BioModelsapplication/xmlhttps://www.ebi.ac.uk/biomodels/model/download/MODEL2109110001?filename=Caruso2020.xmlhttps://www.ebi.ac.uk/biomodels/model/download/MODEL2109110001?filename=Caruso2020.cpsprimaryOK200Emilia ChenNon-curatedordinary differential equation modelL2V4https://www.ebi.ac.uk/biomodels/MODEL210911000133006965falseBioModelsSBMLModelsCaruso2020 Activation of the alternative complement pathway and effects on hemolysis2020MODEL2109110001Caruso A, Vollmer J, Machacek M, Kortvely ECaruso A33006965,
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.. 10, 16.
Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland.
LYO-X GmbH, Allschwil, Switzerland.
Roche Pharma Research and Early Development, Immunology, Infectious Diseases and Ophthalmology (I2O) Discovery and Translational Area, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland.emiliachen1@gmail.comUniversity of CambridgeThe 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.Modeling the activation of the alternative complement pathway and its effects on hemolysis in health and disease.Caruso Antonello A, Vollmer Jannik J, Machacek Matthias M, Kortvely Elod EExtravascular Hemolysis, Hemolysis, Intravascular, Intravascular Hemolysis, Hemolyses, Intravascular Hemolyses, Haemolysis, Extravascular Hemolyses, Haemolyses., hemolysis, Extravascular, activation, hemolyticthe fern with tired blood, Biological Markers, Viral Marker, Intravascular Hemolyses, Surrogate Endpoints, Activity, PNH, Laboratory, nonspecific immune response, NetrinA, Addresses, D430049E23Rik, Biochemical, positive regulation by symbiont of host non-apoptotic programmed cell death, Endpoint, MQD19_17, B-cell receptor complex, ZWILLE, Serum, PINHEAD, Laboratory Markers, Readability, DSmurf, diseases, Roles, Biological, hemolysis by symbiont of host RBCs, Concepts, pathogenesis, diseases and disorders, Research Activity, H5G1.1VHC+H5G1.1VLC, Laboratory Research, integumentum commune, Priorities, average, modification by symbiont of host biological process, Elkh, human disease, reference sample, stimulation by symbiont of host programmed cell death, membrane bound, entire life cycle, EK6, proteins, Sap-2, activation by organism of programmed cell death in other organism during symbiotic interaction, neuroendocrine tumour, Immune, Markers, Solute carrier family 6 member 2, complement activity, Smurf, Viral Markers, Pathologies, Role Concepts, CT27014, NET1, SLC6A5, Homo sapiens disease, Research Priority, cytolysis by organism of host cells, netA, B-lymphocyte receptor complex, Extravascular, CG4943, D-smurf, Intravascular Hemolysis, Elk, ELK, Viral, external covering of organism, Surrogate Endpoint, Neuronally-expressed EPH-related tyrosine kinase, Research Priorities, H5G11, organism surface, SAP2, Biochemical Markers, 9330129L11, Normalcy, Lack, Procedure, antibodies, Biologic Marker, positive regulation by symbiont of host programmed cell death, results, neuroendocrine neoplasm, Hemolysis, Anemia, Role Concept, enhancement of host programmed cell death, Norepinephrine transporter, Marker, Lipid, anemia, hereditary paroxysmal nocturnal hemoglobinuria, Diseases, Role, modulation by symbiont of host system process, EPH-like kinase 6, Individual, ARGONAUTE PROTEIN 10, activation, haemolysis in host, Research and Development, End Points, 5G1.1, DmelCG4943, Complement, life, perturbation by symbiont of host defense response, Immunologic, hEK6, Laboratory Marker, induction by organism of programmed cell death in other organism during symbiotic interaction, hemolytic, modification by symbiont of host morphology or physiology, experimental procedures, organ system, Activities, Marchiafava-Micheli disease, Intravascular, disease, regulation of cytolysis of host cells by symbiont, DmelCG18657, immunoglobulin, MQD19.17, Health, B cell receptor accessory molecule complex, induction by symbiont of host programmed cell death, Patient, integumentary system, Biochemical Marker, hemolysis by symbiont of host red blood cells, activation by symbiont of host programmed cell death, B lymphocyte receptor complex, paroxysmal hemoglobinuria, complement response, Activations, microarray, anaemia (disease), dermal system, anemia (disease), AW488255, lipids, other disease, lifespan, experimental, Clinical Markers, Clinical Marker, dSmurf1, hemolysis, regulation by symbiont of host system process, modulation by