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      Time-course analysis of C3a and C5a quantifies the coupling between the upper and terminal Complement pathways in vitro.

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          Abstract

          An in vitro zymosan-activation of the Complement system, through the lectin and alternative pathways, was performed in pooled human serum over a 24h time-course. Activation was quantitatively monitored by measuring the concentration of the upper Complement pathway fragment, C3a and the terminal pathway fragment, C5a. Upper Complement showed a maximum activation of 39% and the time-to-maximum activation reduced 8-fold, as a highly non-linear function of the zymosan dose. The C3a:C5a molar ratio rose to a maximum of 1100:1, before terminal pathway activation was initiated; indicating a flux threshold. This threshold appears to be exceeded once more than 31% of C3 molecules are activated. Above this threshold, significant activation of terminal pathway was observed; reducing the molar ratio to 17:1. The C5a/C3a molar ratio was used to determine the terminal pathway activation relative to total Complement activation and ranged from 0.1-0.8%. This depicts upper Complement activation to be 49-fold larger than terminal activation, a figure consistent with the observed density of the membrane attack complex in the membrane of cells. Our results thus indicate that the relative activity of opsonisation is ~50-fold greater than membrane attack complex formation, in vitro, in the pooled serum phenotype. The results suggest a potential clinical application, where an in vitro analysis of a patient on admission, or prior to a surgical procedure, would indicate their upper Complement activation capacity, with activation of C3 measured thereafter, or post-operatively. A patient with an exhausted upper Complement capacity may be vulnerable to infections and complications, such as sepsis.

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          Author and article information

          Journal
          J. Immunol. Methods
          Journal of immunological methods
          Elsevier BV
          1872-7905
          0022-1759
          Dec 2015
          : 427
          Affiliations
          [1 ] Biosciences, College of Life and Environmental Sciences, University of Exeter, Stocker Road, Exeter, EX4 4QD, UK.
          [2 ] Biosciences, College of Life and Environmental Sciences, University of Exeter, Stocker Road, Exeter, EX4 4QD, UK. Electronic address: Andrew.m.shaw@exeter.ac.uk.
          Article
          S0022-1759(15)30043-0
          10.1016/j.jim.2015.09.001
          26391915
          97c74827-f545-41b2-ae87-3bbc92f23cf2
          History

          Upper cascade,Lower cascade,Complement,C5a,In vitro,C3a
          Upper cascade, Lower cascade, Complement, C5a, In vitro, C3a

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