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 Groot; Alain J van Gool; Jolein Gloerich; Marien I de Jonge

doi:10.1016/j.ebiom.2019.06.008

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 journal › Article › Academic › peer-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 language	English
Pages (from-to)	303-313
Journal	EBioMedicine
Volume	45
DOIs	https://doi.org/10.1016/j.ebiom.2019.06.008
Publication status	Published - 1 Jul 2019
Externally published	Yes

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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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

@article{418044b25e5a435d89d3f800f5a5ef37,

title = "Biosynthetic homeostasis and resilience of the complement system in health and infectious disease",

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.",

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, infectieziekten",

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

year = "2019",

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doi = "10.1016/j.ebiom.2019.06.008",

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volume = "45",

pages = "303--313",

journal = "EBioMedicine",

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Willems, E, Alkema, W, Keizer-Garritsen, J, Suppers, A, van der Flier, M, Philipsen, RHLA, van den Heuvel, LP, Volokhina, E, van der Molen, RG, Herberg, JA, Levin, M, Wright, VJ, Ahout, IML, Ferwerda, G, Emonts, M, Boeddha, NP, Rivero-Calle, I, Torres, FM, Wessels, HJCT, de Groot, R, van Gool, AJ, Gloerich, J & de Jonge, MI 2019, 'Biosynthetic homeostasis and resilience of the complement system in health and infectious disease', EBioMedicine, vol. 45, pp. 303-313. https://doi.org/10.1016/j.ebiom.2019.06.008

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

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

SN - 2352-3964

VL - 45

SP - 303

EP - 313

JO - EBioMedicine

JF - EBioMedicine

ER -

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

Abstract

Keywords

Access to Document

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Research output

Nailfold capillaroscopy and candidate-biomarker levels in systemic sclerosis-associated pulmonary hypertension: A cross-sectional study

The 3Ranker: An AI-based Algorithm for Finding Non-animal Alternative Methods

Press/Media

Data-onderzoek legt patronen bloot in het belang van gezondheid

'Productontwikkelaars moeten zich verdiepen in de mogelijkheden van Artificial intelligence'

Cite this