organism of defense response of other organism involved in symbiotic interaction, Gene, Normalcies, body system, netrin, Surrogate End Points, Intervention or Procedure, Surrogate Markers, antibody, surface, Hemolyses, BCR complex, Hek6, induction by organism of non-apoptotic programmed cell death in other organism during symbiotic interaction, Gene Products, disease or disorder, Cek6, system, immunoglobulin complex, ENSMUSG00000074119, upregulation by symbiont of host programmed cell death, Extravascular Hemolysis, Normalities, Erp, APUDoma, ERP, Biomarker, induction of non-apoptotic programmed cell death by other organism, anatomical systems, methods, Clinical, Activation, Research, interventionDescription, entire lifespan, experimental section, Biological Marker, Tyrosine-protein kinase receptor EPH-2, Interventional, non-neoplastic, Immunologic Markers, 2.7.10.1, d-smurf, Anemias, SURGICAL AND MEDICAL PROCEDURES., Etrp, Clients, Haemolyses, disorder, NAT1, Development and Research, Immunologic Marker, Net, NET, AGO10, Biologic, Controlled, Individual Health, Intervention Strategies, Controlling, data, C130099E04Rik, disruption by symbiont of host cell, activation by organism of non-apoptotic programmed cell death in other organism, hemolysin activity, Alexion, Proteins, Serum Markers, EPH tyrosine kinase 2, disorders, H5G1.1, End Point, innate immunity, medical condition, neuroendocrine tumor, Dsmurf, net, inherited paroxysmal nocturnal hemoglobinuria, Client, Cell, Immune Marker, Concept, dSmurf, Elizaria, Priority, Surrogate End Point, Smurf ubiquitin ligase, Protein, complement cascade, Research Activities, modulation by symbiont of host defense response, Soliris, condition, H5G1-1, connected anatomical system, induction by organism of programmed cell death in other organism involved in symbiotic interaction, mitigation by symbiont of host defense response, Biologic Markers, opsonin activity, Intervention, Serum Marker, enhancement of host programmed cell death by organism, Normality, body surface, Extravascular Hemolyses, Surrogate, Endpoints, Complement Activations, Mohria, Understanding, CG18657, Surrogate Marker, Protein Gene Products, Gene Proteins, activation by organism of host programmed cell death, EPHT2, Haemolysis, ARGONAUTE 10, B cell receptor activity, acquired paroxysmal nocturnal hemoglobinuria, netrin A, General activity, Immune Markersprojections, OCT, Individual Health, Intravascular Hemolysis, other disease, PlexA2, Intravascular Hemolyses, anatomical protrusion, PLXN2, lamellae, hemolysis, anatomical process, disorders, lamina, flanges, medical condition, Normalcy, Normalcies, AA589422, process of organ, DOI, Hemolysis, Commentary, protrusion, Publication., lamella, Hemolyses, AW457381, Publication, diseases, Diseases, shelf, disease or disorder, condition, diseases and disorders, Individual, activation, flange, organ process, doi, Extravascular Hemolysis, Normalities, average, human disease, Normality, Extravascular Hemolyses, shelves, 2810428A13Rik, ridges, projection, ridge, hemolytic, non-neoplastic, Intravascular, processes, process, disease, Health, Haemolysis, spine, papilla, Haemolyses, disorder, processus, Homo sapiens disease, Viewpoint, Editorial Comment, laminae, Plxn2, Extravascular, mKIAA0463Extravascular Hemolysis, Normalities, average, Individual Health, Intravascular Hemolysis, other disease, human disease, Intravascular Hemolyses, Normality, Extravascular Hemolyses, hemolysis, disorders, Normalcy, Normalcies, hemolytic, Hemolysis, non-neoplastic, Intravascular, disease, Hemolyses, Health, diseases, Haemolysis, Haemolyses, Diseases, disease or disorder, condition, disorder, Homo sapiens disease, diseases and disorders, medical condition., Individual, Extravascular, activationfalseCaruso2020 - Activation of the alternative complement pathway and effects on hemolysis
This model is based on the publication:
Caruso A, Vollmer J, Machacek M, Kortvely E. "Modeling the activation of the alternative complement pathway and its effects on hemolysis in health and disease." PLoS Comput Biol. 2020 Oct 2;16(10):e1008139.
doi: 10.1371/journal.pcbi.1008139
Curation Comment:
Figure 4 has not been able to be reproduced, however authors are in the process of appending the model code to the publication.
2021-09-112021-09-112021-09-11MODEL210911000133006965PW:0000505GO:0045087GO:00304519606BTO:0000089