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Complement Factor I: regulatory nexus, driver of immunopathology, and therapeutic

Lookup NU author(s): Dr Thomas Hallam, Anneliza Andreadi, Professor David KavanaghORCiD



This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).


Complement factor I (FI) is the nexus for classical, lectin and alternative pathwaycomplement regulation. FI is an 88kDa plasma protein that circulates in an inactiveconfiguration until it forms a trimolecular complex with its cofactor and substratewhereupon a structural reorganization allows the catalytic triad to cleave its substrates,C3b and C4b. In keeping with its role as the master complement regulatory enzyme,deficiency has been linked to immunopathology. In the setting of complete FIdeficiency, a consumptive C3 deficiency results in recurrent infections withencapsulated microorganisms. Aseptic cerebral inflammation and vasculiticpresentations are also less commonly observed. Heterozygous mutations in the factor Igene (CFI) have been demonstrated to be enriched in atypical haemolytic uraemicsyndrome, albeit with a very low penetrance. Haploinsufficiency of CFI has also beenassociated with decreased retinal thickness and is a strong risk factor for thedevelopment of age-related macular degeneration.Supplementation of complement FI using plasma purified or recombinant protein haslong been postulated, however, technical difficulties prevented progression into clinicaltrials. It is only using gene therapy that CFI supplementation has reached the clinic withGT005 in phase I/II clinical trials for geographic atrophy.

Publication metadata

Author(s): Hallam T, Sharp S, Andreadi A, Kavanagh D

Publication type: Article

Publication status: Published

Journal: Immunobiology

Year: 2023

Volume: 228

Issue: 5

Print publication date: 01/09/2023

Online publication date: 05/06/2023

Acceptance date: 01/06/2023

Date deposited: 14/07/2023

ISSN (print): 0171-2985

ISSN (electronic): 1878-3279

Publisher: Elsevier GmbH


DOI: 10.1016/j.imbio.2023.152410


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Funder referenceFunder name
Complement UK
Fight for Sight
Macular Society
Medical Research Council
Kidney Research UK
Wellcome Trust