補体と腎臓病 - jsn.or.jp

1 30 clas-sical pathway CP alternative pathway AP lectin pathway LP terminal pathway TP AP 1990 1 C3 C3 glomerulopathy C3G dense deposit disease DDD H genetic 2 2010 DDD C3 C3 glomerulonephritis C3GN C3G 3 membrano proliferative glo-merulonephritis MPGN type 2 MPGN DDD type 1 type 3 C3GN DDD C3GN C3G 4 Kidney Dis-ease Improving Global Outcomes KDIGO C3 2 C3G C3G 5 C3G AP 6.

2 7 IgA 8 C3G C3G atypical hemolytic uremic syndrome aHUS aHUS C3G genetic acquired AP C3G aHUS 9 2018 60 4 537 542 aHUS C3 Cross-talk between atypical hemolytic uremic syndrome and C3 nephropathy associatedwith unregulated complement activation Masashi MIZUNO C3G aHUS C3G aHUS C3G AP C3 H2O C3 H2O B D C3 H2O Bb C3 tick-over ready to fire H H CP AP LP C3 C5 membrane attack complex MAC C3 C3 1 CD46 CD55 CD59 CR1 H H H aHUS C3G I H CD46 membrane cofactor pro-tein MCP aHUS C3G aHUS C3G H Merinero aHUS C3G aHUS H C3b

3 H 538C3 aHUS aHUS/C3 atypical hemolytic uremic syndrome thrombocytopenic microangiopathy membranoproliferative glomerulone-phritis dense deposit disease C3 nephritic factor 9 aHUS*H , I , CD46 mutations C3C3 GNwithTMA**?C3 GNwith MPGN**DDD**C3 Nef**I /H ?Acute/subacute? ?Chronic? C3G H tick-over C3G 9,10 C3 H H aHUS C3G 10 C3G C3 5 Sethi MPGN DDD deposit early component TP C4 11 aHUS throm-bocytopenic microangiopathy TMA C3 C3 aHUS C3G aHUS C3G C3 DDD C3 aHUS C3G C4 5,12,13 aHUS C3G AP aHUS C5a MAC.

4 C5b-9 TP C3G C3b H2O C3bBb AP C3 14 H homo H N C3 iC3b C3G 15,16 17 H TMA C3GN 18,19 C3G TP TP C3G 11 H C3GN C9 20 C3G aHUS 1 aHUS C3 H I 2 TMA 21 C3G aHUS TMA 2013 Manenti C3G 2 aHUS 22 Ankawi C3 C3GN TMA 23 De Vriese H aHUS C3G 24 Merinero H 10 707 aHUS 87 234 C3G 36 A110S Y118 Ifs*4 C192W C1218R R885 Sfs*3 aHUS C3G

5 H decay accelerating activity cofactor H aHUS genetic 539 1 aHUS C3 genetic H H -1 5CD46I B C3 Thrombomodulin Diacylglycerol kinase- 5, 14, 31 C3G H H H H H 25 H -1 -2 -5 multimerization H 25 aHUS C3G C3 C3b H CD46 C3 AP aHUS C3G 14,26 C3 C3/C5 B I C3 H nephritic factor Nef J zsi C3G/aHUS H aHUS B C3 DDD 27 H aHUS 90% SCR19 20 C- 28 aHUS H HF-Ig C3G Nef FH-Ig H C3G aHUS 22 Nef C3GN 4 DDD 8 C3G 12 IgG IgA 29 aHUS C3G aHUS C3G C3G aHUS aHUS TMA 20% / C3G 5

6 AHUS C5 C3G C5 5 aHUS C3G C3G aHUS C3G 540C3 aHUS 2 C3 acquired and genetic abnormalities mutation mutation Allele variant C3/C4/C5 Nephritic factor H I C3b C3 B C3bBb H I CD46 CFHR5 CFHR1-3 C3b C3 C3 C3b Thrombomodulin FH-CFHRs CFHR2-CFHR5 CFHR1-CRHR5 H H C3 CD46 C3b C3 2 3 C3G DDD DDD C3GN C3 heterogeneous 30 C3G C3G C3G 1.

7 Mizuno M, Suzuki Y, Ito Y. Complement regulation and kidney diseases recent knowledge of the double-edged roles of com-plement activation in nephrology. Clin Exp Nephrol 2018 22 3-14. 2. Levy M, Halbwachs-Mecarelli L, Gubler MC, Kohout G, Bense-nouci A, Niaudet P, Hauptmann G, Lesavre P. H deficiency in two brothers with atypical dense intramembranous deposit dis-ease. Kidney Int 1986 30 949-956. 3. Fakhouri F, Fr meaux-Bacchi V, No l LH, Cook HT, Pickering MC. C3 glomerulopathy a new classification. Nat Rev Nephrol 2010 6 8 494-499. 4. Ito N, Ohashi R, Nagata M. C3 glomerulopathy and current dilemmas. Clin Exp Nephrol 2016 21 541-551. 5. Goodship TH, Cook HT, Fakhouri F, Fervenza FC, Fr meaux-Bacchi V, Kavanagh D, Nester CM, Noris M, Pickering MC, Rodr guez de C rdoba S, Roumenina LT, Sethi S, Smith RJ Conference Participants.

8 Atypical hemolytic uremic syndrome and C3 glomerulopathy conclusions from a Kidney Disease Improving Global Outcomes KDIGO Controversies Confer-ence. Kidney Int 2017 91 539-551. 6. Al-Ghaithi B, Chanchlani R, Riedl M, Thorner P, Licht C. C3 glomerulopathy and post-infectious glomerulonephritis define a disease spectrum. Pediatr Nephrol 2016 31 2079-2086. 7. Khalighi MA, Wang S, Henriksen KJ, Bock M, Keswani M, Mee-han SM, Chang A. Revisiting post-infectious glomerulonephritis in the emerging era of C3 glomerulopathy. Clin Kidney J 2016 9 397-402. 8. Zipfel PF, Skerka C, Chen Q, Wiech T, Goodship T, Johnson S, Fremeaux-Bacchi V, Nester C, de C rdoba SR, Noris M, Picker-ing M, Smith R. The role of complement in C3 glomerulopathy. Mol Immunol 2015 67 21-30. 9. Servais A, Fr meaux-Bacchi V, Lequintrec M, Salomon R, Blouin J, Knebelmann B, Gr nfeld JP, Lesavre P, No l LH, Fakhouri F.

9 Primary glomerulonephritis with isolated C3 deposits a new entity which shares common genetic risk factors with haemolytic uraemic syndrome. J Med Genet 2007 44 Merinero HM, Garc a SP, Garc a-Ferna ndez J, Arjona E, Torta-jada A, Rodr guez de Co rdoba S. Complete functional character-541 3 C3 1 a b H FH H I CD46 C3 B FB D FD ACE-I/ARB ACE-I/ARB 2 a b anti-FB, anti-FD Nef, anti-C3, anti-properdin Targeted C Tx Targeted C Tx 3 a b AP LP Targeted C Tx Targeted C Tx C5 Targeted anti-complement therapy ization of disease-associated genetic variants in the complement factor H gene.

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