Mathematical Modelling of Alternative Pathway of Complement System

Bakshi, Suruchi; Cunningham, Fraser; Nichols, Eva-Maria; Biedzka-Sarek, Marta; Neisen, Jessica; Petit-Frere, Sebastien; Bessant, Christina; Bansal, Loveleena; Peletier, L. A.; Zamuner, Stefano; Graaf, Piet H. van der

doi:10.1007/s11538-020-00708-z

Cited by 7 publications

(19 citation statements)

References 56 publications

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“…complexes [12]. In a healthy state (i.e., in the absence of a trigger), the complement system maintains a resting state through a series of liquid phase and cell surface regulatory proteins [13,14].…”

Section: Introductionmentioning

confidence: 99%

“…The complement system, a component of innate immunity, is a bridge between innate and adaptive immunity, providing the first line of defense against microorganisms, and is a necessary process to clear apoptotic cells and immune complexes [ 12 ]. In a healthy state (i.e., in the absence of a trigger), the complement system maintains a resting state through a series of liquid phase and cell surface regulatory proteins [ 13 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

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Vitamin D deficiency leads to the abnormal activation of the complement system

Xie

Bai

et al. 2022

Immunol Res

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Vitamin D deficiency can damage the human immune system, and the complement system is a key component of the immune system. This study aimed to elucidate the mechanism by which vitamin D affects the immune system by analyzing the changes in the protein expression of the complement system under different vitamin D levels. We selected 40 participants and divided them into three groups according to their serum levels of 25-hydroxyvitamin D (25(OH)VD): group A, 25(OH)VD ≥ 40 ng/mL; group B, 30 ng/mL ≤ 25(OH)VD < 40 ng/mL; and group C, 25(OH)VD < 30 ng/mL. Serum samples were subjected to biochemical analysis, followed by proteomic analysis using high-throughput untargeted proteomic techniques. Vitamin D deficiency increased the levels of fasting blood sugar, fasting serum insulin, and homeostasis model assessment (HOMA) of insulin resistance and decreased the secretion of HOMA of β-cell function, which led to insulin resistance and glucose metabolism disorder. Moreover, vitamin D deficiency resulted in the abnormal expression of 56 differential proteins, among which the expression levels of complement factor B, complement component C9, inducible co-stimulator ligand, and peptidase inhibitor 16 significantly changed with the decrease in vitamin D content. Functional enrichment analysis of these differential proteins showed that they were mainly concentrated in functions and pathways related to insulin secretion and inflammation. In conclusion, vitamin D deficiency not only contributes to insulin resistance and glucose metabolism disorder but also causes abnormal protein expression, resulting in the abnormal activation of the complement system. This study provides a novel theoretical basis for further studies on the relationship between vitamin D and the immune system.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Vitamin D deficiency leads to the abnormal activation of the complement system

Xie

Bai

et al. 2022

Immunol Res

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“…Altogether, a competent complement system that spans all three pathways forms a pivotal junction in the fight against pathogens. Knowing this importance, computational models have been assembled to shed light on the dynamics of complement activation and propagation [41][42][43][44][45][46]. However, to our knowledge, a comprehensive model that covers all three pathways of the complement system has not been developed.…”

Section: Introductionmentioning

confidence: 99%

Systems Biology Modeling of the Complement System Under Immune Susceptible Pathogens

