1932

Abstract

The vertebrate complement system consists of sequentially interacting proteins that provide for a rapid and powerful host defense. Nearly 60 proteins comprise three activation pathways (classical, alternative, and lectin) and a terminal cytolytic pathway common to all. Attesting to its potency, nearly half of the system's components are engaged in its regulation. An emerging theme over the past decade is that variations in these inhibitors predispose to two scourges of modern humans. One, occurring most often in childhood, is a rare but deadly thrombomicroangiopathy called atypical hemolytic uremic syndrome. The other, age-related macular degeneration, is the most common form of blindness in the elderly. Their seemingly unrelated clinical presentations and pathologies share the common theme of overactivity of the complement system's alternative pathway. This review summarizes insights gained from contemporary genetics for understanding how dysregulation of this powerful innate immune system leads to these human diseases.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-pathol-012615-044145
2017-01-24
2024-04-16
Loading full text...

Full text loading...

/deliver/fulltext/pathol/12/1/annurev-pathol-012615-044145.html?itemId=/content/journals/10.1146/annurev-pathol-012615-044145&mimeType=html&fmt=ahah

Literature Cited

  1. Gros P, Milder FJ, Janssen BJ. 1.  2008. Complement driven by conformational changes. Nat. Rev. Immunol. 8:48–58 [Google Scholar]
  2. Zhu Y, Thangamani S, Ho B, Ding JL. 2.  2005. The ancient origin of the complement system. EMBO J 24:382–94 [Google Scholar]
  3. Nonaka M, Kimura A. 3.  2006. Genomic view of the evolution of the complement system. Immunogenetics 58:701–13 [Google Scholar]
  4. Walport MJ. 4.  2001. Complement. First of two parts. N. Engl. J. Med. 344:1058–66 [Google Scholar]
  5. Chaplin H, Nasongkla M, Monroe MC. 5.  1981. Quantitation of red blood cell–bound C3d in normal subjects and random hospitalized patients. Br. J. Haematol 48:169–78 [Google Scholar]
  6. Petersen NE, Teisner B, Folkersen J, Svehag SE. 6.  1987. Heterogeneity of C4d and C3d and their complex formation with serum albumin. Acta Pathol. Microbiol. Immunol. Scand. C 95:4129–35 [Google Scholar]
  7. Bubeck D. 7.  2014. The making of a macromolecular machine: assembly of the membrane attack complex. Biochemistry 53:1908–15 [Google Scholar]
  8. Hourcade D, Holers VM, Atkinson JP. 8.  1989. The regulators of complement activation (RCA) gene cluster. Adv. Immunol 45:381–416 [Google Scholar]
  9. Liszewski MK, Post TW, Atkinson JP. 9.  1991. Membrane cofactor protein (MCP or CD46): newest member of the regulators of complement activation gene cluster. . Annu. Rev. Immunol. 9431–55
  10. Zipfel PF, Skerka C. 10.  2009. Complement regulators and inhibitory proteins. Nat. Rev. Immunol. 9:729–40 [Google Scholar]
  11. Lambris JD, Ricklin D, Geisbrecht BV. 11.  2008. Complement evasion by human pathogens. Nat. Rev. Microbiol. 6:132–42 [Google Scholar]
  12. Thurman JM, Holers VM. 12.  2006. The central role of the alternative complement pathway in human disease. J. Immunol. 176:1305–10 [Google Scholar]
  13. Holers VM. 13.  2008. The spectrum of complement alternative pathway-mediated diseases. Immunol. Rev. 223:300–16 [Google Scholar]
  14. Liszewski MK, Atkinson JP. 14.  2015. Complement regulators in human disease: lessons from modern genetics. J. Intern. Med. 277:294–305 [Google Scholar]
  15. Rodriguez de Córdoba S, Hidalgo MS, Pinto S, Tortajada A. 15.  2014. Genetics of atypical hemolytic uremic syndrome (aHUS). Semin. Thromb. Hemost. 40:422–30 [Google Scholar]
