal centers contribute to the pathogenesis of the head and neck lesions of IgG4-related disease, the presence of tertiary lymphoid tissue (TLT) containing germinal centers in IgG4-RKD has rarely been reported. Case presentation We report a 72-year-old Japanese man who had IgG4-related tubulointerstitial nephritis (TIN) with TLT formation incidentally detected in a resected kidney with mass lesion of IgG4-related ureteritis in the ureteropelvic junction. During follow-up for past surgical resection of a bladder tumor, renal dysfunction developed and a ureter mass was found in the right ureteropelvic junction, which was treated by nephroureterectomy after chemotherapy. Pathology revealed no malignancy but abundant IgG4-positive cell infiltration, obliterative phlebitis and storiform fibrosis, confirming the diagnosis of IgG4-related ureteritis. In the resected right kidney, lymphoplasmacytes infiltrated the interstitium with focal distribution in the renal subcapsule and around medium vessels without storiform fibrosis, suggesting the very early stage of IgG4-TIN. Lymphocyte aggregates were also detected at these sites and consisted of B, T, and follicular dendritic cells, indicating TLT formation. IgG4-positive cells infiltrated around TLTs. Conclusions Our case suggests that TLT formation is related with the development of IgG4-TIN and our analysis of distribution of TLT have possibility to elucidate IgG4-TIN pathophysiology.
- Published
- 2021
- Full Text
- View/download PDF
5. The pronounced lung lesions developing in LATY136F knock-in mice mimic human IgG4-related lung disease.
- Author
-
Yuko Waseda, Kazunori Yamada, Keishi Mizuguchi, Kiyoaki Ito, Satoshi Watanabe, Masahiko Zuka, Tamotsu Ishizuka, Marie Malissen, Bernard Malissen, Mitsuhiro Kawano, and Shoko Matsui
- Subjects
Medicine ,Science - Abstract
RationaleImmunoglobulin (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.ObjectivesThe aim of this study is to evaluate whether lung lesions in LATY136F knock-in mice can be a model of IgG4-related lung disease.MethodsLung 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.ResultsIn 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.ConclusionsLATY136F knock-in mice constitute an appropriate model of lung lesions in IgG4-RD.
- Published
- 2021
- Full Text
- View/download PDF
6. LatY136F knock-in mouse model for human IgG4-related disease.
- Author
-
Kazunori Yamada, Masahiko Zuka, Kiyoaki Ito, Keishi Mizuguchi, Yasushi Kakuchi, Tamehito Onoe, Yasunori Suzuki, Masakazu Yamagishi, Shozo Izui, Marie Malissen, Bernard Malissen, and Mitsuhiro Kawano
- Subjects
Medicine ,Science - Abstract
BACKGROUND:The adaptor protein Linker for activation of T cell (LAT) is a key signaling hub used by the T cell antigen receptor. Mutant mice expressing loss-of-function mutations affecting LAT and including a mutation in which tyrosine 136 is replaced by a phenylalanine (LatY136F) develop lymphoproliferative disorder involving T helper type 2 effector cells capable of triggering a massive polyclonal B cell activation that leads to hypergammaglobulinemia G1 and E and to non-resolving inflammation and autoimmunity. The purpose of this study was to evaluate whether the phenotypes of LatY136F knock-in mice resemble the immunohistopathological features of immunoglobulin G4-related disease (IgG4-RD). METHODS:LatY136F knock-in mice were sacrificed at 4-20 weeks of age, and pancreas, kidney, salivary gland and lung were obtained. All organs were stained with hematoxylin-eosin and with Azan for estimation of collagen in fibrosis, and the severity scores of inflammation and fibrosis were evaluated. Immunostainings were performed to analyze the types of infiltrating cells. In addition, the effects of corticosteroid treatment on the development of tissue lesions and serum levels of IgG1 were assessed. RESULTS:Tissue lesions characterized by inflammatory mononuclear cell infiltration and fibrosis were detected in pancreas, kidney, and salivary gland starting from 6 weeks of age. Immunostainings showed pronounced infiltration of plasma cells, CD4-positive T cells, and macrophages. Infiltrating plasma cells predominantly expressed IgG1. The extent of inflammation in pancreas and salivary glands was markedly reduced by corticosteroid treatment. CONCLUSIONS:LatY136F knock-in mice displayed increased production of Th2-type IgG1 (a homologue of human IgG4) and developed multiple organ tissue lesions reminiscent of those seen in patients with IgG4-RD. Moreover, the development of these tissue lesions was highly sensitive to corticosteroid treatment like in IgG4-RD. For these reasons we consider the LatY136F knock-in mouse strain to represent a promising model for human IgG4-RD.
