Complement: A key system for immune surveillance and homeostasis

Nature Immunology

Volumn 11, Issue 9, 2010, Pages 785-797

  Ricklin, Daniel ^a   Hajishengallis, George ^b   Yang, Kun ^a   Lambris, John D ^a  

^a UNIVERSITY OF PENNSYLVANIA   (United States)

^b University of Louisville School of Medicine   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

COMPLEMENT; TOLL LIKE RECEPTOR;

APOPTOSIS; CELLULAR IMMUNITY; CHEMICAL STRUCTURE; COMPLEMENT ACTIVATION; COMPLEMENT DISORDER; HOMEOSTASIS; HUMAN; HUMORAL IMMUNITY; IMMUNITY; IMMUNOREGULATION; IMMUNOSURVEILLANCE; INFLAMMATORY DISEASE; METABOLISM; MICROORGANISM; MOLECULAR DYNAMICS; MOLECULAR INTERACTION; NEOPLASM; PRIORITY JOURNAL; REVIEW; SIGNAL TRANSDUCTION;

APOPTOSIS; COMPLEMENT SYSTEM PROTEINS; DISEASE; GENE EXPRESSION REGULATION; HOMEOSTASIS; HUMANS; IMMUNOLOGIC SURVEILLANCE; SIGNAL TRANSDUCTION;

EID: 77955883153     PISSN: 15292908     EISSN: 15292916     Source Type: Journal    
DOI: 10.1038/ni.1923     Document Type: Review

References (176)

1. Sunyer, J.O., Zarkadis, I.K. & Lambris, J.D. Complement diversity: a mechanism for generating immune diversity? Immunol. Today 19, 519-523 (1998).
2. Gaboriaud, C. et al. Structure and activation of the C1 complex of complement: unraveling the puzzle. Trends Immunol. 25, 368-373 (2004).
3. Wallis, R., Mitchell, D.A., Schmid, R., Schwaeble, W.J. & Keeble, A.H. Paths reunited: Initiation of the classical and lectin pathways of complement activation. Immunobiology 215, 1-11 (2010).
4. Chen, C.B. & wallis, R. Two mechanisms for mannose-binding protein modulation of the activity of its associated serine proteases. J. Biol. Chem. 279, 26058-26065 (2004).
5. Dobó, J. et al. MASP-1, a promiscuous complement protease: structure of its catalytic region reveals the basis of its broad specificity. J. Immunol. 183, 1207-1214 (2009).
6. Rawal, N., rajagopalan, R. & Salvi, V.P. Activation of complement component C5: comparison of C5 convertases of the lectin pathway and the classical pathway of complement. J. Biol. Chem. 283, 7853-7863 (2008).
7. Bexborn, F., Andersson, P.O., Chen, H., Nilsson, B. & ekdahl, K.N. The tick-over theory revisited: formation and regulation of the soluble alternative complement C3 convertase (C3(H2O)Bb). Mol. Immunol. 45, 2370-2379 (2008).
8. Pangburn, M.K., Schreiber, R.D. & Muller-eberhard, H.J. Formation of the initial C3 convertase of the alternative complement pathway. Acquisition of C3b-like activities by spontaneous hydrolysis of the putative thioester in native C3. J. Exp. Med. 154, 856-867 (1981).
9. Pangburn, M.K., Ferreira, V.P. & Cortes, C. Discrimination between host and pathogens by the complement system. Vaccine 26 Suppl 8, I15-I21 (2008).
10. Sahu, A., Kozel, T.R. & Pangburn, M.K. Specificity of the thioester-containing reactive site of human C3 and its significance to complement activation. Biochem. J. 302, 429-436 (1994).
11. Spitzer, D., Mitchell, L.M., Atkinson, J.P. & Hourcade, D.E. Properdin can initiate complement activation by binding specific target surfaces and providing a platform for de novo convertase assembly. J. Immunol. 179, 2600-2608 (2007).
12. Fearon, D.T. & Austen, K.F. Properdin: binding to C3b and stabilization of the C3b-dependent C3 convertase. J. Exp. Med. 142, 856-863 (1975).
