Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Complement in disease: a defence system turning offensive

Nature Reviews Nephrology volume 12, pages 383–401 (2016)Cite this article

Subjects

Key Points

  • The complement system is a critical modulator of immune responses that triages microbial and other threats through pattern recognition, tailored effector functions, and intensive crosstalk with other systems

  • When disrupted by dysregulation or age-related effects, or excessively triggered by acute and chronic tissue damage, biomaterials or transplants, complement can attack host cells and contribute to inflammatory conditions

  • The kidney is particularly sensitive to complement-mediated damage, exemplified by the involvement of complement in several kidney diseases (such as atypical haemolytic uraemic syndrome (aHUS) and C3 glomerulopathies) and in complications of kidney transplantation and haemodialysis

  • Therapeutic complement inhibition is successfully used in paroxysmal nocturnal haemoglobinuria and aHUS, and has shown promise in other clinical conditions, raising hope for improved treatment options for other disorders

Abstract

Although the complement system is primarily perceived as a host defence system, a more versatile, yet potentially more harmful side of this innate immune pathway as an inflammatory mediator also exists. The activities that define the ability of the complement system to control microbial threats and eliminate cellular debris — such as sensing molecular danger patterns, generating immediate effectors, and extensively coordinating with other defence pathways — can quickly turn complement from a defence system to an aggressor that drives immune and inflammatory diseases. These host-offensive actions become more pronounced with age and are exacerbated by a variety of genetic factors and autoimmune responses. Complement can also be activated inappropriately, for example in response to biomaterials or transplants. A wealth of research over the past two decades has led to an increasingly finely tuned understanding of complement activation, identified tipping points between physiological and pathological behaviour, and revealed avenues for therapeutic intervention. This Review summarizes our current view of the key activating, regulatory, and effector mechanisms of the complement system, highlighting important crosstalk connections, and, with an emphasis on kidney disease and transplantation, discusses the involvement of complement in clinical conditions and promising therapeutic approaches.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Mechanisms of differential complement activation and regulation under physiological conditions.
Figure 2: Examples of complement crosstalk with immune cells and defence pathways.
Figure 3: Pathological activation of complement.

Similar content being viewed by others

References

  1. Ricklin, D., Hajishengallis, G., Yang, K. & Lambris, J. D. Complement: a key system for immune surveillance and homeostasis. Nat. Immunol. 11, 785–797 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Ricklin, D. & Lambris, J. D. Complement in immune and inflammatory disorders: pathophysiological mechanisms. J. Immunol. 190, 3831–3838 (2013).

    Article  CAS  PubMed  Google Scholar 

  3. Reis, E. S. et al. Applying complement therapeutics to rare diseases. Clin. Immunol. 161, 225–240 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Merle, N. S., Church, S. E., Fremeaux-Bacchi, V. & Roumenina, L. T. Complement system part I — molecular mechanisms of activation and regulation. Front. Immunol. 6, 262 (2015).

    PubMed  PubMed Central  Google Scholar 

  5. Merle, N. S., Noe, R., Halbwachs-Mecarelli, L., Fremeaux-Bacchi, V. & Roumenina, L. T. Complement system part II: role in immunity. Front. Immunol. 6, 257 (2015).

    PubMed  PubMed Central  Google Scholar 

  6. Mastellos, D. C., Deangelis, R. A. & Lambris, J. D. Complement-triggered pathways orchestrate regenerative responses throughout phylogenesis. Semin. Immunol. 25, 29–38 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Stephan, A. H., Barres, B. A. & Stevens, B. The complement system: an unexpected role in synaptic pruning during development and disease. Annu. Rev. Neurosci. 35, 369–389 (2012).

    Article  CAS  PubMed  Google Scholar 

  8. Kohl, J. The role of complement in danger sensing and transmission. Immunol. Res. 34, 157–176 (2006).

    Article  CAS  PubMed  Google Scholar 

  9. Scott, D. & Botto, M. The paradoxical roles of C1q and C3 in autoimmunity. Immunobiology http://dx.doi.org/10.1016/j.imbio.2015.05.001 (2015).

  10. Kolev, M., Le Friec, G. & Kemper, C. Complement — tapping into new sites and effector systems. Nat. Rev. Immunol. 14, 811–820 (2014).

    Article  CAS  PubMed  Google Scholar 

  11. Harris, C. L., Heurich, M., Rodriguez de Cordoba, S. & Morgan, B. P. The complotype: dictating risk for inflammation and infection. Trends Immunol. 33, 513–521 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Diebolder, C. A. et al. Complement is activated by IgG hexamers assembled at the cell surface. Science 343, 1260–1263 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Kouser, L. et al. Emerging and novel functions of complement protein C1q. Front. Immunol. 6, 317 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Harboe, M. et al. The down-stream effects of mannan-induced lectin complement pathway activation depend quantitatively on alternative pathway amplification. Mol. Immunol. 47, 373–380 (2009).

    Article  CAS  PubMed  Google Scholar 

  15. Harboe, M., Ulvund, G., Vien, L., Fung, M. & Mollnes, T. E. The quantitative role of alternative pathway amplification in classical pathway induced terminal complement activation. Clin. Exp. Immunol. 138, 439–446 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Nilsson, B. & Nilsson Ekdahl, K. The tick-over theory revisited: is C3 a contact-activated protein? Immunobiology 217, 1106–1110 (2012).

