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Complement-induced impairment of the innate immune system during sepsis

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Abstract

The complement system is an integral part of innate immunity and is chiefly responsible for controlling bacterial infections, especially those involving gramnegative organisms. To accomplish this task, serum proteins engage in a series of enzymatic cascades. The cleaved proteins assemble pores on membranous structures, which lead to cell lysis. During this process, powerful inflammatory mediators are produced, including the anaphylatoxins, C5a, C3a, and the membrane attack complex (MAC). Under systemic inflammatory conditions, an overactive complement system may compromise the effectiveness of innate immunity. We review the detrimental effects that are caused by uncontrolled complement activation during sepsis.

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References and Recommended Reading

  1. Wagner JG, Roth RA: Neutrophil migration during endotoxemia. J Leukoc Biol 1999, 66:10–24. This review article eloquently highlights the physiological effects that endotoxemia can have on neutrophil function.

    PubMed  CAS  Google Scholar 

  2. Barrington R, Zhang M, Fischer M, et al.: The role of complement in inflammation and adaptive immunity. Immunol Rev 2001, 180:5–15.

    Article  PubMed  CAS  Google Scholar 

  3. Ward P: The dark side of C5a in sepsis. Nature Rev Immunol 2004, 4:133–142. This review examines our current understanding of sepsis and the role that C5a plays in orchestrating these events. Particular attention is focused on neutrophil dysfunction pertaining to the effects of C5a.

    Article  CAS  Google Scholar 

  4. Riedemann N, Guo R, Ward P: Novel strategies for the treatment of sepsis. Nature Med 2003, 9:517–524.

    Article  PubMed  CAS  Google Scholar 

  5. Boackle S: Complement and autoimmunity. Biomed Pharmacother 2003, 57:269–273.

    Article  PubMed  CAS  Google Scholar 

  6. Nakano Y, Morita S, Kawamoto A, et al.: Elevated complement C3a in plasma from patients with severe acute asthma. J Allerg Clin Immunol 2003, 112:525–530.

    Article  CAS  Google Scholar 

  7. Groeneveld A, Tacx A, Bossink A, et al.: Circulating inflammatory mediators predict shock and mortality in febrile patients with microbial infection. Clin Immunol 2003, 106:106–115.

    Article  PubMed  CAS  Google Scholar 

  8. Marc M, Korosec P, Kosnik M, et al.: Complement factors C3a, C4a, and C5a in chronic obstructive pulmonary disease and asthma. Am J Respir Cell Mol Biol 2004, In press.

  9. Weisman H, Bartow T, Leppo M: Soluble human complement receptor type 1: in vivo inhibitor of complement suppressing post-ischemic myocardial inflammation and necrosis. Science 1990, 249:149–151.

    Article  Google Scholar 

  10. Basta M, Goor F, Luccioli S, et al.: F(ab)’2-mediated neutralization of C3a and C5a anapylatoxins: a novel effector function of immunoglobulins. Nature Med 2003, 9:431–438. This study identifies the structural relationship between anaphylatoxins and immunoglobins.

    Article  PubMed  CAS  Google Scholar 

  11. Taube C, Rha Y, Takeda K, et al.: Inhibition of complement activation decreases airway inflammation and hyperresponsiveness. Am J Respir Crit Care Med 2003, 168:1333–1341.

    Article  PubMed  Google Scholar 

  12. Czermak B, Sarma V, Pierson C, et al.: Protective effects of C5a blockade in sepsis. Nature Med 1999, 5:788–792.

    Article  PubMed  CAS  Google Scholar 

  13. Ahmed NA, McGill S, Yee J, et al.: Mechanisms for the diminished neutrophil exudation to secondary inflammatory sites in infected patients with a systemic inflammatory response (sepsis). Crit Care Med 1999, 27:2459–2468.

    Article  PubMed  CAS  Google Scholar 

  14. Victor VM, Rubio D, de la Fuente M: Comparative study of several lymphocyte functions in two strains of mice with different models of endotoxic shock. Physiol Res 2002, 51:291–298.

    PubMed  CAS  Google Scholar 

  15. Huber-Lang H, Sarma V, Lu K, et al.: Role of C5a in multiorgan failure during sepsis. J Immunol 2001, 166:1193–1199.

    PubMed  CAS  Google Scholar 

  16. Goya T, Morisaki T, Torisu M: Immunologic assessment of host defense impairment in patients with septic multiple organ failure: relationship between complement activation and changes in neutrophil function. Surgery 1994, 115:145–155.

