Although new activation and regulatory mechanisms are still being identified, the basic architecture of the complement system has been known for decades. Two major roles of complement are to control certain bacterial infections and to promote clearance of apoptotic cells. In addition, although inappropriate complement activation has long been proposed to cause tissue damage in human inflammatory and autoimmune diseases, whether this is indeed true has been uncertain. However, recent studies in humans, especially those using newly available biological therapeutics, have now clearly demonstrated the pathophysiologic importance of the complement system in several rare diseases. Beyond these conditions, recent genetic studies have strongly supported an injurious role for complement in a wide array of human inflammatory, degenerative, and autoimmune diseases. This review includes an overview of complement activation, regulatory, and effector mechanisms. It then focuses on new understandings gained from genetic studies, ex vivo analyses, therapeutic trials, and animal models as well as on new research opportunities.


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Literature Cited

  1. Fearon DT, Locksley RM. 1.  1996. The instructive role of innate immunity in the acquired immune response. Science 272:50–54 [Google Scholar]
  2. Brown EJ. 2.  1991. Complement receptors and phagocytosis. Curr. Opin. Immunol. 3:76–82 [Google Scholar]
  3. Carroll MC. 3.  1998. The role of complement and complement receptors in the induction and regulation of immunity. Annu. Rev. Immunol. 16:545–68 [Google Scholar]
  4. Kaya Z, Afanasyeva M, Wang Y, Dohmen KM, Schlichting J. 4.  et al. 2001. Contribution of the innate immune system to autoimmune myocarditis: a role for complement. Nat. Immunol. 2:739–45 [Google Scholar]
  5. Botto M, Walport MJ. 5.  2002. C1q, autoimmunity and apoptosis. Immunobiology 205:395–406 [Google Scholar]
  6. Davies KA, Peters AM, Beynon HLC, Walport MJ. 6.  1992. Immune complex processing in patients with systemic lupus erythematosus. J. Clin. Investig. 90:2075–83 [Google Scholar]
  7. Holers VM, Carroll MC. 7.  2005. Innate autoimmunity. Adv. Immunol. 86:137–57 [Google Scholar]
  8. Markiewski MM, Lambris JD. 8.  2009. Is complement good or bad for cancer patients? A new perspective on an old dilemma. Trends Immunol. 30:286–92 [Google Scholar]
  9. Holers VM. 9.  2005. Complement receptors and the shaping of the natural antibody repertoire. Springer Sem. Immunopathol. 26:405–23 [Google Scholar]
  10. Strey CW, Markiewski M, Matellos D, Tudoran R, Spruce LA. 10.  et al. 2003. The proinflammatory mediators C3a and C5a are essential for liver regeneration. J. Exp. Med. 198:913–23 [Google Scholar]
  11. Yanai R, Thanos A, Connor KM. 11.  2012. Complement involvement in neovascular ocular diseases. Adv. Exp. Med. Biol. 946:161–83 [Google Scholar]
  12. Ricklin D, Hajishengallis G, Yang K, Lambris JD. 12.  2010. Complement: a key system for immune surveillance and homeostasis. Nat. Immunol. 11:785–97 [Google Scholar]
  13. Noris M, Remuzzi G. 13.  2008. Translational mini-review series on complement factor H: therapies of renal diseases associated with complement factor H abnormalities: atypical haemolytic uraemic syndrome and membranoproliferative glomerulonephritis. Clin. Exp. Immunol. 151:199–209 [Google Scholar]
  14. Pickering MC, Cook HT. 14.  2008. Translational mini-review series on complement factor H: renal diseases associated with complement factor H: novel insights from humans and animals. Clin. Exp. Immunol. 151:210–30 [Google Scholar]
  15. Rosse WF, Nishimura J. 15.  2003. Clinical manifestations of paroxysmal nocturnal hemoglobinuria: present state and future problems. Int. J. Hematol. 77:113–20 [Google Scholar]
