Publications by authors named "Anub Mathew Thomas"

3 Publications

  • Page 1 of 1

Complement ratios C3bc/C3 and sC5b-9/C5 do not increase the sensitivity of detecting acute complement activation systemically.

Mol Immunol 2022 01 11;141:273-279. Epub 2021 Dec 11.

Department of Immunology, Oslo University Hospital and University of Oslo, Norway; Division of Emergencies and Critical Care, Oslo University Hospital, Norway. Electronic address:

Background: Complement activation plays an important pathogenic role in numerous diseases. The ratio between an activation product and its parent protein is suggested to be more sensitive to detect complement activation than the activation product itself. In the present study we explored whether the ratio between the activation product and the parent protein for C3 (C3bc/C3) and for C5 (sC5b-9/C5) increased the sensitivity to detect complement activation in acute clinical settings compared to the activation product alone.

Materials And Methods: Samples from patients with acute heart failure following ST-elevated myocardial infarction (STEMI) and from patients with out-of-hospital cardiac arrest (OHCA) were used. C3, C3bc and C5, sC5b-9 were analysed in 629 and 672 patient samples, respectively. Healthy controls (n = 20) served to determine reference cut-off values for activation products and ratios, defined as two SD above the mean.

Results: Increased C3bc/C3- and sC5b-9/C5 ratios were vastly dependent on C3bc and sC5b-9. Thus, 99.5 % and 98.1 % of the increased C3bc/C3- and sC5b-9/C5 ratios were solely dependent on increased C3bc and sC5b-9, respectively. Significantly decreased C3 and C5 caused increased ratios in only 3/600 (0.5 %) and 4/319 (1.3 %) samples, respectively. Strong correlations between C3bc and C3bc/C3-ratio and between sC5b-9 and sC5b-9/C5-ratio were found in the STEMI- (r = 0.926 and r = 0.786, respectively) and the OHCA-population (r = 0.908 and r = 0.843, respectively; p < 0.0001 for all). Importantly, sC5b-9 identified worse outcome groups better than sC5b-9/C5-ratio.

Conclusion: C3bc and sC5b-9 were sensitive markers of complement activation. The ratios of C3bc/C3 and sC5b-9/C5 did not improve detection of complement activation systemically.
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http://dx.doi.org/10.1016/j.molimm.2021.11.016DOI Listing
January 2022

Combined Inhibition of C5 and CD14 Attenuates Systemic Inflammation in a Piglet Model of Meconium Aspiration Syndrome.

Neonatology 2018 27;113(4):322-330. Epub 2018 Feb 27.

Department of Immunology, Oslo University Hospital and K.G. Jebsen IRC, University of Oslo, Oslo, Norway.

Background: Meconium aspiration syndrome (MAS) is a severe lung condition affecting newborns and it can lead to a systemic inflammatory response. We previously documented complement activation and cytokine release in a piglet MAS model. Additionally, we showed ex vivo that meconium-induced inflammation was dependent on complement and Toll-like receptors.

Objectives: To assess the efficacy of the combined inhibition of complement (C5) and CD14 on systemic inflammation induced in a forceful piglet MAS model.

Methods: Thirty piglets were randomly allocated to a treatment group receiving the C5-inhibitor SOBI002 and anti-CD14 (n = 15) and a nontreated control group (n = 15). MAS was induced by intratracheal meconium instillation, and the piglets were observed for 5 h. Complement, cytokines, and myeloperoxidase (MPO) were measured by ELISA.

Results: SOBI002 ablated C5 activity and the formation of the terminal complement complex in vivo. The combined inhibition attenuated the inflammasome cytokines IL-1β and IL-6 by 60 (p = 0.029) and 44% (p = 0.01), respectively, and also MPO activity in the bronchoalveolar fluid by 42% (p = 0.017). Ex vivo experiments in human blood revealed that the combined regimen attenuated meconium-induced MPO release by 64% (p = 0.008), but there was only a negligible effect with single inhibition, indicating a synergic cross-talk between the key molecules C5 and CD14.

Conclusion: Combined inhibition of C5 and CD14 attenuates meconium-induced inflammation in vivo and this could become a future therapeutic regimen for MAS.
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http://dx.doi.org/10.1159/000486542DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6008878PMC
September 2019

Eculizumab-C5 complexes express a C5a neoepitope in vivo: Consequences for interpretation of patient complement analyses.

Mol Immunol 2017 09 10;89:111-114. Epub 2017 Jun 10.

Department of Immunology, Oslo University Hospital Rikshospitalet, Oslo, Norway; K.G. Jebsen Inflammatory Research Center, University of Oslo, Oslo, Norway; Research Laboratory, Nordland Hospital, Bodø, Norway; Faculty of Health Sciences, K.G. Jebsen TREC, University of Tromsø, Tromsø, Norway; Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, Trondheim, Norway. Electronic address:

The complement system has obtained renewed clinical focus due to increasing number of patients treated with eculizumab, a monoclonal antibody inhibiting cleavage of C5 into C5a and C5b. The FDA approved indications are paroxysmal nocturnal haemoglobinuria and atypical haemolytic uremic syndrome, but many other diseases are candidates for complement inhibition. It has been postulated that eculizumab does not inhibit C5a formation in vivo, in contrast to what would be expected since it blocks C5 cleavage. We recently revealed that this finding was due to a false positive reaction in a C5a assay. In the present study, we identified expression of a neoepitope which was exposed on C5 after binding to eculizumab in vivo. By size exclusion chromatography of patient serum obtained before and after infusion of eculizumab, we document that the neoepitope was exposed in the fractions containing the eculizumab-C5 complexes, being positive in this actual C5a assay and negative in others. Furthermore, we confirmed that it was the eculizumab-C5 complexes that were detected in the C5a assay by adding an anti-IgG4 antibody as detection antibody. Competitive inhibition by anti-C5 antibodies localized the epitope to the C5a moiety of C5. Finally, acidification of C5, known to alter C5 conformation, induced a neoepitope reacting identical to the one we explored, in the C5a assays. These data are important for interpretation of complement analyses in patients treated with eculizumab.
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http://dx.doi.org/10.1016/j.molimm.2017.05.021DOI Listing
September 2017
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