- Published
- 2018
- Full Text
- View/download PDF
7. BMP signaling alters aquaporin-4 expression in the mouse cerebral cortex
- Author
-
Kengo Saito, Naoyuki Matsumoto, Kazuya Morita, Yohei Shinmyo, Toshihide Hamabe-Horiike, Hiroshi Kawasaki, and Keishi Mizuguchi
- Subjects
0301 basic medicine ,Science ,Molecular neuroscience ,Article ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Bmp signaling ,medicine ,Animals ,Aquaporin 4 ,Cerebral Cortex ,Multidisciplinary ,Chemistry ,Electroporation ,Development of the nervous system ,Cell biology ,030104 developmental biology ,medicine.anatomical_structure ,In utero ,Cerebral cortex ,Astrocytes ,Bone Morphogenetic Proteins ,Mouse Cerebral Cortex ,Medicine ,sense organs ,030217 neurology & neurosurgery ,Homeostasis ,Signal Transduction - Abstract
Aquaporin-4 (AQP4) is a predominant water channel expressed in astrocytes in the mammalian brain. AQP4 is crucial for the regulation of homeostatic water movement across the blood–brain barrier (BBB). Although the molecular mechanisms regulating AQP4 levels in the cerebral cortex under pathological conditions have been intensively investigated, those under normal physiological conditions are not fully understood. Here we demonstrate that AQP4 is selectively expressed in astrocytes in the mouse cerebral cortex during development. BMP signaling was preferentially activated in AQP4-positive astrocytes. Furthermore, activation of BMP signaling by in utero electroporation markedly increased AQP4 levels in the cerebral cortex, and inhibition of BMP signaling strongly suppressed them. These results indicate that BMP signaling alters AQP4 levels in the mouse cerebral cortex during development.
- Published
- 2021
8. Olfactory dysfunction in LATY136F knock-in mice
- Author
-
Marie Malissen, Fumi Ozaki, Bernard Malissen, Keishi Mizuguchi, Tomokazu Yoshizaki, Kazunori Yamada, Sayaka Yagi-Nakanishi, Satoru Kondo, Mitsuhiro Kawano, Misako Kaneda, Kanazawa University Graduate School of Medical Sciences, 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 Kanazawa Medical University - Division of Hematology and Immunology
- Subjects
Olfactory system ,medicine.medical_specialty ,Taste ,[SDV]Life Sciences [q-bio] ,Cycloheximide ,chemistry.chemical_compound ,Mice ,Olfaction Disorders ,Olfactory Mucosa ,Internal medicine ,Gene knockin ,Olfactory Marker Protein ,medicine ,Animals ,ComputingMilieux_MISCELLANEOUS ,business.industry ,Regeneration (biology) ,General Medicine ,Smell ,Endocrinology ,Behavioral test ,medicine.anatomical_structure ,Otorhinolaryngology ,chemistry ,Immunohistochemistry ,Surgery ,Immunoglobulin G4-Related Disease ,business ,Olfactory epithelium - Abstract
This study examined olfactory dysfunction in LATY136F knock-in mice and its pathogenic mechanism.The olfactory function of LATY136F knock-in mice was assessed by a behavioral test using cycloheximide solution, which has been used as a mice repellant because of its peculiar smell and unpleasant taste. The tests were administered to each group of LATY136F knock-in mice and WT mice at 8, 12, 16, 20, and 24 weeks of age. After the behavioral tests to evaluate olfactory function, the mice were sacrificed for evaluations by immunohistochemistry.Behavioral tests to evaluate olfactory function showed that the LATY136F knock-in mice had a statistically significant level of olfactory dysfunction (P0.05). Histological analysis showed that the thickness of the olfactory epithelium in these mice was thinner than that in the age-matched wild type mice. There was no IgG4-RD like lesion in the olfactory epithelium of LATY136F knock-in mice. Olfactory marker protein and growth-associated protein 43 expressions in the olfactory epithelium of the LATY136F knock-in mice were markedly lesser than those in the wild type mice (P0.05).The present study demonstrated that olfactory disturbances occurred in LATY136F knock-in mice. Furthermore, the mechanism was suggested to be reduced regeneration of the olfactory epithelium.