  16. Papadopoulos MC, Verkman AS. 16.  2012. Aquaporin 4 and neuromyelitis optica. Lancet Neurol. 11:535–44 [Google Scholar]
  17. Holers VM. 17.  2003. The complement system as a therapeutic target in autoimmunity. Clin. Immunol. 107:140–51 [Google Scholar]
  18. Ricklin D, Lambris JD. 18.  2013. Progress and trends in complement therapeutics. Adv. Exp. Med. Biol. 735:1–22 [Google Scholar]
  19. Botto M, Kirschfink M, Macor P, Pickering MC, Wurzner R, Tedesco F. 19.  2009. Complement in human diseases: lessons from complement deficiencies. Mol. Immunol. 46:2774–83 [Google Scholar]
  20. Zipfel PF, Hallstrom T, Riesbeck K. 20.  2013. Human complement control and complement evasion by pathogenic microbes: tipping the balance. Mol. Immunol. 56:152–60 [Google Scholar]
  21. Lachmann PJ, Hughes-Jones NC. 21.  1984. Initiation of complement activation. Springer Semin. Immunopathol. 7:143–62 [Google Scholar]
  22. Doni A, Garlanda C, Bottazzi B, Meri S, Garred P, Mantovani A. 22.  2012. Interactions of the humoral pattern recognition molecule PTX3 with the complement system. Immunobiology 217:1122–28 [Google Scholar]
  23. Muller-Eberhard HJ. 23.  1988. Molecular organization and function of the complement system. Annu. Rev. Biochem. 57:321–47 [Google Scholar]
  24. Nilsson B, Ekdahl KN. 24.  2012. The tick-over theory revisited: Is C3 a contact-activated protein?. Immunobiology 217:1106–10 [Google Scholar]
  25. Lachmann PJ. 25.  2009. The amplification loop of the complement pathways. Adv. Immunol. 104:115–49 [Google Scholar]
  26. Ricklin D. 26.  2012. Manipulating the mediator: modulation of the alternative complement pathway C3 convertase in health, disease and therapy. Immunobiology 217:1057–66 [Google Scholar]
  27. Holers VM, Thurman JM. 27.  2004. The alternative pathway of complement in disease: opportunities for therapeutic targeting. Mol. Immunol. 41:147–52 [Google Scholar]
  28. Runza VL, Schwaeble W, Mannel DN. 28.  2008. Ficolins: novel pattern recognition molecules of the innate immune response. Immunobiology 213:297–306 [Google Scholar]
  29. Gadjeva M, Takahashi K, Thiel S. 29.  2004. Mannan-binding lectin: a soluble pattern recognition molecule. Mol. Immunol. 41:113–21 [Google Scholar]
  30. Reid KBM, Turner MW. 30.  1994. Mammalian lectins in activation and clearance mechanisms involving the complement system. Springer Semin. Immunopathol. 15:307–25 [Google Scholar]
  31. Collard CD, Montalto MC, Reenstra WR, Buras JA, Stahl GL. 31.  2001. Endothelial oxidative stress activates the lectin complement pathway: role of cytokeratin 1. Am. J. Pathol. 159:1045–54 [Google Scholar]
  32. Jordan JE, Montalto MC, Stahl GL. 32.  2001. Inhibition of mannose-binding lectin reduces postischemic myocardial reperfusion injury. Circulation 104:1413–18 [Google Scholar]
  33. Sahu A, Lambris JD. 33.  2001. Structure and biology of complement protein C3, a connecting link between innate and acquired immunity. Immunol. Rev. 180:35–48 [Google Scholar]
  34. Lea SM, Johnson S. 34.  2012. Putting the structure into complement. Immunobiology 217:1117–21 [Google Scholar]
  35. Gros P, Milder FJ, Janssen BJ. 35.  2008. Complement driven by conformational changes. Nat. Rev. Immunol. 8:48–58 [Google Scholar]
  36. Wetsel RA. 36.  1995. Structure, function and cellular expression of complement anaphylatoxin receptors. Curr. Opin. Immunol. 7:48–53 [Google Scholar]
  37. Morgan BP, Gasque P. 37.  1997. Extrahepatic complement biosynthesis: where, when and why?. Clin. Exp. Immunol. 107:1–7 [Google Scholar]
  38. Gadjeva M, Verschoor A, Brockman MA, Jezak H, Shen LM. 38.  et al. 2002. Macrophage-derived complement component C4 can restore humoral immunity in C4-deficient mice. J. Immunol. 169:5489–95 [Google Scholar]
