Miho Karube

Kyorin University, Edo, Tōkyō, Japan

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Publications (9)21.93 Total impact

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    ABSTRACT: Background NETosis, a unique form of cell death of neutrophils, is characterized by the active release of chromatin fibers called NETs, that trap and kill invading microbes extracellularly. Although NETosis plays a crucial role in host defense, excessive NETs formation becomes self-defeating by promoting tissue injury and organ damage. It has been known that NETs are implicated also in the pathogenesis of autoimmune vasculitis such as SLE, RA and ANCA –associated vasculitis (AAV). Objectives We observed NETs formation of neutrophils from MPO-AAV patients which is a majority type of AAV in Asia, examined the effects of anti-MPO antibody and immunosuppressive therapy on the release of NETs in order to investigate the role of NETs and MPO-ANCA in MPO-AAV.We also observed the damage of human renal glomerular endothelial cells (HRGECs) by neutrophils in order to investigate the role of NETs in AAV. Methods Isolated peripheral blood neutrophils from healthy donors, pre/post-treatment MPO-AAV patients were incubated with phorbol myristate acetate (PMA), which is known as a strong inducer of NETs, PMA plus anti-MPO antibody or PMA plus anti-PR3 antibody. Neutrophils were stained with Hoechst 33342, SYTOX Green and the percentage of NETs producing cells were calculated. Brd-U labeled HRGECs stimulated by PMA were co-cultured with neutrophils. A cellular DNA fragmentation ELISA was used to quantitatively determine HRGECs damage. Results Neutrophils from pre-treatment MPO-AAV patients produced much more fiber-like NETs than neutrophils from controls and the shape of fiber-like NETs were different from controls. Anti-MPO antibody increased the release of fiber-like NETs both in controls and MPO-AAV patients. The release of fiber-like NETs decreased in tandem with the decrease of ANCA titer after initial treatment and increased with the rise of ANCA titer in some MPO-AAV patients. Although PMA-stimulated HRGEC were damaged in the presence of neutrophils, HRGEC without PMA stimulation were not damaged. Conclusions Neutrophils from pre-treatment MPO-AAV patients released different type of fiber-like NETs and the amount of fiber-like NETs correlated with the activity of AAV. HRGECs stimulated with PMA were damaged in the presence of neutrophils. These data suggest the release of fiber-like NETs by neutrophils at vascular endothelium is important for the pathogenesis of AAV. References Disclosure of Interest None declared
    Annals of the Rheumatic Diseases 06/2015; 74(Suppl 2):514.1-514. DOI:10.1136/annrheumdis-2015-eular.5780 · 10.38 Impact Factor