13. Harboe, M. & Mollnes, T.E. The alternative complement pathway revisited. J. Cell. Mol. Med. 12, 1074-1084 (2008).
14. Lutz, H.U. & Jelezarova, E. Complement amplification revisited. Mol. Immunol. 43, 2-12 (2006).
15. Müller-eberhard, H.J. The killer molecule of complement. J. Invest. Dermatol. 85, 47s-52s (1985).
16. Markiewski, M.M., Nilsson, B., ekdahl, K.N., Mollnes, T.E. & Lambris, J.D. Complement and coagulation: strangers or partners in crime? Trends Immunol. 28, 184-192 (2007).
17. Huber-Lang, M. et al. Generation of C5a in the absence of C3: a new complement activation pathway. Nat. Med. 12, 682-687 (2006).
18. Selander, B. et al. Mannan-binding lectin activates C3 and the alternative complement pathway without involvement of C2. J. Clin. Invest. 116, 1425-1434 (2006).
19. Atkinson, J.P. & Frank, M.M. Bypassing complement: evolutionary lessons and future implications. J. Clin. Invest. 116, 1215-1218 (2006).
20. Lambris, J.D., ricklin, D. & Geisbrecht, B.V. Complement evasion by human pathogens. Nat. Rev. Microbiol. 6, 132-142 (2008).
21. Cole, D.S. & Morgan, B.P. Beyond lysis: how complement influences cell fate. Clin. Sci. (Lond.) 104, 455-466 (2003).
22. Ward, P.A. Functions of C5a receptors. J. Mol. Med. 87, 375-378 (2009).
23. Rittirsch, D. et al. Functional roles for C5a receptors in sepsis. Nat. Med. 14, 551-557 (2008).
24. Bamberg, C.E. et al. The C5a receptor (C5ar) C5L2 is a modulator of C5ar-mediated signal transduction. J. Biol. Chem. 285, 7633-7644 (2010).
25. Scola, A.M. et al. The role of the N-terminal domain of the complement fragment receptor C5L2 in ligand binding. J. Biol. Chem. 282, 3664-3671 (2007).
26. Klos, A. et al. The role of the anaphylatoxins in health and disease. Mol. Immunol. 46, 2753-2766 (2009).
27. Haas, P.J. & van Strijp, J. Anaphylatoxins: their role in bacterial infection and inflammation. Immunol. Res. 37, 161-175 (2007).
28. Van Lookeren Campagne, M., wiesmann, C. & Brown, E.J. Macrophage complement receptors and pathogen clearance. Cell. Microbiol. 9, 2095-2102 (2007).
29. Krych-Goldberg, M. & Atkinson, J.P. Structure-function relationships of complement receptor type 1. Immunol. Rev. 180, 112-122 (2001).
30. Helmy, K.Y. et al. CrIg: a macrophage complement receptor required for phagocytosis of circulating pathogens. Cell 124, 915-927 (2006).
31. He, J.Q., wiesmann, C. & van Lookeren Campagne, M. A role of macrophage complement receptor CrIg in immune clearance and inflammation. Mol. Immunol. 45, 4041-4047 (2008).
32. Roozendaal, R. & Carroll, M.C. Complement receptors CD21 and CD35 in humoral immunity. Immunol. Rev. 219, 157-166 (2007).
33. Carroll, M.C. Complement and humoral immunity. Vaccine 26 Suppl. 8, I28-I33 (2008).
34. Ogden, C.A. et al. C1q and mannose binding lectin engagement of cell surface calreticulin and CD91 initiates macropinocytosis and uptake of apoptotic cells. J. Exp. Med. 194, 781-795 (2001).
35. Tarr, J. & eggleton, P. Immune function of C1q and its modulators CD91 and CD93. Crit. Rev. Immunol. 25, 305-330 (2005).
36. Lillis, A.P. et al. Murine low-density lipoprotein receptor-related protein 1 (LrP) is required for phagocytosis of targets bearing LrP ligands but is not required for C1q-triggered enhancement of phagocytosis. J. Immunol. 181, 364-373 (2008).
37. Norsworthy, P.J. et al. Murine CD93 (C1qrp) contributes to the removal of apoptotic cells in vivo but is not required for C1q-mediated enhancement of phagocytosis. J. Immunol. 172, 3406-3414 (2004).
38. Zipfel, P.F. & Skerka, C. Complement regulators and inhibitory proteins. Nat. Rev. Immunol. 9, 729-740 (2009).
39. Inal, J.M. et al. Complement C2 receptor inhibitor trispanning: a novel human complement inhibitory receptor. J. Immunol. 174, 356-366 (2005).