  39. Li K, Sacks SH, Zhou W. 39.  2007. The relative importance of local and systemic complement production in ischaemia, transplanation and other pathologies. Mol. Immunol. 44:3866–74 [Google Scholar]
  40. Laufer J, Katz Y, Passwell JH. 40.  2001. Extrahepatic synthesis of complement proteins in inflammation. Mol. Immunol. 38:221–29 [Google Scholar]
  41. Holers VM. 41.  1989. Complement receptors. Year Immunol. 4:231–40 [Google Scholar]
  42. Tuveson DA, Ahearn JM, Matsumoto AK, Fearon DT. 42.  1991. Molecular interactions of complement receptors on B lymphocytes: a CR1/CR2 complex distinct from the CR2/CD19 complex. J. Exp. Med. 173:1083–89 [Google Scholar]
  43. Jozsi M, Prechl J, Bajtay Z, Erdei A. 43.  2001. Complement receptor type 1 (CD35) mediates inhibitory signals in human B lymphocytes. J. Immunol. 168:2782–88 [Google Scholar]
  44. Ogembo JG, Kannan L, Ghiran I, Nicholson-Weller A, Finberg RW. 44.  et al. 2013. Human complement receptor type 1/CD35 is an Epstein-Barr virus receptor. Cell Rep. 3:371–85 [Google Scholar]
  45. Carroll MC. 45.  2000. The role of complement in B cell activation and tolerance. Adv. Immunol. 74:61–88 [Google Scholar]
  46. Helmy KY, Katschke KJ, Gorgani NN, Klvajin NM, Elliott JM. 46.  et al. 2006. CRIg: a macrophage complement receptor required for phagocytosis and circulating pathogens. Cell 124:915–27 [Google Scholar]
  47. Karsten CM, Kohl J. 47.  2012. The immunoglobulin, IgG Fc receptor and complement triangle in autoimmune diseases. Immunobiology 217:1067–79 [Google Scholar]
  48. Ward PA. 48.  2009. Functions of C5a receptors. J. Mol. Med. 87:378 [Google Scholar]
  49. Sacks SH. 49.  2010. Complement fragments C3a and C5a: the salt and pepper of the immune response. Eur. J. Immunol. 40:668–70 [Google Scholar]
  50. Humbles AA, Lu B, Nilsson CA, Lilly C, Israel E. 50.  et al. 2000. A role for the C3a anaphylatoxin receptor in the effector phase of asthma. Nature 406:998–1001 [Google Scholar]
  51. Thurman JM, Lenderink AM, Royer PA, Coleman KE, Zhou J. 51.  et al. 2007. C3a is required for the production of CXC chemokines by tubular epithelial cells after renal ishemia/reperfusion. J. Immunol. 178:1819–28 [Google Scholar]
  52. Liszewski MK, Farries TC, Lublin DM, Rooney IA, Atkinson JP. 52.  1996. Control of the complement system. Adv. Immunol. 61:201–83 [Google Scholar]
  53. Davis AE. 53.  1988. C1 inhibitor and hereditary angioedema. Annu. Rev. Immunol. 6:595–628 [Google Scholar]
  54. Hourcade D, Holers VM, Atkinson JP. 54.  1989. The regulators of complement activation (RCA) gene cluster. Adv. Immunol. 45:381–416 [Google Scholar]
  55. Pangburn MK. 55.  2002. Cutting edge: localization of the host recognition functions of complement factor H at the carboxyl-terminal: implications for hemolytic uremic syndrome. J. Immunol. 169:4702–6 [Google Scholar]
  56. Perkins SJ, Nan R, Li K, Khan S, Miller M. 56.  2012. Complement Factor H–ligand interactions: self-association, multivalency and dissociation constants. Immunobiology 217:281–97 [Google Scholar]
  57. Morgan HP, Schmidt CQ, Guariento M, Blaum BS, Gillespie D. 57.  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]
  58. Pangburn MK, Rawal N, Cortes C, Alam MN, Ferreira VP, Atkinson MAL. 58.  2009. Polyanion-induced self-association of complement factor H: possible mechanism of host protection from an innate immune system. J. Immunol. 182:1061–68 [Google Scholar]
  59. Kemper C, Hourcade DE. 59.  2008. Properdin: New roles in pattern recognition and target clearance. Mol. Immunol. 45:4048–56 [Google Scholar]
  60. Blom AM. 60.  2004. Complement inhibitor C4b-binding protein-friend or foe in the innate immune system?. Mol. Immunol. 40:1333–46 [Google Scholar]
