Immunologic Research

, Volume 34, Issue 2, pp 157–176 | Cite as

The role of complement in danger sensing and transmission

  • Jörg Köhl


Self-non-self discrimination has long been considered the main function of the immune system. Increasing evidence supports the view of the immune system as a network of complex danger sensors and transmitters in which self-non-self discrimination is only one facet. To meet the challenge of danger sensing, the immune system carries a large stock of germline-encoded, highly conserved molecules that can recognize microbial as well as modified host structures. Among those are the Toll-like receptors (TLR), which comprise a dozen membrane-bound pattern-recognition receptors that directly link danger recognition to danger transmission through activation of several distinct cellular signaling pathways. Here, I discuss the function and biology of a complex, evolutionary ancient system, the complement system, which has long been considered critical to host defense. In contrast to TLRs, the complement system senses danger by a panel of soluble molecules that can directly bind to specific complement receptors and/or initiate a complex cascade of proteolytic events that lead to the generation of soluble complement fragments able to bind to another, distinct set of specific complement receptors. As I will outline in this review, complement-mediated danger sensing and the complex transition of this information into distinct cellular activation profiles is critical for tissue homeostasis under steady-state conditions and in response to infection and cell injury. Furthermore, I will discuss recent findings that support a concept of intense cross-talk between the complement system and TLRs, which defines the quality and the magnitude of immune responses in vivo.

Key Words

Complement Immunity Inflammation Danger Toll-like receptor 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Burnet FM: Immunological recognition of self. Science 1961;133:307–311.PubMedGoogle Scholar
  2. 2.
    Billingham RE, Brent L, Medawar PB: Activity acquired tolerance of foreign cells. Nature 1953;172:603–606.PubMedGoogle Scholar
  3. 3.
    Janeway CA: Approaching the asymptote? Evolution and revolution in immunology. Cold Spring Harb Symp Quant Biol 1989;54:1–13.PubMedGoogle Scholar
  4. 4.
    Janeway CA, Medzhitov R: Innate immune recognition. Annu Rev Immunol 2002;20:197–216.PubMedGoogle Scholar
  5. 5.
    Matzinger P: The danger model: a renewed sense of self. Science 2002;296:301–305.PubMedGoogle Scholar
  6. 6.
    Matzinger P: Tolerance, danger, and the extended family. Annu Rev Immunol 1994;12:991–1045.PubMedGoogle Scholar
  7. 7.
    Seong SY, Matzinger P: Hydrophobicity: an ancient damage-associated molecular pattern that initiates innate immune responses. Nat Rev Immunol 2004;4:469–478.PubMedGoogle Scholar
  8. 8.
    Walport MJ: Advances in immunology: complement (first of two parts). N Engl J Med 2001;344:1058–1066.PubMedGoogle Scholar
  9. 9.
    Manderson AP, Botto M, Walport MJ: The role of complement in the development of systemic lupus erythematosus. Annu Rev Immunol 2004;22:431–456.PubMedGoogle Scholar
  10. 10.
    Köhl J: Anaphylatoxins and infectious and non-infectious inflammatory diseases. Mol Immunol 2001;38:175–187.PubMedGoogle Scholar
  11. 11.
    Guo RF, Ward PA: Role of c5a in inflammatory responses. Annu Rev Immunol 2005;23:821–852.PubMedGoogle Scholar
  12. 12.
    Carroll MC: The complement system in regulation of adaptive immunity. Nat Immunol 2004;5:981–986.PubMedGoogle Scholar
  13. 13.
    Hawlisch H, Köhl J: Complement and Toll-like receptors: key regulators of adaptive immune responses. Mol Immunol 2006;43:13–21.PubMedGoogle Scholar
  14. 14.
    Nonaka M, Yoshizaki F: Primitive complement system of invertebrates. Immunol Rev 2004;198:203–215.PubMedGoogle Scholar
  15. 15.
