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We encountered a 64-year-old Japanese woman who developed subarachnoid hemorrhaging (SAH) with multiple cerebral artery stenoses during remission induction therapy for eosinophilic granulomatosis and polyangiitis (EGPA). The treatment involved intensified steroid pulse therapy and continued intravenous cyclophosphamide pulse therapy, which led to beneficial effects. Given the rarity of multiple EGPA-associated cerebral artery stenoses and SAH, it is crucial to differentiate them from other diseases. The mortality rate of EGPA complicated by intracranial hemorrhagic lesions, including SAH, is high. When headache is present at the onset of EGPA, the possibility of SAH must be considered.
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OBJECTIVE: The serum squamous cell carcinoma antigen (SCCA) level is a well-known tumor marker for squamous cell carcinoma. In this study, we examined the impact of immunoglobulin (Ig)-bound macromolecular SCCA on serum SCCA levels measured by 2 different methods. METHODS: Seventy-five serum samples with an SCCA level >5.0 ng/mL as determined by a chemiluminescent immunoassay (CLIA) were also analyzed using a chemiluminescent enzyme immunoassay (CLEIA). The levels of IgG- and IgA-type anti-SCCA antibodies, which form immunoglobulins and macromolecules, respectively, were determined using an enzyme-linked immunosorbent assay. An absorption test was performed to confirm the presence of anti-SCCA antibodies. RESULTS: The correlation coefficient between the values measured by CLEIA and CLIA was 0.768. The ratio of SCCA levels measured by CLEIA to those measured by CLIA in 14 samples with IgG-type anti-SCCA antibodies was significantly lower than that in samples without these antibodies (P < .031). Absorption tests showed that SCCA levels measured by CLIA might be falsely high in samples with IgG-type anti-SCCA antibodies, probably due to reactions with SCCA1. CONCLUSION: The level of SCCA as measured by CLIA and CLEIA methods correlate well, but the presence of SCCA antibodies can affect the results of the CLIA method.
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Receptor-type protein phosphatase α (RPTPα) promotes fibroblast-dependent arthritis and fibrosis, in part, by enhancing the activation of the kinase SRC. Synovial fibroblasts lining joint tissue mediate inflammation and tissue damage, and their infiltration into adjacent tissues promotes disease progression. RPTPα includes an ectodomain and two intracellular catalytic domains (D1 and D2) and, in cancer cells, undergoes inhibitory homodimerization, which is dependent on a D1 wedge motif. Through single-molecule localization and labeled molecule interaction microscopy of migrating synovial fibroblasts, we investigated the role of RPTPα dimerization in the activation of SRC, the migration of synovial fibroblasts, and joint damage in a mouse model of arthritis. RPTPα clustered with other RPTPα and with SRC molecules in the context of actin-rich structures. A known dimerization-impairing mutation in the wedge motif (P210L/P211L) and the deletion of the D2 domain reduced RPTPα-RPTPα clustering; however, it also unexpectedly reduced RPTPα-SRC association. The same mutations also reduced recruitment of RPTPα to actin-rich structures and inhibited SRC activation and cellular migration. An antibody against the RPTPα ectodomain that prevented the clustering of RPTPα also inhibited RPTPα-SRC association and SRC activation and attenuated fibroblast migration and joint damage in arthritic mice. A catalytically inactivating RPTPα-C469S mutation protected mice from arthritis and reduced SRC activation in synovial fibroblasts. We conclude that RPTPα clustering retains it to actin-rich structures to promote SRC-mediated fibroblast migration and can be modulated through the extracellular domain.
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Actinas , Artrite , Animais , Camundongos , Análise por Conglomerados , Fibroblastos/metabolismo , Fosfoproteínas Fosfatases , Proteínas Tirosina Fosfatases/metabolismo , Proteínas Tirosina Fosfatases Classe 4 Semelhantes a Receptores/genética , Proteínas Tirosina Fosfatases Classe 4 Semelhantes a Receptores/metabolismoRESUMO
Glutamine metabolism and the mechanistic target of rapamycin (mTOR) pathway are activated cooperatively in the differentiation and activation of inflammatory immune cells. But the combined inhibition of both pathways was rarely investigated. This study investigated how inhibiting both glutamine metabolism with 6-diazo-5-oxo-L-norleucine (DON) and mTOR with rapamycin affects immune cells and the arthritis in a mouse model. We revealed that rapamycin and DON additively suppressed CD4+ T cell proliferation, and both of them inhibited Th17 cell differentiation. While DON inhibited the differentiation of dendritic cells and macrophages and facilitated that of Ly6G+ granulocytic (G)-MDSCs more strongly than did rapamycin, G-MDSCs treated with rapamycin but not DON suppressed CD4+ T cell proliferation in vitro. The combination of rapamycin and DON significantly suppressed the arthritis in SKG mice more strongly than did each monotherapy in vivo. The numbers of CD4+ T and Th17 cells in the spleen were lowest in mice treated with the combination therapy. Thus, combined treatment with rapamycin and DON additively ameliorated the arthritis in SKG mice, possibly by suppressing CD4+ T cell proliferation and Th17 differentiation. These results suggest the combination of rapamycin and DON may be a potential novel therapy for arthritis.