40. Kim, D.D. & Song, W.C. Membrane complement regulatory proteins. Clin. Immunol. 118, 127-136 (2006).
41. Jalili, A. et al. Fifth complement cascade protein (C5) cleavage fragments disrupt the SDF-1/CXCr4 axis: Further evidence that innate immunity orchestrates the mobilization of hematopoietic stem/progenitor cells. Exp. Hematol. 38, 321-332 (2010).
42. Ratajczak, M.Z., reca, R., wysoczynski, M., Yan, J. & ratajczak, J. Modulation of the SDF-1-CXCr4 axis by the third complement component (C3)\implications for Trafficking of CXCr4+ stem cells. Exp. Hematol. 34, 986-995 (2006).
43. MacLaren, R., Cui, W. & Cianflone, K. Adipokines and the immune system: an adipocentric view. Adv. Exp. Med. Biol. 632, 1-21 (2008).
44. Sahu, A. & Lambris, J.D. Structure and biology of complement protein C3, a connecting link between innate and acquired immunity. Immunol. Rev. 180, 35-48 (2001).
45. Rooijakkers, S.H. et al. Structural and functional implications of the alternative complement pathway C3 convertase stabilized by a staphylococcal inhibitor. Nat. Immunol. 10, 721-727 (2009).
46. Wu, J. et al. Structure of complement fragment C3b-factor H and implications for host protection by complement regulators. Nat. Immunol. 10, 728-733 (2009).
47. Oliva, C., Turnbough, C.L. Jr. & Kearney, J.F. CD14-Mac-1 interactions in Bacillus anthracis spore internalization by macrophages. Proc. Natl. Acad. Sci. USA 106, 13957-13962 (2009).
48. Wang, M. et al. Fimbrial proteins of Porphyromonas gingivalis mediate in vivo virulence and exploit TLr2 and complement receptor 3 to persist in macrophages. J. Immunol. 179, 2349-2358 (2007).
49. Flierman, R. & Daha, M.R. The clearance of apoptotic cells by complement. Immunobiology 212, 363-370 (2007).
50. 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).
51. Cole, D.S., Hughes, T.R., Gasque, P. & Morgan, B.P. Complement regulator loss on apoptotic neuronal cells causes increased complement activation and promotes both phagocytosis and cell lysis. Mol. Immunol. 43, 1953-1964 (2006).
52. Gullstrand, B., Martensson, U., Sturfelt, G., Bengtsson, A.A. & Truedsson, L. Complement classical pathway components are all important in clearance of apop-totic and secondary necrotic cells. Clin. Exp. Immunol. 156, 303-311 (2009).
53. Gershov, D., Kim, S., Brot, N. & elkon, K.B. C-reactive protein binds to apoptotic cells, protects the cells from assembly of the terminal complement components, and sustains an antiinflammatory innate immune response: implications for systemic autoimmunity. J. Exp. Med. 192, 1353-1364 (2000).
54. Lowell, C.A. rewiring phagocytic signal transduction. Immunity 24, 243-245 (2006).
55. Kim, S., Elkon, K.B. & Ma, X. Transcriptional suppression of interleukin-12 gene expression following phagocytosis of apoptotic cells. Immunity 21, 643-653 (2004).
56. Mevorach, D., Mascarenhas, J.O., Gershov, D. & elkon, K.B. Complement-dependent clearance of apoptotic cells by human macrophages. J. Exp. Med. 188, 2313-2320 (1998).
57. Morelli, A.E. et al. Internalization of circulating apoptotic cells by splenic marginal zone dendritic cells: dependence on complement receptors and effect on cytokine production. Blood 101, 611-620 (2003).
58. Verbovetski, I. et al. Opsonization of apoptotic cells by autologous iC3b facilitates clearance by immature dendritic cells, down-regulates Dr and CD86, and up-regu-lates CC chemokine receptor 7. J. Exp. Med. 196, 1553-1561 (2002).
59. Markiewski, M.M. et al. The regulation of liver cell survival by complement. J. Immunol. 182, 5412-5418 (2009).
60. Nozaki, M. et al. Drusen complement components C3a and C5a promote choroidal neovascularization. Proc. Natl. Acad. Sci. USA 103, 2328-2333 (2006).
61. Hajishengallis, G. & Lambris, J.D. Crosstalk pathways between Toll-like receptors and the complement system. Trends Immunol. 31, 154-163 (2010).