    Article  CAS  PubMed  Google Scholar 

  17. Morgan, B. P. The membrane attack complex as an inflammatory trigger. Immunobiology http://dx.doi.org/10.1016/j.imbio.2015.04.006 (2015).

  18. Taylor, R. P. & Lindorfer, M. A. The role of complement in mAb-based therapies of cancer. Methods 65, 18–27 (2014).

    Article  CAS  PubMed  Google Scholar 

  19. Klos, A., Wende, E., Wareham, K. J. & Monk, P. N. International Union of Basic and Clinical Pharmacology. LXXXVII. Complement peptide C5a, C4a, and C3a receptors. Pharmacol. Rev. 65, 500–543 (2013); erratum 66, 466 (2014)

    Article  CAS  PubMed  Google Scholar 

  20. Coulthard, L. G. & Woodruff, T. M. Is the complement activation product C3a a proinflammatory molecule? Re-evaluating the evidence and the myth. J. Immunol. 194, 3542–3548 (2015).

    Article  CAS  PubMed  Google Scholar 

  21. Nordahl, E. A. et al. Activation of the complement system generates antibacterial peptides. Proc. Natl Acad. Sci. USA 101, 16879–16884 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Ghebrehiwet, B., Hosszu, K. K., Valentino, A., Ji, Y. & Peerschke, E. I. Monocyte expressed macromolecular C1 and C1q receptors as molecular sensors of danger: implications in SLE. Front. Immunol. 5, 278 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Helmy, K. Y. et al. CRIg: a macrophage complement receptor required for phagocytosis of circulating pathogens. Cell 124, 915–927 (2006).

    Article  CAS  PubMed  Google Scholar 

  24. Zeerleder, S. C1-inhibitor: more than a serine protease inhibitor. Semin. Thromb. Hemost 37, 362–374 (2011).

    Article  CAS  PubMed  Google Scholar 

  25. Matsushita, M., Endo, Y. & Fujita, T. Structural and functional overview of the lectin complement pathway: its molecular basis and physiological implication. Arch. Immunol. Ther. Exp. (Warsz) 61, 273–283 (2013).

    Article  CAS  Google Scholar 

  26. Clark, S. J. & Bishop, P. N. Role of factor H and related proteins in regulating complement activation in the macula, and relevance to age-related macular degeneration. J. Clin. Med. 4, 18–31 (2015).

    Article  CAS  PubMed  Google Scholar 

  27. Reis, E. S. et al. C5a receptor-dependent cell activation by physiological concentrations of desarginated C5a: insights from a novel label-free cellular assay. J. Immunol. 189, 4797–4805 (2012).

    Article  CAS  PubMed  Google Scholar 

  28. Lesher, A. M., Nilsson, B. & Song, W. C. Properdin in complement activation and tissue injury. Mol. Immunol. 56, 191–198 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Kemper, C., Atkinson, J. P. & Hourcade, D. E. Properdin: emerging roles of a pattern-recognition molecule. Annu. Rev. Immunol. 28, 131–155 (2010).

    Article  CAS  PubMed  Google Scholar 

  30. Marsh, J. E., Zhou, W. & Sacks, S. H. Local tissue complement synthesis — fine tuning a blunt instrument. Arch. Immunol. Ther. Exp. (Warsz.) 49, S41–S46 (2001).

    Google Scholar 

  31. Conway, E. M. Reincarnation of ancient links between coagulation and complement. J. Thromb. Haemost. 13, S121–S132 (2015).

    Article  CAS  PubMed  Google Scholar 

  32. Ritis, K. et al. A novel C5a receptor-tissue factor cross-talk in neutrophils links innate immunity to coagulation pathways. J. Immunol. 177, 4794–4802 (2006).

    Article  CAS  PubMed  Google Scholar 

  33. Rayes, J. et al. The interaction between factor H and VWF increases factor H cofactor activity and regulates VWF prothrombotic status. Blood 123, 121–125 (2014).

    Article  CAS  PubMed  Google Scholar 

  34. Speth, C. et al. Complement and platelets: mutual interference in the immune network. Mol. Immunol. 67, 108–118 (2015).

    Article  CAS  PubMed  Google Scholar 

  35. Hamad, O. A. et al. Contact activation of C3 enables tethering between activated platelets and polymorphonuclear leukocytes via CD11b/CD18. Thromb. Haemost. 114, 1207–1217 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  36. Ali, H. Regulation of human mast cell and basophil function by anaphylatoxins C3a and C5a. Immunol. Lett. 128, 36–45 (2010).

    Article  CAS  PubMed  Google Scholar 

  37. Bohlson, S. S., O'Conner, S. D., Hulsebus, H. J., Ho, M. M. & Fraser, D. A. Complement, c1q, and c1q-related molecules regulate macrophage polarization. Front. Immunol. 5, 402 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Camous, L. et al. Complement alternative pathway acts as a positive feedback amplification of neutrophil activation. Blood 117, 1340–1349 (2011).