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Artrite/metabolismo , Glutamina/metabolismo , Serina-Treonina Quinases TOR/antagonistas & inibidores , Animais , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/metabolismo , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Dendríticas/citologia , Células Dendríticas/efeitos dos fármacos , Diazo-Oxo-Norleucina/farmacologia , Feminino , Terapia de Imunossupressão , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Células Supressoras Mieloides/citologia , Células Supressoras Mieloides/efeitos dos fármacos , Sirolimo/farmacologia , Serina-Treonina Quinases TOR/metabolismo , Células Th17/efeitos dos fármacos , Células Th17/imunologiaRESUMO
Rheumatoid vasculitis is a rare etiology for pulmonary hypertension (PH) in patients with connective tissue disease. We encountered a case of acute PH crisis in a case with rheumatoid vasculitis eight months after undergoing adalimumab reduction. Since no repetition of arthralgia occurred after the adalimumab reduction, we decided to not increase the dose of adalimumab. However, hemodynamic collapse thereafter developed and even though steroid pulse therapy was administered, the patient nevertheless died. The autopsy showed clusters of acute and chronic inflammation around the remodeled pulmonary arteries along with micro-thrombi in the vessel lumen. We should consider the possibility of critical worsening of PH as a phenotype of vasculitis related to immunosuppressive therapy reduction.
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Adalimumab/efeitos adversos , Artrite Reumatoide/tratamento farmacológico , Hipertensão Pulmonar/etiologia , Vasculite Reumatoide/induzido quimicamente , Adalimumab/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Humanos , Inflamação , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Myeloid-derived suppressor cells (MDSCs) are a highly heterogeneous population of immature myeloid cells with immunosuppressive function. Although their function in tumor-bearing conditions is well studied, less is known about the role of MDSCs in various organs under non-neoplastic inflammatory conditions. MAIN BODY: MDSCs are divided into two subpopulations, G-MDSCs and M-MDSCs, and their distribution varies between organs. MDSCs negatively control inflammation in inflamed organs such as the lungs, joints, liver, kidneys, intestines, central nervous system (CNS), and eyes by suppressing T cells and myeloid cells. MDSCs also regulate fibrosis in the lungs, liver, and kidneys and help repair CNS injuries. MDSCs in organs are plastic and can differentiate into osteoclasts and tolerogenic dendritic cells according to the microenvironment under non-neoplastic inflammatory conditions. CONCLUSION: This article summarizes recent findings about MDSCs under inflammatory conditions, especially with respect to their function and differentiation in specific organs.
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OBJECTIVE: SKG mice develop interstitial lung disease (ILD) resembling rheumatoid arthritis-associated ILD in humans. The aim of this study was to clarify the mechanism underlying the lung pathology by analyzing lung-infiltrating cells in SKG mice with ILD. METHODS: We assessed the severity of zymosan A (ZyA)-induced ILD in SKG mice histologically, and we examined lung-infiltrating cells by flow cytometry. Total lung cells and isolated monocytic myeloid-derived suppressor cells (MDSCs) were cultured in vitro with granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4. The proliferation of 5,6-carboxyfluorescein diacetate N-succinimidyl ester-labeled naive T cells cocultured with isolated CD11b+Gr-1dim cells and MDSCs was evaluated by flow cytometry. CD11b+Gr-1dim cells were adoptively transferred to ZyA-treated SKG mice. RESULTS: MDSCs, Th17 cells, and group 1 and 3 innate lymphoid cells (ILC1s and ILC3s) were increased in the lungs; the proportion of these cells varied with ILD severity. In this process, we found that a unique cell population, CD11b+Gr-1dim cells, was expanded in the severely inflamed lungs. Approximately half of the CD11b+Gr-1dim cells expressed CD11c. CD11b+Gr-1dim cells were induced from monocytic MDSCs with GM-CSF in vitro and were considered tolerogenic because they suppressed T cell proliferation. These CD11b+Gr-1dim cells have never been described previously, and we termed them CD11b+Gr-1dim tolerogenic dendritic cell (DC)-like cells. Th17 cells, ILC1s, and ILC3s in the inflamed lung produced GM-CSF, which may have expanded CD11b+Gr-1dim tolerogenic DC-like cells in vivo. Furthermore, adoptive transfer of CD11b+Gr-1dim tolerogenic DC-like cells significantly suppressed progression of ILD in SKG mice. CONCLUSION: We identified unique suppressive myeloid cells that were differentiated from monocytic MDSCs in SKG mice with ILD, and we termed them CD11b+Gr-1dim tolerogenic DC-like cells.
