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Targeted MRM assay Complement System for Complement deficiencies

ABSTRACT: Complement deficiencies are difficult to diagnose due to 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. 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. 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. Our study shows the potential clinical utility of profiling circulating complement proteins as a comprehensive read-oud 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.

ORGANISM(S): Homo Sapiens

SUBMITTER: Jolein Gloerich

PROVIDER: PXD022416 | panorama | Wed Dec 09 00:00:00 GMT 2020

REPOSITORIES: PanoramaPublic

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Project description:Objectives: To understand the crosstalk between the immune system and keratinization in psoriatic skin, using a systems biology approach based on transcriptomics, proteomics and microbiome profiling. Methods: We collected the skin tissue biopsies and swabs in both lesion and non-lesion skin of 13 patients with psoriasis (PsO), 15 patients with psoriatic arthritis (PsA), and healthy skin from 12 patients with ankylosing spondylitis (AS). We performed transcriptome sequencing and metagenomics profiling on the local skin sites to study the similarities and differences in the molecular profiles between the three conditions. To assess the systemic nature of the disease, we performed a high-throughput proteome profiling to study the profiles of proteins circulating in the serum of the same donors. Results: We found that lesion and non-lesional samples were remarkably different in terms of their transcriptome profiles. Functional annotation of differentially expressed genes (DEGs) showed a major enrichment in neutrophil activation. By using co-expression gene networks, we identified a gene module that was associated with local psoriasis severity at the site of biopsy. From this module, we extracted a “core” set of genes that were functionally involved in neutrophil activation, epidermal cell differentiation and response to bacteria. Skin microbiome analysis revealed that the abundance of Enhydrobacter, Micrococcus and Leptotrichia were significantly correlated with the “core network” of genes. We further identified 39 circulating proteins from the serum that were significantly correlated with the corresponding local skin gene expression, highlighting systemic aberrations due to skin disease. Integration of “core” genes identified from skin with circulating protein profiles revealed PI3 as a key biomarker for psoriasis. Conclusions: We identified a core network that regulates inflammation and hyper-keratinization in psoriatic skin, and is associated with local disease severity and microbiome composition. Multi-omics analysis identified PI3 as a psoriasis-specific biomarker for disease severity and potential target for treatment strategies.

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Targeted MRM assay Complement System for Complement deficiencies

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