  16. Riedl M, Fakhouri F, Le Quintrec M, Noone DG, Jungraithmayr TC. 16.  et al. 2014. Spectrum of complement-mediated thrombotic microangiopathies: pathogenetic insights identifying novel treatment approaches. Semin. Thromb. Hemost. 40:444–64 [Google Scholar]
  17. Warwicker P, Goodship THJ, Donne RL, Pirson Y, Nicholls A. 17.  et al. 1998. Genetic studies into inherited and sporadic hemolytic uremic syndrome. Kidney Int 53:836–44 [Google Scholar]
  18. Kavanagh D, Richards A, Atkinson JP. 18.  2008. Complement regulatory genes and hemolytic uremic syndromes. Annu. Rev. Med. 59:293–309 [Google Scholar]
  19. Pirson Y, Lefebvre C, Arnout C, van Ypersele de Strihou C. 19.  1987. Hemolytic uremic syndrome in three adult siblings: a familial study and evolution. Clin. Nephrol. 28:250–55 [Google Scholar]
  20. Richards A, Kemp EJ, Liszewski MK, Goodship JA, Lampe AK. 20.  et al. 2003. Mutations in human complement regulator, membrane cofactor protein (CD46), predispose to development of familial hemolytic uremic syndrome. PNAS 100:12966–71 [Google Scholar]
  21. Liszewski MK, Leung M, Cui W, Subramanian VB, Parkinson J. 21.  et al. 2000. Dissecting sites important for complement regulatory activity in membrane cofactor protein (MCP; CD46). J. Biol. Chem. 275:37692–701 [Google Scholar]
  22. Liszewski MK, Atkinson JP. 22.  2015. Complement regulator CD46: genetic variants and disease associations. Hum. Genomics 9:7 [Google Scholar]
  23. Kavanagh D, Goodship TH, Richards A. 23.  2013. Atypical hemolytic uremic syndrome. Semin. Nephrol. 33:508–30 [Google Scholar]
  24. Marinozzi MC, Vergoz L, Rybkine T, Ngo S, Bettoni S. 24.  et al. 2014. Complement factor B mutations in atypical hemolytic uremic syndrome—disease-relevant or benign?. J. Am. Soc. Nephrol. 25:2053–65 [Google Scholar]
  25. Sinha A, Gulati A, Saini S, Blanc C, Gupta A. 25.  et al. 2014. Prompt plasma exchanges and immunosuppressive treatment improves the outcomes of anti-factor H autoantibody-associated hemolytic uremic syndrome in children. Kidney Int 85:1151–60 [Google Scholar]
  26. Schramm EC, Roumenina LT, Rybkine T, Chauvet S, Vieira-Martins P. 26.  et al. 2015. Mapping interactions between complement C3 and regulators using mutations in atypical hemolytic uremic syndrome. Blood 125:2359–69 [Google Scholar]
  27. Wu J, Wu YQ, Ricklin D, Janssen BJ, Lambris JD, Gros P. 27.  2009. Structure of complement fragment C3b-factor H and implications for host protection by complement regulators. Nat. Immunol. 10:728–33 [Google Scholar]
  28. Kajander T, Lehtinen MJ, Hyvarinen S, Bhattacharjee A, Leung E. 28.  et al. 2011. Dual interaction of factor H with C3d and glycosaminoglycans in host-nonhost discrimination by complement. PNAS 108:2897–902 [Google Scholar]
  29. Morgan HP, Schmidt CQ, Guariento M, Blaum BS, Gillespie D. 29.  et al. 2011. Structural basis for engagement by complement factor H of C3b on a self surface. Nat. Struct. Mol. Biol. 18:463–70 [Google Scholar]
  30. Forneris F, Wu J, Xue X, Ricklin D, Lin Z. 30.  et al. 2016. Regulators of complement activity mediate inhibitory mechanisms through a common C3b-binding mode. EMBO J 35:1133–49 [Google Scholar]
  31. Vivarelli M, Emma F. 31.  2014. Treatment of C3 glomerulopathy with complement blockers. Semin. Thromb. Hemost. 40:472–77 [Google Scholar]
  32. Khandhadia S, Cipriani V, Yates JR, Lotery AJ. 32.  2012. Age-related macular degeneration and the complement system. Immunobiology 217:127–46 [Google Scholar]
  33. Warwick A, Khandhadia S, Ennis S, Lotery A. 33.  2014. Age-related macular degeneration: a disease of systemic or local complement dysregulation?. J. Clin. Med. 3:1234–57 [Google Scholar]
  34. Schramm EC, Clark SJ, Triebwasser MP, Raychaudhuri S, Seddon JM, Atkinson JP. 34.  2014. Genetic variants in the complement system predisposing to age-related macular degeneration: a review. Mol. Immunol. 61:118–25 [Google Scholar]
