Faculty Profiles - MIZUNO, Masashi

Papers - MIZUNO, Masashi

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A protein toxin from the sea anemone Phyllodiscus semoni targets the kidney and causes a renal injury resembling haemolytic uremic syndrome. Reviewed

Mizuno M., Nozaki M., Morine N., Suzuki N., Nishikawa K., Morgan BP., Matsuo S.

Am. J. Pathol. Vol. 171 page： 402-414 2007.8

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)

Envenomation by the sea anemone Phyllodiscus semoni causes fulminant dermatitis and, rarely, acute renal failure in humans. Here, we investigated whether the venom extracted from the nematocysts (PsTX-T) was nephrotoxic when administered intravenously in rats and whether PsTX-T induced activation of the complement system. Although small dose of PsTX-T induced acute tubular necrosis in rats resembling pathology seen in patients, kidneys displayed glomerular injury with glomerular endothelial damage, thrombus formation, mesangiolysis, and partial rupture of glomerular basement membrane, accompanied by severe tubular necrosis at 24 hours after administration of 0.03 mg of PsTX-T per animal, similar to the glomerular findings typical of severe hemolytic uremic syndrome. The early stage injury was accompanied by specific PsTX-T binding, massive complement C3b, and membrane attack complex deposition in glomeruli in the regions of injury and decreased glomerular expression of complement regulators. A pathogenic role for complement was confirmed by demonstrating that systemic complement inhibition reduced renal injury. The isolated nephrotoxic component, a 115-kd protein toxin (PsTX-115), was shown to cause identical renal pathology. The demonstration that PsTX-T and PsTX-115 were highly nephrotoxic acting via induction of complement activation suggests that inhibition of complement might be used to prevent acute renal damage following envenomation by P. semoni.

A protein toxin from the sea anemone Phyllodiscus semoni targets the kidney and causes a severe renal injury with predominant glomerular endothelial damage. International coauthorship International journal Open Access

Mizuno, M; Nozaki, M; Morine, N; Suzuki, N; Nishikawa, K; Morgan, BP; Matsuo, S

AMERICAN JOURNAL OF PATHOLOGY Vol. 171 ( 2 ) page： 402 - 414 2007.8

CD55 in rat male reproductive tissue: Differential expression in testis and expression of a unique truncated isoform on spermatozoa International coauthorship International journal

Mizuno, M; Donev, RM; Harris, CL; Morgan, BP

MOLECULAR IMMUNOLOGY Vol. 44 ( 7 ) page： 1613 - 1622 2007.3

Immunisation with CD46 generates a strong autoantibody response targeting the spermatozoal acrosome in rat Reviewed International coauthorship International journal

Mizuno, M; Harris, CL; Morgan, BP

MOLECULAR IMMUNOLOGY Vol. 44 ( 1-3 ) page： 216 - 216 2007.1

High levels of complement C3a receptor in the glomeruli of inflamed human lupus nephritis. Reviewed

Mizuno M., Blanchin S., Gasque P., Nishikawa K., Matsuo S.

Am. J. Kidney Dis. Vol. 49 page： 598-606 2007

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Taking into consideration the key role of the complement system in renal diseases, we investigated molecular and cellular properties of the human complement C3a receptor (C3aR) in vitro and in situ, looking at its expression in several human renal pathological states. METHODS: Several antibodies were generated and used for immunohistochemistry and Western blot analyses to address C3aR expression and its regulation in vitro on cell lines of myeloid cells and nonmyeloid cell lineages. Furthermore, C3aR distribution was investigated in control nephrectomized kidneys and 116 biopsy specimens from patients with renal diseases, including lupus nephritis (lupus-N). RESULTS: C3aR is a highly N-glycosylated protein with an apparent molecular mass of 65 to 95 kd expressed by myeloid and endothelial cells. C3aR is particularly upregulated in response to interferon gamma treatment, but was unaffected by the other inflammatory cytokines, such as tumor necrosis factor alpha and transforming growth factor beta. In normal human kidney, C3aR staining was not observed. However, glomerular C3aR staining was detected in 42.9% of lupus-N specimens in association with immunoglobulin G immune-complex depositions. Staining intensity correlated with disease severity. C3aR was found in the endothelial area of 81.3% of samples classified as World Health Organization class IV with active lesions. Conversely, C3aR was not detected by means of immunohistochemistry in kidneys from patients with other renal diseases. CONCLUSION: Our data indicate that C3aR expression is tightly regulated and altered in certain disease conditions. C3aR may be used as a unique biomarker of diagnosis and disease activity in patients with lupus-N.