    Article  CAS  PubMed  Google Scholar 

  39. Wang, H., Wang, C., Zhao, M. H. & Chen, M. Neutrophil extracellular traps can activate alternative complement pathways. Clin. Exp. Immunol. 181, 518–527 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Wu, M. C. et al. The receptor for complement component C3a mediates protection from intestinal ischemia-reperfusion injuries by inhibiting neutrophil mobilization. Proc. Natl Acad. Sci. USA 110, 9439–9444 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  41. Hsieh, C. C. et al. The role of complement component 3 (C3) in differentiation of myeloid-derived suppressor cells. Blood 121, 1760–1768 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Markiewski, M. M. et al. Modulation of the antitumor immune response by complement. Nat. Immunol. 9, 1225–1235 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Son, M., Santiago-Schwarz, F., Al-Abed, Y. & Diamond, B. C1q limits dendritic cell differentiation and activation by engaging LAIR-1. Proc. Natl Acad. Sci. USA 109, E3160–E3167 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  44. Li, K. et al. Functional modulation of human monocytes derived DCs by anaphylatoxins C3a and C5a. Immunobiology 217, 65–73 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Hawlisch, H. et al. C5a negatively regulates toll-like receptor 4-induced immune responses. Immunity 22, 415–426 (2005).

    Article  CAS  PubMed  Google Scholar 

  46. Kemper, C. & Kohl, J. Novel roles for complement receptors in T cell regulation and beyond. Mol. Immunol. 56, 181–190 (2013).

    Article  CAS  PubMed  Google Scholar 

  47. Dunkelberger, J., Zhou, L., Miwa, T. & Song, W. C. C5aR expression in a novel GFP reporter gene knockin mouse: implications for the mechanism of action of C5aR signaling in T cell immunity. J. Immunol. 188, 4032–4042 (2012).

    Article  CAS  PubMed  Google Scholar 

  48. Karsten, C. M. et al. Monitoring and cell-specific deletion of C5aR1 using a novel floxed GFP–C5aR1 reporter knock-in mouse. J. Immunol. 194, 1841–1855 (2015).

    Article  CAS  PubMed  Google Scholar 

  49. Cardone, J. et al. Complement regulator CD46 temporally regulates cytokine production by conventional and unconventional T cells. Nat. Immunol. 11, 862–871 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Le Friec, G. et al. The CD46–Jagged1 interaction is critical for human TH1 immunity. Nat. Immunol. 13, 1213–1221 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Ghannam, A., Fauquert, J. L., Thomas, C., Kemper, C. & Drouet, C. Human complement C3 deficiency: Th1 induction requires T cell-derived complement C3a and CD46 activation. Mol. Immunol. 58, 98–107 (2014).

    Article  CAS  PubMed  Google Scholar 

  52. Liszewski, M. K. et al. Intracellular complement activation sustains T cell homeostasis and mediates effector differentiation. Immunity 39, 1143–1157 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Iwasaki, A. & Medzhitov, R. Control of adaptive immunity by the innate immune system. Nat. Immunol. 16, 343–353 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Hajishengallis, G. & Lambris, J. D. Crosstalk pathways between Toll-like receptors and the complement system. Trends Immunol. 31, 154–163 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Morgan, B. P. & Gasque, P. Extrahepatic complement biosynthesis: where, when and why? Clin. Exp. Immunol. 107, 1–7 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Leemans, J. C., Kors, L., Anders, H. J. & Florquin, S. Pattern recognition receptors and the inflammasome in kidney disease. Nat. Rev. Nephrol. 10, 398–414 (2014).

    Article  CAS  PubMed  Google Scholar 

  57. Cheung, K. P., Kasimsetty, S. G. & McKay, D. B. Innate immunity in donor procurement. Curr. Opin. Organ Transplant. 18, 154–160 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. McCullough, J. W., Renner, B. & Thurman, J. M. The role of the complement system in acute kidney injury. Semin. Nephrol. 33, 543–556 (2013).

    Article  CAS  PubMed  Google Scholar 

  59. Noris, M. & Remuzzi, G. Glomerular diseases dependent on complement activation, including atypical hemolytic uremic syndrome, membranoproliferative glomerulonephritis, and C3 glomerulopathy: core curriculum 2015. Am. J. Kidney Dis. 66, 359–375 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  60. Sacks, S. H. & Zhou, W. The role of complement in the early immune response to transplantation. Nat. Rev. Immunol. 12, 431–442 (2012).

    Article  CAS  PubMed  Google Scholar 

  61. Song, W. C. Crosstalk between complement and toll-like receptors. Toxicol. Pathol. 40, 174–182 (2012).

    Article  CAS  PubMed  Google Scholar 

  62. Bosmann, M. et al. Complement activation product C5a is a selective suppressor of TLR4-induced, but not TLR3-induced, production of IL-27(p28) from macrophages. J. Immunol. 188, 5086–5093 (2012).

    Article  CAS  PubMed  Google Scholar 

  63. Seow, V. et al. Inflammatory responses induced by lipopolysaccharide are amplified in primary human monocytes but suppressed in macrophages by complement protein C5a. J. Immunol. 191, 4308–4316 (2013).

    Article  CAS  PubMed  Google Scholar 

  64. Ling, G. S. et al. Integrin CD11b positively regulates TLR4-induced signalling pathways in dendritic cells but not in macrophages. Nat. Commun. 5, 3039 (2014).

    Article  CAS  PubMed  Google Scholar 

  65. Zou, L. et al. Complement factor B is the downstream effector of TLRs and plays an important role in a mouse model of severe sepsis. J. Immunol. 191, 5625–5635 (2013).

