藤田 30-35

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1 68 (1): (2009) 30 平成 20 年日本大学医学会秋季学術大会同窓会学術奨励賞受賞講演 1) 2) F.J. Dixon, C.B. Wilson 3) 3 4, 5) 1 (classical pathway) 2 C1q 2 (alternative pathway) initiation C3 2 C3 C3 (H 2O) 6) 3 (lectin pathway) C3 5, 7) (Fig. 1) C3 C3b H I C3c C3d C3d C3d (PSAGN) (MPGN) I. 7, 8) (Table 1) Fig. 1 Three pathways of complement activation 5). 20 ( )

2 68 (1) Table 1 Complement profiles in glomerulonephritides 7) Disease CH50 Serum C3 Serum C4 Factor B Activating pathway Glomerular deposition PSAGN A > C C3, C4, P, C5b 9, MBL MPGN (1) A < C C3, P, C5b 9 MPGN (2) A C3, P, C5b 9 Lupus N A < C C3, C4, C1q, C5b 9, MBL MN C3, C5b 9 IgA-N C3, P, C5b 9, MBL Pu-N C3, P, C5b 9, MBL FSGS C3, C5b 9 MCNS ( ) ANCA-N pauci immune ( ) Goodpasture C3, C5b 9 TIN C3, C5b 9 HCV-N cold activation MBL PSAGN: postatreptcoccal acute glomerulonephritis, MPGN: membranoproliferative glomerulonephritis, LUPUS N: lupus nephritis, MN: membranous nephropathy, IgA-N: IgA nephropathy, Pu-N: purpura nephropathy, FSGS: focal segmental glomerulosclerosis, MCNS: minimal change nephrotic syndrome, TIN: tublo-interstitial nephritis, ANCA-N: anti-neutrophil cytosomal antibody related nephropathy, HCV-N: heatitis C virus related nephropathy, MBL: mannose binding lectin, A: alternative complement pathway, C: classical complement pathway native C3 C3d native C3 9) C3c C3d 10) C3 in situ hybridization 11) C3 6) II. PSAGN AGN 12) PSAGN Rodoriguez-Iturbe neuraminidase neuraminidase neuraminidase PSAGN neuraminidase Table 2 % inhibition of C3Nef activity by additional Factor H 16) C3bBb stabilizing activity Per cent Patient EDTA-GVB H I H + I inhibition Non-hypo Hypo The C3bBb stabilizing activities of three non-hypo patients and two hypo patients were further investigated following addition of factor I. Even when factors H and I were added simultaneously, the C3NeF of the non-hypo patients was inhibited, but that of the hypo patients was not. in vitro 2 13) III. MPGN West C3bBb C3 nephritic factor (C3Nef) C3Nef C3bBb C3bBb MPGN C3Nef 14) C5

C5b 9 TIN C3, C5b 9 HCV-N cold activation MBL PSAGN: postatreptcoccal acute glomerulonephritis, MPGN: membranoproliferative glomerulonephritis, LUPUS N: lupus nephritis, MN: membranous nephropathy,

3 32 Fig. 2 Competitive deposition between C5b-9 (MAC) and Factor H on glomerular epithlium during complement activation 18). Inhibition of C3 breakdown (A) and Factor B breakdown (B) by NANA. The activation of C3 and Factor B was estimated by enzyme immunoassay in incubation mixtures consisting of NHS with various concentrations of NANA and 10 mg/ml of LPS as an activator of the alternative complement pathway. C3 or Factor B in NHS was cleaved into the break-down products after incubation witbout NANA, but was significantly linle cleaved in the presence of NANA respectively. These data suggest that NANA might inhibit C3 and Factor B cleavage via complement activation. Fig. 3 N-acetyl neuraminic acid (NANA) inhibits the activation of alternative complement pathway 20). 15) C3Nef Factor H 16) (Table 2) membrane attack complex (MAC) Factor H 17 19) (Fig. 2) AGN MPGN 20) in vitro 2 20) (Fig. 3) IV. 2 AGN IgA HCV 21 25) (Fig. 4) V. 2 C3, Factor B, Factor D Chylomicron ASP (acylation stimulating protein, C3a desarg)

alternative complement pathway. C3 or Factor B in NHS was cleaved into the break-down products after incubation witbout NANA, but was significantly linle cleaved in the presence of NANA respectively.

