Electroluminescent TCC, C3dg and fB/Bb epitope assays for profiling Complement cascade activation in vitro using an activated Complement serum calibration standard

Vuuren, Bettine Jansen van; Bergseth, Grethe; Mollnes, Tom Eirik; Shaw, Andrew M.

doi:10.1016/j.jim.2013.11.010

“…The data used for model training was taken from the study of Morad et al [ 35 ] and is given in the Supporting Information ( S2 Table ). In this study, we assumed zymosan A differentially activated the lectin pathway, consistent with the study of Morad et al [ 35 ] and several previous studies [ 36 – 38 ]. However, the role of zymosan may be more complex, as it may activate all three complement pathways under certain conditions.…”

Section: Resultssupporting

confidence: 77%

Reduced order modeling and analysis of the human complement system

Sagar

¹

,

Dai

²

,

Minot

³

et al. 2017

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Complement is an important pathway in innate immunity, inflammation, and many disease processes. However, despite its importance, there are few validated mathematical models of complement activation. In this study, we developed an ensemble of experimentally validated reduced order complement models. We combined ordinary differential equations with logical rules to produce a compact yet predictive model of complement activation. The model, which described the lectin and alternative pathways, was an order of magnitude smaller than comparable models in the literature. We estimated an ensemble of model parameters from in vitro dynamic measurements of the C3a and C5a complement proteins. Subsequently, we validated the model on unseen C3a and C5a measurements not used for model training. Despite its small size, the model was surprisingly predictive. Global sensitivity and robustness analysis suggested complement was robust to any single therapeutic intervention. Only the simultaneous knockdown of both C3 and C5 consistently reduced C3a and C5a formation from all pathways. Taken together, we developed a validated mathematical model of complement activation that was computationally inexpensive, and could easily be incorporated into pre-existing or new pharmacokinetic models of immune system function. The model described experimental data, and predicted the need for multiple points of therapeutic intervention to fully disrupt complement activation.

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“…1 Morad et al [34] and is given in Table T2. In this study, we assumed zymosan A 281 differentially activated the lectin pathway, consistent with the study of Morad et al [34] 282 and several previous studies [35][36][37]. However, the role of zymosan may be more 283 complex, as it may activate all three complement pathways under certain conditions.…”

supporting

confidence: 83%

Reduced order modeling and analysis of the human complement system

Sagar

¹

,

Dai

²

,

Minot

³

et al. 2016

Preprint

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Complement is an important pathway in innate immunity, inflammation, and many disease processes. However, despite its importance, there are few validated mathematical models of complement activation. In this study, we developed an ensemble of experimentally validated reduced order complement models. We combined ordinary differential equations with logical rules to produce a compact yet predictive model of complement activation. The model, which described the lectin and alternative pathways, was an order of magnitude smaller than comparable models in the literature. We estimated an ensemble of model parameters from in vitro dynamic measurements of the C3a and C5a complement proteins. Subsequently, we validated the model on unseen C3a and C5a measurements not used for model training. Despite its small size, the model was surprisingly predictive. Global sensitivity and robustness analysis suggested complement was robust to any single therapeutic intervention. Only the simultaneous knockdown of both C3 and C5 consistently reduced C3a and C5a formation from all pathways. Taken together, we developed a validated mathematical model of complement activation that was computationally inexpensive, and could easily be incorporated into pre-existing or new pharmacokinetic models of immune system function. The model described experimental data, and predicted the need for multiple points of therapeutic intervention to fully disrupt complement activation.

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“…Complement activation biomarker soluble C5b-9 terminal complement complex (TCC) was determined in EDTA plasma using ELISA, following previously established protocols, and quantified as complement arbitrary units per milliliter (CAU/mL) [ 19 ]. Optical density measurements were acquired through utilization of an MRX microplate reader (Dynex Technologies, Denkendorf, Germany) [ 20 ].…”

Section: Methodsmentioning

confidence: 99%

Potential Biomarkers for the Earlier Diagnosis of Kidney and Liver Damage in Acute Intermittent Porphyria

Storjord,

Wahlin,

Karlsen

et al. 2023

Life

1

0

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Acute intermittent porphyria (AIP) is an inherited metabolic disorder associated with complications including kidney failure and hepatocellular carcinoma, probably caused by elevations in the porphyrin precursors porphobilinogen (PBG) and delta-aminolevulinic acid (ALA). This study explored differences in modern biomarkers for renal and hepatic damage between AIP patients and controls. Urine PBG testing, kidney injury panels, and liver injury panels, including both routine and modern biomarkers, were performed on plasma and urine samples from AIP cases and matched controls (50 and 48 matched pairs, respectively). Regarding the participants’ plasma, the AIP cases had elevated kidney injury marker-1 (KIM-1, p = 0.0002), fatty acid-binding protein-1 (FABP-1, p = 0.04), and α-glutathione S-transferase (α-GST, p = 0.001) compared to the matched controls. The AIP cases with high PBG had increased FABP-1 levels in their plasma and urine compared to those with low PBG. In the AIP cases, KIM-1 correlated positively with PBG, CXCL10, CCL2, and TCC, and the liver marker α-GST correlated positively with IL-13, CCL2, and CCL4 (all p < 0.05). In conclusion, KIM-1, FABP-1, and α-GST could represent potential early indicators of renal and hepatic damage in AIP, demonstrating associations with porphyrin precursors and inflammatory markers.

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Electroluminescent TCC, C3dg and fB/Bb epitope assays for profiling Complement cascade activation in vitro using an activated Complement serum calibration standard

Cited by 8 publications

References 30 publications

Reduced order modeling and analysis of the human complement system

Reduced order modeling and analysis of the human complement system

Reduced order modeling and analysis of the human complement system

Potential Biomarkers for the Earlier Diagnosis of Kidney and Liver Damage in Acute Intermittent Porphyria

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