  35. Bora NS, Matta B, Lyzogubov VV, Bora PS. 35.  2015. Relationship between the complement system, risk factors and prediction models in age-related macular degeneration. Mol. Immunol. 63:176–83 [Google Scholar]
  36. Fritsche LG, Fariss RN, Stambolian D, Abecasis GR, Curcio CA, Swaroop A. 36.  2014. Age-related macular degeneration: genetics and biology coming together. Annu. Rev. Genomics Hum. Genet. 15:151–71 [Google Scholar]
  37. Wagner EK, Raychaudhuri S, Villalonga MB, Java A, Triebwasser MP. 37.  et al. 2016. Mapping rare, deleterious mutations in factor H: association with early onset, drusen burden, and lower antigenic levels in familial AMD. Sci. Rep. 6:31531 [Google Scholar]
  38. Hageman GS, Luthert PJ, Victor Chong NH, Johnson LV, Anderson DH, Mullins RF. 38.  2001. An integrated hypothesis that considers drusen as biomarkers of immune-mediated processes at the RPE-Bruch's membrane interface in aging and age-related macular degeneration. Prog. Retin. Eye Res. 20:705–32 [Google Scholar]
  39. Mullins RF, Aptsiauri N, Hageman GS. 39.  2001. Structure and composition of drusen associated with glomerulonephritis: implications for the role of complement activation in drusen biogenesis. Eye 15:390–95 [Google Scholar]
  40. Recalde S, Tortajada A, Subias M, Anter J, Blasco M. 40.  et al. 2016. Molecular basis of factor H R1210C association with ocular and renal diseases. J. Am. Soc. Nephrol. 27:1305–11 [Google Scholar]
  41. Hageman GS, Anderson DH, Johnson LV, Hancox LS, Taiber AJ. 41.  et al. 2005. A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. PNAS 102:7227–32 [Google Scholar]
  42. Edwards AO, Ritter R 3rd, Abel KJ, Manning A, Panhuysen C, Farrer LA. 42.  2005. Complement factor H polymorphism and age-related macular degeneration. Science 308:421–24 [Google Scholar]
  43. Haines JL, Hauser MA, Schmidt S, Scott WK, Olson LM. 43.  et al. 2005. Complement factor H variant increases the risk of age-related macular degeneration. Science 308:419–21 [Google Scholar]
  44. Klein RJ, Zeiss C, Chew EY, Tsai JY, Sackler RS. 44.  et al. 2005. Complement factor H polymorphism in age-related macular degeneration. Science 308:385–89 [Google Scholar]
  45. Edwards AO, Ritter R III, Abel KJ, Manning A Panhuysen C, Farrer LA. 45.  2005. Complement factor H polymorphism and age-related macular degeneration. Science 308:421–24 [Google Scholar]
  46. Sofat R, Casas JP, Webster AR, Bird AC, Mann SS. 46.  et al. 2012. Complement factor H genetic variant and age-related macular degeneration: effect size, modifiers and relationship to disease subtype. Int. J. Epidemiol. 41:250–62 [Google Scholar]
  47. Hakobyan S, Tortajada A, Harris CL, de Cordoba SR, Morgan BP. 47.  2010. Variant-specific quantification of factor H in plasma identifies null alleles associated with atypical hemolytic uremic syndrome. Kidney Int 78:782–88 [Google Scholar]
  48. Herbert AP, Makou E, Chen ZA, Kerr H, Richards A. 48.  et al. 2015. Complement evasion mediated by enhancement of captured factor H: implications for protection of self-surfaces from complement. J. Immunol. 195:4986–98 [Google Scholar]
  49. Clark SJ, Bishop PN, Day AJ. 49.  Complement factor H and age-related macular degeneration: the role of glycosaminoglycan recognition in disease pathology. Biochem. Soc. Trans. 38:1342–48 [Google Scholar]
  50. Sjoberg AP, Trouw LA, Clark SJ, Sjolander J, Heinegard D. 50.  et al. 2007. The factor H variant associated with age-related macular degeneration (His-384) and the non-disease-associated form bind differentially to C-reactive protein, fibromodulin, DNA, and necrotic cells. J. Biol. Chem. 282:10894–900 [Google Scholar]