62. Dunkelberger, J.R. & Song, W.C. Complement and its role in innate and adaptive immune responses. Cell Res. 20, 34-50 (2010).
63. Zhang, X. et al. regulation of Toll-like receptor-mediated inflammatory response by complement in vivo. Blood 110, 228-236 (2007).
64. Guo, R.F., riedemann, N.C. & ward, P.A. role of C5a-C5ar interaction in sepsis. Shock 21, 1-7 (2004).
65. Kaczorowski, D.J. et al. Pivotal Advance: The pattern recognition receptor ligands lipopolysaccharide and polyinosine-polycytidylic acid stimulate factor B synthesis by the macrophage through distinct but overlapping mechanisms. J. Leukoc. Biol. published online, doi: 10.1189/jlb.0809588 (22 April 2010).
66. Chen, N.J. et al. C5L2 is critical for the biological activities of the anaphylatoxins C5a and C3a. Nature 446, 203-207 (2007).
67. Wang, M. et al. Microbial hijacking of complement-Toll-like receptor crosstalk. Sci. Signal. 3, ra11 (2010).
68. Weaver, D.J. Jr. et al. C5a receptor-deficient dendritic cells promote induction of Treg and Th17 cells. Eur. J. Immunol. 40, 710-721 (2010).
69. Ip, W.K.e., Takahashi, K., Moore, K.J., Stuart, L.M. & ezekowitz, R.A.B. Mannose-binding lectin enhances Toll-like receptors 2 and 6 signaling from the phagosome. J. Exp. Med. 205, 169-181 (2008).
70. Lappegård, K.T. et al. Human genetic deficiencies reveal the roles of complement in the inflammatory network: lessons from nature. Proc. Natl. Acad. Sci. USA 106, 15861-15866 (2009).
71. Zarewych, D.M., Kindzelskii, A.L., Todd, R.F. & Petty, H.R. LPS induces CD14 association with complement receptor 3, which is reversed by neutrophil adhesion. J. Immunol. 156, 430-433 (1996).
72. Kagan, J.C. "Complementing" toll signaling. Sci. Signal. 3, pe15 (2010).
73. Harokopakis, E., Albzreh, M.H., Martin, M.H. & Hajishengallis, G. TLr2 transmodu-lates monocyte adhesion and transmigration via rac1-and PI3K-mediated inside-out signaling in response to Porphyromonas gingivalis fimbriae. J. Immunol. 176, 7645-7656 (2006).
74. Kagan, J.C. & Medzhitov, R. Phosphoinositide-mediated adaptor recruitment controls Toll-like receptor signaling. Cell 125, 943-955 (2006).
75. 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).
76. Krarup, A., wallis, R., Presanis, J.S., Gal, P. & Sim, R.B. Simultaneous activation of complement and coagulation by MBL-associated serine protease 2. PLoS ONE 2, e623 (2007).
77. Ghebrehiwet, B., Silverberg, M. & Kaplan, A.P. Activation of the classical pathway of complement by Hageman factor fragment. J. Exp. Med. 153, 665-676 (1981).
78. Bergmann, S. & Hammerschmidt, S. Fibrinolysis and host response in bacterial infections. Thromb. Haemost. 98, 512-520 (2007).
79. Ward, P.A. The dark side of C5a in sepsis. Nat. Rev. Immunol. 4, 133-142 (2004).
80. 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).
81. Fischer, M.B. et al. Dependence of germinal center B cells on expression of CD21/CD35 for survival. Science 280, 582-585 (1998).
82. Croix, D.A. et al. Antibody response to a T-dependent antigen requires B cell expression of complement receptors. J. Exp. Med. 183, 1857-1864 (1996).
83. Thornton, B.P., vetvicka, V. & ross, G.D. Function of C3 in a humoral response: iC3b/C3dg bound to an immune complex generated with natural antibody and a primary antigen promotes antigen uptake and the expression of co-stimulatory molecules by all B cells, but only stimulates immunoglobulin synthesis by antigen-specific B cells. Clin. Exp. Immunol. 104, 531-537 (1996).
84. Guinamard, R., Okigaki, M., Schlessinger, J. & ravetch, J.V. Absence of marginal zone B cells in Pyk-2-deficient mice defines their role in the humoral response. Nat. Immunol. 1, 31-36 (2000).
85. Haas, K.M. et al. Complement receptors CD21/35 link innate and protective immunity during Streptococcus pneumoniae infection by regulating IgG3 antibody responses. Immunity 17, 713-723 (2002).