  61. Morgan BP, Berg CW, Harris CL. 61.  2005. “Homologous restriction” in complement lysis: roles of membrane complement regulators. Xenotransplantation 12:258–65 [Google Scholar]
  62. Inal JM, Hui KM, Miot S, Lange S, Ramirez MI. 62.  et al. 2005. Complement C2 receptor inhibitor trispanning: a novel human complement inhibitory receptor. J. Immunol. 174:356–66 [Google Scholar]
  63. Holmquist E, Okroj M, Nodin B, Jirstrom K, Blom AM. 63.  2013. Sushi domain-containing protein 4 (SUSD4) inhibits complement by disrupting the formation of the classical C3 convertase. FASEB J. 27:62355–66 [Google Scholar]
  64. Matthews KW, Mueller-Ortiz SL, Wetsel RA. 64.  2004. Carboxypeptidase N: a pleiotropic regulator of inflammation. Mol. Immunol. 40:785–93 [Google Scholar]
  65. Song JJ, Hwang I, Cho KH, Garcia MA, Kim AJ. 65.  et al. 2011. Plasma carboxypeptidase B downregulates inflammatory responses in autoimmune arthritis. J. Clin. Investig. 121:3517–27 [Google Scholar]
  66. de Cordoba SR, Tortajada A, Harris CL, Morgan BP. 66.  2012. Complement dysregulation and disease: from genes and proteins to diagnostics and drugs. Immunobiology 217:1034–46 [Google Scholar]
  67. Jozsi M, Zipfel PF. 67.  2008. Factor H family proteins and human diseases. Trends Immunol. 29:380–87 [Google Scholar]
  68. Hughes AE, Orr N, Esfandiary H, Diaz-Torres M, Goodship T, Chakravarthy U. 68.  2006. A common CFH haplotype,with deletion of CFHR1 and CFHR3, is associated with lower risk of age-related macular degeneration. Nat. Genet. 38:1173–77 [Google Scholar]
  69. Skerka C, Zipfel PF. 69.  2008. Complement factor H related proteins in immune diseases. Vaccine 26:Suppl. 8I9–14 [Google Scholar]
  70. Goicoechea de Jorge E, Caesar JJE, Malik TH, Paten M, Colledge M. 70.  et al. 2013. Dimerization of complement factor H-related proteins modulates complement activation in vivo. Proc. Natl. Acad. Sci. USA 110:4685–90 [Google Scholar]
  71. Tortajada A, Yebenes H, Abarrategui-Garrido C, Anter J, Garcia-Fernandez JM. 71.  et al. 2013. C3 glomerulopathy-associated CFHR1 mutation alters FHR oligomerization and complement regulation. J. Clin. Investig. 123:2434–46 [Google Scholar]
  72. Markiewski MM, Nilsson B, Ekdahl KN, Mollnes TE, Lambris JD. 72.  2007. Complement and coagulation: strangers or partners in crime?. Trends Immunol. 28:184–92 [Google Scholar]
  73. Schulz C, Engelmann B, Massberg S. 73.  2013. Crossroads of coagulation and innate immunity: the case of deep vein thrombosis. J. Thromb. Haemost. 11:Suppl. 1233–41 [Google Scholar]
  74. Huber-Lang M, Sarma JV, Zetoune FS, Rittirsch D, Neff TA. 74.  et al. 2006. Generation of C5a in the absence of C3: a new complement activation pathway. Nat. Med. 12:682–87 [Google Scholar]
  75. Takahashi K, Chang W-C, Takahashi M, Pavlov V, Ishida Y. 75.  et al. 2011. Mannose-binding lectin and its associated proteases (MASPs) mediate coagulation and its deficiency is a risk factor in developing complications from infection, including disseminated intravascular coagulation. Immunobiology 216:96–102 [Google Scholar]
  76. Shahl AL, Sartz L, Karpman D. 76.  2011. Complement activation on platelet-leukocyte complexes and microparticles in enterohemorrhagic Escherichia coli-induced hemolytic uremic syndrome. Blood 117:5503–13 [Google Scholar]
  77. Amaru U, Flierl MA, Rittirsch D, Klos A, Chen H. 77.  et al. 2010. Molecular intercommunication between the complement and coagulation systems. J. Immunol. 185:5628–36 [Google Scholar]
  78. Barratt-Due A, Pischke SE, Brekke O-L, Thorgersen EB, Nielsen EW. 78.  et al. 2012. Bride and groom in systemic inflammation: The bells ring for complement and Toll in cooperation. Immunobiology 217:1047–56 [Google Scholar]
  79. Zhang X, Kimura Y, Fang C, Zhou L, Sfyroera G. 79.  et al. 2007. Regulation of Toll-like receptor-mediated inflammatory response by complement in vivo. Blood 110:228–36 [Google Scholar]