  51. Haapasalo K, Jarva H, Siljander T, Tewodros W, Vuopio-Varkila J, Jokiranta TS. 51.  2008. Complement factor H allotype 402H is associated with increased C3b opsonization and phagocytosis of Streptococcus pyogenes. . Mol. Microbiol. 70:583–94 [Google Scholar]
  52. Clark SJ, Higman VA, Mulloy B, Perkins SJ, Lea SM. 52.  et al. 2006. His-384 allotypic variant of factor H associated with age-related macular degeneration has different heparin binding properties from the non-disease-associated form. J. Biol. Chem. 281:24713–20 [Google Scholar]
  53. Clark SJ, Perveen R, Hakobyan S, Morgan BP, Sim RB. 53.  et al. 2010. Impaired binding of the age-related macular degeneration-associated complement factor H 402H allotype to Bruch's membrane in human retina. J. Biol. Chem. 285:30192–202 [Google Scholar]
  54. Raychaudhuri S, Iartchouk O, Chin K, Tan PL, Tai AK. 54.  et al. 2011. A rare penetrant mutation in CFH confers high risk of age-related macular degeneration. Nat. Genet. 43:1232–36 [Google Scholar]
  55. Manuelian T, Hellwage J, Meri S, Caprioli J, Noris M. 55.  et al. 2003. Mutations in factor H reduce binding affinity to C3b and heparin and surface attachment to endothelial cells in hemolytic uremic syndrome. J. Clin. Investig. 111:1181–90 [Google Scholar]
  56. Jozsi M, Heinen S, Hartmann A, Ostrowicz CW, Hälbich S. 56.  et al. 2006. Factor H and atypical hemolytic uremic syndrome: mutations in the C-terminus cause structural changes and defective recognition functions. J. Am. Soc. Nephrol. 17:170–77 [Google Scholar]
  57. Servais A, Fremeaux-Bacchi V, Lequintrec M, Salomon R, Blouin J. 57.  et al. 2007. Primary glomerulonephritis with isolated C3 deposits: a new entity which shares common genetic risk factors with haemolytic uraemic syndrome. J. Med. Genet 44193–99 [Google Scholar]
  58. Sanchez-Corral P, Perez-Caballero D, Huarte O, Simckes A, Goicoechea E. 58.  et al. 2002. Structural and functional characterization of factor H mutations associated with atypical hemolytic uremic syndrome. Am. J. Hum. Genet. 71:1285–95 [Google Scholar]
  59. Yu Y, Triebwasser MP, Wong EK, Schramm EC, Thomas B. 59.  et al. 2014. Whole-exome sequencing identifies rare, functional CFH variants in families with macular degeneration. Hum. Mol. Genet. 23:5283–93 [Google Scholar]
  60. Servais A, Noël LH, Roumenina LT, Le Quintrec M, Ngo S. 60.  et al. 2012. Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies. Kidney Int 82:454–64 [Google Scholar]
  61. Fakhouri F, Roumenina L, Provot F, Sallee M, Caillard S. 61.  et al. 2010. Pregnancy-associated hemolytic uremic syndrome revisited in the era of complement gene mutations. J. Am. Soc. Nephrol. 21:859–67 [Google Scholar]
  62. Bradley DT, Zipfel PF, Hughes AE. 62.  2011. Complement in age-related macular degeneration: a focus on function. Eye 25:683–93 [Google Scholar]
  63. Triebwasser MP, Roberson ED, Yu Y, Schramm EC, Wagner EK. 63.  et al. 2015. Rare variants in the functional domains of complement factor H are associated with age-related macular degeneration. Investig. Ophthalmol. Visual Sci. 56:6873–78 [Google Scholar]
  64. Noris M, Caprioli J, Bresin E, Mossali C, Pianetti G. 64.  et al. 2010. Relative role of genetic complement abnormalities in sporadic and familial aHUS and their impact on clinical phenotype. Clin. J. Am. Soc. Nephrol. 5:1844–59 [Google Scholar]
  65. Dragon-Durey M-A, Loirat C, Cloarec S, Macher M-A, Blouin J. 65.  et al. 2005. Anti-factor H autoantibodies associated with atypical hemolytic uremic syndrome. J. Am. Soc. Nephrol. 16:555–63 [Google Scholar]
  66. Jozsi M, Licht C, Strobel S, Zipfel SL, Richter H. 66.  et al. 2008. Factor H autoantibodies in atypical hemolytic uremic syndrome correlate with CFHR1/CFHR3 deficiency. Blood 111:1512–14 [Google Scholar]