    Article  CAS  PubMed  Google Scholar 

  66. Triantafilou, M., Hughes, T. R., Morgan, B. P. & Triantafilou, K. Complementing the inflammasome. Immunology 147, 152–164 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Asgari, E. et al. C3a modulates IL-1β secretion in human monocytes by regulating ATP efflux and subsequent NLRP3 inflammasome activation. Blood 122, 3473–3481 (2013).

    Article  CAS  PubMed  Google Scholar 

  68. Laudisi, F. et al. Cutting edge: the NLRP3 inflammasome links complement-mediated inflammation and IL-1β release. J. Immunol. 191, 1006–1010 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Triantafilou, K., Hughes, T. R., Triantafilou, M. & Morgan, B. P. The complement membrane attack complex triggers intracellular Ca2+ fluxes leading to NLRP3 inflammasome activation. J. Cell Sci. 126, 2903–2913 (2013).

    Article  CAS  PubMed  Google Scholar 

  70. Samstad, E. O. et al. Cholesterol crystals induce complement-dependent inflammasome activation and cytokine release. J. Immunol. 192, 2837–2845 (2014).

    Article  CAS  PubMed  Google Scholar 

  71. Benoit, M. E., Clarke, E. V., Morgado, P., Fraser, D. A. & Tenner, A. J. Complement protein C1q directs macrophage polarization and limits inflammasome activity during the uptake of apoptotic cells. J. Immunol. 188, 5682–5693 (2012).

    Article  CAS  PubMed  Google Scholar 

  72. Pinto, M. R., Melillo, D., Giacomelli, S., Sfyroera, G. & Lambris, J. D. Ancient origin of the complement system: emerging invertebrate models. Adv. Exp. Med. Biol. 598, 372–388 (2007).

    Article  PubMed  Google Scholar 

  73. Flajnik, M. F. Re-evaluation of the immunological Big Bang. Curr. Biol. 24, R1060–R1065 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Sunyer, J. O. et al. Evolution of complement as an effector system in innate and adaptive immunity. Immunol. Res. 27, 549–564 (2003).

    Article  CAS  PubMed  Google Scholar 

  75. Carroll, M. C. & Isenman, D. E. Regulation of humoral immunity by complement. Immunity 37, 199–207 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Dempsey, P. W., Allison, M. E., Akkaraju, S., Goodnow, C. C. & Fearon, D. T. C3d of complement as a molecular adjuvant: bridging innate and acquired immunity. Science 271, 348–350 (1996).

    Article  CAS  PubMed  Google Scholar 

  77. Humphrey, J. H., Grennan, D. & Sundaram, V. The origin of follicular dendritic cells in the mouse and the mechanism of trapping of immune complexes on them. Eur. J. Immunol. 14, 859–864 (1984).

    Article  CAS  PubMed  Google Scholar 

  78. Karsten, C. M. & Kohl, J. The immunoglobulin, IgG Fc receptor and complement triangle in autoimmune diseases. Immunobiology 217, 1067–1079 (2012).

    Article  CAS  PubMed  Google Scholar 

  79. Huang, Z. Y. et al. Interaction of two phagocytic host defense systems: Fcγ receptors and complement receptor 3. J. Biol. Chem. 286, 160–168 (2011).

    Article  CAS  PubMed  Google Scholar 

  80. Karsten, C. M. et al. Anti-inflammatory activity of IgG1 mediated by Fc galactosylation and association of FcγRIIB and dectin-1. Nat. Med. 18, 1401–1406 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Bosmann, M. & Ward, P. A. The inflammatory response in sepsis. Trends Immunol. 34, 129–136 (2013).

    Article  CAS  PubMed  Google Scholar 

  82. Ward, P. A. The dark side of C5a in sepsis. Nat. Rev. Immunol. 4, 133–142 (2004).

    Article  CAS  PubMed  Google Scholar 

  83. Silasi-Mansat, R. et al. Complement inhibition decreases early fibrogenic events in the lung of septic baboons. J. Cell. Mol. Med. 19, 2549–2563 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Silasi-Mansat, R. et al. Complement inhibition decreases the procoagulant response and confers organ protection in a baboon model of Escherichia coli sepsis. Blood 116, 1002–1010 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Barratt-Due, A. et al. Combined inhibition of complement C5 and CD14 markedly attenuates inflammation, thrombogenicity, and hemodynamic changes in porcine sepsis. J. Immunol. 191, 819–827 (2013).

    Article  CAS  PubMed  Google Scholar 

  86. Egge, K. H. et al. The anti-inflammatory effect of combined complement and CD14 inhibition is preserved during escalating bacterial load. Clin. Exp. Immunol. 181, 457–467 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Burk, A. M. et al. Early complementopathy after multiple injuries in humans. Shock 37, 348–354 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  88. Ganter, M. T. et al. Role of the alternative pathway in the early complement activation following major trauma. Shock 28, 29–34 (2007).

    Article  CAS  PubMed  Google Scholar 

  89. Huber-Lang, M., Kovtun, A. & Ignatius, A. The role of complement in trauma and fracture healing. Semin. Immunol. 25, 73–78 (2013).

