Complement: a Key System for Immune Surveillance and Homeostasis

Overview

Journal Nat Immunol

Date 2010 Aug 20

PMID 20720586

Citations 1681

Authors

Daniel Ricklin

George Hajishengallis

Kun Yang

John D Lambris

Affiliations

Soon will be listed here.

Abstract

Nearly a century after the significance of the human complement system was recognized, we have come to realize that its functions extend far beyond the elimination of microbes. Complement acts as a rapid and efficient immune surveillance system that has distinct effects on healthy and altered host cells and foreign intruders. By eliminating cellular debris and infectious microbes, orchestrating immune responses and sending 'danger' signals, complement contributes substantially to homeostasis, but it can also take action against healthy cells if not properly controlled. This review describes our updated view of the function, structure and dynamics of the complement network, highlights its interconnection with immunity at large and with other endogenous pathways, and illustrates its multiple roles in homeostasis and disease.

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References

Fischer W, Hugli T . Regulation of B cell functions by C3a and C3a(desArg): suppression of TNF-alpha, IL-6, and the polyclonal immune response. J Immunol. 1997; 159(9):4279-86. View

Ward P . The dark side of C5a in sepsis. Nat Rev Immunol. 2004; 4(2):133-42. DOI: 10.1038/nri1269. View

Gaboriaud C, Thielens N, Gregory L, Rossi V, Fontecilla-Camps J, Arlaud G . Structure and activation of the C1 complex of complement: unraveling the puzzle. Trends Immunol. 2004; 25(7):368-73. DOI: 10.1016/j.it.2004.04.008. View

Kumar V, Ali S, Konrad S, Zwirner J, Verbeek J, Schmidt R . Cell-derived anaphylatoxins as key mediators of antibody-dependent type II autoimmunity in mice. J Clin Invest. 2006; 116(2):512-20. PMC: 1359043. DOI: 10.1172/JCI25536. View

Shushakova N, Skokowa J, Schulman J, Baumann U, Zwirner J, Schmidt R . C5a anaphylatoxin is a major regulator of activating versus inhibitory FcgammaRs in immune complex-induced lung disease. J Clin Invest. 2002; 110(12):1823-30. PMC: 151656. DOI: 10.1172/JCI16577. View

Hajishengallis G, Lambris J . Crosstalk pathways between Toll-like receptors and the complement system. Trends Immunol. 2010; 31(4):154-63. PMC: 2849859. DOI: 10.1016/j.it.2010.01.002. View

Hotamisligil G . Inflammation and metabolic disorders. Nature. 2006; 444(7121):860-7. DOI: 10.1038/nature05485. View

Hashimoto M, Hirota K, Yoshitomi H, Maeda S, Teradaira S, Akizuki S . Complement drives Th17 cell differentiation and triggers autoimmune arthritis. J Exp Med. 2010; 207(6):1135-43. PMC: 2882841. DOI: 10.1084/jem.20092301. View

Ghebrehiwet B, Silverberg M, Kaplan A . Activation of the classical pathway of complement by Hageman factor fragment. J Exp Med. 1981; 153(3):665-76. PMC: 2186101. DOI: 10.1084/jem.153.3.665. View

10.

Rooijakkers S, Wu J, Ruyken M, van Domselaar R, Planken K, Tzekou A . Structural and functional implications of the alternative complement pathway C3 convertase stabilized by a staphylococcal inhibitor. Nat Immunol. 2009; 10(7):721-7. PMC: 2729104. DOI: 10.1038/ni.1756. View

11.

Haines J, Hauser M, Schmidt S, Scott W, Olson L, Gallins P . Complement factor H variant increases the risk of age-related macular degeneration. Science. 2005; 308(5720):419-21. DOI: 10.1126/science.1110359. View

12.

Guo R, Riedemann N, Ward P . Role of C5a-C5aR interaction in sepsis. Shock. 2003; 21(1):1-7. DOI: 10.1097/01.shk.0000105502.75189.5e. View

13.

Inal J, Hui K, Miot S, Lange S, Ramirez M, Schneider B . Complement C2 receptor inhibitor trispanning: a novel human complement inhibitory receptor. J Immunol. 2004; 174(1):356-66. DOI: 10.4049/jimmunol.174.1.356. View

14.

Hageman G, Anderson D, Johnson L, Hancox L, Taiber A, Hardisty L . A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. Proc Natl Acad Sci U S A. 2005; 102(20):7227-32. PMC: 1088171. DOI: 10.1073/pnas.0501536102. View

15.

Klein R, Zeiss C, Chew E, Tsai J, Sackler R, Haynes C . Complement factor H polymorphism in age-related macular degeneration. Science. 2005; 308(5720):385-9. PMC: 1512523. DOI: 10.1126/science.1109557. View

16.

Zhang X, Kimura Y, Fang C, Zhou L, Sfyroera G, Lambris J . Regulation of Toll-like receptor-mediated inflammatory response by complement in vivo. Blood. 2007; 110(1):228-36. PMC: 1896115. DOI: 10.1182/blood-2006-12-063636. View

17.

la Sala A, Gadina M, Kelsall B . G(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. 2005; 175(5):2994-9. DOI: 10.4049/jimmunol.175.5.2994. View

18.

Zipfel P, Skerka C . Complement regulators and inhibitory proteins. Nat Rev Immunol. 2009; 9(10):729-40. DOI: 10.1038/nri2620. View

19.

Karp C, Wysocka M, Wahl L, Ahearn J, Cuomo P, Sherry B . Mechanism of suppression of cell-mediated immunity by measles virus. Science. 1996; 273(5272):228-31. DOI: 10.1126/science.273.5272.228. View

20.

Kim D, Song W . Membrane complement regulatory proteins. Clin Immunol. 2005; 118(2-3):127-36. DOI: 10.1016/j.clim.2005.10.014. View