  67. Hofer J, Janecke AR, Zimmerhackl LB, Riedl M, Rosales A. 67.  et al. 2013. Complement factor H-related protein 1 deficiency and factor H antibodies in pediatric patients with atypical hemolytic uremic syndrome. Clin. J. Am. Soc. Nephrol. 8:407–15 [Google Scholar]
  68. Liszewski MK, Kemper C, Price JD, Atkinson JP. 68.  2005. Emerging roles and new functions of CD46. Springer Semin. Immunopathol. 27:345–58 [Google Scholar]
  69. Cardone J, Le Friec G, Kemper C. 69.  2011. CD46 in innate and adaptive immunity: an update. Clin. Exp. Immunol. 164:301–11 [Google Scholar]
  70. Yamamoto H, Fara AF, Dasgupta P, Kemper C. 70.  2013. CD46: the ‘multitasker’ of complement proteins. Int. J. Biochem. Cell Biol. 45:2808–20 [Google Scholar]
  71. Kemper C, Atkinson JP. 71.  2007. T-cell regulation: with complements from innate immunity. Nat. Rev. Immunol. 7:9–18 [Google Scholar]
  72. Cattaneo R. 72.  2004. Four viruses, two bacteria, and one receptor: membrane cofactor protein (CD46) as pathogens' magnet. J. Virol. 78:4385–88 [Google Scholar]
  73. Liszewski MK, Bertram P, Leung MK, Hauhart R, Zhang L, Atkinson JP. 73.  2008. Smallpox inhibitor of complement enzymes (SPICE): regulation of complement activation on cells and mechanism of its cellular attachment. J. Immunol. 181:4199–207 [Google Scholar]
  74. Ojha H, Panwar HS, Gorham RD Jr, Morikis D, Sahu A. 74.  2014. Viral regulators of complement activation: structure, function and evolution. Mol. Immunol. 61:89–99 [Google Scholar]
  75. Granoff DM. 75.  2009. Relative importance of complement-mediated bactericidal and opsonic activity for protection against meningococcal disease. Vaccine 27:Suppl. 2B117–25 [Google Scholar]
  76. Kolev M, Le Friec G, Kemper C. 76.  2014. Complement—tapping into new sites and effector systems. Nat. Rev. Immunol. 14:811–20 [Google Scholar]
  77. Kolev M, Dimeloe S, Le Friec G, Navarini A, Arbore G. 77.  et al. 2015. Complement regulates nutrient influx and metabolic reprogramming during Th1 cell responses. Immunity 42:1033–47 [Google Scholar]
  78. Astier AL. 78.  2008. T-cell regulation by CD46 and its relevance in multiple sclerosis. Immunology 124:149–54 [Google Scholar]
  79. Liszewski MK, Kolev M, Le Friec G, Leung M, Bertram PG. 79.  et al. 2013. Intracellular complement activation sustains T cell homeostasis and mediates effector differentiation. Immunity 39:1143–57 [Google Scholar]
  80. Esparza-Gordillo J, Goicoechea de Jorge E, Buil A, Carreras Berges L, López-Trascasa M. 80.  et al. 2005. Predisposition to atypical hemolytic uremic syndrome involves the concurrence of different susceptibility alleles in the regulators of complement activation gene cluster in 1q32. Hum. Mol. Genet 14:703–12 Corrigendum, Hum. Mol. Genet. 14:1107 [Google Scholar]
  81. Saunders RE, Abarrategui-Garrido C, Frémeaux-Bacchi V, Goicoechea de Jorge E, Goodship TH. 81.  et al. 2007. The interactive factor H-atypical hemolytic uremic syndrome mutation database and website: update and integration of membrane cofactor protein and factor I mutations with structural models. Hum. Mutat. 28:222–34 [Google Scholar]
  82. Sullivan M, Erlic Z, Hoffmann MM, Arbeiter K, Patzer L. 82.  et al. 2010. Epidemiological approach to identifying genetic predispositions for atypical hemolytic uremic syndrome. Ann. Hum. Genet. 74:17–26 [Google Scholar]
  83. Meri S. 83.  2013. Complement activation in diseases presenting with thrombotic microangiopathy. Eur. J. Intern. Med. 24:496–502 [Google Scholar]
  84. Noris M, Brioschi S, Caprioli J, Todeschini M, Bresin E. 84.  et al. 2003. Familial haemolytic uraemic syndrome and an MCP mutation. Lancet 362:1542–47 [Google Scholar]