    Fujita T, Matsushita M, Endo Y: The lectin-complement Dathway—its role in innate immunity and evolution. Immunol Rev 2004;198:185–202.PubMedGoogle Scholar
  16. 16.
    Sahu A, Kozel TR, Pangburn MK: Specificity of the thioester-containing reactive site of human C3 and its significance to complement activation. Biochem J 1994;302 (Pt 2):429–436.PubMedGoogle Scholar
  17. 17.
    Klein MA, Kaeser PS, Schwarz P, et al.: Complement facilitates early prion pathogenesis. Nat Med 2001;7:488–492.PubMedGoogle Scholar
  18. 18.
    Storrs SB, Kolb WP, Olson MS: C1q binding and C1 activation by various isolated cellular membranes. J Immunol 1983;131:416–422.PubMedGoogle Scholar
  19. 19.
    Peitsch MC, Tschopp J, Kress A, Isliker H: Antibody-independent activation of the complement system by mitochondria is mediated by cardiolipin. Biochem J 1988;249:495–500.PubMedGoogle Scholar
  20. 20.
    Kovascovics T, Tschopp J, Kress A, Isliker H: Antibody-independent activation of C1, the first component of complement, by cardiolipin. J Immunol 1985;135:2695–2700.Google Scholar
  21. 21.
    Ghebrehiwet B, Randazzo BP, Dunn JT, Silverberg M, Kaplan AP: Mechanisms of activation of the classical pathway of complement by Hageman factor fragment. J Clin Invest 1983;71:1450–1456.PubMedGoogle Scholar
  22. 22.
    Garlanda C, Bottazzi B, Bastone A, Mantovani A: Pentraxins at the crossroads between innate immunity, inflammation, matrix deposition, and female fertility. Annu Rev Immunol 2005;23:337–366.PubMedGoogle Scholar
  23. 23.
    Turner MW: The role of mannose-bindinglectin in health and disease. Mol Immunol 2003;40:423–429.PubMedGoogle Scholar
  24. 24.
    Ogden CA, deCathelineau A, Hoffmann PR, et al: C1q and mannose binding lectin engagement of cell surface calreticulin and CD91 initiates macropinocytosis and uptake of apoptotic cells. J Exp Med 2001;194: 781–795.PubMedGoogle Scholar
  25. 25.
    Janssen BJ, Huizinga EG, Raaijmakers HC, et al: Structures of complement component C3 provide insights into the function and evolution of immunity. Nature 2005;437:505–511.PubMedGoogle Scholar
  26. 26.
    Selberg O, Hecker H, Martin M, et al: Discrimination of sepsis and systemic inflammatory response syndrome by determination of circulating plasma concentrations of procalcitonin, protein complement 3a, and interleukin-6. Crit Care Med 2000;28:2793–2798.PubMedGoogle Scholar
  27. 27.
    Pangburn MK, Schreiber RD, Muller-Eberhard HJ: 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 1981;154:856–867.PubMedGoogle Scholar
  28. 28.
    Ghebrehiwet B, Peerschke EI: cC1q-R (calreticulin) and gC1q-R/p33: ubiquitously expressed multi-ligand binding cellular proteins involved in inflammation and infection. Mol Immunol 2004;41:173–183.PubMedGoogle Scholar
  29. 29.
    Guan E, Robinson SL, Goodman EB, Tenner AJ: Cell-surface protein identified on phagocytic cells modulates the C1q-mediated enhancement of phagocytosis. J Immunol 1994;152:4005–4016.PubMedGoogle Scholar
  30. 30.
    Botto M, Dell'Agnola C, Bygrave AE, et al: Homozygous C1q deficiency causes glomerulonephritis associated with multiple apoptotic bodies. Nat Genet 1998;19:56–59.PubMedGoogle Scholar
  31. 31.
    Walport MJ, Davies KA, Botto M: C1q and systemic lupus erythematosus. Immunobiology 1998;199:265–285.PubMedGoogle Scholar
  32. 32.