    Article  CAS  PubMed  Google Scholar 

  90. Rafail, S. et al. Complement deficiency promotes cutaneous wound healing in mice. J. Immunol. 194, 1285–1291 (2015).

    Article  CAS  PubMed  Google Scholar 

  91. Brennan, F. H. et al. The complement receptor C5aR controls acute inflammation and astrogliosis following spinal cord injury. J. Neurosci. 35, 6517–6531 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Chen, M., Daha, M. R. & Kallenberg, C. G. The complement system in systemic autoimmune disease. J. Autoimmun. 34, J276–286 (2010).

    Article  CAS  PubMed  Google Scholar 

  93. Chen, M. & Kallenberg, C. G. ANCA-associated vasculitides — advances in pathogenesis and treatment. Nat. Rev. Rheumatol. 6, 653–664 (2010).

    Article  CAS  PubMed  Google Scholar 

  94. Banz, Y. & Rieben, R. Role of complement and perspectives for intervention in ischemia-reperfusion damage. Ann. Med. 44, 205–217 (2012).

    Article  CAS  PubMed  Google Scholar 

  95. Zipfel, P. F. et al. The role of complement in C3 glomerulopathy. Mol. Immunol. 67, 21–30 (2015).

    Article  CAS  PubMed  Google Scholar 

  96. Orsini, F., De Blasio, D., Zangari, R., Zanier, E. R. & De Simoni, M. G. Versatility of the complement system in neuroinflammation, neurodegeneration and brain homeostasis. Front. Cell. Neurosci. 8, 380 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Veerhuis, R., Nielsen, H. M. & Tenner, A. J. Complement in the brain. Mol. Immunol. 48, 1592–1603 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Hovland, A. et al. The complement system and toll-like receptors as integrated players in the pathophysiology of atherosclerosis. Atherosclerosis 241, 480–494 (2015).

    Article  CAS  PubMed  Google Scholar 

  99. Morgan, B. P. The role of complement in neurological and neuropsychiatric diseases. Expert Rev. Clin. Immunol. 11, 1109–1119 (2015).

    Article  CAS  PubMed  Google Scholar 

  100. Patzelt, J., Verschoor, A. & Langer, H. F. Platelets and the complement cascade in atherosclerosis. Front. Physiol. 6, 49 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  101. McHarg, S., Clark, S. J., Day, A. J. & Bishop, P. N. Age-related macular degeneration and the role of the complement system. Mol. Immunol. 67, 43–50 (2015).

    Article  CAS  PubMed  Google Scholar 

  102. Ekdahl, K. N. et al. Innate immunity activation on biomaterial surfaces: a mechanistic model and coping strategies. Adv. Drug Deliv. Rev. 63, 1042–1050 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Grumach, A. S. & Kirschfink, M. Are complement deficiencies really rare? Overview on prevalence, clinical importance and modern diagnostic approach. Mol. Immunol. 61, 110–117 (2014).

    Article  CAS  PubMed  Google Scholar 

  104. Risitano, A. M. Paroxysmal nocturnal hemoglobinuria and other complement-mediated hematological disorders. Immunobiology 217, 1080–1087 (2012).

    Article  CAS  PubMed  Google Scholar 

  105. Rodriguez, E., Rallapalli, P. M., Osborne, A. J. & Perkins, S. J. New functional and structural insights from updated mutational databases for complement factor H, Factor I, membrane cofactor protein and C3. Biosci. Rep. 34, 5 (2014).

    Article  CAS  Google Scholar 

  106. Hageman, G. S. et al. A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. Proc. Natl Acad. Sci. USA 102, 7227–7232 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Weismann, D. et al. Complement factor H binds malondialdehyde epitopes and protects from oxidative stress. Nature 478, 76–81 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Heurich, M. et al. Common polymorphisms in C3, factor B, and factor H collaborate to determine systemic complement activity and disease risk. Proc. Natl Acad. Sci. USA 108, 8761–8766 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  109. Kurts, C., Panzer, U., Anders, H. J. & Rees, A. J. The immune system and kidney disease: basic concepts and clinical implications. Nat. Rev. Immunol. 13, 738–753 (2013).

    Article  CAS  PubMed  Google Scholar 

  110. Song, D., Zhou, W., Sheerin, S. H. & Sacks, S. H. Compartmental localization of complement component transcripts in the normal human kidney. Nephron 78, 15–22 (1998).

    Article  CAS  PubMed  Google Scholar 

  111. Noris, M. & Remuzzi, G. Overview of complement activation and regulation. Semin. Nephrol. 33, 479–492 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Clark, S. J. et al. Tissue-specific host recognition by complement factor H is mediated by differential activities of its glycosaminoglycan-binding regions. J. Immunol. 190, 2049–2057 (2013).

    Article  CAS  PubMed  Google Scholar 

  113. Jozsi, M., Tortajada, A., Uzonyi, B., Goicoechea de Jorge, E. & Rodriguez de Cordoba, S. Factor H-related proteins determine complement-activating surfaces. Trends Immunol. 36, 374–384 (2015).

    Article  CAS  PubMed  Google Scholar 

  114. Noris, M., Mescia, F. & Remuzzi, G. STEC-HUS, atypical HUS and TTP are all diseases of complement activation. Nat. Rev. Nephrol. 8, 622–633 (2012).