  85. Richards A, Liszewski MK, Kavanagh D, Fang CJ, Moulton EA. 85.  et al. 2007. Implications of the initial mutations in membrane cofactor protein (MCP; CD46) leading to atypical hemolytic uremic syndrome. Mol. Immunol. 44:111–22 [Google Scholar]
  86. Bresin E, Rurali E, Caprioli J, Sanchez-Corral P, Fremeaux-Bacchi V. 86.  et al. 2013. Combined complement gene mutations in atypical hemolytic uremic syndrome influence clinical phenotype. J. Am. Soc. Nephrol. 24:475–86 [Google Scholar]
  87. Rodriguez E, Rallapalli PM, Osborne AJ, Perkins SJ. 87.  2014. New functional and structural insights from updated mutational databases for complement factor H, factor I, membrane cofactor protein and C3. Biosci. Rep. 34:5e00146 [Google Scholar]
  88. Esparza-Gordillo J, Goicoechea de Jorge E, Buil A, Carreras Berges L, López-Trascasa M. 88.  et al. 2005. Predisposition to atypical hemolytic uremic syndrome involves the concurrence of different susceptibility alleles in the regulators of complement activation gene cluster in 1q32. Hum. Mol. Genet. 14:703–12 [Google Scholar]
  89. Fang CJ, Fremeaux-Bacchi V, Liszewski MK, Pianetti G, Noris M. 89.  et al. 2008. Membrane cofactor protein mutations in atypical hemolytic uremic syndrome (aHUS), fatal Stx-HUS, C3 glomerulonephritis, and the HELLP syndrome. Blood 111:624–32 [Google Scholar]
  90. Fremeaux-Bacchi V, Sanlaville D, Menouer S, Blouin J, Dragon-Durey MA. 90.  et al. 2007. Unusual clinical severity of complement membrane cofactor protein-associated hemolytic-uremic syndrome and uniparental isodisomy. Am. J. Kidney Dis. 49:323–29 [Google Scholar]
  91. Noris M, Capriloli Bresin E, Mossali C, Pianetti G. 91.  et al. 2010. Relative role of genetic complement abnormalities in sporadic and familial aHUS and their impact on clinical phenotype. Clin. J. Am. Soc. Nephrol. 5:1844–59 [Google Scholar]
  92. Lyzogubov V, Wu X, Jha P, Tytarenko R, Triebwasser M. 92.  et al. 2014. Complement regulatory protein CD46 protects against choroidal neovascularization in mice. Am. J. Pathol. 184:2537–48 [Google Scholar]
  93. Molina H, Wong W, Kinoshita T, Brenner C, Foley S, Holers VM. 93.  1992. Distinct receptor and regulatory properties of recombinant mouse complement receptor 1 (CR1) and Crry, the two genetic homologues of human CR1. J. Exp. Med. 175:121–29 [Google Scholar]
  94. Hasegawa E, Sweigard H, Husain D, Olivares AM, Chang B. 94.  et al. 2014. Characterization of a spontaneous retinal neovascular mouse model. PLOS ONE 9:e106507 [Google Scholar]
  95. Nagai N, Lundh von Leithner P, Izumi-Nagai K, Hosking B, Chang B. 95.  et al. 2014. Spontaneous CNV in a novel mutant mouse is associated with early VEGF-A-driven angiogenesis and late-stage focal edema, neural cell loss, and dysfunction. Investig. Ophthalmol. Visual Sci. 55:3709–19 [Google Scholar]
  96. Lyzogubov VV, Bora PS, Wu X, Horn LE, de Roque R. 96.  et al. 2016. The complement regulatory protein CD46 deficient mouse spontaneously develops dry-type age-related macular degeneration–like phenotype. Am. J. Pathol. 186:2088–104 [Google Scholar]
  97. Nilsson SC, Kalchishkova N, Trouw LA, Fremeaux-Bacchi V, Villoutreix BO, Blom AM. 97.  2010. Mutations in complement factor I as found in atypical hemolytic uremic syndrome lead to either altered secretion or altered function of factor I. Eur. J. Immunol. 40:172–85 [Google Scholar]
  98. Seddon JM, Yu Y, Miller EC, Reynolds R, Tan PL. 98.  et al. 2013. Rare variants in CFI, C3 and C9 are associated with high risk of advanced age-related macular degeneration. Nat. Genet. 45:1366–70 [Google Scholar]