  80. Wang M, Krauss JL, Domon H, Hosur KB, Liang S. 80.  et al. 2010. Microbial hijacking of complement-Toll-like receptor crosstalk. Sci. Signal. 3:109ra11 [Google Scholar]
  81. Song WC. 81.  2012. Crosstalk between complement and Toll-like receptors. Tox. Path. 40:174–82 [Google Scholar]
  82. Fang C, Zhang X, Miwa T, Song WC. 82.  2009. Complement promotes the development of inflammatory T-helper 17 cells through synergistic interaction with Toll-like receptor signaling and IL-6 production. Blood 114:1005–15 [Google Scholar]
  83. Hawlisch H, Belkaid Y, Baelder R, Hildeman D, Gerard C, Kohl J. 83.  2005. C5a negatively regulates Toll-like receptor 4-induced immune responses. Immunity 22:415–26 [Google Scholar]
  84. Waggoner SN, Cruise MW, Kassel R, Hahn YS. 84.  2005. gC1q receptor ligation selectively down-regulates human IL-12 production through activation of the phosphoinositide 3-kinase pathway. J. Immunol. 175:4706–14 [Google Scholar]
  85. Dempsey P, Allison M, Akkaraju S, Goodnow C, Fearon D. 85.  1996. C3d of complement as a molecular adjuvant: bridging innate and acquired immunity. Science 271:348–50 [Google Scholar]
  86. Phan TG, Grigorova I, Okada T, Cyster JG. 86.  2007. Subcapsular encounter and complement-dependent transport of immune complexes by lymph node B cells. Nat. Immunol. 8:992–1000 [Google Scholar]
  87. Baelder R, Fuchs B, Bautsch W, Zwirner J, Kohl J. 87.  et al. 2005. Pharmacological targeting of anaphylatoxin receptors during the effector phase of allergic asthma suppresses airway hyperresponsiveness and airway inflammation. J. Immunol. 174:783–89 [Google Scholar]
  88. Strainic MG, Shevach EM, An F, Lin F, Medof ME. 88.  2013. Absence of signaling into CD4+ cells via C3aR and C5aR enables autoinductive TGF-β1 signaling and induction of Foxp3+ regulatory T cells. Nat. Immunol. 14:162–71 [Google Scholar]
  89. Cardone J, Le Friec G, Kemper C. 89.  2011. CD36 in innate and adaptive immunity: an update. Clin. Exp. Immunol. 164:301–11 [Google Scholar]
  90. Le Friec G, Sheppard D, Whiteman P, Karsten CM, Shamoun SA. 90.  et al. 2012. The CD46-Jagged1 interaction is critical for human TH1 immunity. Nat. Immunol. 13:1213–21 [Google Scholar]
  91. Perkins SJ, Goodship THJ. 91.  2002. Molecular modeling of mutations in the C-terminal domains of factor H of human complement: a new insight into hemolytic uremic syndrome. J. Mol. Biol. 316:217–24 [Google Scholar]
  92. Pickering MC, Goicoechea de Jorge E, Martinez-Barricarte R, Recalde S, Garcia-Layana A. 92.  et al. 2007. Spontaneous hemolytic uremic syndrome triggered by complement factor H lacking surface recognition domains. J. Exp. Med. 204:1249–56 [Google Scholar]
  93. Rose KL, Paixao-Cavalcante D, Fish J, Manderson AP, Malik TH. 93.  et al. 2008. Factor I is required for the development of membranoproliferative glomerulonephritis in factor H-deficient mice. J. Clin. Investig. 118:608–18 [Google Scholar]
  94. Fakhouri F, Fremeaux-Bacchi V, Noel LH, Cook HT, Pickering MC. 94.  2010. C3 glomerulopathy: a new classification. Nat. Rev. Nephrol. 6:494–99 [Google Scholar]
  95. Gale DP, Goicoechea de Jorge E, Cook HT, Martinez-Barricarte R, Hadjisavvas A. 95.  et al. 2010. Identification of a mutation in complement factor H-related protein 5 in patients of Cypriot origin with glomerulonephritis. Lancet 376:794–801 [Google Scholar]
  96. Malik TH, Lavin PJ, Goicoechea de Jorge E, Vernon KA, Rose KL. 96.  et al. 2012. A hybrid CFHR3-1 gene causes familial C3 glomerulopathy. J. Am. Soc. Nephrol. 23:1155–60 [Google Scholar]
  97. Fang CJ, Fremeaux-Bacchi V, Liszewski MK, Pianetti G, Noris M. 97.  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]
