Modeling the activation of the alternative complement pathway and its effects on hemolysis in health and disease.
Journal
PLoS computational biology
ISSN: 1553-7358
Titre abrégé: PLoS Comput Biol
Pays: United States
ID NLM: 101238922
Informations de publication
Date de publication:
10 2020
10 2020
Historique:
received:
19
11
2019
accepted:
09
07
2020
entrez:
2
10
2020
pubmed:
3
10
2020
medline:
28
1
2021
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 33006965
doi: 10.1371/journal.pcbi.1008139
pii: PCOMPBIOL-D-19-02013
pmc: PMC7531836
doi:
Substances chimiques
Antibodies, Monoclonal, Humanized
0
Complement Inactivating Agents
0
eculizumab
A3ULP0F556
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1008139Déclaration de conflit d'intérêts
Antonello Caruso and Elod Kortvely are employees and shareholders of F. Hoffmann-La Roche AG. Jannik Vollmer and Matthias Machacek are employees of LYO-X.
Références
Science. 2005 Apr 15;308(5720):419-21
pubmed: 15761120
Nat Genet. 2016 Feb;48(2):134-43
pubmed: 26691988
J Am Soc Nephrol. 2013 Jan;24(1):53-65
pubmed: 23204401
Biochem J. 1986 May 1;235(3):723-30
pubmed: 3638964
Biosystems. 1996;39(3):173-85
pubmed: 8894121
Am J Blood Res. 2015 Jun 15;5(1):30-3
pubmed: 26171282
Am J Clin Pathol. 2015 Apr;143(4):558-65
pubmed: 25780008
Mol Immunol. 2013 Dec 15;56(3):232-9
pubmed: 23787367
Blood. 2017 Feb 23;129(8):970-980
pubmed: 28028023
Blood. 2005 Dec 1;106(12):3699-709
pubmed: 16051736
J Clin Invest. 1989 Jul;84(1):7-17
pubmed: 2738160
PLoS One. 2018 Jun 6;13(6):e0198644
pubmed: 29874282
J Immunol Methods. 2015 Feb;417:86-96
pubmed: 25536073
Proc Natl Acad Sci U S A. 2005 May 17;102(20):7227-32
pubmed: 15870199
Blood. 1991 Aug 1;78(3):820-9
pubmed: 1713516
Science. 2005 Apr 15;308(5720):385-9
pubmed: 15761122
Am J Hum Genet. 2005 Jul;77(1):149-53
pubmed: 15895326
Mol Immunol. 2017 Sep;89:111-114
pubmed: 28610663
PLoS One. 2016 Mar 31;11(3):e0152337
pubmed: 27031863
Proc Natl Acad Sci U S A. 1983 Sep;80(17):5430-4
pubmed: 6225118
Nat Genet. 2013 Apr;45(4):433-9, 439e1-2
pubmed: 23455636
Biochem Soc Trans. 2004 Feb;32(Pt 1):21-7
pubmed: 14748705
Nat Rev Nephrol. 2018 Jan;14(1):26-47
pubmed: 29199277
Mol Immunol. 2009 Sep;46(14):2753-66
pubmed: 19477527
Eur J Hum Genet. 2009 Jan;17(1):100-4
pubmed: 18685559
Infect Immun. 1977 Apr;16(1):124-8
pubmed: 406201
J Immunol. 1974 Jul;113(1):348-58
pubmed: 4134064
Eur J Haematol. 2013 Jan;90(1):16-24
pubmed: 23046169
FASEB J. 2018 Jan;32(1):123-129
pubmed: 28855277
Proc Natl Acad Sci U S A. 2011 May 24;108(21):8761-6
pubmed: 21555552