    PubMed  CAS  Google Scholar 

  17. Etheredge E, Spitzer J: Chronic endotoxemia reversibly alters respiratory burst activity of circulating neutrophils. J Surg Res 1993, 55:261–268.

    Article  PubMed  CAS  Google Scholar 

  18. Kajdacsy-Balla A, Doi E, Lerner M, et al.: Dose-response effect of in vivo administration of endotoxin on polymorphonuclear leukocytes oxidative burst. Shock 1996, 5:357–361.

    Article  PubMed  CAS  Google Scholar 

  19. Huber-Lang M, Younkin E, Sarma V, et al.: Complementinduced impairment of innate immunity during sepsis. J Immunol 2002, 169:3223–3231. This study offers a mechanistic explanation for neutrophil dysfunction and correlates this with C5a ligation.

    PubMed  CAS  Google Scholar 

  20. Sprong T, Brandtzaeg P, Fung M, et al.: Inhibition of C5ainduced inflammation with preserved C5b-9-mediated bactericidal activity in a human whole blood model of meningococcal sepsis. Blood 2003, 102:3702–3710.

    Article  PubMed  CAS  Google Scholar 

  21. Simms H, D’Amico, Burchard R: Untreated intrabdominal sepsis: lack of synergism between polymorphonuclear leukocytes (PMN) complement receptors CR1/CR2 and IgG receptor FcRIII. J Trauma 1990, 30:1027–1031.

    Article  PubMed  CAS  Google Scholar 

  22. Fierro I, Barja-Fidalgo C, Cunha F, et al.: The involvement of nitric oxide in the anti-Candida albicans activity of rat neutrophils. Immunology 1996, 89:295–300.

    Article  PubMed  CAS  Google Scholar 

  23. Martins P, Kallas, Esper G, et al.: Upregulation of reactive oxygen species generation and phagocytosis, and increased apoptosis in human neutrophils during severe sepsis and septic shock. Shock 2003, 20:208–212.

    Article  PubMed  CAS  Google Scholar 

  24. Shih HC, Su CH, Lee CH: Superoxide production of neutrophils after severe injury: impact of subsequent surgery and sepsis. Am J Emerg Med 1999, 17:15–18.

    Article  PubMed  CAS  Google Scholar 

  25. Lanser M, Brown G, Mora R, et al.: Trama serum suppresses superoxide production by normal neutrophils. Arch Surg 1986, 121:157–161.

    PubMed  CAS  Google Scholar 

  26. Zimmerman J, Millard J, Farrin-Rusk C: Septic plasma suppresses superoxide anion synthesis by normal homologous polymorphonuclear leukocytes. Crit Care Med 1989, 17:1241–1249.

    Article  PubMed  CAS  Google Scholar 

  27. Mollnes T, Brekke O, Fung M, et al.: Essential role of C5a receptor in E coli-induced oxidative burst and phagocytosis revealed by a novel lepirudin-based human whole blood model of inflammation. Blood 2002, 100:1869–1877.

    PubMed  CAS  Google Scholar 

  28. Kharazmi A, Anderson L, Baek L, et al.: Endotoxemia and enhanced generation of oxygen radicals by neutrophils from patients undergoing cardiopulmonary bypass. J Thorac Cardiac Surg 1989, 98:381–385.

    CAS  Google Scholar 

  29. Cerasoli F, McKenna P, Rosalia D, et al.: Superoxide anion release from blood and bone marrow neutrophils is altered by endotoxemia. Circ Res 1990, 67:154–165.

    PubMed  CAS  Google Scholar 

  30. Chenoweth D, Hugli T: Demonstration of specific C5a receptor on intact human polymorphonuclear leukocytes. Proc Natl Acad Sci U S A 1978, 75:3943–3947.

    Article  PubMed  CAS  Google Scholar 

  31. Gerard N, Hodges M, Drazen J, et al.: Characterization of a receptor of C5a anaphylatoxin on eosinophils. J Biol Chem 1989, 264:1760–1766.

    PubMed  CAS  Google Scholar 

  32. Hwang J, Fraser I, Choi S, et al.: Analysis of C5a-mediated chemotaxis by lentiviral delivery of small interfering RNA. Proc Natl Acad Sci 2004, 100:488–493.

    Article  CAS  Google Scholar 

  33. Nataf S, Stahel PF, Davoust N, et al.: Complement anaphylatoxin receptors on neurons: new tricks for old receptors? Trends Neurosci 1999, 22:397–402.

