The alternative complement pathway revisited

Abstract

Introduction Methods to study and modify the alternative pathway Influence of AP amplification on the effect of specific activation of the other initial pathways Properdin Influence of AP in deficiency states Complement in sepsis Concluding remarks Alternative pathway amplification plays a major role for the final effect of initial specific activation of the classical and lectin complement pathways, but the quantitative role of the amplification is insufficiently investigated. In experimental models of human diseases in which a direct activation of alternative pathway has been assumed, this interpretation needs revision placing a greater role on alternative amplification. We recently documented that the alternative amplification contributed to 80–90% of C5 activation when the initial activation was highly specific for the classical pathway. The recent identification of properdin as a recognition factor directly initiating alternative pathway activation, like C1q in the classical and mannose‐binding lectin in the lectin pathway, initiates a renewed interest in the reaction mechanisms of complement. Complement and Toll‐like receptors, including the CD14 molecule, are two main upstream recognition systems of innate immunity, contributing to the inflammatory reaction in a number of conditions including ischaemia‐reperfusion injury and sepsis. These systems act as ‘double‐edged swords’, being protective against microbial invasion, but harmful to the host when activated improperly or uncontrolled. Combined inhibition of complement and Toll‐like receptors/CD14 should be explored as a treatment regimen to reduce the overwhelming damaging inflammatory response during sepsis. The alternative pathway should be particularly considered in this regard, due to its uncontrolled amplification in sepsis. The alternative pathway should be regarded as a dual system, namely a recognition pathway principally similar to the classical and lectin pathways, and an amplification mechanism, well known, but quantitatively probably more important than generally recognized.

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93. 93.

    Mollnes TE, Jokiranta TS, Truedsson L, Nilsson B, Rodriguez de CS, Kirschfink M. Complement analysis in the 21st century. Mol Immunol. 2007;44:3838-49.

    Not in our library10.1016/j.molimm.2007.06.150

94. 94.

    Seelen MA, Roos A, Wieslander J, Mollnes TE, Sjoholm AG, Wurzner R, Loos M, Tedesco F, Sim RB, Garred P, Alexopoulos E, Turner MW, Daha MR. Functional analysis of the classical, alternative, and MBL pathways of the complement system: standardization and validation of a simple ELISA. J Immunol Methods. 2005;296:187-98.

    Not in our library10.1016/j.jim.2004.11.016

95. 95.

    Oberholzer A, Oberholzer C, Moldawer LL. Sepsis syndromes: understanding the role of innate and acquired immunity. Shock. 2001;16:83-96.

    Not in our library10.1097/00024382-200116020-00001

96. 96.

    Riedemann NC, Guo RF, Ward PA. The enigma of sepsis. J Clin Invest. 2003;112:460-7.

    Not in our library10.1172/jci19523

97. 97.

    Riedemann NC, Guo RF, Ward PA. Novel strategies for the treatment of sepsis. Nat Med. 2003;9:517-24.

    Not in our library10.1038/nm0503-517

98. 98.

    Kutko MC, Calarco MP, Flaherty MB, Helmrich RF, Ushay HM, Pon S, Greenwald BM. Mortality rates in pediatric septic shock with and without multiple organ system failure. Pediatr Crit Care Med. 2003;4:333-7.

    Not in our library10.1097/01.pcc.0000074266.10576.9b

99. 99.

    Aggarwal R, Sarkar N, Deorari AK, Paul VK. Sepsis in the newborn. Indian J Pediatr. 2001;68:1143-7.

    Not in our library10.1007/bf02722932

100. 100.

     Marshall JC. Such stuff as dreams are made on: mediator-directed therapy in sepsis. Nat Rev Drug Discov. 2003;2:391-405.

     Not in our library10.1038/nrd1084

101. 101.

     Hotchkiss RS, Karl IE. The pathophysiology and treatment of sepsis. N Engl J Med. 2003;348:138-50.

     Not in our library10.1056/nejmra021333

102. 102.

     van Deuren M, Brandtzaeg P, Van Der Meer JW. Update on meningococcal disease with emphasis on pathogenesis and clinical management. Clin Microbiol Rev. 2000;13:144-66.