86. Da Costa, X.J. et al. Humoral response to herpes simplex virus is complement-dependent. Proc. Natl. Acad. Sci. USA 96, 12708-12712 (1999).
87. desArg: suppression of TNF-α, IL-6, and the polyclonal immune response. J. Immunol. 159, 4279-4286 (1997).
88. Ottonello, L. et al. rC5a directs the in vitro migration of human memory and naive tonsillar B lymphocytes: implications for B cell trafficking in secondary lymphoid tissues. J. Immunol. 162, 6510-6517 (1999).
89. Shushakova, N. et al. C5a anaphylatoxin is a major regulator of activating versus inhibitory Fcγrs in immune complex-induced lung disease. J. Clin. Invest. 110, 1823-1830 (2002).
90. Kumar, V. et al. Cell-derived anaphylatoxins as key mediators of antibody-dependent type II autoimmunity in mice. J. Clin. Invest. 116, 512-520 (2006).
91. Gustavsson, S., Kinoshita, T. & Heyman, B. Antibodies to murine complement receptor 1 and 2 can inhibit the antibody response in vivo without inhibiting T helper cell induction. J. Immunol. 154, 6524-6528 (1995).
92. Kopf, M., Abel, B., Gallimore, A., Carroll, M. & Bachmann, M.F. Complement component C3 promotes T-cell priming and lung migration to control acute influenza virus infection. Nat. Med. 8, 373-378 (2002).
93. Nakayama, Y. et al. C3 promotes expansion of CD8+ and CD4+ T cells in a Listeria monocytogenes infection. J. Immunol. 183, 2921-2931 (2009).
94. Kaya, Z. et al. Contribution of the innate immune system to autoimmune myocarditis: a role for complement. Nat. Immunol. 2, 739-745 (2001).
95. 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).
96. Sacks, S.H. Complement fragments C3a and C5a: The salt and pepper of the immune response. Eur. J. Immunol. 40, 668-670 (2010).
97. Strainic, M.G. et al. Locally produced complement fragments C5a and C3a provide both costimulatory and survival signals to naive CD4+ T cells. Immunity 28, 425-435 (2008).
98. Li, K. et al. Cyclic AMP plays a critical role in C3a-receptor-mediated regulation of dendritic cells in antigen uptake and T-cell stimulation. Blood 112, 5084-5094 (2008).
99. Peng, Q. et al. Dendritic cell function in allostimulation is modulated by C5ar signaling. J. Immunol. 183, 6058-6068 (2009).
100. Longhi, M.P., Harris, C.L., Morgan, B.P. & Gallimore, A. Holding T cells in check\a new role for complement regulators? Trends Immunol. 27, 102-108 (2006).
101. Wagner, C. et al. The complement receptor 1, Cr1 (CD35), mediates inhibitory signals in human T-lymphocytes. Mol. Immunol. 43, 643-651 (2006).
102. Le Friec, G. & Kemper, C. Complement: coming full circle. Arch. Immunol. Ther. Exp. (Warsz.) 57, 393-407 (2009).
103. Price, J.D. et al. Induction of a regulatory phenotype in human CD4+ T cells by streptococcal M protein. J. Immunol. 175, 677-684 (2005).
104. Köhl, J. et al. A regulatory role for the C5a anaphylatoxin in type 2 immunity in asthma. J. Clin. Invest. 116, 783-796 (2006).
105. Zhang, X. et al. A protective role for C5a in the development of allergic asthma associated with altered levels of B7-H1 and B7-DC on plasmacytoid dendritic cells. J. Immunol. 182, 5123-5130 (2009).
106. Drouin, S.M., Corry, D.B., Hollman, T.J., Kildsgaard, J. & wetsel, R.A. Absence of the complement anaphylatoxin C3a receptor suppresses Th2 effector functions in a murine model of pulmonary allergy. J. Immunol. 169, 5926-5933 (2002).
107. Finkelman, F.D., Hogan, S.P., Hershey, G.K., rothenberg, M.E. & wills-Karp, M. Importance of cytokines in murine allergic airway disease and human asthma. J. Immunol. 184, 1663-1674 (2010).
108. Liu, J. et al. IFN-γ and IL-17 production in experimental autoimmune encephalomyelitis depends on local APC-T cell complement production. J. Immunol. 180, 5882-5889 (2008).
