The alternative complement pathway revisited
- PMID: 18419792
- PMCID: PMC3865650
- DOI: 10.1111/j.1582-4934.2008.00350.x
The alternative complement pathway revisited
Abstract
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 ischemia-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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References
-
- Walport MJ. Complement. First of two parts. N Engl J Med. 2001;344:1058–66. - PubMed
-
- Mollnes TE, Song WC, Lambris JD. Complement in inflammatory tissue damage and disease. Trends Immunol. 2002;23:61–4. - PubMed
-
- Volanakis JE, Kaplan MH. Interaction of C-reactive protein complexes with the complement system. II. Consumption of guinea pig complement by CRP complexes: requirement for human C1q. J Immunol. 1974;113:9–17. - PubMed
-
- Kang YS, Do Y, Lee HK, Park SH, Cheong C, Lynch RM, Loeffler JM, Steinman RM, Park CG. A dominant complement fixation pathway for pneumococcal polysaccha-rides initiated by SIGN-R1 interacting with C1q. Cell. 2006;125:47–58. - PubMed
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