  99. Kavanagh D, Yu Y, Schramm EC, Triebwasser M, Wagner EK. 99.  et al. 2015. Rare genetic variants in the CFI gene are associated with advanced age-related macular degeneration and commonly result in reduced serum factor I levels. Hum. Mol. Genet. 24:3861–70 [Google Scholar]
  100. Janssen BJ, Huizinga EG, Raaijmakers HC, Roos A, Daha MR. 100.  et al. 2005. Structures of complement component C3 provide insights into the function and evolution of immunity. Nature 437:505–11 [Google Scholar]
  101. Frémeaux-Bacchi V, Miller EC, Liszewski MK, Strain L, Blouin J. 101.  et al. 2008. Mutations in complement C3 predispose to development of atypical hemolytic uremic syndrome. Blood 112:4948–52 [Google Scholar]
  102. Sartz L, Olin AI, Kristoffersson AC, Stahl AL, Johansson ME. 102.  et al. 2012. A novel C3 mutation causing increased formation of the C3 convertase in familial atypical hemolytic uremic syndrome. J. Immunol. 188:2030–37 [Google Scholar]
  103. Martinez-Barricarte R, Heurich M, Valdes-Cañedo F, Vazquez-Martul E, Torreira E. 103.  et al. 2010. Human C3 mutation reveals a mechanism of dense deposit disease pathogenesis and provides insights into complement activation and regulation. J. Clin. Investig. 120:3702–12 [Google Scholar]
  104. Helgason H, Sulem P, Duvvari MR, Luo H, Thorleifsson G. 104.  et al. 2013. A rare nonsynonymous sequence variant in C3 is associated with high risk of age-related macular degeneration. Nat. Genet. 45:1371–74 [Google Scholar]
  105. Duvvari MR, Paun CC, Buitendijk GH, Saksens NT, Volokhina EB. 105.  et al. 2014. Analysis of rare variants in the C3 gene in patients with age-related macular degeneration. PLOS ONE 9:e94165 [Google Scholar]
  106. Heurich M, Martinez-Barricarte R, Francis NJ, Roberts DL, Rodriguez de Córdoba S. 106.  et al. 2011. Common polymorphisms in C3, factor B, and factor H collaborate to determine systemic complement activity and disease risk. PNAS 108:8761–66 [Google Scholar]
  107. Abrera-Abeleda MA, Nishimura C, Frees K, Jones M, Maga T. 107.  et al. 2011. Allelic variants of complement genes associated with dense deposit disease. J. Am. Soc. Nephrol. 22:1551–59 [Google Scholar]
  108. Blom AM, Villoutreix BO, Dahlback B. 108.  2004. Complement inhibitor C4b-binding protein—friend or foe in the innate immune system?. Mol. Immunol. 40:1333–46 [Google Scholar]
  109. Blom AM, Bergstrom F, Edey M, Diaz-Torres M, Kavanagh D. 109.  et al. 2008. A novel non-synonymous polymorphism (p.Arg240His) in C4b-binding protein is associated with atypical hemolytic uremic syndrome and leads to impaired alternative pathway cofactor activity. J. Immunol. 180:6385–91 [Google Scholar]
  110. Martinez-Barricarte R, Goicoechea de Jorge E, Montes T, Layana AG, Rodriguez de Córdoba S. 110.  2009. Lack of association between polymorphisms in C4b-binding protein and atypical haemolytic uraemic syndrome in the Spanish population. Clin. Exp. Immunol. 155:59–64 [Google Scholar]
  111. Kavanagh D, Burgess R, Spitzer D, Richards A, Diaz-Torres ML. 111.  et al. 2007. The decay accelerating factor mutation I197V found in hemolytic uraemic syndrome does not impair complement regulation. Mol. Immunol. 44:3162–67 [Google Scholar]
  112. Brodbeck WG, Mold C, Atkinson JP, Medof ME. 112.  2000. Cooperation between decay-accelerating factor and membrane cofactor protein in protecting cells from autologous complement attack. J. Immunol. 165:3999–4006 [Google Scholar]
  113. Liszewski MK, Leung MK, Schraml B, Goodship TH, Atkinson JP. 113.  2007. Modeling how CD46 deficiency predisposes to atypical hemolytic uremic syndrome. Mol. Immunol. 44:1559–68 [Google Scholar]
  114. Zimmerhackl LB, Besbas N, Jungraithmayr T, van de Kar N, Karch H. 114.  et al. 2006. Epidemiology, clinical presentation, and pathophysiology of atypical and recurrent hemolytic uremic syndrome. Semin. Thromb. Hemost. 32:113–20 [Google Scholar]
