Dataset Information

Quantitative multiplex profiling of the complement system to diagnose complement-mediated diseases.

ABSTRACT:

Objectives

Complement deficiencies are difficult to diagnose because of the variability of symptoms and the complexity of the diagnostic process. Here, we applied a novel 'complementomics' approach to study the impact of various complement deficiencies on circulating complement levels.

Methods

Using a quantitative multiplex mass spectrometry assay, we analysed 44 peptides to profile 34 complement proteins simultaneously in 40 healthy controls and 83 individuals with a diagnosed deficiency or a potential pathogenic variant in 14 different complement proteins.

Results

Apart from confirming near or total absence of the respective protein in plasma of complement-deficient patients, this mass spectrometry-based profiling method led to the identification of additional deficiencies. In many cases, partial depletion of the pathway up- and/or downstream of the absent protein was measured. This was especially found in patients deficient for complement inhibitors, such as angioedema patients with a C1-inhibitor deficiency. The added value of complementomics was shown in three patients with poorly defined complement deficiencies.

Conclusion

Our study shows the potential clinical utility of profiling circulating complement proteins as a comprehensive read-out of various complement deficiencies. Particularly, our approach provides insight into the intricate interplay between complement proteins due to functional coupling, which contributes to the better understanding of the various disease phenotypes and improvement of care for patients with complement-mediated diseases.

SUBMITTER: Willems E

PROVIDER: S-EPMC7724921 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Publications

Quantitative multiplex profiling of the complement system to diagnose complement-mediated diseases.

Willems Esther E Lorés-Motta Laura L Zanichelli Andrea A Suffritti Chiara C van der Flier Michiel M van der Molen Renate G RG Langereis Jeroen D JD van Drongelen Joris J van den Heuvel Lambert P LP Volokhina Elena E van de Kar Nicole Caj NC Keizer-Garritsen Jenneke J Levin Michael M Herberg Jethro A JA Martinon-Torres Federico F Wessels Hans Jtc HJ de Breuk Anita A Fauser Sascha S Hoyng Carel B CB den Hollander Anneke I AI de Groot Ronald R van Gool Alain J AJ Gloerich Jolein J de Jonge Marien I MI

Clinical & translational immunology 20201209 12

<h4>Objectives</h4>Complement deficiencies are difficult to diagnose because of the variability of symptoms and the complexity of the diagnostic process. Here, we applied a novel 'complementomics' approach to study the impact of various complement deficiencies on circulating complement levels.<h4>Methods</h4>Using a quantitative multiplex mass spectrometry assay, we analysed 44 peptides to profile 34 complement proteins simultaneously in 40 healthy controls and 83 individuals with a diagnosed de ...[more]

PMID: 33318796

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Project description:The complement system plays critical roles in development, homeostasis, and regeneration in the central nervous system (CNS) throughout life; however, complement dysregulation in the CNS can lead to damage and disease. Complement proteins, regulators, and receptors are widely expressed throughout the CNS and, in many cases, are upregulated in disease. Genetic and epidemiological studies, cerebrospinal fluid (CSF) and plasma biomarker measurements and pathological analysis of post-mortem tissues have all implicated complement in multiple CNS diseases including multiple sclerosis (MS), neuromyelitis optica (NMO), neurotrauma, stroke, amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). Given this body of evidence implicating complement in diverse brain diseases, manipulating complement in the brain is an attractive prospect; however, the blood-brain barrier (BBB), critical to protect the brain from potentially harmful agents in the circulation, is also impermeable to current complement-targeting therapeutics, making drug design much more challenging. For example, antibody therapeutics administered systemically are essentially excluded from the brain. Recent protocols have utilized "Trojan horse" techniques to transport therapeutics across the BBB or used osmotic shock or ultrasound to temporarily disrupt the BBB. Most research to date exploring the impact of complement inhibition on CNS diseases has been in animal models, and some of these studies have generated convincing data; for example, in models of MS, NMO, and stroke. There have been a few recent clinical trials of available anti-complement drugs in CNS diseases associated with BBB impairment, for example the use of the anti-C5 monoclonal antibody (mAb) eculizumab in NMO, but for most CNS diseases there have been no human trials of anti-complement therapies. Here we will review the evidence implicating complement in diverse CNS disorders, from acute, such as traumatic brain or spine injury, to chronic, including demyelinating, neuroinflammatory, and neurodegenerative diseases. We will discuss the particular problems of drug access into the CNS and explore ways in which anti-complement therapies might be tailored for CNS disease.

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Dataset Information

Quantitative multiplex profiling of the complement system to diagnose complement-mediated diseases.

Objectives

Methods

Results

Conclusion

Publications

Quantitative multiplex profiling of the complement system to diagnose complement-mediated diseases.

Similar Datasets

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