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Antígeno CD11b/imunologia , Células Dendríticas/fisiologia , Doenças Pulmonares Intersticiais/fisiopatologia , Pulmão/citologia , Células Supressoras Mieloides/fisiologia , Transferência Adotiva/métodos , Animais , Diferenciação Celular , Proliferação de Células , Técnicas de Cocultura/métodos , Células Dendríticas/imunologia , Modelos Animais de Doenças , Citometria de Fluxo , Fluoresceínas , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Interleucina-4/imunologia , Pulmão/imunologia , Pulmão/patologia , Doenças Pulmonares Intersticiais/induzido quimicamente , Doenças Pulmonares Intersticiais/imunologia , Camundongos , Células Supressoras Mieloides/imunologia , Receptores de Quimiocinas , Succinimidas , Linfócitos T/fisiologia , Células Th17/fisiologia , ZimosanRESUMO
BACKGROUND: The recent findings of cancer-specific metabolic changes, including increased glucose and glutamine consumption, have provided new therapeutic targets for consideration. Fibroblast-like synoviocytes (FLS) from rheumatoid arthritis (RA) patients exhibit several tumor cell-like characteristics; however, the role of glucose and glutamine metabolism in the aberrant proliferation of these cells is unclear. Here, we evaluated the role of these metabolic pathways in RA-FLS proliferation and in autoimmune arthritis in SKG mice. METHODS: The expression of glycolysis- or glutaminolysis-related enzymes was evaluated by real-time polymerase chain reaction (PCR) and Western blotting, and the intracellular metabolites were evaluated by metabolomic analyses. The effects of glucose or glutamine on RA-FLS cell growth were investigated using glucose- or glutamine-free medium. Glutaminase (GLS)1 small interfering RNA (siRNA) and the GLS1 inhibitor compound 968 were used to inhibit GLS1 in RA-FLS, and compound 968 was used to study the effect of GLS1 inhibition in zymosan A-injected SKG mice. RESULTS: GLS1 expression was increased in RA-FLS, and metabolomic analyses revealed that glutamine metabolism was increased in RA-FLS. RA-FLS proliferation was reduced under glutamine-deprived, but not glucose-deprived, conditions. Cell growth of RA-FLS was inhibited by GLS1 siRNA transfection or GLS1 inhibitor treatment. Treating RA-FLS with either interleukin-17 or platelet-derived growth factor resulted in increased GLS1 levels. Compound 968 ameliorated the autoimmune arthritis and decreased the number of Ki-67-positive synovial cells in SKG mice. CONCLUSIONS: Our results suggested that glutamine metabolism is involved in the pathogenesis of RA and that GLS1 plays an important role in regulating RA-FLS proliferation, and may be a novel therapeutic target for RA.
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Artrite Experimental/patologia , Artrite Reumatoide/patologia , Fibroblastos/patologia , Glutaminase/metabolismo , Sinoviócitos/patologia , Animais , Artrite Experimental/enzimologia , Artrite Reumatoide/enzimologia , Western Blotting , Proliferação de Células/fisiologia , Feminino , Fibroblastos/enzimologia , Técnicas de Silenciamento de Genes , Glutamina/metabolismo , Imuno-Histoquímica , Camundongos , Reação em Cadeia da Polimerase em Tempo Real , Sinoviócitos/enzimologiaRESUMO
A 78-year-old female with massive pericardial effusion fulfilled diagnostic criteria for immunoglobulin G4 (IgG4)-related disease. Although her adenosine deaminase (ADA) level in the pericardial effusion was high, all the tests for tuberculosis infection were negative. Immunostaining of the pericardium biopsy specimen revealed remarkably increased IgG4-positive cells. This is the first report describing IgG4-related pericarditis with elevated ADA level. We also demonstrate the elevated interleukin-10 (IL-10) level in pericardial fluid and IL-10-producing T-cells in the pericardium.
