Biosynthetic homeostasis and resilience of the complement system in health and infectious diseaseResearch in context
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
Affiliations
Esther Willems
Section Pediatric Infectious Diseases, Laboratory of Medical Immunology, Department of Laboratory Medicine, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands; Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands; Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen, The Netherlands; Corresponding author at: Section Pediatric Infectious Diseases, Laboratory of Medical Immunology, Department of Laboratory Medicine, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
Wynand Alkema
Centre for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
Jenneke Keizer-Garritsen
Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen, The Netherlands
Anouk Suppers
Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen, The Netherlands
Michiel van der Flier
Department of Pediatrics, University Medical Center Utrecht, Utrecht, The Netherlands
Ria H.L.A. Philipsen
Section Pediatric Infectious Diseases, Laboratory of Medical Immunology, Department of Laboratory Medicine, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands; Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands
Lambert P. van den Heuvel
Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen, The Netherlands; Amalia Children's Hospital, Radboud University Medical Center, Nijmegen, The Netherlands
Elena Volokhina
Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen, The Netherlands; Amalia Children's Hospital, Radboud University Medical Center, Nijmegen, The Netherlands
Renate G. van der Molen
Section Pediatric Infectious Diseases, Laboratory of Medical Immunology, Department of Laboratory Medicine, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
Jethro A. Herberg
Department of Medicine, Section for Paediatrics, Imperial College London, London, UK
Michael Levin
Department of Medicine, Section for Paediatrics, Imperial College London, London, UK
Victoria J. Wright
Department of Medicine, Section for Paediatrics, Imperial College London, London, UK
Inge M.L. Ahout
Amalia Children's Hospital, Radboud University Medical Center, Nijmegen, The Netherlands
Gerben Ferwerda
Section Pediatric Infectious Diseases, Laboratory of Medical Immunology, Department of Laboratory Medicine, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands; Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands
Marieke Emonts
Department of Paediatric Immunology, Infectious Diseases and Allergy, Great North Children's Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK; Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK; NIHR Newcastle Biomedical Research Centre based at Newcastle upon Tyne Hospitals NHS Trust and Newcastle University, Newcastle upon Tyne, UK
Navin P. Boeddha
Intensive Care and Department of Pediatric Surgery, Erasmus MC-Sophia Children's Hospital, University Medical Center Rotterdam, Rotterdam, Netherlands
Irene Rivero-Calle
Translational Pediatrics and Infectious Diseases, Hospital Clínico Universitario de Santiago, Instituto de Investigación Sanitaria de Santiago, Santiago de Compostela, Galicia, Spain
Federico Martinon Torres
Translational Pediatrics and Infectious Diseases, Hospital Clínico Universitario de Santiago, Instituto de Investigación Sanitaria de Santiago, Santiago de Compostela, Galicia, Spain
Hans J.C.T. Wessels
Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen, The Netherlands
Ronald de Groot
Section Pediatric Infectious Diseases, Laboratory of Medical Immunology, Department of Laboratory Medicine, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands; Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands
Alain J. van Gool
Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen, The Netherlands
Jolein Gloerich
Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen, The Netherlands
Marien I. de Jonge
Section Pediatric Infectious Diseases, Laboratory of Medical Immunology, Department of Laboratory Medicine, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands; Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands
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: Targeted mass spectrometry, Multiple reaction monitoring (MRM), Complement system, Infectious disease, C-reactive protein (CRP), Clusterin