  98. Salmon JE, Heuser C, Triebwasser M, Liszewski MK, Kavanagh D. 98.  et al. 2013. Mutations in complement regulatory proteins predispose to preeclampsia: a genetic analysis of the PROMISSE cohort. PLoS Med. 8:3e1001013 [Google Scholar]
  99. Girardi G, Yarilin D, Thurman JM, Holers VM, Salmon JE. 99.  2006. Complement activation induces dysregulation of angiogenic factors and causes fetal rejection and growth restriction. J. Exp. Med. 203:2165–75 [Google Scholar]
  100. Qing X, Redecha PB, Burmeister MA, Tomlinson S, D'Agati VD. 100.  et al. 2011. Targeted inhibition of complement activation prevents features of preeclampsia in mice. Kidney Int. 79:331–39 [Google Scholar]
  101. Heurich M, Martinez-Barricarte R, Francis NJ, Roberts DL, Rodriguez de Cordoba S. 101.  et al. 2011. Common polymorphisms in C3, factor B, and factor H collaborate to determine systemic complement activity and disease risk. Proc. Natl. Acad. Sci. USA 108:8761–66 [Google Scholar]
  102. Risitano AM. 102.  2012. Paroxysmal nocturnal hemoglobinuria and other complement-mediated hematological disorders. Immunobiology 217:1080–87 [Google Scholar]
  103. Rother RP, Rollins SA, Mojcik CF, Brodsky RA, Bell L. 103.  2007. Discovery and development of the complement inhibitor eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria. Nat. Biotech. 25:1256–64 [Google Scholar]
  104. Risitano AM, Notaro R, Marando L, Serio B, Ranaldi D. 104.  et al. 2009. Complement fraction 3 binding on erythrocytes as an additional mechanism of disease in paroxysmal nocturnal hemoglobinuria patients treated by eculizumab. Blood 113:4094–100 [Google Scholar]
  105. Zipfel PF, Skerka C, Hellwage J, Jokiranta ST, Meri S. 105.  et al. 2002. Factor H family proteins: on complement, microbes and human diseases. Biochem. Soc. Trans. 30:971–78 [Google Scholar]
  106. Nester CM, Brophy PD. 106.  2012. Eculizumab in the treatment of aytpical haemolytic uraemic syndrome and other complement-mediated renal diseases. Curr. Opin. Pediatr. 25:225–31 [Google Scholar]
  107. Schmidtko J, Peine S, El-Housseini Y, Pascual M, Meier P. 107.  2013. Treatment of atypical hemolytic uremic syndrome and thrombotic microangiopathies: a focus on eculizumab. Am. J. Kidney Dis. 61:289–99 [Google Scholar]
  108. Pittock SJ, Lennon VA, McKeon A, Mandrekar J, Weinshenker BG. 108.  et al. 2013. Eculizumab in AQP4-IgG-positive relapsing neuromyelitis optica spectrum disorders: an open-label pilot study. Lancet Neurol. 12:554–62 [Google Scholar]
  109. Christiansen SC, Zuraw BL. 109.  2009. Update on therapeutic developments for hereditary angioedema. Allergy Asthma Proc. 30:500–5 [Google Scholar]
  110. Gehrs KM, Anderson DH, Johnson LV, Hageman GS. 110.  2006. Age-related macular degeneration: emerging pathogenetic and therapeutic concepts. Ann. Med. 38:450–71 [Google Scholar]
  111. Khandhadia S, Lotery A. 111.  2010. Oxidation and age-related macular degeneration: insights from molecular biology. Expert Rev. Mol. Med. 12:e34 [Google Scholar]
  112. Jha P, Bora PS, Bora NS. 112.  2007. The role of the complement system in ocular diseases including uveitis and macular degeneration. Mol. Immunol. 44:3901–8 [Google Scholar]
  113. Rohrer B, Coughlin B, Kunchithapautham K, Long Q, Tomlinson S. 113.  et al. 2011. The alternative pathway is required, but not alone sufficient, for retinal pathology in mouse laser-induced choroidal neovascularization. Mol. Immunol. 48:e1–e8 [Google Scholar]
  114. Bora NS, Kaliappan S, Jha P, Xu Q, Sohn JH. 114.  et al. 2006. Complement activation via alternative pathway is critical in the development of laser-induced choroidal neovascularization: role of factor B and factor H. J. Immunol. 177:1872–78 [Google Scholar]
