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.

Quantitative multiplex profiling of the complement system to diagnose complement‐mediated diseases

“…In many cases, we observed an additional reduction through functional coupling of complement factors within the pathways down-or upstream of the deficient protein, although not fully depleted. That other complement proteins were not totally depleted, especially when a complement inhibitor is deficient, emphasises the previously observed resilience of the complement system 19 even in severe complement deficiencies.…”

“…The development, accuracy and reproducibility of the assay have been established previously. 19 The assay was further improved by implementing pure (> 98%) instead of crude (> 50%) heavy isotopelabelled internal peptide standards for absolute quantification. For clinical implementation, the assay needs additional diagnostic validation, according to clinical mass spectrometry standards.…”

“…The preparation and analysis were performed according to an optimised version of the previous method. 19 A subset of 44 peptides was selected based on performance and redundancy for the current assay (Supplementary table 5). The sample preparation was automated using a pipetting robot (TECAN, M€ annedorf, Switzerland).…”

Soluble Membrane Attack Complex: Biochemistry and Immunobiology

“…This study, and a number of others, have shown that terminal pathway proteins comprising the MAC (C6-C9) are significantly lower in pre-term and full term infants, as are proteins of the classical and alterative pathways [reviewed in ( 82 )]. In addition, a recent study determined that the blood levels of C9 in children less than one year of age were significantly lower compared to adults, and adult levels were reached between two and eighteen years of age ( 83 ). These studies indicate that sMAC levels in are lower in children, in part, because the concentration of proteins that compose the MAC are lower.…”

IgG4 Autoantibodies Attenuate Systemic Lupus Erythematosus Progression by Suppressing Complement Consumption and Inflammatory Cytokine Production

“…Our results showed that C3 and C4 consumption, as well as C5b-9 deposition on HEp-2 cells co-cultured with SLE serum and HEp-2 cells, decreased significantly following treatment with IgG4 autoantibodies (but not control IgG4) in a concentrationdependent manner. It has been confirmed that complement abnormalities (4) and the function of complement molecules influence IC processing and transportation (7,42). In addition, the ICs that can effectively activate complement molecules show greater pathological significance, with significantly more ICs found in SLE patients that were closely associated with SLE-related disease activities (43).…”