    Shariat-Madar Z, Mahdi F, Schmaier AH: Assembly and activation of the plasma kallikrein/kinin system: a new interpretation. Int Immunopharmacol 2002;2:1841–1849.PubMedGoogle Scholar
  33. 33.
    Kittlesen DJ, Chianese-Bullock KA, Yao ZQ, Braciale TJ, Hahn YS: Interaction between complement receptor gC1qR and hepatitis C virus core protein inhibits T-lymphocyte proliferation. J Clin Invest 2000;106:1239–1249.PubMedCrossRefGoogle Scholar
  34. 34.
    Reinagel ML, Taylor RP: Transfer of immune complexes from erythrocyte CR1 to mouse macrophages. J Immunol 2000;164:1977–1985.PubMedGoogle Scholar
  35. 35.
    Birmingham DJ, Hebert LA: CR1 and CR1-like: the primate immune adherence receptors. Immunol Rev 2001;180:100–111.PubMedGoogle Scholar
  36. 36.
    Fallman M, Andersson R, Andersson T: Signaling properties of CR3 (CD11b/CD18) and CR1 (CD35) in relation to phagocytosis of complement-opsonized particles. J Immunol 1993;151:330–338.PubMedGoogle Scholar
  37. 37.
    Krych-Goldberg M, Atkinson JP: Structure-function relationships of complement receptor type 1. Immunol Rev 2001;180:112–122.PubMedGoogle Scholar
  38. 38.
    Stoute JA: Complement-regulatory proteins in severe malaria: too little or too much of a good thing? Trends Parasitol 2005;21:218–223.PubMedGoogle Scholar
  39. 39.
    Fischer E, Delibrias C, Kazatchkine MD: Expression of CR2 (the C3dg/EBV receptor, CD21) on normal human peripheral blood T lymphocytes. J Immunol 1991; 146:865–869.PubMedGoogle Scholar
  40. 40.
    Levy E, Ambrus J, Kahl L, et al.: T lymphocyte expression of complement receptor 2 (CR2/CD21): a role in adhesive cell-cell interactions and dysregulation in a patient with systemic lupus erythematosus (SLE). Clin Exp Immunol 1992;90:235–244.PubMedCrossRefGoogle Scholar
  41. 41.
    Pratt JR, Basheer SA, Sacks SH: Local synthesis of complement component C3 regulates acute renal transplant rejection. Nat Med 2002;8:582–587.PubMedGoogle Scholar
  42. 42.
    Dempsey PW, Allison ME, Akkaraju S, Goodnow CC, Fearon DT: C3d of complement as a molecular adjuvant: bridging innate and acquired immunity. Science 1996;271:348–350.PubMedGoogle Scholar
  43. 43.
    Ahearn JM, Fischer MB, Croix D, et al: Disruption of the Cr2 locus results in a reduction in B-1a cells and in an impaired B cell response to T-dependent antigen. Immunity 1996;4:251–262.PubMedGoogle Scholar
  44. 44.
    Fearon DT, Carroll MC: Regulation of B lymphocyte responses to foreign and self-antigens by the CD19/CD21 complex. Annu Rev Immunol 2000; 18:393–422.PubMedGoogle Scholar
  45. 45.
    Holers VM: Complement receptors and the shaping of the natural antibody repertoire. Springer Semin Immunopathol 2005;26:405–423.PubMedGoogle Scholar
  46. 46.
    Fleming SD, Shea-Donohue T, Guthridge JM, et al: Mice deficient in complement receptors 1 and 2 lack a tissue injury-inducing subset of the natural antibody repertoire. J Immunol 2002;169:2126–2133.PubMedGoogle Scholar
  47. 47.
    Fleming SD, Egan RP, Chai C, et al: Anti-phospholipid antibodies restore mesenteric ischemia/reperfusion-induced injury in complement receptor 2/complement receptor 1-deficient mice. J Immunol 2004;173: 7055–7061.PubMedGoogle Scholar
  48. 48.