  115. Nozaki M, Raisler BJ, Sakuria E, Sarma JV, Barnum SR. 115.  et al. 2006. Drusen complement components C3a and C5a promote choroidal neovascularization. Proc. Natl. Acad. Sci. USA 103:2328–33 [Google Scholar]
  116. Cashman SM, Ramo K, Kumar-Singh R. 116.  2011. A non membrane-targeted human soluble CD59 attenuates choroidal neovascularization in a model of age-related macular degeneration. PLoS ONE 6:e19078 [Google Scholar]
  117. Joseph K, Kulik L, Couglin B, Coughlin B, Kunchithapautham K. 117.  et al. 2013. Oxidative stress sensitizes retinal pigmented epithelial (RPE) cells to complement-mediated injury in a natural antibody-, lectin pathway-, and phospholipid epitope-dependent manner. J. Biol. Chem. 288:12753–65 [Google Scholar]
  118. Bao L, Haas M, Kraus DM, Hack BK, Rakstang JK. 118.  et al. 2003. Administration of a soluble recombinant complement C3 inhibitor protects against renal disease in MRL/lpr mice. J. Am. Soc. Nephrol. 14:670–79 [Google Scholar]
  119. Elliott MK, Jarmi T, Ruiz P, Xu Y, Holers VM, Gilkeson GS. 119.  2004. Effects of complement factor D deficiency on the renal disease of MRL/lpr mice. Kidney Int. 65:129–38 [Google Scholar]
  120. Sekine H, Kinser TT, Qiao F, Martinez E, Paulling E. 120.  et al. 2011. The benefit of targeted and selective inhibition of the alternative complement pathway for modulating autoimmunity and renal disease in MRL/lpr mice. Arthritis Rheum. 63:1076–85 [Google Scholar]
  121. Sekine H, Ruiz P, Gilkeson GS, Tomlinson S. 121.  2011. The dual role of complement in the progression of renal disease in NZB/W F(1) mice and alternative pathway inhibition. Mol. Immunol. 49:317–23 [Google Scholar]
  122. Calero I, Sanz I. 122.  2010. Targeting B cells for the treatment of SLE: the beginning of the end or the end of the beginning?. Discov. Med. 10:416–24 [Google Scholar]
  123. Liu Z, Davidson A. 123.  2011. BAFF and selection of autoreactive B cells. Trends Immunol. 32:388–94 [Google Scholar]
  124. Cohen-Solal J, Diamond B. 124.  2011. Lessons from an anti-DNA autoantibody. Mol. Immunol. 48:1328–31 [Google Scholar]
  125. Carroll MC. 125.  2004. A protective role for innate immunity in systemic lupus erythematosus. Nat. Rev. Immunol. 4:825–31 [Google Scholar]
  126. Prodeus A, Goerg S, Shen L-M, Pozdnyakova OO, Chu L. 126.  et al. 1998. A critical role for complement in maintenance of self-tolerance. Immunity 9:721–31 [Google Scholar]
  127. Boackle SA, Culhane KK, Brown JM, Haas M, Bao L. 127.  et al. 2004. CR1/CR2 deficiency alters IgG3 autoantibody production and IgA glomerular deposition in the MRL/lpr model of SLE. Autoimmunity 37:111–23 [Google Scholar]
  128. Silman AJ. 128.  1994. Epidemiology of rheumatoid arthritis. APMIS 102:721–28 [Google Scholar]
  129. Silman AJ, Hochberg MC. 129.  1993. Rheumatoid arthritis. Epidemiology of the Rheumatic Diseases AJ Silman, MC Hochberg 7–68 New York: Oxford Univ. Press [Google Scholar]
  130. Arend WP. 130.  2001. The innate immune system in rheumatoid arthritis. Arthritis Rheum. 44:2224–34 [Google Scholar]
  131. Firestein GS. 131.  2003. Evolving concepts of rheumatoid arthritis. Nature 423:356–61 [Google Scholar]
  132. Cooke TD, Hurd ER, Jasin HE, Bienenstock H, Ziff M. 132.  1975. Identification of immunoglobulins and complement in rheumatoid articular collagenous tissues. Arthritis Rheum. 18:541–51 [Google Scholar]
  133. Linton SM, Morgan BP. 133.  1999. Complement activation and inhibition in experimental models of arthritis. Mol. Immunol. 36:905–14 [Google Scholar]
  134. Neumann E, Barnum SR, Tarner IH, Echols J, Fleck M. 134.  et al. 2002. Local production of complement proteins in rheumatoid arthritis synovium. Arthritis Rheum. 46:934–45 [Google Scholar]