- Published
- 2022
9. Tertiary lymphoid tissue in early‐stage IgG4-related tubulointerstitial nephritis incidentally detected with a tumor lesion of the ureteropelvic junction: a case report
- Author
-
Kiyoaki Ito, Tatsuhito Miyanaga, Hiroshi Fuji, Takeshi Zoshima, Dai Inoue, Mitsuhiro Kawano, Ryo Nishioka, Motoko Yanagita, Keishi Mizuguchi, Ichiro Mizushima, Yuki Sato, Kazunori Yamada, and Satoshi Hara
- Subjects
Male ,0301 basic medicine ,Nephrology ,Pathology ,medicine.medical_specialty ,Case Report ,Tertiary lymphoid tissue ,lcsh:RC870-923 ,Severity of Illness Index ,Lesion ,03 medical and health sciences ,0302 clinical medicine ,Fibrosis ,Internal medicine ,parasitic diseases ,Humans ,Medicine ,Kidney Pelvis ,Aged ,030203 arthritis & rheumatology ,Incidental Findings ,Kidney ,Follicular dendritic cells ,integumentary system ,Ureteral Neoplasms ,business.industry ,fungi ,Germinal center ,Ureteritis ,medicine.disease ,lcsh:Diseases of the genitourinary system. Urology ,Kidney Neoplasms ,Tertiary Lymphoid Structures ,030104 developmental biology ,medicine.anatomical_structure ,Immunoglobulin G ,IgG4-related kidney disease ,Nephritis, Interstitial ,IgG4-related tubulointerstitial nephritis ,medicine.symptom ,business ,Kidney disease - Abstract
Background IgG4-related kidney disease causes renal impairment of unknown pathogenesis that may progress to kidney failure. Although ectopic germinal centers contribute to the pathogenesis of the head and neck lesions of IgG4-related disease, the presence of tertiary lymphoid tissue (TLT) containing germinal centers in IgG4-RKD has rarely been reported. Case presentation We report a 72-year-old Japanese man who had IgG4-related tubulointerstitial nephritis (TIN) with TLT formation incidentally detected in a resected kidney with mass lesion of IgG4-related ureteritis in the ureteropelvic junction. During follow-up for past surgical resection of a bladder tumor, renal dysfunction developed and a ureter mass was found in the right ureteropelvic junction, which was treated by nephroureterectomy after chemotherapy. Pathology revealed no malignancy but abundant IgG4-positive cell infiltration, obliterative phlebitis and storiform fibrosis, confirming the diagnosis of IgG4-related ureteritis. In the resected right kidney, lymphoplasmacytes infiltrated the interstitium with focal distribution in the renal subcapsule and around medium vessels without storiform fibrosis, suggesting the very early stage of IgG4-TIN. Lymphocyte aggregates were also detected at these sites and consisted of B, T, and follicular dendritic cells, indicating TLT formation. IgG4-positive cells infiltrated around TLTs. Conclusions Our case suggests that TLT formation is related with the development of IgG4-TIN and our analysis of distribution of TLT have possibility to elucidate IgG4-TIN pathophysiology.