    Carroll MC: The complement system in B cell regulation. Mol Immunol 2004;41:141–146.PubMedGoogle Scholar
  49. 49.
    Pangburn MK: Host recognition and target differentiation by factor H, aregulator of the alternative pathway of complement. Immunopharmacology 2000;49:149–157.PubMedGoogle Scholar
  50. 50.
    Agramonte-Hevia J, Gonzalez-Arenas A, Barrera D, Velasco-Velazquez M: Gram-negative bacteria and phagocytic cell interaction mediated by complement receptor 3. FEMS Immunol Med Microbiol 2002; 34:255–266.PubMedGoogle Scholar
  51. 51.
    Jones SL, Knaus UG, Bokoch GM, Brown EJ: Two signaling mechanisms for activation of alphaM beta2 avidity in polymorphonuclear neutrophils. J Biol Chem 1998;273:10556–10566.PubMedGoogle Scholar
  52. 52.
    Mastrangelo AM, Jeitner TM, Eaton JW: Oleic acid increases cell surface expression and activity of CD11b on human neutrophils. J Immunol 1998;161:4268–4275.PubMedGoogle Scholar
  53. 53.
    Newton RA, Hogg N: The human S100 protein MRP-14 is a novel activator of the beta 2 integrin Mac-1 on neutrophils. J Immunol 1998;160:1427–1435.PubMedGoogle Scholar
  54. 54.
    Marth T, Kelsall BL: Regulation of interleukin-12 by complement receptor 3 signaling. J Exp Med 1997; 185:1987–1995.PubMedGoogle Scholar
  55. 55.
    Murphy KM, Reiner SL: The lineage decisions of helper T cells. Nat Rev Immunol 2002;2:933–944.PubMedGoogle Scholar
  56. 56.
    Jones J, Morgan BP: Apoptosis is associated with reduced expression of complement regulatory molecules, adhesion molecules and other receptors on polymorphonuclear leucocytes: functional relevance and role in inflammation. Immunology 1995;86:651–660.PubMedGoogle Scholar
  57. 57.
    Elward K, Griffiths M, Mizuno M, et al: CD46 plays a key role in tailoring innate immune recognition of apoptotic and necrotic cells. J Biol Chem 2005;280:36342–36354.PubMedGoogle Scholar
  58. 58.
    Karp CL, Wysocka M, Wahl LM, et al: Mechanism of suppression of cell-mediated immunity by measles virus. Science 1996;273:228–231.PubMedGoogle Scholar
  59. 59.
    Liszewski MK, Kemper C, Price JD, Atkinson JP: Emerging roles and new functions of CD46. Springer Semin Immunopathol 2005;27:345–358.PubMedGoogle Scholar
  60. 60.
    Kemper C, Chan AC, Green JM, et al: Activation of human CD4+ cells with CD3 and CD46 induces a T-regulatory cell 1 phenotype. Nature 2003;421:388–392.PubMedGoogle Scholar
  61. 61.
    Höpken UE, Lu B, Gerard NP, Gerard C: The C5a chemoattractant receptor mediates mucosal defence to infection. Nature 1996;383:86–89.PubMedGoogle Scholar
  62. 62.
    Ward PA: The dark side of C5a in sepsis. Nat Rev Immunol 2004;4:133–142.PubMedGoogle Scholar
  63. 63.
    Wang Y, Rollins SA, Madri JA, Matis LA: Anti-C5 monoclonal antibody therapy prevents collagen-induced arthritis and ameliorates established disease. Proc Natl Acad Sci USA 1995;92:8955–8959.PubMedGoogle Scholar
  64. 64.
    Ji H, Ohmura K, Mahmood U, et al: Arthritis critically dependent on innate immune system players. Immunity 2002;16:157–168.PubMedGoogle Scholar
  65. 65.