よく使う利尿薬について習熟する　スピロノラクトン Invited

水野正司、伊藤恭彦

Medicina Vol. 44 page： 359-342 2007

Immunization with autologous CD46 in rats generates a strong autoantibody response that targets spermatozoa. Reviewed

Mizuno M., Harris CL., Morgan BP.

J. Reprod. Immunol. Vol. 73 page： 135-147 2007

【特集:これだけは知っておきたい分子腎臓学2007】 C5a. Invited

水野正司、湯澤由紀夫、松尾清一

腎と透析 Vol. 63 page： 580-582 2007

Complement membrane attack is required for endplate damage and clinical disease in passive experimental myasthenia gravis in Lewis rats Reviewed International coauthorship International journal Open Access

J. Chamberlain-Banoub, J. W. Neal, M. Mizuno, C. L. Harris, B. P. Morgan

CLINICAL AND EXPERIMENTAL IMMUNOLOGY Vol. 146 ( 2 ) page： 278 - 286 2006.11

Language：English Publishing type：Research paper (scientific journal) Publisher：BLACKWELL PUBLISHING

Myasthenia gravis (MG) is a debilitating and potentially fatal neuromuscular disease characterized by the generation of autoantibodies reactive with nicotinic acetylcholine receptors (AChR) that cause loss of AChR from the neuromuscular endplate with resultant failure of neuromuscular transmission. A role for complement (C) in the pathology of human MG has been suggested based upon identification of C activation products in plasma and deposited at the endplate in MG. In the rat model, experimental autoimmune MG (EAMG), C depletion or inhibition restricts clinical disease, further implicating C in pathology. The mechanisms by which C activation drives pathology in MG and EAMG are unclear. Here we provide further evidence implicating C and specifically the membrane attack complex (MAC) in the Lewis rat passive EAMG model of MG. Rats deficient in C6, an essential component of the MAC, were resistant to disease induction and endplate destruction was reduced markedly compared to C6-sufficient controls. After reconstitution with C6, disease severity and endplate destruction in the C6-deficient rats was equivalent to that in controls. The data confirm the essential role of the MAC in the destruction of the endplate in EAMG and raise the prospect of specific MAC inhibition as an alternative therapy in MG patients resistant to conventional treatments.

DOI： 10.1111/j.1365-2249.2006.03198.x

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The membrane attack pathway of complement drives pathology in passively induced experimental autoimmune myasthenia gravis in mice Reviewed International coauthorship International journal Open Access

B. P. Morgan, J. Chamberlain-Banoub, J. W. Neal, W. Song, M. Mizuno, C. L. Harris

CLINICAL AND EXPERIMENTAL IMMUNOLOGY Vol. 146 ( 2 ) page： 294 - 302 2006.11

Language：English Publishing type：Research paper (scientific journal) Publisher：BLACKWELL PUBLISHING

The human neuromuscular disease myasthenia gravis (MG) is characterized by the generation of autoantibodies reactive with nicotinic acetylcholine receptors (AChR) that cause loss of AChR from the neuromuscular end-plate with resultant failure of neuromuscular transmission. A role for complement (C) in AChR loss has been suggested based uponmorphological identification of C at the end-plate in MG and from the effects of C inhibition in murine models. Here we provide further evidence implicating C, and specifically the membrane attack complex (MAC), in a mouse model of MG. Mice deficient in the C regulators Daf1 and/or Cd59a were tested in the model. Wild-type mice were resistant to disease while mice deficient in Daf1 had mild disease symptoms with evidence of C activation and AChR loss at end-plates. Cd59a-deficient mice had very mild disease with some muscle inflammation and essentially undamaged end-plates. In contrast, mice deficient in both C regulators developed a severe paralytic disease with marked muscle inflammation and loss of end-plates. Inhibition of MAC assembly abrogated clinical disease in these double-deficient mice, demonstrating conclusively that MAC formation was driving pathology in the model. These findings provoke us to suggest that current anti-C therapeutics targeting MAC assembly will be beneficial in MG patients resistant to conventional therapies.