- Published
- 2021
10. The pronounced lung lesions developing in LATY136F knock-in mice mimic human IgG4-related lung disease
- Author
-
Satoshi Watanabe, Masahiko Zuka, Keishi Mizuguchi, Kazunori Yamada, Marie Malissen, Shoko Matsui, Yuko Waseda, Bernard Malissen, Tamotsu Ishizuka, Mitsuhiro Kawano, Kiyoaki Ito, Fukui University of Technology, Kanazawa University (KU), Centre d'Immunologie de Marseille - Luminy (CIML), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Centre d'Immunophénomique (CIPHE), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Toyama, and DUMENIL, Anita
- Subjects
Lung Diseases ,0301 basic medicine ,Lung Development ,Pathology ,Physiology ,Organogenesis ,medicine.medical_treatment ,[SDV]Life Sciences [q-bio] ,Salivary Glands ,White Blood Cells ,Mice ,0302 clinical medicine ,Animal Cells ,Fibrosis ,Immune Physiology ,Medicine and Health Sciences ,Lymphocytes ,skin and connective tissue diseases ,Immune Response ,Innate Immune System ,Kidney ,Multidisciplinary ,biology ,Animal Models ,3. Good health ,[SDV] Life Sciences [q-bio] ,Cytokine ,medicine.anatomical_structure ,Experimental Organism Systems ,Cytokines ,Medicine ,Anatomy ,Cellular Types ,Antibody ,medicine.symptom ,Research Article ,medicine.medical_specialty ,Immune Cells ,Science ,T cell ,Immunology ,Mutation, Missense ,Mouse Models ,Mice, Transgenic ,Inflammation ,Research and Analysis Methods ,03 medical and health sciences ,Model Organisms ,Signs and Symptoms ,Exocrine Glands ,medicine ,Animals ,Adaptor Proteins, Signal Transducing ,Blood Cells ,Lung ,Bronchiectasis ,business.industry ,Biology and Life Sciences ,Membrane Proteins ,Cell Biology ,Molecular Development ,medicine.disease ,respiratory tract diseases ,Disease Models, Animal ,030104 developmental biology ,Amino Acid Substitution ,Immune System ,Animal Studies ,Lesions ,biology.protein ,Immunoglobulin G4-Related Disease ,Clinical Medicine ,business ,Organism Development ,Digestive System ,030217 neurology & neurosurgery ,Developmental Biology - Abstract
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.
- Published
- 2021
11. Cytopathological findings of primary pulmonary Ewing family of tumors with EWSR1 translocation: A case report
- Author
-
Keishi Mizuguchi, Hitomi Onishi, Yuki Mitani, Hiroshi Minato, and Jun Kawai
- Subjects
Pulmonary and Respiratory Medicine ,Pathology ,medicine.medical_specialty ,Ewing family of tumors ,CD99 ,Population ,Case Report ,Case Reports ,lung ,03 medical and health sciences ,0302 clinical medicine ,Biopsy ,medicine ,030212 general & internal medicine ,education ,education.field_of_study ,elderly man ,Lung ,medicine.diagnostic_test ,biology ,business.industry ,Chromogranin A ,General Medicine ,medicine.anatomical_structure ,Oncology ,EWSR1 ,030220 oncology & carcinogenesis ,biology.protein ,Aspiration cytology ,Immunohistochemistry ,business ,Fluorescence in situ hybridization - Abstract
Primary pulmonary neoplasms of the Ewing family of tumors (EFT) are extremely rare and usually occur in adolescents or young adults. Only about 40 cases of pulmonary EFT have been reported in English literature, and no cytological studies have been documented. In this report, we describe the cytopathological findings of a primary pulmonary EFT in an elderly patient. A 70-year-old man sought care because of a progressing cough and dyspnea. Chest computed tomography revealed a circumscribed mass of 6 cm in the left upper lobe. Fine needle aspiration cytology and core needle biopsy revealed uniform round cell proliferation. The predominant population consisted of cells with thickened nuclear membranes, finely dispersed chromatin, single distinct nucleoli, and indistinct cytoplasm. The other population consisted of smaller cells with darker chromatin. The cytoplasm stained positive for periodic acid–Schiff stain and was digested by diastase. Immunohistochemistry showed positivity for MIC2 (CD99), and focal positivity for neuron specific enolase, synaptophysin, and chromogranin A. Fluorescence in situ hybridization (FISH) revealed EWSR1 translocation. Although rare, pulmonary EFT cannot be disregarded, regardless of age. When two populations of uniform, round cells are observed, immunohistochemistry with MIC2 (CD99) and cytogenetic analysis by reverse transcription polymerase chain reaction or FISH should be considered. Cytological diagnosis may play an important role in the early diagnosis and treatment of pulmonary EFT.
