Dataset Information

Bakshi2020 - Truncated minimal model of alternative pathway of complement system

ABSTRACT: This model is based on the publication: "Mathematical Modelling of Alternative Pathway of Complement System". Suruchi Bakshi, Fraser Cunningham, Eva-Maria Nichols, Marta Biedzka-Sarek, Jessica Neisen, Sebastien Petit-Frere, Christina Bessant, Loveleena Bansal, Lambertus A Peletier, Stefano Zamuner, Piet H van der Graaf DOI: 10.1007/s11538-020-00708-z Comment: This model is based on the truncated minimal model equations (Eq. B.1) from the manuscript, which simulate depletion of factor H. Abstract: The complement system (CS) is an integral part of innate immunity and can be activated via three different pathways. The alternative pathway (AP) has a central role in the function of the CS. The AP of complement system is implicated in several human disease pathologies. In the absence of triggers, the AP exists in a time-invariant resting state (physiological steady state). It is capable of rapid, potent and transient activation response upon challenge with a trigger. Previous models of AP have focused on the activation response. In order to understand the molecular machinery necessary for AP activation and regulation of a physiological steady state, we built parsimonious AP models using experimentally supported kinetic parameters. The models further allowed us to test quantitative roles played by negative and positive regulators of the pathway in order to test hypotheses regarding their mechanisms of action, thus providing more insight into the complex regulation of AP.

DISEASE(S): Complement Deficiency

SUBMITTER: Emilia Chen

PROVIDER: BIOMD0000001016 | BioModels | 2021-07-20

REPOSITORIES: BioModels

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Publications

Mathematical Modelling of Alternative Pathway of Complement System.

Bakshi Suruchi S Cunningham Fraser F Nichols Eva-Maria EM Biedzka-Sarek Marta M Neisen Jessica J Petit-Frere Sebastien S Bessant Christina C Bansal Loveleena L Peletier Lambertus A LA Zamuner Stefano S van der Graaf Piet H PH

Bulletin of mathematical biology 20200215 2

The complement system (CS) is an integral part of innate immunity and can be activated via three different pathways. The alternative pathway (AP) has a central role in the function of the CS. The AP of complement system is implicated in several human disease pathologies. In the absence of triggers, the AP exists in a time-invariant resting state (physiological steady state). It is capable of rapid, potent and transient activation response upon challenge with a trigger. Previous models of AP have ...[more]

PMID: 32062771

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Project description:Background: Age-related macular degeneration (AMD) is caused by the degeneration of the macular photoreceptors. This is preceded by development of subretinal protein aggregates (drusen) and degeneration of the macular retinal pigment epithelium (RPE). The underlying pathogenesis remains unknown, but the immune system is suspected to play a key role in it. Aging of the immune system, immunosenescence, includes changes in T cell sub-populations and results in low-level chronic inflammation. Because AMD exclusively occurs in patients over 55 years of age, we hypothesize that aging of the T cell compartment may be implicated in AMD pathogenesis. Methodology and principal findings: Using an in vitro co-culture system, we investigated the effects of activated T cells on a human RPE cell line (ARPE-19). Differential gene expression in the RPE cells of complement factor genes was identified using microarrays, and selected gene transcripts from the alternative complement pathway were validated by q-RT-PCR. Protein expression was determined by ELISA and immunoblotting. Co-culture with activated T cells increased RPE mRNA and protein expression of complement component C3, factors B, H, H-like 1, CD46, CD59, and clusterin, in a dose-dependent manner. Conclusions: RPE cells responded to inflammatory assault caused by exposure to T cell-derived cytokines by upregulating expression of many complement factors from the alternative pathway. This may have implications for RPE ability to deal with complement attack, and opsonization and removal of debris from the RPE-choroidal interface. We speculate that regulation of the complement system in response to inflammatory assault may play a vital role in RPE pathology and drusen biogenesis. Experiment Overall Design: 10 samples investigating variations of co-cultures of RPE cells and T-cells. Variable parameters include the cell type, the co-culturing of the counter-part cell type and the orientation of the system (apical vs basolateral).

Dataset Information

Bakshi2020 - Truncated minimal model of alternative pathway of complement system

Publications

Mathematical Modelling of Alternative Pathway of Complement System.

Similar Datasets

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