     Not in our library10.1128/cmr.13.1.144-166.2000

103. 103.

     Brandtzaeg P, Mollnes TE, Kierulf P. Complement activation and endotoxin levels in systemic meningococcal disease. J Infect Dis. 1989;160:58-65.

     Not in our library10.1093/infdis/160.1.58

104. 104.

     Brandtzaeg P, Hogasen K, Kierulf P, Mollnes TE. The excessive complement activation in fulminant meningococcal sep-ticemia is predominantly caused by alternative pathway activation. J Infect Dis. 1996;173:647-55.

     Not in our library10.1093/infdis/173.3.647

105. 105.

     Ward PA. The dark side of C5a in sepsis. Nat Rev Immunol. 2004;4:133-42.

     Not in our library10.1038/nri1269

106. 106.

     Ward PA. Role of the complement in experimental sepsis. J Leukoc Biol. 2008;83:467-70.

     Not in our library10.1189/jlb.0607376

107. 107.

     Heumann D, Roger T. Initial responses to endotoxins and Gram-negative bacteria. Clin Chim Acta. 2002;323:59-72.

     Not in our library10.1016/s0009-8981(02)00180-8

108. 108.

     Dobrovolskaia MA, Vogel SN. Toll receptors, CD14, and macrophage activation and deactivation by LPS. Microbes Infect. 2002;4:903-14.

     Not in our library10.1016/s1286-4579(02)01613-1

109. 109.

     Brekke OL, Christiansen D, Fure H, Fung M, Mollnes TE. The role of complement C3 opsonization, C5a receptor, and CD14 in E. coli-induced up-regulation of granulocyte and monocyte CD11b/CD18 (CR3), phagocytosis, and oxidative burst in human whole blood. J Leukoc Biol. 2007;81:1404-13.

     Not in our library10.1189/jlb.0806538

110. 110.

     Sprong T, Moller AS, Bjerre A, Wedege E, Kierulf P, Van Der Meer JW, Brandtzaeg P, van DM, Mollnes TE. Complement activation and complementdependent inflammation by Neisseria meningitidis are independent of lipopolysaccharide. Infect Immun. 2004;72:3344-9.

     Not in our library10.1128/iai.72.6.3344-3349.2004

111. 111.

     Marchant A, Tielemans C, Husson C, Gastaldello K, Schurmans T, de Groote D, Duchow J, Vanherweghem L, Goldman M. Cuprophane haemodialysis induces upregulation of LPS receptor (CD14) on monocytes: role of complement activation. Nephrol Dial Transplant. 1996;11:657-62.

     Not in our library10.1093/oxfordjournals.ndt.a027355

112. 112.

     Yamada M, Oritani K, Kaisho T, Ishikawa J, Yoshida H, Takahashi I, Kawamoto S, Ishida N, Ujiie H, Masaie H, Botto M, Tomiyama Y, Matsuzawa Y. Complement C1q regulates LPS-induced cytokine production in bone marrow-derived dendritic cells. Eur J Immunol. 2004;34:221-30.

     Not in our library10.1002/eji.200324026

113. 113.

     Ip WK, Takahashi K, Moore KJ, Stuart LM, Ezekowitz RA. Mannose-binding lectin enhances Toll-like receptors 2 and 6 signaling from the phagosome. J Exp Med. 2008;205:169-8.

     Not in our library10.1084/jem.20071164

114. 114.

     Mollnes TE, Christiansen D, Brekke OL, Espevik T. Hypothesis: combined inhibition of complement and CD14 as treatment regimen to attenuate the inflammatory response. Adv Exp Med Biol. 2008.

     Not in our library

Cited by papers we hold 5

• Anaphylatoxins spark the flame in early autoimmunity · 2022
  Not checked
• Complement factor H contributes to mortality in humans and mice with bacterial meningitis · 2019
  Not checked
• A high-throughput, bead-based, antigen-specific assay to assess the ability of antibodies to induce complement activation · 2019
  No notice
• The Alternative Complement System Mediates Cell Death in Retinal Ischemia Reperfusion Injury · 2018
  Not checked
• Complement System Part I – Molecular Mechanisms of Activation and Regulation · 2015
  No notice

Reads

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