  • La Presse Médicale 04/2013; 42(4):701-702. DOI:10.1016/j.lpm.2013.02.117 · 1.08 Impact Factor
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    Clinical and Experimental Nephrology 06/2011; 15(4). DOI:10.1007/s10157-011-0481-6 · 2.02 Impact Factor
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    ABSTRACT: Myeloperoxidase-type antineutrophil cytoplasmic antibody (MPO-ANCA)-associated vasculitis may manifest various organ symptoms. Treatment allows recovery from early, but severe, organ involvement. However, the relationship between the initial organ involvement and the eventual clinical course has not been studied in this disease. Therefore, the current study evaluated 30 patients who were hospitalized and then categorized into ten clinical subtypes based on organ involvement. The relationship of these subtypes to development of clinical features, patient survival, kidney prognosis, and relapse were evaluated over an average observation period of 4.3 years. During this study, the most common clinical features were lung and kidney involvement. Twenty-one patients already manifested clinical features around the time of admission and did not commonly present new symptoms as long as they were receiving the treatment for vasculitis. In contrast, as far as pulmonary involvement type at the initial time was concerned and in those not being treated for vasculitis, 7 of the 12 patients progressed to pulmo-renal involvement and 5 of them went onto renal failure. Progression to renal failure also occurred frequently in patients with pulmo-renal type manifesting at the initial time. Thirteen patients died, including three patients due to vasculitis of systemic type, seven due to infections, and three due to malignancy. Death due to vasculitis occurred in the early phase of treatment and was associated with either pulmonary hemorrhage or gastrointestinal bleeding. Infectious death occurred throughout the entire course of treatment, mostly in patients with pulmo-renal or pulmonary type, and tended to be associated with opportunistic organisms. Death with malignancy was observed after several years of treatment. Regarding renal prognosis, ten patients underwent hemodialysis. At initiation of hemodialysis, nine patients had pulmo-renal type and only one had renal type. A relapse was observed in ten patients, mainly in patients with pulmo-renal or pulmonary type, and it occurred after about 2.7 years, even with treatment. Such relapses manifested in a similar manner to their initial clinical subtypes. These results suggest that pulmo-renal type as well as pulmonary type have a high chance to progress to renal failure or systemic type, and they were fairly commonly associated with vasculitic or infectious death. Therefore, classification of clinical subtypes at the initial time and on admission is meaningful to some extent for predicting patient survival, kidney prognosis, and relapse, in addition to indicating the appropriate treatment regimen.
    Modern Rheumatology 07/2009; 19(4):420-6. DOI:10.1007/s10165-009-0182-0 · 2.40 Impact Factor
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    ABSTRACT: Myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA)-associated vasculitis frequently induces crescentic glomerulonephritis. However, a few cases have so far been reported to have only tubulointerstitial (TI) nephritis without any apparent glomerular lesions. We recently treated three similar cases. Therefore, their pathological features as well as clinical manifestations were studied in detail. The pathological study was performed with immunohistochemical staining using various antibodies to the vascular endothelial cell surface markers, von Willebrand factor, type IV collagen, cytokeratin, E-cadherin, and MPO in addition to the routine histochemical examination. The study disclosed the loss of CD34 endothelial cell surface markers with and without the destruction of type IV collagen (capillary basement membrane) in the peritubular capillaries, even though the glomeruli showed good staining of these factors. Electron microscopy showed breaks in the capillary basement membrane. The loss of CD34 staining was associated with the infiltration of a few mononuclear cells and neutrophils in the lumen of peritubular capillaries and the surrounding interstitial tissues. The cytokeratin staining in the tubular epithelial cells was also diminished around these areas. Tubulitis was demonstrated with or without the destruction of the tubular basement membrane. The clinical manifestations of these three cases were only a few red blood cells and granular casts in the urinary sediment as well as slightly increased beta2-microglobulin in the urine, but no proteinuria. Based on these findings, the loss of CD34 vascular endothelial markers occurs in the early phase of the disease because of the MPO, which is presumed to have burst out from the infiltrated, activated neutrophils. This MPO, which releases proteolytic enzymes and radical oxygen species, acts on tissue destruction, namely the lysis of endothelial cell membranes as well as vascular basement membranes in the peritubular capillary. This mechanism eventually proceeds to the destruction of the peritubular capillary walls (vasculitis). This pathogenesis is thought to play an important role in the pathogenesis of TI nephritis, which is associated with MPO-ANCA vasculitis.
    Clinical and Experimental Nephrology 07/2009; 13(6):605-13. DOI:10.1007/s10157-009-0200-8 · 2.02 Impact Factor
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    ABSTRACT: A 77-year-old woman developed nephrotic syndrome associated with type III hyperlipoproteinemia (III HLP) and increased apolipoprotein E (apo E). Apo E analysis disclosed E2/E3 heterozygosity in phenotypic and genotypic expressions, without any other mutations. A renal biopsy showed intraluminal and subendothelial thrombus-like deposits in the dilated capillary loops of the glomerulus that stained positive for lipids and apo E. Electron microscopy revealed tiny granular particles in the capillary lumina, as well as between the glomerular basement membrane and the endothelial cells. It was therefore concluded that III HLP associated with apo E2/E3 heterozygosity could induce lipoprotein glomerulopathy-like disease and nephrotic syndrome.
    Clinical and Experimental Nephrology 07/2007; 11(2):174-9. DOI:10.1007/s10157-007-0469-4 · 2.02 Impact Factor
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    ABSTRACT: Class IV-G (A/C) diffuse lupus nephritis and tubulointerstitial (TI) nephritis in a 31-year old woman was studied by light, immunofluorescence (IF), and electron microscopy (EM), to determine the pathogenesis of the TI lesions. The light microscopic findings showed peritubular capillaritis in the interstitium, with ruptures in the capillary structure, lysis of the surrounding tubular basement membrane (TBM), extravasated red blood cells (RBCs), the infiltration of neutrophils and mononuclear cells, and edema. The IF study revealed IgG, IgA, IgM, C1q, C3, and C4 depositions along the TBM, on the capillary walls, and in the interstitium proper. The EM study disclosed the deposition of immune complexes in the TBM, the capillary wall, and the interstitium proper. Based on these findings, the TI nephritis in this patient was considered to be due to peritubular capillaritis secondary to the immune complex depositions in the capillary wall of the interstitium.
    Clinical and Experimental Nephrology 07/2006; 10(2):146-51. DOI:10.1007/s10157-006-0405-z · 2.02 Impact Factor

  • Nihon Naika Gakkai Zasshi 12/2002; 91(11):3278-81. DOI:10.2169/naika.91.3278

  • Nihon Toseki Igakkai Zasshi 01/1999; 32(12):1433-1438. DOI:10.4009/jsdt.32.1433