    Boos L, Campbell IL, Ames R, Wetsel RA, Barnum SR: Deletion of the complement anaphylatoxin C3a receptor attenuates, whereas ectopic experssion of C3a in the brain exacerbates, experimental autoimmune encephalomyelitis. J Immunol 2004;173:4708–4714.PubMedGoogle Scholar
  66. 66.
    Gerard NP, Gerard C: Complemet in allergy and asthma. Curr Opin Immunol 2002;14:705–708.PubMedGoogle Scholar
  67. 67.
    Hawlisch H, Wills-Karp M, Karp CL, Köhl J: The anaphylatoxins bridge innate and adaptive immune responses in allergic asthma. Mol Immunol 2004; 41:123–131.PubMedGoogle Scholar
  68. 68.
    Wills-Karp M, Köhl J: New insights into the role of the complement pathway in allergy and asthma. Curr Allergy Asthma Rep 2005;5:362–359.PubMedGoogle Scholar
  69. 69.
    Crass T, Raffetseder U, Martin U, et al: Expression cloning of the human C3a anaphylatoxin receptor (C3aR) from differentiated U-937 cells. Eur J Immunol 1996;26:1944–1950.PubMedGoogle Scholar
  70. 70.
    Ames RS, Li Y, Sarau HM, et al: Molecular cloning and characterization of the human anaphylatoxin C3a receptor. J Biol Chem 1996;271:20231–20234.PubMedGoogle Scholar
  71. 71.
    Gerard NP, Gerard C: The chemotactic receptor for human C5a anaphylatoxin. Nature 1991;349:614–617.PubMedGoogle Scholar
  72. 72.
    Boulay F, Mery L, Tardif M, Brouchon L, Vignais P: Expression cloning of a receptor for C5a anaphylatoxin on differentiated HL-60 cells. Biochemistry 1991; 30:2993–2999.PubMedGoogle Scholar
  73. 73.
    Norgauer J, Dobos G, Kownatzki E, et al: Complement fragment C3a stimulates Ca2+ influx in neutrophils via a pertussis-toxin-sensitive G protein. Eur J Biochem 1993;217:289–294PubMedGoogle Scholar
  74. 74.
    Zwirner J, Götze O, Moser A, et al: Blood-and skinderived monocytes/macrophages respond to C3a but not to C3a(des Arg) with a transient release of calcium via a pertussis toxin-sensitive signal transduction pathway. Eur J Immunol 1997;27:2317–2322.PubMedGoogle Scholar
  75. 75.
    Buhl AM, Osawa S, Johnson GL: Mitogen-activated protein kinase activation requires two signal inputs from the human anaphylatoxin C5a receptor. J Biol Chem 1995;270:19828–19832.PubMedGoogle Scholar
  76. 76.
    Vanek M, Hawkins LD, Gusovsky F: Coupling of the C5a receptor to Gi in U-937 cells and in cells transfected with C5a receptor cDNA. Mol Pharmacol 1994;46:832–839.PubMedGoogle Scholar
  77. 77.
    Schraufstatter IU, Trieu K, Sikora L, Sriramarao P, DiScipio R: Complement c3a and c5a induce different signal transduction cascades in endothelial cells. J Immunol 2002;169:2102–2110.PubMedGoogle Scholar
  78. 78.
    Lo RK, Cheung H, Wong YH: Constitutively active G(alpha) 16 stimultes STAT3 via a c-Src/JAK- and ERK-dependent mechanism. J Biol Chem 2003;278: 52154–52165.PubMedGoogle Scholar
  79. 79.
    Strey CW, Markiewski M, Mastellos D, et al: The proinflammatory mediators C3a and C5a are essential for liver regeneration. J Exp Med 2003;198: 913–923.PubMedGoogle Scholar
  80. 80.
    Krymskaya VP, Orsini MJ, Eszterhas AJ, et al: Mechanisms of proliferation synergy by receptor tyrosine kinase and G protein-coupled receptor activation in human airway smooth muscle. Am J Respir Cell Mol Biol 2000;23:546–554.PubMedGoogle Scholar
  81. 81.