109. Fang, C., Zhang, X., Miwa, T. & Song, W.C. Complement promotes the development of inflammatory T-helper 17 cells through synergistic interaction with Toll-like receptor signaling and interleukin-6 production. Blood 114, 1005-1015 (2009).
110. Hawlisch, H. et al. C5a negatively regulates toll-like receptor 4-induced immune responses. Immunity 22, 415-426 (2005).
111. i-protein- dependent inhibition of IL-12 production is mediated by activation of the phosphatidylinositol 3-kinase-protein 3 kinase B/Akt pathway and JNK. J. Immunol. 175, 2994-2999 (2005).
112. Goriely, S., Neurath, M.F. & Goldman, M. How microorganisms tip the balance between interleukin-12 family members. Nat. Rev. Immunol. 8, 81-86 (2008).
113. Waggoner, S.N., Cruise, M.W., Kassel, R. & Hahn, Y.S. gC1q receptor ligation selectively down-regulates human IL-12 production through activation of the phospho-inositide 3-kinase pathway. J. Immunol. 175, 4706-4714 (2005).
114. Karp, C.L. et al. Mechanism of suppression of cell-mediated immunity by measles virus. Science 273, 228-231 (1996).
115. Marth, T. & Kelsall, B.L. regulation of interleukin-12 by complement receptor 3 signaling. J. Exp. Med. 185, 1987-1995 (1997). (Pubitemid 27247085)
116. Hajishengallis, G., Shakhatreh, M.-A.K., wang, M. & Liang, S. Complement receptor 3 blockade promotes IL-12-mediated clearance of Porphyromonas gingivalis and negates its virulence in vivo. J. Immunol. 179, 2359-2367 (2007).
117. Manderson, A.P., Botto, M. & walport, M.J. The role of complement in the development of systemic lupus erythematosus. Annu. Rev. Immunol. 22, 431-456 (2004).
118. Vaknin-Dembinsky, A., Murugaiyan, G., Hafler, D.A., Astier, A.L. & weiner, H.L. Increased IL-23 secretion and altered chemokine production by dendritic cells upon CD46 activation in patients with multiple sclerosis. J. Neuroimmunol. 195, 140-145 (2008).
119. Braun, M.C., Lahey, E. & Kelsall, B.L. Selective suppression of IL-12 production by chemoattractants. J. Immunol. 164, 3009-3017 (2000).
120. Hashimoto, M. et al. Complement drives Th17 cell differentiation and triggers autoimmune arthritis. J. Exp. Med. 207, 1135-1143 (2010).
121. Botto, M. et al. Complement in human diseases: lessons from complement deficiencies. Mol. Immunol. 46, 2774-2783 (2009).
122. Pettigrew, H.D., Teuber, S.S. & Gershwin, M.E. Clinical significance of complement deficiencies. Ann. NY Acad. Sci. 1173, 108-123 (2009).
123. Lachmann, P.J. & Smith, R.A. Taking complement to the clinic\has the time finally come? Scand. J. Immunol. 69, 471-478 (2009).
124. Ricklin, D. & Lambris, J.D. Complement-targeted therapeutics. Nat. Biotechnol. 25, 1265-1275 (2007).
125. Wagner, E. & Frank, M.M. Therapeutic potential of complement modulation. Nat. Rev. Drug Discov. 9, 43-56 (2010).
126. Okroj, M., Heinegard, D., Holmdahl, R. & Blom, A.M. rheumatoid arthritis and the complement system. Ann. Med. 39, 517-530 (2007).
127. Zhang, X. & Kohl, J. A complex role for complement in allergic asthma. Expert Rev. Clin. Immunol. 6, 269-277 (2010).
128. Holers, V.M. The spectrum of complement alternative pathway-mediated diseases. Immunol. Rev. 223, 300-316 (2008).
129. Markiewski, M.M. & Lambris, J.D. The role of complement in inflammatory diseases from behind the scenes into the spotlight. Am. J. Pathol. 171, 715-727 (2007).
130. Nilsson, B., Korsgren, O., Lambris, J.D & Ekdahl, K.N. Can Cells and Biomaterials in Therapeutic Medicine Be Shielded from Innate Immune Recognition? Trends Immunol. 31, 32-38 (2010).
