TY - JOUR
T1 - Biosynthetic homeostasis and resilience of the complement system in health and infectious disease
AU - Willems, Esther
AU - Alkema, Wynand
AU - Keizer-Garritsen, Jenneke
AU - Suppers, Anouk
AU - van der Flier, Michiel
AU - Philipsen, Ria H L A
AU - van den Heuvel, Lambert P
AU - Volokhina, Elena
AU - van der Molen, Renate G
AU - Herberg, Jethro A
AU - Levin, Michael
AU - Wright, Victoria J
AU - Ahout, Inge M L
AU - Ferwerda, Gerben
AU - Emonts, Marieke
AU - Boeddha, Navin P
AU - Rivero-Calle, Irene
AU - Torres, Federico Martinon
AU - Wessels, Hans J C T
AU - de Groot, Ronald
AU - van Gool, Alain J
AU - Gloerich, Jolein
AU - de Jonge, Marien I
N1 - Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.
PY - 2019/7/1
Y1 - 2019/7/1
N2 - 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.
AB - 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.
KW - adolescents
KW - adults
KW - c-reactive protein/genetics
KW - children
KW - communicable diseases/genetics
KW - complement activation/genetics
KW - complement system proteins/chemistry
KW - females
KW - homeostasis
KW - inflammation/genetics
KW - males
KW - mass spectrometry
KW - infectieziekten
U2 - 10.1016/j.ebiom.2019.06.008
DO - 10.1016/j.ebiom.2019.06.008
M3 - Article
C2 - 31262714
VL - 45
SP - 303
EP - 313
JO - EBioMedicine
JF - EBioMedicine
SN - 2352-3964
ER -