    Ohno M, Hirata T, Enomoto M, et al: A putative chemoattractant receptor, C5L2, is expressed in granulocyte and immature dendritic cells, but not in mature dendritic cells. Mol Immunol 2000;37:407–412.PubMedGoogle Scholar
  82. 82.
    Cain SA, Monk PN: The orphan receptor C5L2 has high affinity binding sites for complement fragments C5a and C5a des-Arg(74). J Biol Chem 2002;277: 7165–7169.PubMedGoogle Scholar
  83. 83.
    Okinaga S, Slattery D, Humbles A, et al: C5L2, a nonsignaling C5A binding protein. Biochemistry 2003;42:9406–9415.PubMedGoogle Scholar
  84. 84.
    Gerard NP, Lu B, Liu P, et al: An anti-inflammatory function for the complement anaphylatoxin C5a binding protein, C5L2. J Biol Chem 2005;280:39677–39680.PubMedGoogle Scholar
  85. 85.
    Neff TA, Guo RF, Neff SB, et al: Relationship of acute lung inflammatory injury to Fas/FasL system. Am J Pathol 2005;166:685–694.PubMedGoogle Scholar
  86. 86.
    Fischer WH, Jagels MA, Hugli TE: Regulation of IL-6 synthesis in human peripheral blood mononuclear cells by C3a and C3a(desArg). J Immunol 1999; 162:453–459.PubMedGoogle Scholar
  87. 87.
    Fischer WH, Hugli TE: Regulation of B cell functions by C3a and C3a(desArg): suppression of TNF-alpha, IL-6, and the polyclonal immune response. J Immunol 1997;159:4279–4286.PubMedGoogle Scholar
  88. 88.
    Takabayashi T, Vannier E, Burke JF, et al: Both C3a and C3a(desArg) regulate interleukin-6 synthesis in human peripheral blood monouclear cells. J Infect Dis 1998; 177:1622–1628.PubMedGoogle Scholar
  89. 89.
    Francis K, Lewis BM, Akatsu H, et al: Complement C3a receptors in the pituitary gland: a novel pathway by which an innate immune molecule releases hormones involved in the control of inflammation. FASEB J 2003;17:2266–2268.PubMedGoogle Scholar
  90. 90.
    Cianflone K: Acylation stimulating protein and the adipocyte. J Endocrinol 1997;155:203–206PubMedGoogle Scholar
  91. 91.
    Kalant D, Cain SA, Maslowska M, et al: The chemoattractant receptor-like protein C5L2 binds the C3a desArg77/acylation-stimulating protein. J Biol Chem 2003;278:11123–11129.PubMedGoogle Scholar
  92. 92.
    Okinaga S, Slattery DM, Humbles A, et al: C5L2, a nonsignaling C5a binding protein. Biochemistry 2003;42:9406–9415.PubMedGoogle Scholar
  93. 93.
    Nordahl EA, Rydengard V, Nyberg P, et al: Activation of the complement system generates antibacterial peptides. Proc Natl Acad Sci USA 2004;101:16879–16884.PubMedGoogle Scholar
  94. 94.
    Yang D, Biragyn A, Hoover DM, Lubkowski J, Oppenheim JJ: Multiple roles of antimicrobial defensins, cathelicidins, and eosinophil-derived neurotoxin in host defense. Annu Rev Immunol 2004;22:181–215.PubMedGoogle Scholar
  95. 95.
    Monsinjon T, Gasque P, Chan P, et al: Regulation by complement C3a and C5a anaphylatoxins of cytokine production in human umbilical vein endothelial cells. FASEB J 2003;17:1003–1014.PubMedGoogle Scholar
  96. 96.
    Braun MC, Reins RY, Li TB, et al: Renal expression of the C3a receptor and functional responses of primary huma proximal tubular epithelial cells. J Immunol 2004;173:4190–4196.PubMedGoogle Scholar
  97. 97.