4 68 (1) 2009 補体系の活性化と腎糸球体障害 33 Fig. 4 Complement activation through the lectin pathway on glomerulus23). Fig. 5 Complement components are produced from adipocyte and activated by chylomicron via the ASP-adipsin pathway7). 症が誘発され27) 肥満関連腎症ではアラキドン酸代謝酵素を巻き込んだ糸球体硬化を惹起している可能性を報告しました28) (Fig. 7) 糖尿病では血管合併症は蛋白質の糖化や糸球体過剰濾過などが主因とされ免疫反応は一部の糖尿病でおこる稀な病態と考えられてきました私達は補体活性が免疫反応の枠を超えて引き起こされる点に着目し糖尿病モデル動物に補体活性阻止薬を投与して腎障害の進行を抑制させました29) また 2 型糖尿病患者で補体活性化産物が増加していることを報告し30) 合併症の増悪因子として補体系の活性化にも注意が必要で Fig. 6 Chylomicron-rich serum accelerates C3 tick-over by regulating the role of Factor H26). (Fig. 5) 私達は ASP 形成の過程で Chylomicron により C3 tick-over が亢進し Factor H の作用が抑制されることで補体第 2 経路がゆっくりと活性化されることを報告しました26) (Fig. 6) この活性化により糖尿病では腎合併あると喚起を促す事ができました (Fig. 8) 結語私達は腎傷害の発症機序の解明と進展阻止という遠大な計画のもとに色々な検討を行って参りました特に補体系の活性化による糸球体障害という点に着目し一定の

7) 糖尿病では血管合併症は蛋白質の糖化や糸球体過剰濾過などが主因とされ免疫反応は一部の糖尿病でおこる稀な病態と考えられてきました私達は補体活性が免疫反応の枠を超えて引き起こされる点に着目し糖尿病モデル動物に補体活性阻止薬を投与して腎障害の進行を抑制させました29) また 2 型糖尿病患者で補体活性化産物が増加していることを報告し30) 合

5 藤田宜是 34 日大医誌 Fig. 7 ASP and MAC were significantly increased in diabetic patients but were not elevated in patients with minimal change nephrotic syndrome27). Fig. 8 Complement inhibitor (K-76 COONa) regulates glomerular injury in diabetic rats (OLETF)30). 成果をあげることが出来ましたひとえに諸先輩方の御助力のおかげだと感謝しています此の場を借りて御礼申し上げます補体活性は上述のように外来抗原の暴露によるもの自己抗体の産生や免疫複合体によるもの代謝異常による非特異的な活性化など多彩でこれからも目標到達への道程は遠いかも知れません此の度の受賞を励みにさらなる努力と精進に勤めたいと存じますありがとうございました文献 1) Couser WG. Mediation of immune glomerular injury. Journal of Clinical Investigation 1993; 71: ) Masugi M. Die Allergie und Ihre Pathologische Bedeutung. Transactiones Societatis Pathologiae Japonicae 1939; 29: ) Dixon FJ, Wilson CB, Marquardt H. Experimental Immunologic Glomerulonephritis. In: Hamburger J, Crosnier J, Maxwell M, editors. Advances in Nephrology from the Necker Hospital. Chicago: Year Book Medical Publishers Inc, 1971: ) Walport MJ. Complement: First of two parts. New England Journal of Medicine 2001; 344: ) Brown KM, Sacks SH, Sheerin NS. Mechanisms of disease: the complement system in renal injury-new ways of looking at an old foe. Nature Clinical Practice Nephrology 2007; 3: ) Pangburn MK, Meler-Eberhard HJ. Relation of a putative thioester bond in C3 to activation of the alternative pathway and the binding of C3b to biological targets of complement. Journal of Experimental Medicine 1980; 152: ) 藤田宜是福家吉伸松本紘一補体系の活性化と腎組織障害慢性腎臓病における最近の展開日大医学雑誌 2008; 67: ) 大井洋之関正人藤田宜是小島弘之波多野道信補体系と腎炎腎と透析 1984; 17 9) 藤田宜是腎疾患に於ける C3 分解産物測定の臨床的意義とその経時的変動からみた補体活性の検討日本腎臓学会雑誌 1982; 24: ) Kojima H, Ohi H, Miyaji H, Seki M, Fujita T, Hatano M. Localization of C3d in renal tissues of patients with membranous nephropathy and IgA nephropathy. The Japanese Journal of Nephrology 1987; 29: ) Ohsawa I, Ohi H, Endo M, Fujita T, Kanmatsuse K, Nonaka M. Novel estimate of histologic activity in human glomerulonephritis by detection of complement components C3 messenger RNA. Clinical and Experimental Nephrology 1998; 2:

Couser WG. Mediation of immune glomerular injury. Journal of Clinical Investigation 1993; 71: 808 811. 2) Masugi M. Die Allergie und Ihre Pathologische Bedeutung.

