Journal article
Generation of multiple fluid-phase C3b:plasma protein complexes during complement activation: possible implications in C3 glomerulopathies
The Journal of immunology (1950), Vol.192(3), pp.1220-1230
02/01/2014
DOI: 10.4049/jimmunol.1302288
PMCID: PMC3897554
PMID: 24367026
Abstract
The complement system is tightly regulated to safeguard against tissue damage that results from unwanted activation. The key step of C3 cleavage to C3b is regulated by multiple mechanisms that control the initiation and extent of activation. This study demonstrated that C3b:plasma protein complexes form in the fluid-phase during complement activation. Several different plasma proteins displayed a discrete high molecular SDS-resistant band when any of the three complement activating pathways were triggered in normal human serum or plasma. Serum depleted of individual complement proteins revealed that C3 and factors B and D were essential for complex formation. Inactivation of the thioester bond in C3 also prevented complex formation. In vitro, complexes could be generated using four purified proteins-C3, factor B, factor D, and target protein-and Mg(2+) to allow C3 convertase formation. These studies showed that the complexes consisted of a plasma protein covalently bound to C3b in a 1:1 molar ratio; the C3b portion was rapidly degraded by factors H and I. Analysis of plasma samples from patients with dense deposit disease and C3 glomerulonephritis demonstrated that C3b:protein complexes form spontaneously in the blood of patients with dense deposit disease and, to a lesser extent, in C3 glomerulonephritis patients, but not in healthy controls. This finding supports the underlying hypothesis that these C3 glomerulopathies are diseases of fluid-phase complement dysregulation. These complexes could normally function as a passive mechanism to intercept C3b from depositing on host cells. However, excessive generation and/or defective clearance of fluid-phase C3b:protein complexes may have pathological consequences.
Details
- Title: Subtitle
- Generation of multiple fluid-phase C3b:plasma protein complexes during complement activation: possible implications in C3 glomerulopathies
- Creators
- Mahalakshmi Ramadass - Department of Pathology, Stony Brook University School of Medicine, Stony Brook, NY 11794Berhane GhebrehiwetRichard J SmithRichard R Kew
- Resource Type
- Journal article
- Publication Details
- The Journal of immunology (1950), Vol.192(3), pp.1220-1230
- DOI
- 10.4049/jimmunol.1302288
- PMID
- 24367026
- PMCID
- PMC3897554
- NLM abbreviation
- J Immunol
- ISSN
- 0022-1767
- eISSN
- 1550-6606
- Publisher
- United States
- Grant note
- AI084178 / NIAID NIH HHS R01 GM063769 / NIGMS NIH HHS R56 GM063769 / NIGMS NIH HHS GM063769 / NIGMS NIH HHS R56 AI060866 / NIAID NIH HHS R01 AI084178 / NIAID NIH HHS AI060866 / NIAID NIH HHS R01 AI060866 / NIAID NIH HHS
- Language
- English
- Date published
- 02/01/2014
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Molecular Physiology and Biophysics; Anatomy and Cell Biology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Otolaryngology; Internal Medicine
- Record Identifier
- 9984006466502771
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