131. Kourtzelis, I. et al. Complement anaphylatoxin C5a contributes to hemodialysis-associated thrombosis. Blood 116, 631-639 (2010)
132. Warren, O.J. et al. The inflammatory response to cardiopulmonary bypass: part 1\mechanisms of pathogenesis. J. Cardiothorac. Vasc. Anesth. 23, 223-231 (2009).
133. Mullins, R.F., russell, S.R., Anderson, D.H. & Hageman, G.S. Drusen associated with aging and age-related macular degeneration contain proteins common to extracellular deposits associated with atherosclerosis, elastosis, amyloidosis, and dense deposit disease. FASEB J. 14, 835-846 (2000).
134. Anderson, D.H. et al. The pivotal role of the complement system in aging and age-related macular degeneration: hypothesis re-visited. Prog. Retin. Eye Res. 29, 95-112 (2010).
135. Edwards, A.O. et al. Complement factor H polymorphism and age-related macular degeneration. Science 308, 421-424 (2005).
136. 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).
137. Haines, J.L. et al. Complement factor H variant increases the risk of age-related macular degeneration. Science 308, 419-421 (2005).
138. Klein, R.J. et al. Complement factor H polymorphism in age-related macular degeneration. Science 308, 385-389 (2005).
139. Gehrs, K.M., Jackson, J.R., Brown, E.N., Allikmets, R. & Hageman, G.S. Complement, age-related macular degeneration and a vision of the future. Arch. Ophthalmol. 128, 349-358 (2010).
140. Skerka, C. et al. Autoimmune forms of thrombotic microangiopathy and membra-noproliferative glomerulonephritis: Indications for a disease spectrum and common pathogenic principles. Mol. Immunol. 46, 2801-2807 (2009).
141. Noris, M. & remuzzi, G. Atypical hemolytic-uremic syndrome. N. Engl. J. Med. 361, 1676-1687 (2009).
142. Alexander, J.J., Anderson, A.J., Barnum, S.R., Stevens, B. & Tenner, A.J. The comple-Ment cascade: Yin-Yang in neuroinflammation\neuro-protection and-degeneration. J. Neurochem. 107, 1169-1187 (2008).
143. Fonseca, M.I. et al. Treatment with a C5ar antagonist decreases pathology and enhances behavioral performance in murine models of Alzheimer's disease. J. Immunol. 183, 1375-1383 (2009).
144. Markiewski, M.M., DeAngelis, R.A. & Lambris, J.D. Complexity of complement activation in sepsis. J. Cell. Mol. Med. 12, 2245-2254 (2008).
145. Silasi-Mansat, R. et al. Complement inhibition decreases the procoagulant response and confers organ protection in a baboon model of E. coli sepsis. Blood published online, doi: 10.1182/blood-2010-02-269746 (13 May 2010).
146. Diepenhorst, G.M., van Gulik, T.M. & Hack, C.E. Complement-mediated ischemia-reperfusion injury: lessons learned from animal and clinical studies. Ann. Surg. 249, 889-899 (2009).
147. Tsonis, P.A., Lambris, J.D. & Del rio-Tsonis, K. To regeneration.with complement. Adv. Exp. Med. Biol. 586, 63-70 (2006).
148. Markiewski, M.M., DeAngelis, R.A. & Lambris, J.D. Liver inflammation and regeneration: two distinct biological phenomena or parallel pathophysiologic processes? Mol. Immunol. 43, 45-56 (2006).
149. Hillebrandt, S. et al. Complement factor 5 is a quantitative trait gene that modifies liver fibrogenesis in mice and humans. Nat. Genet. 37, 835-843 (2005).
150. Addis-Lieser, E., Kohl, J. & Chiaramonte, M.G. Opposing regulatory roles of complement factor 5 in the development of bleomycin-induced pulmonary fibrosis. J. Immunol. 175, 1894-1902 (2005).
151. Schafer, D.P. & Stevens, B. Synapse elimination during development and disease: immune molecules take centre stage. Biochem. Soc. Trans. 38, 476-481 (2010).
152. Stevens, B. et al. The classical complement cascade mediates CNS synapse elimination. Cell 131, 1164-1178 (2007).
153. Loeffler, D.A., Camp, D.M. & Conant, S.B. Complement activation in the Parkinson's disease substantia nigra: an immunocytochemical study. J. Neuroinflammation 3, 29 (2006).
154. Ingram, G., Hakobyan, S., robertson, N.P. & Morgan, B.P. Complement in multiple sclerosis: its role in disease and potential as a biomarker. Clin. Exp. Immunol. 155, 128-139 (2009).