    Laudes IJ, Chu JC, Huber-Lang M, et al: Expression and function of C5a receptor in mouse microvascular endothelial cells. J Immunol 2002;169:5962–5970.PubMedGoogle Scholar
  98. 98.
    Drouin SM, Kildsgaard J, Haviland, J, et al: Expression of the complement anaphylatoxin C3a and C5a receptors on bronchial epithelial and smooth muscle cells in models of sepsis and asthma. J Immunol 2001;166: 2025–2032.PubMedGoogle Scholar
  99. 99.
    Addis-Lieser E, Köhl J, Chiaramonte MG: Opposing regulatory roles of complement factor 5 in the development of bleomycin-induced pulmonary fibrosis. J Immunol 2005;175:1894–1902.PubMedGoogle Scholar
  100. 100.
    Hillebrandt S, Wasmuth HE, Weiskirchen R, et al: Complement factor 5 is a quantitative trait gene that modifies liver fibrogenesis in mice and humans. Nat Genet 2005;37:835–843.PubMedGoogle Scholar
  101. 101.
    Fayyazi A, Scheel O, Werfel T, et al: The C5a receptor is expressed in normal renal proximal tubular but not in normal pulmonary or hepatic epithelial cells. Immunology 2000;99:38–45.PubMedGoogle Scholar
  102. 102.
    Zahedi R, Braun M, Wetsel RA, et al: The C5a receptor is expressed by human renal proximal tubular epithelial cells. Clin Exp Immunol 2000;121:226–233.PubMedGoogle Scholar
  103. 103.
    Haviland DL, McCoy RL, Whitehead WT, et al: Cellular expression of the C5a anaphylatoxin receptor (C5aR): demonstration of C5aR on nonmyeloid cells of the liver and lung. J Immunol 1995;154:1861–1869.PubMedGoogle Scholar
  104. 104.
    O'Barr SA, Caguioa J, Gruol D, et al: Neuronal expression of a functional receptor for the C5a complement activation fragment. J Immunol 2001;166:4154–4162.PubMedGoogle Scholar
  105. 105.
    Osaka H, McGinty A, Hoepken UE, et al: Expression of C5a receptor in mouse brain: role in signal transduction and neurodegeneration. Neuroscience 1999;88:1073–1082.PubMedGoogle Scholar
  106. 106.
    Markiewski MM, Deangelis RA, Lambris JD: Liver inflammation and regeneration: two distinct biological phenomena or parallel pathophysiologic processes? Mol Immunol 2006;43:45–56.PubMedGoogle Scholar
  107. 107.
    McWilliam AS, Napoli S, Marsh AM, et al: Dendritic cells are recruited into the airway epithelium during the inflammatory response to a broad spectrum of stimuli. J Exp Med 1996;184:2429–2432.PubMedGoogle Scholar
  108. 108.
    Morelli A, Larregina A, Chuluyan E, Kolkowski E, Fainboim L: Functional expression and modulation of C5a receptor (CD88) on skin dendritic cells. Adv Exp Med Biol 1997;417:133–138.PubMedGoogle Scholar
  109. 109.
    Morelli A, Larregina A, Chuluyan I, Kolkowski E, Fainboim L: Expression and modulation of C5a receptor (CD88) on skin dendritic cells. Chemotactic effect of C5a on skin migratory dendritic cells. Immunology 1996;89:126–134.PubMedGoogle Scholar
  110. 110.
    Kirchhoff K, Wienmann O, Zwirner J, et al: Detection of anaphylatoxin receptors on CD83+dendritic cells derived from human skin. Immunology 2001;103:210–217.PubMedGoogle Scholar
  111. 111.
    Yang D, Chen Q, Stoll S, et al: Differential regulation of responsiveness to fMLP and C5a upon dendritic cell maturation: correlation with receptor expression. J Immunol 2000;165:2694–2702.PubMedGoogle Scholar
  112. 112.