DOI： 10.1111/j.1365-2249.2006.03205.x

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Spermatogenic cells distal to the blood-testis barrier in rats lack C3 convertase regulators and may be at risk of complement-mediated injury.

Mizuno M, Harris CL, Morgan BP

Journal of reproductive immunology Vol. 69 ( 1 ) page： 23 - 34 2006.2

Complement and complement regulators in the male reproductive system Reviewed International coauthorship International journal

CL Harris, M Mizuno, BP Morgan

MOLECULAR IMMUNOLOGY Vol. 43 ( 1-2 ) page： 57 - 67 2006.1

Language：English Publishing type：Research paper (scientific journal) Publisher：PERGAMON-ELSEVIER SCIENCE LTD

Spermatozoa are almost unique among cells in that they must survive transplantation into a foreign host in order to perform their physiological role. The biggest hurdle to overcome is innate immune defence that will target the invaders in the female genital tract. Complement is a major player in innate immunity and is present in the female genital tract. Spermatozoa must therefore evade complement attack if they are to reach their goal. Complement evasion is achieved by the presence of complement regulators both in seminal plasma and on the spermatozoa. Here we discuss the parts played by complement and complement regulators in permitting spermatozoa to survive long enough to reach the oocyte, in clearance of the excess spermatozoa that have outlived their usefulness and in aiding activation of spermatozoa to engage the oocyte. In particular, we focus on the unique distribution patterns of complement regulators on spermatozoa, patterns that strongly suggest roles in spermatozoal development and oocyte binding. An understanding of these roles will inform studies of their contribution to fertility and infertility in man. (c) 2005 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.molimm.2005.06.026

Web of Science

PubMed

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Stage-specific expression of CD55 isoforms during spermiogenesis in the rat

Mizuno, M; Harris, CL; Donev, RM; Spiller, OB; Morgan, BP

MOLECULAR IMMUNOLOGY Vol. 43 ( 1-2 ) page： 156 - 156 2006.1

The membrane attack pathway of complement drives pathology in experimental autoimmune myasthenia gravis in mice. Reviewed

Morgan BP., Chamberlain-Banoub J., Neal JW.,Song W., Mizuno M., Harris CL.

Clin Exp Immunol Vol. 146 page： 294-302 2006

Complement and complement regulators in the male reproductive system. Invited Reviewed

Harris CL., Mizuno M., Morgan BP.

Mol Immunol Vol. 43 page： 57-67 2006

Complement membrane attack is required for endplate damage and clinical disease in experimental myasthenia gravis in Lewis rats. Reviewed

Chamberlain-Banoub J., Neal JW., Mizuno M., Harris CL., Morgan BP.

Clin Exp Immunol Vol. 146 page： 278-286 2006

CD55 expression in rat male reproductive tissue: Differential expression in testis and expression of a unique truncated isoform on spermatozoa. Reviewed

Mizuno M., Donev RM., Harris CL., Morgan BP.

Mol. Immunol. Vol. 44 page： 1624-1633 2006

A review of current knowledge of the complement system and the therapeutic opportunities in inflammatory arthritis. Invited Reviewed

Mizuno M.

Curr Med Chem Vol. 13 page： 1707-1717 2006

Unique expression patterns of membrane complement regulators and C3 in rat testes and spermatozoa delineate the blood-testis barrier and suggest distinct functional roles in germ cell development. Reviewed

Mizuno M., Harris CL., Morgan BP.

J Reprod Immunol Vol. 69 page： 23-34 2006

Mizuno M, Harris CL, Morgan BP

J Reprod Immunol Vol. 69 page： 23-34 2006

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Papers - MIZUNO, Masashi