    Article  CAS  PubMed  Google Scholar 

  115. Kenawy, H. I., Boral, I. & Bevington, A. Complement-coagulation cross-talk: a potential mediator of the physiological activation of complement by low pH. Front. Immunol. 6, 215 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. George, J. N. & Nester, C. M. Syndromes of thrombotic microangiopathy. N. Engl. J. Med. 371, 654–666 (2014).

    Article  CAS  PubMed  Google Scholar 

  117. Riedl, M. et al. Spectrum of complement-mediated thrombotic microangiopathies: pathogenetic insights identifying novel treatment approaches. Semin. Thromb. Hemost 40, 444–464 (2014).

    Article  CAS  PubMed  Google Scholar 

  118. Mele, C., Remuzzi, G. & Noris, M. Hemolytic uremic syndrome. Semin. Immunopathol. 36, 399–420 (2014).

    Article  CAS  PubMed  Google Scholar 

  119. Noris, M. et al. Dynamics of complement activation in aHUS and how to monitor eculizumab therapy. Blood 124, 1715–1726 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Frimat, M. et al. Complement activation by heme as a secondary hit for atypical hemolytic uremic syndrome. Blood 122, 282–292 (2013).

    Article  CAS  PubMed  Google Scholar 

  121. Zuber, J. et al. Use of eculizumab for atypical haemolytic uraemic syndrome and C3 glomerulopathies. Nat. Rev. Nephrol. 8, 643–657 (2012).

    Article  CAS  PubMed  Google Scholar 

  122. Cofiell, R. et al. Eculizumab reduces complement activation, inflammation, endothelial damage, thrombosis, and renal injury markers in aHUS. Blood 125, 3253–3262 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Morgan, B. P. & Harris, C. L. Complement, a target for therapy in inflammatory and degenerative diseases. Nat. Rev. Drug Discov. 14, 857–877 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Meri, S. Complement activation in diseases presenting with thrombotic microangiopathy. Eur. J. Intern. Med. 24, 496–502 (2013).

    Article  CAS  PubMed  Google Scholar 

  125. Morigi, M. et al. Alternative pathway activation of complement by Shiga toxin promotes exuberant C3a formation that triggers microvascular thrombosis. J. Immunol. 187, 172–180 (2011).

    Article  CAS  PubMed  Google Scholar 

  126. Nester, C. M. & Brophy, P. D. Eculizumab in the treatment of atypical haemolytic uraemic syndrome and other complement-mediated renal diseases. Curr. Opin. Pediatr. 25, 225–231 (2013).

    Article  CAS  PubMed  Google Scholar 

  127. Pecoraro, C. et al. Treatment of congenital thrombotic thrombocytopenic purpura with eculizumab. Am. J. Kidney Dis. 66, 1067–1070 (2015).

    Article  CAS  PubMed  Google Scholar 

  128. Phillips, E. H. et al. The role of ADAMTS-13 activity and complement mutational analysis in differentiating acute thrombotic microangiopathies. J. Thromb. Haemost. 14, 175–185 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Tsai, E., Chapin, J., Laurence, J. C. & Tsai, H. M. Use of eculizumab in the treatment of a case of refractory, ADAMTS13-deficient thrombotic thrombocytopenic purpura: additional data and clinical follow-up. Br. J. Haematol. 162, 558–559 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  130. Pickering, M. C. et al. C3 glomerulopathy: consensus report. Kidney Int. 84, 1079–1089 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  131. Cook, H. T. & Pickering, M. C. Histopathology of MPGN and C3 glomerulopathies. Nat. Rev. Nephrol. 11, 14–22 (2015).

    Article  CAS  PubMed  Google Scholar 

  132. Servais, A. et al. Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies. Kidney Int. 82, 454–464 (2012).

    Article  CAS  PubMed  Google Scholar 

  133. Martinez-Barricarte, R. et al. Human C3 mutation reveals a mechanism of dense deposit disease pathogenesis and provides insights into complement activation and regulation. J. Clin. Invest. 120, 3702–3712 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Xiao, X., Pickering, M. C. & Smith, R. J. C3 glomerulopathy: the genetic and clinical findings in dense deposit disease and C3 glomerulonephritis. Semin. Thromb. Hemost. 40, 465–471 (2014).

    Article  CAS  PubMed  Google Scholar 

  135. Damman, J. et al. Hypoxia and complement-and-coagulation pathways in the deceased organ donor as the major target for intervention to improve renal allograft outcome. Transplantation 99, 1293–1300 (2015).

    Article  CAS  PubMed  Google Scholar 

  136. Amura, C. R. et al. Complement activation and toll-like receptor-2 signaling contribute to cytokine production after renal ischemia/reperfusion. Mol. Immunol. 52, 249–257 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Farrar, C. A. et al. Collectin-11 detects stress-induced L-fucose pattern to trigger renal epithelial injury. J. Clin. Invest. 126, 1911–19 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  138. Muller, T. F., Kraus, M., Neumann, C. & Lange, H. Detection of renal allograft rejection by complement components C5A and TCC in plasma and urine. J. Lab. Clin. Med. 129, 62–71 (1997).

    Article  CAS  PubMed  Google Scholar 

  139. Stites, E., Le Quintrec, M. & Thurman, J. M. The complement system and antibody-mediated transplant rejection. J. Immunol. 195, 5525–5531 (2015).