  135. Banda NK, Thurman JM, Kraus D, Wood A, Carroll MC. 135.  et al. 2006. Alternative complement pathway activation is essential for inflammation and joint destruction in the passive transfer model of collagen-induced arthritis. J. Immunol. 177:1904–12 [Google Scholar]
  136. Banda NK, Takahashi K, Wood AK, Holers VM, Arend WP. 136.  2007. Pathogenic complement activation in collagen antibody-induced arthritis in mice requires amplification by the alternative pathway. J. Immunol. 179:4101–9 [Google Scholar]
  137. Banda NK, Hyatt S, Antonioli AH, White JT, Glogowska M. 137.  et al. 2012. Role of C3a receptors, C5a receptors, and complement protein C6 deficiency in collagen antibody-induced arthritis in mice. J. Immunol. 188:1469–78 [Google Scholar]
  138. Happonen KE, Heinegard D, Saxne T, Blom AM. 138.  2012. Interactions of the complement system with molecules of extracellular matrix: relevance for joint diseases. Immunobiology 217:1088–96 [Google Scholar]
  139. Kuhn KA, Cozine CL, Tomooka B, Robinson WH, Holers VM. 139.  2008. Complement receptor CR2/CR1 deficiency protects mice from collagen-induced arthritis and associates with reduced autoantibodies to type II collagen and citrullinated antigens. Mol. Immunol. 45:2808–19 [Google Scholar]
  140. Stevens B, Allen NJ, Vazquez LE, Howell GR, Christopherson KS. 140.  et al. 2007. The classical complement cascade mediates CNS synapse elimination. Cell 131:1164–78 [Google Scholar]
  141. Fonseca MI, Ager RR, Chu SH, Yazan O, Sanderson SD. 141.  et al. 2009. Treatment with a C5aR antagonist decreases pathology and enhances behavioral performance in murine models of Alzheimer's disease. J. Immunol. 183:1375–83 [Google Scholar]
  142. Fu W, Wojtkiewicz G, Weissleder R, Benoist C, Mathis D. 142.  2012. Early window of diabetes determinism in NOD mice, dependent on the complement receptor CRIg, identified by noninvasive imaging. Nat. Immunol. 13:361–68 [Google Scholar]
  143. Silasi-Mansat R, Zhu H, Popescu NI, Peer G, Sfyroera G. 143.  et al. 2010. Complement inhibition decreases the procoagulant response and confers organ protection in a baboon model of Escherichia coli sepsis. Blood 116:1002–10 [Google Scholar]
  144. Taylor RP, Lindorfer MA. 144.  2014. The role of complement in mAb-based therapies of cancer. Methods 6518–27
  145. Elvington M, Huang Y, Morgan BP, Qiao F, van Rooijen N. 145.  et al. 2012. A targeted complement-dependent strategy to improve the outcome of mAb therapy, and characterization in a murine model of metastatic cancer. Blood 119:6043–51 [Google Scholar]
  146. Markiewski MM, DeAngelis RA, Benencia F, Ricklin-Lichtsteiner SK, Koutoulaki A. 146.  et al. 2008. Modulation of the antitumor immune response by complement. Nat. Immunol. 9:1225–35 [Google Scholar]
  147. He S, Atkinson C, Qiao F, Cianflone K, Chen C, Tomlinson S. 147.  2009. A complement-dependent balance between hepatic ischemia/reperfusion injury and liver regeneration in mice. J. Clin. Investig. 119:2304–16 [Google Scholar]
  148. Nilsson B, Ekdahl KN. 148.  2012. Complement diagnostics: concepts, indications, and practical guidelines. Clin. Dev. Immunol. 2012:962702 doi: 10.1155/2012/962702 [Google Scholar]
  149. Parkes M, Cortes A, van Heel DA, Brown MA. 149.  2013. Genetic insights into common pathways and complex relationships among immune-mediated diseases. Nat. Rev. Genet. 14:661–73 [Google Scholar]
  150. Thurman JM, Kulik L, Orth H, Wong M, Renner B. 150.  et al.2103 Detection of complement activation using monoclonal antibodies against C3d. J. Clin. Investig. 123:2218–30 [Google Scholar]
  151. Holers VM, Rohrer B, Tomlinson S. 151.  2103. CR2-mediated targeting of complement inhibitors: bench-to-bedside using a novel strategy for site-specific complement modulation. Adv. Exp. Med. Biol. 735:137–54 [Google Scholar]

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