J Immunol. 2001 Feb 15;166(4):2635-42
pubmed: 11160326
J Biol Chem. 1998 Jul 3;273(27):16828-35
pubmed: 9642242
N Engl J Med. 2007 Aug 9;357(6):553-61
pubmed: 17634448
Infect Immun. 1975 Jun;11(6):1235-43
pubmed: 806523
PLoS Comput Biol. 2011 Jan 20;7(1):e1001059
pubmed: 21283780
PLoS One. 2017 Nov 20;12(11):e0187373
pubmed: 29155837
Semin Immunopathol. 2012 Jan;34(1):151-65
pubmed: 21811895
J Immunol Methods. 2015 Dec;427:13-8
pubmed: 26391915
Immunobiology. 2012 Nov;217(11):1080-7
pubmed: 22964233
Blood. 2007 Sep 15;110(6):2190-2
pubmed: 17554058
Dis Markers. 2015;2015:635670
pubmed: 26819490
Biochem Soc Trans. 2002 Nov;30(Pt 6):1006-10
pubmed: 12440962
Bull Math Biol. 2020 Feb 15;82(2):33
pubmed: 32062771
J Immunol. 2002 Nov 1;169(9):4702-6
pubmed: 12391176
Adv Exp Med Biol. 2013;735:155-72
pubmed: 23402025
Mol Immunol. 2018 Oct;102:89-119
pubmed: 30121124
Adv Exp Med Biol. 2010;703:9-24
pubmed: 20711704
In Vitro Cell Dev Biol. 1988 May;24(5):481-6
pubmed: 3286602
Cytometry. 2000 Aug 15;42(4):223-33
pubmed: 10934341
Nat Genet. 2007 Oct;39(10):1200-1
pubmed: 17767156
J Biol Chem. 1984 Jun 25;259(12):7857-63
pubmed: 6736027
Immunol Rev. 2008 Jun;223:300-16
pubmed: 18613844
Blood. 2015 Jul 9;126(2):278-9
pubmed: 26160188
Nat Biotechnol. 2007 Nov;25(11):1256-64
pubmed: 17989688
Nat Genet. 2006 Apr;38(4):458-62
pubmed: 16518403
Math Biosci. 2009 Dec;222(2):127-43
pubmed: 19854207
J Exp Med. 1981 Sep 1;154(3):856-67
pubmed: 6912277
Blood Transfus. 2017 Mar;15(2):182-187
pubmed: 28263177
Biochemistry. 1983 Jan 4;22(1):178-85
pubmed: 6219696
Microbiol Immunol. 1986;30(5):461-8
pubmed: 3747864
Philos Trans R Soc Lond B Biol Sci. 2017 Aug 5;372(1726):
pubmed: 28630159
Science. 2005 Apr 15;308(5720):421-4
pubmed: 15761121
Ann N Y Acad Sci. 1983;421:291-8
pubmed: 6586103
J Exp Med. 1977 Jul 1;146(1):22-33
pubmed: 559720
J Virol. 2004 Sep;78(17):9446-57
pubmed: 15308738
Clin Exp Immunol. 1975 Jul;21(1):109-14
pubmed: 52423
Cell Tissue Res. 2011 Jan;343(1):227-35
pubmed: 20838815
MAbs. 2015;7(1):110-9
pubmed: 25530170
Blood Res. 2017 Sep;52(3):207-211
pubmed: 29043236
Clin Exp Immunol. 2004 Dec;138(3):439-46
pubmed: 15544620
Nat Commun. 2016 Feb 04;7:10587
pubmed: 26841837
Nat Biotechnol. 2007 Nov;25(11):1265-75
pubmed: 17989689
Clin Diagn Lab Immunol. 2003 Nov;10(6):982-9
pubmed: 14607856
J Appl Physiol (1985). 2001 Feb;90(2):511-9
pubmed: 11160049
Scand J Immunol. 1992 Jul;36(1):79-87
pubmed: 1535452
J Immunol. 2018 Apr 15;200(8):2786-2797
pubmed: 29531168
Proc Natl Acad Sci U S A. 1983 Aug;80(16):5066-70
pubmed: 6576376