6 68 (1) ) Fujita T, Ohi H, Seki M, Miyaji H, Hatano M. Clinical Evaluation and Characterization of A Unique C3 Breakdown Factor Detected in A Patient with Acute Glomerulonephritis. Nephron 1987; 47: ) Fujita T, Ohi H, Endo M, Ohsawa I, Kanmatsuse K. The Role of Sialidase in the Development of Hypocomplementemia in Postinfectious Acute Glomerulonephritis. Clinical Immunology 1999; 92: ) Ohi H, Watanabe S, Seki M, Fujita T, Ohmori F, Hatano M. C5 Measurement in Membranoproliferative Glomerulonephritis Patients with C3 Nephritic Factor. Nephron 1987; 47: ) Ohi H, Watanabe S, Fujita T, Seki M, Hatano M. Detection of C3bBb-stabilizing activity (C3 nephritic factor) in the serum from patients with membranoproliferative glomerulonephritis. Journal of Immunological Methods 1990; 31: ) Ohi H, Watanabe S, Fujita T, Yasugi T. Significance of C3 nephritic factor (C3NeF) in non-hypocomplementemic serum with membranoproliferative glomerulonephritis (MPGN). Clinical and Experimental Immunology 1992; 89: ) Tamano M, Fuke Y, Endo M, Ohsawa I, Fujita T, Ohi H. Urinary complement factor H in renal disease, Nephron 2002; 92: ) Endo M, Fuke Y, Tamano M, Hidaka M, Ohsawa I, Fujita T, Ohi H. Glomerular Deposition and Urinary Excretion of Complement Factor H in Idiopathic Membranous Nephropathy, Nephron Clinical Practice 2004; 97: c147 c ) Fuke Y, Fujita T, Satomura A, Endo M, Matsumoto M. The role of complement activation, detected by urinary C5b-9 and urinary factor H, in the excretion of urinary albumin in cisplatin nephropathy. Clinical Nephrology (in press). 20) Fujita T, Satomura S, Hidaka M, Ohsawa I, Endo M, Ohi H. Inhibitory Effect of Free Sialic Acid on Complement Activation and its Significannce in Hypocomplementemic Glomerulonephritis, Journal of Clinical Laboratory Analysis 1999; 13: ) Endo M, Ohi H, Ohsawa I, Fujita T, Matsushita M, Fujita T. Glomerular deposition of mannnose-binding lectin (MBL) indicates a novel mechanism of complement activation in IgA nephropathy. Nephrology Dialysis Transplantation 1998; 13: ) Ohsawa I, Ohi H, Endo M, Fujita T, Matsushita M, Fujita T. Evidence of lectin complement pathway activation in poststreptococcal glomerulonephritis. Kidney International 56: ) Endo M, Ohi H, Ohsawa I, Fujita T, Matsushita M, Fujita T. Complement activation through the lectin pathway in patients with Henoch-Schlein purpura nephritis. American Journal of Kidney Diseases 2000; 35: ) Endo M, Ohsawa I, Ohi H, Fujita T, Matsushita M, Fujita T. Mannose-binding lectin contributes to glomerulonephritis induced by hepatitis C virus infection, Nephron 2001; 87: ) 2007; 66: ) Fujita T, Fujioka T, Murakami T, Satomura A, Fuke Y, Matsumoto K. Chylomicron accelerates C3 tick-over by regulating the role of Factor H, leading to overproduction of acylation stimulating protein. Journal of Clinical Laboratory Analysis 2007; 21: ) Therapeutic Research 2007; 28: ) 2008; 50: ) 1992; 35: ) Fujita T, Ohi H, Komatsu K, Endo M, Ohsawa I, Kanmatsuse K. Complement Activation Accelerates Glomerular Injury in Diabetic Rats. Nephron 1999; 81:

Clinical Immunology 1999; 92: 91 102. 14) Ohi H, Watanabe S, Seki M, Fujita T, Ohmori F, Hatano M. C5 Measurement in Membranoproliferative Glomerulonephritis Patients with C3 Nephritic Factor.

CHEMOTHERAPY

CHEMOTHERAPY VOL.41 S-2 Laboratory and clinical evaluation of teicoplanin CHEMOTHERAPY AUG. 1993 VOL.41 S-2 Laboratory and clinical evaluation of teicoplanin Table 1. Comparative in vitro activity of teicoplanin