    Lambrecht BN, Hammad H: Taking our breath away: dendritic cells in the pathogenesis of asthma. Nat Rev Immunol 2003;3:994–1003.PubMedGoogle Scholar
  113. 113.
    Humbles AA, Lu B, Nilsson CA, et al: A role for the C3a anaphylatoxin receptor in the effector phase of asthma. Nature 2000;406:1001.Google Scholar
  114. 114.
    Krug N, Tschernig T, Erpenbeck VJ, Hohlfeld JM, Köhl J: Complement factors c3a and c5a are increased in bronchoalveolar lavage fluid after segmental allergen provocation in subjects with asthma. Am J Respir Crit Care Med 2001;164:1841–1843.PubMedGoogle Scholar
  115. 115.
    Köhl J, Baelder R., Lewkowich IP, et al: A regulatory role for the C5a anaphylatoxin on type 2 immunity in asthma. J Clin Invest 2006;116 (In Press).Google Scholar
  116. 116.
    Wittmann M, Zwirner J, Larsson VA, et al: C5a suppresses the production of IL-12 by IFN-gamma-primed and lipopolysaccharide-challenged human monocytes. J Immunol 1999;162:6763–6769.PubMedGoogle Scholar
  117. 117.
    Braun MC, Lahey E, Kelsall BL: Selective suppression of IL-12 production by chemoattractants. J Immunol 2000;164:3009–3017.PubMedGoogle Scholar
  118. 118.
    Karp CL, Grupe A, Schadt E, et al: Identification of complement factor 5 as a susceptibility locus for experimental allergic asthma. Nat Immunol 2000;1:221–226.PubMedGoogle Scholar
  119. 119.
    Hawlisch H, Belkaid Y, Baelder R, et al: C5a negatively regulates Toll-like receptor 4-induced immune responses. Immunity 2005;22:415–426.PubMedGoogle Scholar
  120. 120.
    Wang Y, Hu Q, Madri JA, et al: Amelioration of lupuslike autoimmune disease in NZB/WF1 mice after treatment with a blocking monoclonal antibody specific for complement component C5. Proc Natl Acad Sci USA 1996;93:8563–8568.PubMedGoogle Scholar
  121. 121.
    Tsuji RF, Kawikova I, Ramabhadran R, et al: Early local generation of C5a initiates the elicitation of contact sensitivity by leading to early T cell recruitment. J Immunol 2000;165:1588–1598.PubMedGoogle Scholar
  122. 122.
    Gervais F, Desforges C, Skamene E: The C5-sufficient A/J congenic mouse strain. Inflammatory response and resistance to Listeria monocytogenes. J Immunol 1989;142:2057–2060.PubMedGoogle Scholar
  123. 123.
    Sam H, Stevenson MM: Early IL-12 p70, but not p40, production by splenic macrophages correlates with host resistance to blood-stage Plasmodium chabaudi AS malaria. Clin Exp Immunol 1999;117:343–349.PubMedGoogle Scholar
  124. 124.
    Blatteis CM, Li S, Li Z, Perlik V, Feleder C: Signaling the brain in systemic inflammation: the role of complement. Front Biosci 2004;9:915–931.PubMedGoogle Scholar
  125. 125.
    Shushaskova N, Skokowa J, Schulman J, et al: C5a anaphylatoxin is a major regulator of activating versus inhibitory FegammaRs in immune complex-induced lung disease. J Clin Invest 2002;110:1823–1830.Google Scholar
  126. 126.
    Godau J, Heller T, Hawlisch H, et al. C5a initiates the inflammatory cascade in immune complex peritonitis. J Immunol 2004;173:3437–3445.PubMedGoogle Scholar

Copyright information

© Humana Press Inc 2006

Authors and Affiliations

  1. 1.Division of Molecular ImmunologyCincinnati Children's Hospital Research FoundationCincinnati

Personalised recommendations