    Article  PubMed  CAS  Google Scholar 

  34. Barnum S, Ames R, Maycox P, et al.: Expression of the complement C3a and C5a receptors after permanent focal ischemia: an alternative interpretation. Gila 2002, 38:169–173.

    Article  Google Scholar 

  35. Riedemann N, Guo R, Neff T, et al.: Increased C5a receptor expression in sepsis. J Clin Invest 2002, 110:101–108.

    Article  PubMed  CAS  Google Scholar 

  36. Huber-Lang M, Riedeman N, Sarma V, et al.: Protection of innate immunity by C5aR antagonist in septic mice. FASEB J 2002, 16:1567–1574.

    Article  PubMed  CAS  Google Scholar 

  37. Guo R, Riedemann N, Bernacki K, et al.: Neutrophil C5a receptor and the outcome in a rat model of sepsis. FASEB J 2003, 17:1889–1891.

    PubMed  CAS  Google Scholar 

  38. Furebring M, Hakansson L, Venge P, et al.: Expression of the C5a receptor (CD88) on granulocytes and monocytes in patients with severe sepsis. Crit Care 2002, 6:363–370.

    Article  PubMed  Google Scholar 

  39. 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.

    PubMed  CAS  Google Scholar 

  40. Harkin D, Romaschin A, Taylor S, et al.: Complement C5a receptor antagonist attenuates multiple organ injury in a model of ruptured abdominal aortic aneurysm. J Vasc Surg 2004, 39:196–206.

    Article  PubMed  Google Scholar 

  41. Grant E, Picarella D, Burwell T, et al.: Essential role for the C5a receptor in regulating the effector phase of synovial infiltration and joint destruction in experimental arthritis. J Exp Med 2002, 196:1461–1471.

    Article  PubMed  CAS  Google Scholar 

  42. Hattori R, Hamilton K, McEver R, et al.: Complement proteins C5b-9 induce secretion of high molecular weight multimers of endothelial von Willebrand factor and translocation of granule membrane protein GMP-140 to the cell surface. J Biol Chem 1989, 264:9053–9060.

    PubMed  CAS  Google Scholar 

  43. Kilgore K, Shen J, Miller B, et al.: Enhancement by the complement membrane attack complex of tumor necrosis factor-induced endothelial cell expression of E selectin and ICAM-1. J Immunol 1995, 155:1434–1441.

    PubMed  CAS  Google Scholar 

  44. Topham P, Haydar S, Kuphal R, et al.: Complement-mediated injury reversibly disrupts glomerular epithelial cell actin microfilaments and focal adhesions. Kidney Int 1999, 55:1763–1775.

    Article  PubMed  CAS  Google Scholar 

  45. Takano T, Cybulsky A: Complement C5b-9 mediated arachidonic acid metabolism in glomerular epithelial cells. Am J Pathol 2000, 156:2091–2101.

    PubMed  CAS  Google Scholar 

  46. Mead R, Singhrao S, Neal J, et al.: The membrane attack complex of complement causes severe demyelination associated with acute axonal injury. J Immunol 2002, 168:458–465.

    PubMed  CAS  Google Scholar 

  47. Gasque P, Dean Y, McGreal E, et al.: Complement components of the innate immune system in health and disease in the CNS. Immunopharmacology 2000, 49:171–186.

    Article  PubMed  CAS  Google Scholar 

  48. Graham R, Leslie Q, Nielsen C: The classical and alternative pathways of complement activation play distinct roles in spontaneous C3 fragment deposition and membrane attack complex (MAC) formation on human B lymphocytes. Immunology 2004, 111:86–90.

    Article  Google Scholar 

  49. Niculescu F, Soane L, Badea T, et al.: Tyrosine phosphorylation and activation of Janus kinase 1 and stat 3 by sublytic C5b-9 complement complex in aortic endothelial cells. Immunopharmacology 1999, 42:187–193.

    Article  PubMed  CAS  Google Scholar 

  50. Badea T, Jae-Hyun P, Soane L, et al.: Sublytic terminal complement attack induces c-fos transcriptional activation in myotubes. J Neuroimmunol 2003, 142:58–66.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Pathology, University of Michigan Medical School, 1301 Catherine Road, 48109-0602, Ann Arbor, MI, USA

    Eric A. Albrecht PhD & Peter A. Ward MD

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  1. Eric A. Albrecht PhD
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  2. Peter A. Ward MD
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Albrecht, E.A., Ward, P.A. Complement-induced impairment of the innate immune system during sepsis. Curr Allergy Asthma Rep 4, 359–364 (2004). https://doi.org/10.1007/s11882-004-0084-3

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