- Published
- 2016
12. Lat(Y136F) knock-in mouse model for human IgG4-related disease
- Author
-
Yasushi Kakuchi, Tamehito Onoe, Yasunori Suzuki, Bernard Malissen, Kiyoaki Ito, Shozo Izui, Masakazu Yamagishi, Masahiko Zuka, Kazunori Yamada, Mitsuhiro Kawano, Marie Malissen, Keishi Mizuguchi, Department of Molecular Biosciences [Lawrence], University of Kansas [Lawrence] (KU), Kanazawa University (KU), Human Information Processing Laboratory - Japanese Advances Institute of Science and Technology [Ishikawa] (HIP/JAIST), JAIST - Ishikawa - Japon, University of Geneva [Switzerland], Centre d'Immunologie de Marseille - Luminy (CIML), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Université de Genève = University of Geneva (UNIGE), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and DUMENIL, Anita
- Subjects
Pathology ,lcsh:Medicine ,Kidney ,Pathology and Laboratory Medicine ,medicine.disease_cause ,Mouse models ,Autoimmunity ,Mice ,White Blood Cells ,0302 clinical medicine ,Adrenal Cortex Hormones ,Animal Cells ,Fibrosis ,Medicine and Health Sciences ,Medicine ,Gene Knock-In Techniques ,lcsh:Science ,Lung ,Immune Response ,Plasma cells ,Multidisciplinary ,biology ,Salivary gland ,Animal Models ,3. Good health ,Phenotype ,medicine.anatomical_structure ,Experimental Organism Systems ,030220 oncology & carcinogenesis ,[SDV.IMM]Life Sciences [q-bio]/Immunology ,Anatomy ,Cellular Types ,medicine.symptom ,Antibody ,Research Article ,medicine.medical_specialty ,[SDV.IMM] Life Sciences [q-bio]/Immunology ,Phenylalanine ,Immune Cells ,T cell ,Immunology ,Endocrine System ,Inflammation ,Salivary glands ,Research and Analysis Methods ,03 medical and health sciences ,Exocrine Glands ,Model Organisms ,Signs and Symptoms ,Diagnostic Medicine ,Animals ,Humans ,Pancreas ,Adaptor Proteins, Signal Transducing ,030203 arthritis & rheumatology ,Blood Cells ,business.industry ,lcsh:R ,Membrane Proteins ,Biology and Life Sciences ,Kidneys ,Renal System ,Cell Biology ,Phosphoproteins ,medicine.disease ,Disease Models, Animal ,Mononuclear cell infiltration ,Mutation ,Leukocytes, Mononuclear ,biology.protein ,Lesions ,Tyrosine ,lcsh:Q ,IgG4-related disease ,Immunoglobulin G4-Related Disease ,business ,Digestive System ,Developmental Biology - Abstract
International audience; Background The adaptor protein Linker for activation of T cell (LAT) is a key signaling hub used by the T cell antigen receptor. Mutant mice expressing loss-of-function mutations affecting LAT and including a mutation in which tyrosine 136 is replaced by a phenylalanine (Lat(Y136F)) develop lymphoproliferative disorder involving T helper type 2 effector cells capable of triggering a massive polyclonal B cell activation that leads to hypergammaglobulinemia G1 and E and to non-resolving inflammation and autoimmunity. The purpose of this study was to evaluate whether the phenotypes of Lat(Y136F) knock-in mice resemble the immunohistopathological features of immunoglobulin G4-related disease (IgG4-RD).Methods Lat(Y136F) knock-in mice were sacrificed at 4-20 weeks of age, and pancreas, kidney, salivary gland and lung were obtained. All organs were stained with hematoxylin-eosin and with Azan for estimation of collagen in fibrosis, and the severity scores of inflammation and fibrosis were evaluated. Immunostainings were performed to analyze the types of infiltrating cells. In addition, the effects of corticosteroid treatment on the development of tissue lesions and serum levels of IgG1 were assessed.Results Tissue lesions characterized by inflammatory mononuclear cell infiltration and fibrosis were detected in pancreas, kidney, and salivary gland starting from 6 weeks of age. Immunostainings showed pronounced infiltration of plasma cells, CD4-positive T cells, and macrophages. Infiltrating plasma cells predominantly expressed IgG1. The extent of inflammation in pancreas and salivary glands was markedly reduced by corticosteroid treatment.Conclusions Lat(Y136F) knock-in mice displayed increased production of Th2-type IgG1 (a homologue of human IgG4) and developed multiple organ tissue lesions reminiscent of those seen in patients with IgG4-RD. Moreover, the development of these tissue lesions was highly sensitive to corticosteroid treatment like in IgG4-RD. For these reasons we consider the Lat(Y136F) knock-in mouse strain to represent a promising model for human IgG4-RD.
- Published
- 2018
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.