  115. Caprioli J, Noris M, Brioschi S, Pianetti G, Castelletti F. 115.  et al. 2006. Genetics of HUS: the impact of MCP, CFH and IF mutations on clinical presentation, response to treatment, and outcome. Blood 108:1267–79 [Google Scholar]
  116. Hillmen P, Young NS, Schubert J, Brodsky RA, Socié G. 116.  et al. 2006. The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria. N. Engl. J. Med. 355:1233–43 [Google Scholar]
  117. Zuber J, Fakhouri F, Roumenina LT, Loirat C, Frémeaux-Bacchi V. 117.  2012. Use of eculizumab for atypical haemolytic uraemic syndrome and C3 glomerulopathies. Nat. Rev. Nephrol. 8:643–57 [Google Scholar]
  118. Pickering MC, Warren J, Rose KL, Carlucci F, Wang Y. 118.  et al. 2006. Prevention of C5 activation ameliorates spontaneous and experimental glomerulonephritis in factor H-deficient mice. PNAS 103:9649–54 [Google Scholar]
  119. Pickering MC, Goicoechea de Jorge E, Martinez-Barricarte R, Recalde S, Garcia-Layana A. 119.  et al. 2007. Spontaneous hemolytic uremic syndrome triggered by complement factor H lacking surface recognition domains. J. Exp. Med. 204:1249–56 [Google Scholar]
  120. Pickering MC, Goicoechea de Jorge E, Martinez-Barricarte R, Recalde S, Garcia-Layana KL. 120.  et al. 2007. Spontaneous hemolytic uremic syndrome triggered by complement factor H lacking surface recognition domains. J. Exp. Med. 204:1249–56 [Google Scholar]
  121. Gruppo RA, Rother RP. 121.  2009. Eculizumab for congenital atypical hemolytic-uremic syndrome. N. Engl. J. Med. 360:544–46 [Google Scholar]
  122. Nurnberger J, Witzke O, Saez AO, Vester U, Baba HA. 122.  et al. 2009. Eculizumab for atypical hemolytic-uremic syndrome. N. Engl. J. Med. 360:542–44 [Google Scholar]
  123. Legendre CM, Licht C, Muus P, Greenbaum LA, Babu S. 123.  et al. 2013. Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome. N. Engl. J. Med. 368:2169–81 [Google Scholar]
  124. Licht C, Greenbaum LA, Muus P, Babu S, Bedrosian CL. 124.  et al. 2015. Efficacy and safety of eculizumab in atypical hemolytic uremic syndrome from 2-year extensions of phase 2 studies. Kidney Int 87:1061–73 [Google Scholar]
  125. Walle JV, Delmas Y, Ardissino G, Wang J, Kincaid JF, Haller H. 125.  2016. Improved renal recovery in patients with atypical hemolytic uremic syndrome following rapid initiation of eculizumab treatment. J. Nephrol. doi:10.1007/s40620-016-0288-3. In press
  126. Okumi M, Tanabe K. 126.  2016. Prevention and treatment of atypical hemolytic uremic syndrome after kidney transplantation. Nephrology 21:Suppl. 19–13 [Google Scholar]
  127. Pickering MC, Cook HT, Warren J, Bygrave AE, Moss J. 127.  et al. 2002. Uncontrolled C3 activation causes membranoproliferative glomerulonephritis in mice deficient in complement factor H. Nat. Genet. 31:424–28 [Google Scholar]
  128. Bomback AS. 128.  2014. Eculizumab in the treatment of membranoproliferative glomerulonephritis. Nephron. Clin. Pract. 128:270–76 [Google Scholar]
  129. Bomback AS, Appel GB. 129.  2012. Pathogenesis of the C3 glomerulopathies and reclassification of MPGN. Nat. Rev. Nephrol. 8:634–42 [Google Scholar]
  130. Herlitz LC, Bomback AS, Markowitz GS, Stokes MB, Smith RN. 130.  et al. 2012. Pathology after eculizumab in dense deposit disease and C3 GN. J. Am. Soc. Nephrol. 23:1229–37 [Google Scholar]
  131. Bomback AS, Smith RJ, Barile GR, Zhang Y, Heher EC. 131.  et al. 2012. Eculizumab for dense deposit disease and C3 glomerulonephritis. Clin. J. Am. Soc. Nephrol. 7:748–56 [Google Scholar]
/content/journals/10.1146/annurev-pathol-012615-044145
Loading
/content/journals/10.1146/annurev-pathol-012615-044145
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error