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Complement activity is regulated in C3 glomerulopathy by IgG–factor H fusion proteins with and without properdin targeting domains
C3 glomerulopathy is characterized by accumulation of complement C3 within glomeruli. Causes include, but are not limited to, abnormalities in factor H, the major negative regulator of the complement alternative pathway. Factor H-deficient (Cfh(-/-)) mice develop C3 glomerulopathy together with a re...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7863913/ https://www.ncbi.nlm.nih.gov/pubmed/33129896 http://dx.doi.org/10.1016/j.kint.2020.09.028 |
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author | Gilmore, Alyssa C. Zhang, Yuchun Cook, H. Terence Lavin, Deborah P. Katti, Suresh Wang, Yi Johnson, Krista K. Kim, SungKwon Pickering, Matthew C. |
author_facet | Gilmore, Alyssa C. Zhang, Yuchun Cook, H. Terence Lavin, Deborah P. Katti, Suresh Wang, Yi Johnson, Krista K. Kim, SungKwon Pickering, Matthew C. |
author_sort | Gilmore, Alyssa C. |
collection | PubMed |
description | C3 glomerulopathy is characterized by accumulation of complement C3 within glomeruli. Causes include, but are not limited to, abnormalities in factor H, the major negative regulator of the complement alternative pathway. Factor H-deficient (Cfh(-/-)) mice develop C3 glomerulopathy together with a reduction in plasma C3 levels. Using this model, we assessed the efficacy of two fusion proteins containing the factor H alternative pathway regulatory domains (FH(1-5)) linked to either a non-targeting mouse immunoglobulin (IgG-FH(1-5)) or to an anti-mouse properdin antibody (Anti-P-FH(1-5)). Both proteins increased plasma C3 and reduced glomerular C3 deposition to an equivalent extent, suggesting that properdin-targeting was not required for FH(1-5) to alter C3 activation in either plasma or glomeruli. Following IgG-FH(1-5) administration, plasma C3 levels temporally correlated with changes in factor B levels whereas plasma C5 levels correlated with changes in plasma properdin levels. Notably, the increases in plasma C5 and properdin levels persisted for longer than the increases in C3 and factor B. In Cfh(-/-) mice IgG-FH(1-5) reduced kidney injury during accelerated serum nephrotoxic nephritis. Thus, our data demonstrate that IgG-FH(1-5) restored circulating alternative pathway activity and reduced glomerular C3 deposition in Cfh(-/-) mice and that plasma properdin levels are a sensitive marker of C5 convertase activity in factor H deficiency. The immunoglobulin conjugated FH(1-5) protein, through its comparatively long plasma half-life, may be a potential therapy for C3 glomerulopathy. |
format | Online Article Text |
id | pubmed-7863913 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-78639132021-02-16 Complement activity is regulated in C3 glomerulopathy by IgG–factor H fusion proteins with and without properdin targeting domains Gilmore, Alyssa C. Zhang, Yuchun Cook, H. Terence Lavin, Deborah P. Katti, Suresh Wang, Yi Johnson, Krista K. Kim, SungKwon Pickering, Matthew C. Kidney Int Basic Research C3 glomerulopathy is characterized by accumulation of complement C3 within glomeruli. Causes include, but are not limited to, abnormalities in factor H, the major negative regulator of the complement alternative pathway. Factor H-deficient (Cfh(-/-)) mice develop C3 glomerulopathy together with a reduction in plasma C3 levels. Using this model, we assessed the efficacy of two fusion proteins containing the factor H alternative pathway regulatory domains (FH(1-5)) linked to either a non-targeting mouse immunoglobulin (IgG-FH(1-5)) or to an anti-mouse properdin antibody (Anti-P-FH(1-5)). Both proteins increased plasma C3 and reduced glomerular C3 deposition to an equivalent extent, suggesting that properdin-targeting was not required for FH(1-5) to alter C3 activation in either plasma or glomeruli. Following IgG-FH(1-5) administration, plasma C3 levels temporally correlated with changes in factor B levels whereas plasma C5 levels correlated with changes in plasma properdin levels. Notably, the increases in plasma C5 and properdin levels persisted for longer than the increases in C3 and factor B. In Cfh(-/-) mice IgG-FH(1-5) reduced kidney injury during accelerated serum nephrotoxic nephritis. Thus, our data demonstrate that IgG-FH(1-5) restored circulating alternative pathway activity and reduced glomerular C3 deposition in Cfh(-/-) mice and that plasma properdin levels are a sensitive marker of C5 convertase activity in factor H deficiency. The immunoglobulin conjugated FH(1-5) protein, through its comparatively long plasma half-life, may be a potential therapy for C3 glomerulopathy. Elsevier 2021-02 /pmc/articles/PMC7863913/ /pubmed/33129896 http://dx.doi.org/10.1016/j.kint.2020.09.028 Text en © 2020 International Society of Nephrology. Published by Elsevier Inc. http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Basic Research Gilmore, Alyssa C. Zhang, Yuchun Cook, H. Terence Lavin, Deborah P. Katti, Suresh Wang, Yi Johnson, Krista K. Kim, SungKwon Pickering, Matthew C. Complement activity is regulated in C3 glomerulopathy by IgG–factor H fusion proteins with and without properdin targeting domains |
title | Complement activity is regulated in C3 glomerulopathy by IgG–factor H fusion proteins with and without properdin targeting domains |
title_full | Complement activity is regulated in C3 glomerulopathy by IgG–factor H fusion proteins with and without properdin targeting domains |
title_fullStr | Complement activity is regulated in C3 glomerulopathy by IgG–factor H fusion proteins with and without properdin targeting domains |
title_full_unstemmed | Complement activity is regulated in C3 glomerulopathy by IgG–factor H fusion proteins with and without properdin targeting domains |
title_short | Complement activity is regulated in C3 glomerulopathy by IgG–factor H fusion proteins with and without properdin targeting domains |
title_sort | complement activity is regulated in c3 glomerulopathy by igg–factor h fusion proteins with and without properdin targeting domains |
topic | Basic Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7863913/ https://www.ncbi.nlm.nih.gov/pubmed/33129896 http://dx.doi.org/10.1016/j.kint.2020.09.028 |
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