Dataset Information

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.

SUBMITTER: Willems E

PROVIDER: S-EPMC6642076 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Willems Esther E Alkema Wynand W Keizer-Garritsen Jenneke J Suppers Anouk A van der Flier Michiel M Philipsen Ria H L A RHLA van den Heuvel Lambert P LP Volokhina Elena E van der Molen Renate G RG Herberg Jethro A JA Levin Michael M Wright Victoria J VJ Ahout Inge M L IML Ferwerda Gerben G Emonts Marieke M Boeddha Navin P NP Rivero-Calle Irene I Torres Federico Martinon FM Wessels Hans J C T HJCT de Groot Ronald R van Gool Alain J AJ Gloerich Jolein J de Jonge Marien I MI

EBioMedicine 20190629

<h4>Background</h4>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.<h4>Methods</h4>With a newly developed multiplex mass spectrometry-based method we ana ...[more]

PMID: 31262714

Similar Datasets

Project description:BackgroundThere are several definitions of resilience in health systems, many of which share some characteristics, but no agreed-upon framework is universally accepted. Here, we review the concept of resilience, identifying its definitions, attributes, antecedents and consequences, and present the findings of a concept analysis of health system resilience.MethodsWe follow Schwarz-Barcott and Kim's hybrid model, which consists of three phases: theoretical, fieldwork and final analysis. We identified the concept definitions, attributes, antecedents and consequences of health system resilience and constructed an evidence-informed framework on the basis of the findings of this review. We searched PubMed, PsycINFO, CINAHL Complete, EBSCOhost-Academic Search and Premier databases and downloaded identified titles and abstracts on Covidence. We screened 3357 titles and removed duplicate and ineligible records; two reviewers then screened each title, and disagreements were resolved by discussion with the third reviewer. From the 130 eligible manuscripts, we identified the definitions, attributes, antecedents and consequences using a pre-defined data extraction form.ResultsResilience antecedents are decentralization, available funds, investments and resources, staff environment and motivation, integration and networking and finally, diversification of staff. The attributes are the availability of resources and funds, adaptive capacity, transformative capacity, learning and advocacy and progressive leadership. The consequences of health system resilience are improved health system performance, a balanced governance structure, improved expenditure and financial management of health and maintenance of health services that support universal health coverage (UHC) throughout crises.ConclusionA resilient health system maintains quality healthcare through times of crisis. During the coronavirus disease 2019 (COVID-19) epidemic, several seemingly robust health systems were strained under the increased demand, and services were disrupted. As such, elements of resilience should be integrated into the functions of a health system to ensure standardized and consistent service quality and delivery. We offer a systematic, evidence-informed method for identifying the attributes of health system resilience, intending to eventually be used to develop a measuring tool to evaluate a country's health system resilience performance.

Project description:The complement system is an intricate defense network that rapidly removes invading pathogens. Although many complement regulators are present to protect host cells under homeostasis, the impairment of Factor H (FH) regulatory mechanism has been associated with several autoimmune and inflammatory diseases. To understand the dynamics involved in the pivotal balance between activation and regulation, we have developed a comprehensive computational model of the alternative and classical pathways of the complement system. The model is composed of 290 ordinary differential equations with 142 kinetic parameters that describe the state of complement system under homeostasis and disorder through FH impairment. We have evaluated the state of the system by generating concentration-time profiles for the biomarkers C3, C3a-desArg, C5, C5a-desArg, Factor B (FB), Ba, Bb, and fC5b-9 that are influenced by complement dysregulation. We show that FH-mediated disorder induces substantial levels of complement activation compared to homeostasis, by generating reduced levels of C3 and FB, and to a lesser extent C5, and elevated levels of C3a-desArg, Ba, Bb, C5a-desArg, and fC5b-9. These trends are consistent with clinically observed biomarkers associated with complement-mediated diseases. Furthermore, we introduced therapy states by modeling known inhibitors of the complement system, a compstatin variant (C3 inhibitor) and eculizumab (C5 inhibitor). Compstatin demonstrates strong restorative effects for early-stage biomarkers, such as C3a-desArg, FB, Ba, and Bb, and milder restorative effects for late-stage biomarkers, such as C5a-desArg and fC5b-9, whereas eculizumab has strong restorative effects on late-stage biomarkers, and negligible effects on early-stage biomarkers. These results highlight the need for patient-tailored therapies that target early complement activation at the C3 level, or late-stage propagation of the terminal cascade at the C5 level, depending on the specific FH-mediated disease and the manifestations of a patient's genetic profile in complement regulatory function.

Project description:The concept of health system resilience has gained popularity in the global health discourse, featuring in UN policies, academic articles and conferences. While substantial effort has gone into the conceptualization of health system resilience, there has been no review of how the concept has been operationalized in empirical studies. We conducted an empirical review in three databases using systematic methods. Findings were synthesized using descriptive quantitative analysis and by mapping aims, findings, underlying concepts and measurement approaches according to the resilience definition by Blanchet et al. We identified 71 empirical studies on health system resilience from 2008 to 2019, with an increase in literature in recent years (62% of studies published since 2017). Most studies addressed a specific crisis or challenge (82%), most notably infectious disease outbreaks (20%), natural disasters (15%) and climate change (11%). A large proportion of studies focused on service delivery (48%), while other health system building blocks were side-lined. The studies differed in terms of their disciplinary tradition and conceptual background, which was reflected in the variety of concepts and measurement approaches used. Despite extensive theoretical work on the domains which constitute health system resilience, we found that most of the empirical literature only addressed particular aspects related to absorptive and adaptive capacities, with legitimacy of institutions and transformative resilience seldom addressed. Qualitative and mixed methods research captured a broader range of resilience domains than quantitative research. The review shows that the way in which resilience is currently applied in the empirical literature does not match its theoretical foundations. In order to do justice to the complexities of the resilience concept, knowledge from both quantitative and qualitative research traditions should be integrated in a comprehensive assessment framework. Only then will the theoretical 'resilience idea' be able to prove its usefulness for the research community.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets