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Factor H facilitates the clearance of GBM bound iC3b by controlling C3 activation in fluid phase

Dense deposit disease (DDD) is strongly associated with the uncontrolled activation of the complement alternative pathway. Factor H (CFH)-deficient (Cfh(−/−)) mice spontaneously develop C3 deposition along the glomerular basement membrane (GBM) with subsequent development of glomerulonephritis with...

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Autores principales: Paixão-Cavalcante, Danielle, Hanson, Steven, Botto, Marina, Cook, H. Terence, Pickering, Matthew C.
Formato: Texto
Lenguaje:English
Publicado: Pergamon Press 2009
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2697322/
https://www.ncbi.nlm.nih.gov/pubmed/19411110
http://dx.doi.org/10.1016/j.molimm.2009.03.030
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author Paixão-Cavalcante, Danielle
Hanson, Steven
Botto, Marina
Cook, H. Terence
Pickering, Matthew C.
author_facet Paixão-Cavalcante, Danielle
Hanson, Steven
Botto, Marina
Cook, H. Terence
Pickering, Matthew C.
author_sort Paixão-Cavalcante, Danielle
collection PubMed
description Dense deposit disease (DDD) is strongly associated with the uncontrolled activation of the complement alternative pathway. Factor H (CFH)-deficient (Cfh(−/−)) mice spontaneously develop C3 deposition along the glomerular basement membrane (GBM) with subsequent development of glomerulonephritis with features of DDD, a lesion dependent on C3 activation. In order to understand the role of CFH in preventing renal damage associated with the dysregulation of the alternative pathway we administered purified mouse CFH (mCFH) to Cfh(−/−) mice. 24 h following the administration of mCFH we observed an increase in plasma C3 levels with presence of intact C3 in circulation showing that mCFH restored control of C3 activation in fluid phase. mCFH resulted in the reduction of iC3b deposition along the GBM. The exogenous mCFH was readily detectable in plasma but critically not in association with C3 along the GBM. Thus, the reduction in GBM C3 was dependent on the ability of mCFH to regulate C3 activation in plasma. Western blot analysis of glomeruli from Cfh(−/−) mice demonstrated the presence of iC3b. Our data show that the C3 along the GBM in Cfh(−/−) mice is the C3 fragment iC3b and that this is derived from plasma C3 activation. The implication is that successful therapy of DDD is likely to be achieved by therapies that inhibit C3 turnover in plasma.
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spelling pubmed-26973222009-06-23 Factor H facilitates the clearance of GBM bound iC3b by controlling C3 activation in fluid phase Paixão-Cavalcante, Danielle Hanson, Steven Botto, Marina Cook, H. Terence Pickering, Matthew C. Mol Immunol Article Dense deposit disease (DDD) is strongly associated with the uncontrolled activation of the complement alternative pathway. Factor H (CFH)-deficient (Cfh(−/−)) mice spontaneously develop C3 deposition along the glomerular basement membrane (GBM) with subsequent development of glomerulonephritis with features of DDD, a lesion dependent on C3 activation. In order to understand the role of CFH in preventing renal damage associated with the dysregulation of the alternative pathway we administered purified mouse CFH (mCFH) to Cfh(−/−) mice. 24 h following the administration of mCFH we observed an increase in plasma C3 levels with presence of intact C3 in circulation showing that mCFH restored control of C3 activation in fluid phase. mCFH resulted in the reduction of iC3b deposition along the GBM. The exogenous mCFH was readily detectable in plasma but critically not in association with C3 along the GBM. Thus, the reduction in GBM C3 was dependent on the ability of mCFH to regulate C3 activation in plasma. Western blot analysis of glomeruli from Cfh(−/−) mice demonstrated the presence of iC3b. Our data show that the C3 along the GBM in Cfh(−/−) mice is the C3 fragment iC3b and that this is derived from plasma C3 activation. The implication is that successful therapy of DDD is likely to be achieved by therapies that inhibit C3 turnover in plasma. Pergamon Press 2009-06 /pmc/articles/PMC2697322/ /pubmed/19411110 http://dx.doi.org/10.1016/j.molimm.2009.03.030 Text en © 2009 Elsevier Ltd. https://creativecommons.org/licenses/by/3.0/ Open Access under CC BY 3.0 (https://creativecommons.org/licenses/by/3.0/) license
spellingShingle Article
Paixão-Cavalcante, Danielle
Hanson, Steven
Botto, Marina
Cook, H. Terence
Pickering, Matthew C.
Factor H facilitates the clearance of GBM bound iC3b by controlling C3 activation in fluid phase
title Factor H facilitates the clearance of GBM bound iC3b by controlling C3 activation in fluid phase
title_full Factor H facilitates the clearance of GBM bound iC3b by controlling C3 activation in fluid phase
title_fullStr Factor H facilitates the clearance of GBM bound iC3b by controlling C3 activation in fluid phase
title_full_unstemmed Factor H facilitates the clearance of GBM bound iC3b by controlling C3 activation in fluid phase
title_short Factor H facilitates the clearance of GBM bound iC3b by controlling C3 activation in fluid phase
title_sort factor h facilitates the clearance of gbm bound ic3b by controlling c3 activation in fluid phase
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2697322/
https://www.ncbi.nlm.nih.gov/pubmed/19411110
http://dx.doi.org/10.1016/j.molimm.2009.03.030
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