Biosynthetic homeostasis and resilience of the complement system in health and infectious disease

Esther Willems, Wynand Alkema, Jenneke Keizer-Garritsen, Anouk Suppers, Michiel van der Flier, Ria H L A Philipsen, Lambert P van den Heuvel, Elena Volokhina, Renate G van der Molen, Jethro A Herberg, Michael Levin, Victoria J Wright, Inge M L Ahout, Gerben Ferwerda, Marieke Emonts, Navin P Boeddha, Irene Rivero-Calle, Federico Martinon Torres, Hans J C T Wessels, Ronald de GrootAlain J van Gool, Jolein Gloerich, Marien I de Jonge

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

BACKGROUND: The complement system is a central component of the innate immune system. Constitutive biosynthesis of complement proteins is essential for homeostasis. Dysregulation as a consequence of genetic or environmental cues can lead to inflammatory syndromes or increased susceptibility to infection. However, very little is known about steady state levels in children or its kinetics during infection.

METHODS: With a newly developed multiplex mass spectrometry-based method we analyzed the levels of 32 complement proteins in healthy individuals and in a group of pediatric patients infected with bacterial or viral pathogens.

FINDINGS: In plasma from young infants we found reduced levels of C4BP, ficolin-3, factor B, classical pathway components C1QA, C1QB, C1QC, C1R, and terminal pathway components C5, C8, C9, as compared to healthy adults; whereas the majority of complement regulating (inhibitory) proteins reach adult levels at very young age. Both viral and bacterial infections in children generally lead to a slight overall increase in complement levels, with some exceptions. The kinetics of complement levels during invasive bacterial infections only showed minor changes, except for a significant increase and decrease of CRP and clusterin, respectively.

INTERPRETATION: The combination of lower levels of activating and higher levels of regulating complement proteins, would potentially raise the threshold of activation, which might lead to suppressed complement activation in the first phase of life. There is hardly any measurable complement consumption during bacterial or viral infection. Altogether, expression of the complement proteins appears surprisingly stable, which suggests that the system is continuously replenished. FUND: European Union's Horizon 2020, project PERFORM, grant agreement No. 668303.

Original languageEnglish
Pages (from-to)303-313
JournalEBioMedicine
Volume45
DOIs
Publication statusPublished - 1 Jul 2019
Externally publishedYes

Keywords

  • adolescents
  • adults
  • c-reactive protein/genetics
  • children
  • communicable diseases/genetics
  • complement activation/genetics
  • complement system proteins/chemistry
  • females
  • homeostasis
  • inflammation/genetics
  • males
  • mass spectrometry

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  • Cite this

    Willems, E., Alkema, W., Keizer-Garritsen, J., Suppers, A., van der Flier, M., Philipsen, R. H. L. A., van den Heuvel, L. P., Volokhina, E., van der Molen, R. G., Herberg, J. A., Levin, M., Wright, V. J., Ahout, I. M. L., Ferwerda, G., Emonts, M., Boeddha, N. P., Rivero-Calle, I., Torres, F. M., Wessels, H. J. C. T., ... de Jonge, M. I. (2019). Biosynthetic homeostasis and resilience of the complement system in health and infectious disease. EBioMedicine, 45, 303-313. https://doi.org/10.1016/j.ebiom.2019.06.008