    Article  CAS  PubMed  Google Scholar 

  140. Pratt, J. R., Basheer, S. A. & Sacks, S. H. Local synthesis of complement component C3 regulates acute renal transplant rejection. Nat. Med. 8, 582–587 (2002).

    Article  CAS  PubMed  Google Scholar 

  141. Strainic, M. G., Shevach, E. M., An, F., Lin, F. & Medof, M. E. 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, 162–171 (2013).

    Article  CAS  PubMed  Google Scholar 

  142. van der Touw, W. et al. Cutting edge: receptors for C3a and C5a modulate stability of alloantigen-reactive induced regulatory T cells. J. Immunol. 190, 5921–5925 (2013).

    Article  CAS  PubMed  Google Scholar 

  143. Marsh, J. E. et al. The allogeneic T and B cell response is strongly dependent on complement components C3 and C4. Transplantation 72, 1310–1318 (2001).

    Article  CAS  PubMed  Google Scholar 

  144. Thomas, K. A., Valenzuela, N. M. & Reed, E. F. The perfect storm: HLA antibodies, complement, FcγRs, and endothelium in transplant rejection. Trends Mol. Med. 21, 319–329 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Chen Song, S. et al. Complement inhibition enables renal allograft accommodation and long-term engraftment in presensitized nonhuman primates. Am. J. Transplant. 11, 2057–2066 (2011).

    Article  CAS  PubMed  Google Scholar 

  146. Fremeaux-Bacchi, V. & Legendre, C. M. The emerging role of complement inhibitors in transplantation. Kidney Int. 88, 967–973 (2015).

    Article  CAS  PubMed  Google Scholar 

  147. DeAngelis, R. A., Reis, E. S., Ricklin, D. & Lambris, J. D. Targeted complement inhibition as a promising strategy for preventing inflammatory complications in hemodialysis. Immunobiology 217, 1097–1105 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Kourtzelis, I. et al. Complement anaphylatoxin C5a contributes to hemodialysis-associated thrombosis. Blood 116, 631–639 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Ricklin, D. & Lambris, J. D. Complement in immune and inflammatory disorders: therapeutic interventions. J. Immunol. 190, 3839–3847 (2013).

    Article  CAS  PubMed  Google Scholar 

  150. Licht, C. et al. Efficacy and safety of eculizumab in atypical hemolytic uremic syndrome from 2-year extensions of phase 2 studies. Kidney Int. 87, 1061–1073 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Wong, E. K. & Kavanagh, D. Anticomplement C5 therapy with eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome. Transl. Res. 165, 306–320 (2015).

    Article  CAS  PubMed  Google Scholar 

  152. Eskandary, F., Wahrmann, M., Muhlbacher, J. & Bohmig, G. A. Complement inhibition as potential new therapy for antibody-mediated rejection. Transpl. Int. 29, 392–402 (2016).

    Article  CAS  PubMed  Google Scholar 

  153. Stegall, M. D. et al. Terminal complement inhibition decreases antibody-mediated rejection in sensitized renal transplant recipients. Am. J. Transplant. 11, 2405–2413 (2011).

    Article  CAS  PubMed  Google Scholar 

  154. Cornell, L. D., Schinstock, C. A., Gandhi, M. J., Kremers, W. K. & Stegall, M. D. Positive crossmatch kidney transplant recipients treated with eculizumab: outcomes beyond 1 year. Am. J. Transplant. 15, 1293–2302 (2015).

    Article  CAS  PubMed  Google Scholar 

  155. Ricklin, D. & Lambris, J. D. Therapeutic control of complement activation at the level of the central component C3. Immunobiology http://dx.doi.org/10.1016/j.imbio.2015.06.012 (2015).

  156. Zhang, Y. et al. Soluble CR1 therapy improves complement regulation in C3 glomerulopathy. J. Am. Soc. Nephrol. 24, 1820–1829 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Sacks, S. et al. Targeting complement at the time of transplantation. Adv. Exp. Med. Biol. 735, 247–255 (2013).

    Article  CAS  PubMed  Google Scholar 

  158. US National Library of Science. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT02247531 (2016).

  159. US National Library of Science. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT02247479 (2016).

  160. Zhang, Y. et al. Compstatin analog Cp40 inhibits complement dysregulation in vitro in C3 glomerulopathy. Immunobiology 220, 993–998 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Risitano, A. M. et al. Peptide inhibitors of C3 activation as a novel strategy of complement inhibition for the treatment of paroxysmal nocturnal hemoglobinuria. Blood 123, 2094–2101 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Reis, E. S. et al. Therapeutic C3 inhibitor Cp40 abrogates complement activation induced by modern hemodialysis filters. Immunobiology 220, 476–482 (2015).

    Article  CAS  PubMed  Google Scholar 

  163. US National Library of Science. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT02264639 (2016).

  164. US National Library of Science. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT02503332 (2016).

  165. US National Library of Science. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT02588833 (2016).

  166. US National Library of Science. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT02502903 (2015).

  167. US National Library of Science. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT02222545 (2015).

  168. Vo, A. A. et al. A phase I/II placebo-controlled trial of C1-inhibitor for prevention of antibody-mediated rejection in HLA sensitized patients. Transplantation 99, 299–308 (2015).

