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Abrogation of immune complex glomerulonephritis by native carboxypeptidase and pharmacological antagonism of the C5a receptor
Activation of complement generates C5a which leads to signaling through C5aR1. This is tightly controlled, including by the plasma proteins factor H (FH) and carboxypeptidase N. Here we studied a chronic serum sickness (CSS) model of glomerulonephritis (GN) in which there is an active humoral immune...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5037280/ https://www.ncbi.nlm.nih.gov/pubmed/26166765 http://dx.doi.org/10.1038/cmi.2015.45 |
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author | Alexander, Jessy J. Chaves, Lee D. Chang, Anthony Dighe, Shruti Jacob, Alexander Quigg, Richard J. |
author_facet | Alexander, Jessy J. Chaves, Lee D. Chang, Anthony Dighe, Shruti Jacob, Alexander Quigg, Richard J. |
author_sort | Alexander, Jessy J. |
collection | PubMed |
description | Activation of complement generates C5a which leads to signaling through C5aR1. This is tightly controlled, including by the plasma proteins factor H (FH) and carboxypeptidase N. Here we studied a chronic serum sickness (CSS) model of glomerulonephritis (GN) in which there is an active humoral immune response, formation of glomerular immune complexes (ICs), and resulting glomerular inflammation. The antibody response, glomerular IC deposition, the degree of GN, and consequent renal functional insufficiency in CSS were all worse in FH−/− mice compared to wild-type FH+/+ animals. This was ameliorated in the former by giving a C5aR1 antagonist for the final 3 weeks of the 5-week protocol. In contrast, blocking CP-mediated inactivation of C5a increased these disease measures. Thus, complement regulation by both plasma FH and CP to limit the quantity of active C5a is important in conditions where the humoral immune response is directed to a continuously present foreign antigen. Signaling through C5aR1 enhances the humoral immune response as well as the inflammatory response to ICs that have formed in glomeruli. Both effects are relevant even after disease has begun. Thus, pharmacological targeting of C5a in IC-mediated GN has potential clinical relevance. |
format | Online Article Text |
id | pubmed-5037280 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-50372802016-10-04 Abrogation of immune complex glomerulonephritis by native carboxypeptidase and pharmacological antagonism of the C5a receptor Alexander, Jessy J. Chaves, Lee D. Chang, Anthony Dighe, Shruti Jacob, Alexander Quigg, Richard J. Cell Mol Immunol Research Article Activation of complement generates C5a which leads to signaling through C5aR1. This is tightly controlled, including by the plasma proteins factor H (FH) and carboxypeptidase N. Here we studied a chronic serum sickness (CSS) model of glomerulonephritis (GN) in which there is an active humoral immune response, formation of glomerular immune complexes (ICs), and resulting glomerular inflammation. The antibody response, glomerular IC deposition, the degree of GN, and consequent renal functional insufficiency in CSS were all worse in FH−/− mice compared to wild-type FH+/+ animals. This was ameliorated in the former by giving a C5aR1 antagonist for the final 3 weeks of the 5-week protocol. In contrast, blocking CP-mediated inactivation of C5a increased these disease measures. Thus, complement regulation by both plasma FH and CP to limit the quantity of active C5a is important in conditions where the humoral immune response is directed to a continuously present foreign antigen. Signaling through C5aR1 enhances the humoral immune response as well as the inflammatory response to ICs that have formed in glomeruli. Both effects are relevant even after disease has begun. Thus, pharmacological targeting of C5a in IC-mediated GN has potential clinical relevance. Nature Publishing Group 2016-09 2015-07-13 /pmc/articles/PMC5037280/ /pubmed/26166765 http://dx.doi.org/10.1038/cmi.2015.45 Text en Copyright © 2016 Chinese Society of Immunology and The University of Science and Technology http://creativecommons.org/licenses/by-nc-nd/3.0/legalcode This license allows readers to copy, distribute and transmit the Contribution as long as it is attributed back to the author. Readers may not alter, transform or build upon the Contribution, or use the article for commercial purposes. Please read the full legal code for further details at http://creativecommons.org/licenses/by-nc-nd/3.0/legalcode |
spellingShingle | Research Article Alexander, Jessy J. Chaves, Lee D. Chang, Anthony Dighe, Shruti Jacob, Alexander Quigg, Richard J. Abrogation of immune complex glomerulonephritis by native carboxypeptidase and pharmacological antagonism of the C5a receptor |
title | Abrogation of immune complex glomerulonephritis by native carboxypeptidase and pharmacological antagonism of the C5a receptor |
title_full | Abrogation of immune complex glomerulonephritis by native carboxypeptidase and pharmacological antagonism of the C5a receptor |
title_fullStr | Abrogation of immune complex glomerulonephritis by native carboxypeptidase and pharmacological antagonism of the C5a receptor |
title_full_unstemmed | Abrogation of immune complex glomerulonephritis by native carboxypeptidase and pharmacological antagonism of the C5a receptor |
title_short | Abrogation of immune complex glomerulonephritis by native carboxypeptidase and pharmacological antagonism of the C5a receptor |
title_sort | abrogation of immune complex glomerulonephritis by native carboxypeptidase and pharmacological antagonism of the c5a receptor |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5037280/ https://www.ncbi.nlm.nih.gov/pubmed/26166765 http://dx.doi.org/10.1038/cmi.2015.45 |
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