155. Boyajyan, A., Khoyetsyan, A. & Chavushyan, A. Alternative complement pathway in schizophrenia. Neurochem. Res. 35, 894-898 (2010).
156. Mayilyan, K.R., weinberger, D.R. & Sim, R.B. The complement system in schizophrenia. Drug News Perspect. 21, 200-210 (2008).
157. Carmona-Fontaine, C. et al. C3 controls neural crest migration during embryo development. 6th Int. Conf. Innate Immunity 44, 36 (2009).
158. Shinjyo, N., Stahlberg, A., Dragunow, M., Pekny, M. & Pekna, M. Complement-derived anaphylatoxin C3a regulates in vitro differentiation and migration of neural progenitor cells. Stem Cells 27, 2824-2832 (2009).
159. Raisz, L.G. Potential impact of selective cyclooxygenase-2 inhibitors on bone metabolism in health and disease. Am. J. Med. 110 Suppl 3A, 43S-45S (2001).
160. Niculescu, F. & rus, H. Mechanisms of signal transduction activated by sublytic assembly of terminal complement complexes on nucleated cells. Immunol. Res. 24, 191-199 (2001).
161. Raisz, L.G., Sandberg, A.L., Goodson, J.M., Simmons, H.A. & Mergenhagen, S.E. Complement-dependent stimulation of prostaglandin synthesis and bone resorption. Science 185, 789-791 (1974).
162. Nicholson-weller, A. & Halperin, J.A. Membrane signaling by complement C5b-9, the membrane attack complex. Immunol. Res. 12, 244-257 (1993).
163. De Pablo, P., Chapple, I.L., Buckley, C.D. & Dietrich, T. Periodontitis in systemic rheumatic diseases. Nat. Rev. Rheumatol. 5, 218-224 (2009).
164. Krauss, J.L., Potempa, J., Lambris, J.D. & Hajishengallis, G. Complementary Tolls in the periodontium: how periodontal bacteria modify complement and Toll-like receptor responses to prevail in the host. Periodontol. 2000 52, 141-162 (2010).
165. McCoy, J.M., wicks, J.R. & Audoly, L.P. The role of prostaglandin e2 receptors in the pathogenesis of rheumatoid arthritis. J. Clin. Invest. 110, 651-658 (2002).
166. Chai, L., Song, Y.-Q., Zee, K.-Y. & Leung, W.K. Single nucleotide polymorphisms of complement component 5 and periodontitis. J. Periodontal Res. 45, 301-308 (2010).
167. Chang, M. et al. A large-scale rheumatoid arthritis genetic study identifies association at chromosome 9q33.2. PLoS Genet. 4, e1000107 (2008).
168. Fischetti, F. et al. Selective therapeutic control of C5a and the terminal complement complex by anti-C5 single-chain Fv in an experimental model of antigen-induced arthritis in rats. Arthritis Rheum. 56, 1187-1197 (2007).
169. Williams, A.S., Mizuno, M., richards, P.J., Holt, D.S. & Morgan, B.P. Deletion of the gene encoding CD59a in mice increases disease severity in a murine model of rheumatoid arthritis. Arthritis Rheum. 50, 3035-3044 (2004).
170. Hotamisligil, G.S. Inflammation and metabolic disorders. Nature 444, 860-867 (2006).
171. Wellen, K.E. & Hotamisligil, G.S. Inflammation, stress, and diabetes. J. Clin. Invest. 115, 1111-1119 (2005).
172. Muscari, A. et al. Serum C3 is a stronger inflammatory marker of insulin resistance than C-reactive protein, leukocyte count, and erythrocyte sedimentation rate: comparison study in an elderly population. Diabetes Care 30, 2362-2368 (2007).
173. Ohinata, K. & Yoshikawa, M. Food intake regulation by central complement system. Adv. Exp. Med. Biol. 632, 35-46 (2008).
174. Markiewski, M.M. & Lambris, J.D. Is complement good or bad for cancer patients? A new perspective on an old dilemma. Trends Immunol. 30, 286-292 (2009).
175. Markiewski, M.M. et al. Modulation of the antitumor immune response by complement. Nat. Immunol. 9, 1225-1235 (2008).
176. Mantovani, A., Allavena, P., Sica, A. & Balkwill, F. Cancer-related inflammation. Nature 454, 436-444 (2008).