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Adenosina Desaminase/análise , Hipergamaglobulinemia , Imunoglobulina G/imunologia , Interleucina-10/análise , Líquido Pericárdico/imunologia , Pericardite Tuberculosa/diagnóstico , Pericardite , Idoso , Diagnóstico Diferencial , Feminino , Humanos , Hipergamaglobulinemia/complicações , Hipergamaglobulinemia/diagnóstico , Hipergamaglobulinemia/imunologia , Masculino , Gravidade do Paciente , Derrame Pericárdico/diagnóstico , Derrame Pericárdico/etiologia , Derrame Pericárdico/imunologia , Pericardite/diagnóstico , Pericardite/etiologia , Pericardite/imunologia , Pericárdio/imunologiaRESUMO
BACKGROUND: Endothelin-1 (ET-1) is important in the pathogenesis of systemic sclerosis (SSc). ET-1 binds two receptors, endothelin type A (ETA) and endothelin type B (ETB). Dual ETA/ETB receptor antagonists and a selective ETA receptor antagonist are used clinically to treat SSc, and the effect of these antagonists on fibroblast activation has been described. However, the role of ETB receptor signaling in fibrogenesis is less clear. This study was conducted to evaluate the profibrotic function of ETB receptor signaling in a murine model of bleomycin (BLM)-induced scleroderma. METHODS: We used ETB receptor-knockout (ETBKO) mice, which are genetically rescued from lethal intestinal aganglionosis by an ETB receptor transgene driven by the human dopamine ß-hydroxylase (DßH)-gene promoter, and wild-type mice with DßH-ETB (WT). BLM or phosphate-buffered saline (PBS) was administered subcutaneously by osmotic minipump, and skin fibrosis was assessed by dermal thickness, subcutaneous fat atrophy, and myofibroblast count in the dermis. Dermal fibroblasts isolated from ETBKO and WT mice were cultured in vitro, stimulated with BLM or ET-1, and the expression of profibrotic genes was compared by quantitative PCR. RESULTS: Dermal thickness, subcutaneous fat atrophy, and myofibroblast counts in the dermis were significantly reduced in ETBKO mice compared to WT mice, after BLM treatment. Compared with wild-type, dermal fibroblasts isolated from ETBKO mice showed lower gene expressions of α-smooth muscle actin and collagen 1α1 in response to BLM or ET-1 stimulation in vitro. CONCLUSIONS: ET-1-ETB receptor signaling is involved in skin sclerosis and in collagen synthesis by dermal fibroblasts.
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Receptor de Endotelina B/metabolismo , Escleroderma Sistêmico/metabolismo , Escleroderma Sistêmico/patologia , Transdução de Sinais/fisiologia , Animais , Antibióticos Antineoplásicos/toxicidade , Bleomicina/toxicidade , Colágeno Tipo I/metabolismo , Modelos Animais de Doenças , Endotelina-1/metabolismo , Fibroblastos/metabolismo , Fibrose/metabolismo , Fibrose/patologia , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Reação em Cadeia da Polimerase , Pele/metabolismo , Pele/patologiaRESUMO
This report concerns a case of granulomatosis with polyangiitis (GPA) (Wegener's granulomatosis (WG)) with bronchus narrowing. Although nasal biopsy had been performed three times, no positive histology for GPA (WG) could be obtained. Flexible bronchoscopy revealed diffuse erythema, edema of the mucosa and stenosis of the right mainstem bronchus. Transbronchial biopsy identified granuloma with giant cells. These findings led to a diagnosis of GPA (WG). This case suggests that biopsy from the bronchus is useful for diagnosis of GPA (WG).
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Biópsia/métodos , Brônquios/patologia , Broncoscopia/métodos , Granulomatose com Poliangiite/diagnóstico , Constrição Patológica/diagnóstico , Constrição Patológica/etiologia , Granulomatose com Poliangiite/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Tomografia Computadorizada por Raios XRESUMO
This case report describes findings in a 61-year-old woman who manifested scleritis, small pulmonary nodules, otitis media, periaortitis, and progressive epidural spinal tumor, associated with elevated serum myeloperoxidase anti-neutrophil cytoplasmic antibody (MPO-ANCA) levels. She was clinically diagnosed with Wegener's granulomatosis, although vasculitis was not diagnosed due to the lack of typical histological findings. We discuss the differential diagnosis in this patient, and the association of MPO-ANCA with periaortitis or epidural spinal tumor.
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Neoplasias Epidurais/complicações , Granulomatose com Poliangiite/complicações , Fibrose Retroperitoneal/complicações , Neoplasias Epidurais/patologia , Feminino , Granulomatose com Poliangiite/patologia , Humanos , Inflamação/patologia , Pessoa de Meia-Idade , Fibrose Retroperitoneal/patologia , Vértebras TorácicasRESUMO
The objective of this study is to clarify the characteristics and imaging results of Japanese patients with giant cell arteritis (GCA). Eight patients with biopsy-proven GCA were enrolled. Their clinical data and imaging results were retrospectively examined from their medical records. All the patients met the criteria for the classification of GCA by the American College of Rheumatology. Although the clinical manifestations are similar to those previously reported, none of the eight patients presented ocular symptoms, and half of them presented jaw claudication. Ultrasonography (US) of temporal artery showed the halo sign in all the patients. Fluorodeoxyglucose positron emission tomography (FDG-PET) was performed in four patients and indicated the presence of aortitis of the patients. US is a quick and noninvasive test to detect inflammation of temporal artery, and FDG-PET is very helpful for early diagnosis of aortitis in GCA. Awareness of the disease and appropriate imaging tests will result in diagnosis of GCA.