et al. 2021

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The complement system is assembled from a network of proteins that function to bring about the first line of defense of the body against invading pathogens. However, complement deficiencies or invasive pathogens can hijack complement to subsequently increase susceptibility of the body to infections. Moreover, invasive pathogens are increasingly becoming resistant to the currently available therapies. Hence, it is important to gain insights into the highly dynamic interaction between complement and invading microbes in the frontlines of immunity. Here, we developed a mathematical model of the complement system composed of 670 ordinary differential equations with 328 kinetic parameters, which describes all three complement pathways (alternative, classical, and lectin) and includes description of mannose-binding lectin, collectins, ficolins, factor H-related proteins, immunoglobulin M, and pentraxins. Additionally, we incorporate two pathogens: (type 1) complement susceptible pathogen and (type 2) Neisseria meningitidis located in either nasopharynx or bloodstream. In both cases, we generate time profiles of the pathogen surface occupied by complement components and the membrane attack complex (MAC). Our model shows both pathogen types in bloodstream are saturated by complement proteins, whereas MACs occupy <<1.0% of the pathogen surface. Conversely, the MAC production in nasopharynx occupies about 1.5–10% of the total N. meningitidis surface, thus making nasal MAC levels at least about eight orders of magnitude higher. Altogether, we predict complement-imbalance, favoring overactivation, is associated with nasopharynx homeostasis. Conversely, orientating toward complement-balance may cause disruption to the nasopharynx homeostasis. Thus, for sporadic meningococcal disease, our model predicts rising nasal levels of complement regulators as early infection biomarkers.

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“…Modeling techniques offer a means to formalize the available biological knowledge into a quantitative description of the system dynamics and obtain a reproducible testbed. A few models of the complement system have been developed, aiming to enhance our understanding of homeostasis and regulation [35][36][37][38][39][40][41]. Hirayama and co-workers [35] first studied CP activation by linear systems analysis to investigate its stability and controllability.…”

Section: Introductionmentioning

confidence: 99%

“…More recently, Sagar and colleagues [ 38 ] developed a reduced model for the LP and AP capable of mimicking C3a and C5a kinetics in vitro, but which did not describe the terminal pathway beyond the formation of the C5 convertase. Bakshi and co-workers [ 41 ] developed two parsimonious models of the AP that took into account the synthesis and degradation of precursors with the aim to understand the steady-state response of the pathway. A model of the AP and CP that aimed at including all relevant molecules and reactions was presented by Zewde and colleagues [ 39 , 40 ], describing pathway interactions with pathogen surfaces and host cells in an in vitro setting.…”

Section: Introductionmentioning

confidence: 99%

Modeling the activation of the alternative complement pathway and its effects on hemolysis in health and disease

Caruso

Vollmer²,

Macháček³

et al. 2020

PLoS Comput Biol

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The complement system is a powerful mechanism of innate immunity poised to eliminate foreign cells and pathogens. It is an intricate network of >35 proteins, which, once activated, leads to the tagging of the surface to be eliminated, produces potent chemoattractants to recruit immune cells, and inserts cytotoxic pores into nearby lipid surfaces. Although it can be triggered via different pathways, its net output is largely based on the direct or indirect activation of the alternative pathway. Complement dysregulation or deficiencies may cause severe pathologies, such as paroxysmal nocturnal hemoglobinuria (PNH), where a lack of complement control proteins leads to hemolysis and life-threatening anemia. The complexity of the system poses a challenge for the interpretation of experimental data and the design of effective pharmacological therapies. To address this issue, we developed a mathematical model of the alternative complement pathway building on previous modelling efforts. The model links complement activation to the hemolytic activity of the terminal alternative pathway, providing an accurate description of pathway activity as observed in vitro and in vivo, in health and disease. Through adjustment of the parameters describing experimental conditions, the model was capable of reproducing the results of an array of standard assays used in complement research. To demonstrate its clinical applicability, we compared model predictions with clinical observations of the recovery of hematological biomarkers in PNH patients treated with the complement inhibiting anti-C5 antibody eculizumab. In conclusion, the model can enhance the understanding of complement biology and its role in disease pathogenesis, help identifying promising targets for pharmacological intervention, and predict the outcome of complement-targeting pharmacological interventions.

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Mathematical Modelling of Alternative Pathway of Complement System

Cited by 7 publications

References 56 publications

Vitamin D deficiency leads to the abnormal activation of the complement system

Vitamin D deficiency leads to the abnormal activation of the complement system

Systems Biology Modeling of the Complement System Under Immune Susceptible Pathogens

Modeling the activation of the alternative complement pathway and its effects on hemolysis in health and disease

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