    Article  CAS  PubMed  Google Scholar 

  169. ChemoCentryx. ChemoCentryx announces positive results in phase II ANCA-associated vasculitis CLEAR trial of orally administered complement 5a receptor inhibitor CCX168. http://ir.chemocentryx.com/releasedetail.cfm?releaseid=948998 (2016).

  170. US National Library of Science. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT02384317 (2016).

  171. US National Library of Science. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT02464891 (2015).

  172. US National Library of Science. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT02246595 (2016).

  173. Hillmen, P. et al. Long-term safety and efficacy of sustained eculizumab treatment in patients with paroxysmal nocturnal haemoglobinuria. Br. J. Haematol. 162, 62–73 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Wu, M. A., Zanichelli, A., Mansi, M. & Cicardi, M. Current treatment options for hereditary angioedema due to C1 inhibitor deficiency. Expert Opin. Pharmacother. 17, 27–40 (2016).

    Article  CAS  PubMed  Google Scholar 

  175. Banda, N. K. et al. Mechanisms of mannose-binding lectin-associated serine proteases-1/3 activation of the alternative pathway of complement. Mol. Immunol. 49, 281–289 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Dobo, J. et al. Multiple roles of complement MASP-1 at the interface of innate immune response and coagulation. Mol. Immunol. 61, 69–78 (2014).

    Article  CAS  PubMed  Google Scholar 

  177. Arnold, J. N., Royle, L., Dwek, R. A., Rudd, P. M. & Sim, R. B. Human immunoglobulin glycosylation and the lectin pathway of complement activation. Adv. Exp. Med. Biol. 564, 27–43 (2005).

    Article  CAS  PubMed  Google Scholar 

  178. Amara, U. et al. Molecular intercommunication between the complement and coagulation systems. J. Immunol. 185, 5628–5636 (2010).

    Article  CAS  PubMed  Google Scholar 

  179. Inforzato, A. et al. PTX3 as a paradigm for the interaction of pentraxins with the complement system. Semin. Immunol. 25, 79–85 (2013).

    Article  CAS  PubMed  Google Scholar 

  180. Csincsi, A. I. et al. Factor H-related protein 5 interacts with pentraxin 3 and the extracellular matrix and modulates complement activation. J. Immunol. 194, 4963–4973 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Trouw, L. A., Blom, A. M. & Gasque, P. Role of complement and complement regulators in the removal of apoptotic cells. Mol. Immunol. 45, 1199–1207 (2008).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank Deborah McClellan for editing the manuscript before submission. J.D.L. also thanks Ralph and Sallie Weaver for the generous endowment of his professorship. Given the broad scope of this Review, we often refer to specialized review articles rather than primary literature, and we have only been able to include selected examples of the breadth of transformative work in the field; we therefore thank all our colleagues who are not specifically cited for their great contributions and their understanding. This work was supported by grants from the US NIH (AI068730, AI030040, DE021685) and the National Science Foundation (grant No. 1423304) and by funding from the European Community's Seventh Framework Programme, under grant agreement number 602699 (DIREKT).

Author information

Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, University of Pennsylvania, 401 Stellar Chance, 422 Curie Boulevard, Philadelphia, 19104, Pennsylvania, USA

    Daniel Ricklin, Edimara S. Reis & John D. Lambris

Authors
  1. Daniel Ricklin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Edimara S. Reis
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. John D. Lambris
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed to researching data for the article, discussion of the article's content, writing, and review/editing of the manuscript before submission.

Corresponding authors

Correspondence to Daniel Ricklin or John D. Lambris.

Ethics declarations

Competing interests

J.D.L and D.R. are inventors of patents or patent applications that describe the use of complement inhibitors for therapeutic purposes. J.D.L. is the founder of Amyndas Pharmaceuticals, which is developing complement inhibitors. E.S.R. declares no competing interests.

PowerPoint slides

Related links

Related links

DATABASES

FH aHUS mutation database

Glossary

Convertase

A protein complex transiently formed by an opsonin (C3b, C4b) and a protease fragment (Bb, C2b), which activates complement components C3 or C5 and promotes opsonization, amplification and/or generation of effector molecules.

Anaphylatoxin

A widely used term for complement effector fragments C3a and C5a, which are released upon activation of C3 and C5, respectively, and exert numerous immunomodulatory, chemotactic and/or cell-activating functions.

Opsonization

The process of depositing complement proteins on a particle surface to facilitate its removal. In the complement system, C3b, C4b (and their degradation fragments) and C1q facilitate phagocytosis via their receptors on immune cells.

Amplification

A major function of the 'alternative pathway' of complement, whereby convertase-mediated deposition of C3b on a targeted surface enables the formation of additional C3 convertases and deposition of more C3b. In absence of regulators, these events lead to rapid opsonization of the attacked cell or particle.

Consumption

A result of continuous and poorly controlled activation of complement components in the circulation, leading to a depletion of the native plasma protein and affecting the responsiveness of the cascade.

Fluid phase

Refers to complement activity in the circulation rather than on the targeted surface. Fluid-phase activation maintains alertness of the complement system (tick-over) but needs to be tightly controlled by soluble complement regulators.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ricklin, D., Reis, E. & Lambris, J. Complement in disease: a defence system turning offensive. Nat Rev Nephrol 12, 383–401 (2016). https://doi.org/10.1038/nrneph.2016.70

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrneph.2016.70

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing