| dc.identifier.uri | http://hdl.handle.net/11401/76496 | |
| dc.description.sponsorship | This work is sponsored by the Stony Brook University Graduate School in compliance with the requirements for completion of degree. | en_US |
| dc.format | Monograph | |
| dc.format.medium | Electronic Resource | en_US |
| dc.language.iso | en_US | |
| dc.publisher | The Graduate School, Stony Brook University: Stony Brook, NY. | |
| dc.type | Dissertation | |
| dcterms.abstract | The complement system is tightly regulated in order 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, and complexes could function as a passive mechanism to intercept C3b from depositing on host cells. Several different plasma proteins displayed a discrete high molecular weight, 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 by hydroxylamine treatment also prevented formation of these complexes. In vitro, complexes could be generated using four purified proteins: C3, factor B, factor D and a target protein along with Mg2+ to allow formation of the C3 convertase. These studies showed that the complexes consisted of a plasma protein covalently bound to C3b in a 1:1 molar ratio. Moreover, the C3b portion of the complexes was rapidly degraded by factors H and I, and complexes formed spontaneously in factor H and factor I depleted serum, indicating that loss of complement regulation facilitates complex formation. Thus, plasma samples from individuals with diseases of fluid phase complement dysregulation were examined. C3b:protein complexes were detected in the blood of patients with dense deposit disease (DDD) and to a lesser extent in C3 glomerulonephritis (C3GN) patients, but not in healthy controls. This finding supports the premise that these two C3 glomerulopathies are fluid-phase diseases of complement dysregulation. It is also possible that excessive generation and/or defective clearance of fluid-phase C3b:protein complexes contributes to the disease pathogenesis. Finally, in contrast to proteins in the native state, C3b more readily attaches to plasma proteins in their non-native unfolded state (chemically or thermally denatured), suggesting that C3 functions as an extracellular chaperone. Circulating C3b:protein complexes could be diagnostic and/or pathogenic in certain conditions of complement dysregulation. | |
| dcterms.available | 2017-09-20T16:50:26Z | |
| dcterms.contributor | Furie, Martha | en_US |
| dcterms.contributor | Kew, Richard R. | en_US |
| dcterms.contributor | Ghebrehiwet, Berhane | en_US |
| dcterms.contributor | Koller, Antonius | en_US |
| dcterms.contributor | Kaplan, Allen. | en_US |
| dcterms.creator | Ramadass, Mahalakshmi | |
| dcterms.dateAccepted | 2017-09-20T16:50:26Z | |
| dcterms.dateSubmitted | 2017-09-20T16:50:26Z | |
| dcterms.description | Department of Molecular and Cellular Biology. | en_US |
| dcterms.extent | 150 pg. | en_US |
| dcterms.format | Monograph | |
| dcterms.format | Application/PDF | en_US |
| dcterms.identifier | http://hdl.handle.net/11401/76496 | |
| dcterms.issued | 2015-08-01 | |
| dcterms.language | en_US | |
| dcterms.provenance | Made available in DSpace on 2017-09-20T16:50:26Z (GMT). No. of bitstreams: 1
Ramadass_grad.sunysb_0771E_11500.pdf: 92285977 bytes, checksum: e7369d8e890d94c263dedbdd247f5163 (MD5)
Previous issue date: 2013 | en |
| dcterms.publisher | The Graduate School, Stony Brook University: Stony Brook, NY. | |
| dcterms.subject | Immunology | |
| dcterms.subject | C3, C3 Glomerulopathies, Complement, Dense Deposit Disease, Extracellular chaperone, Thioester | |
| dcterms.title | Generation of Multiple Fluid-Phase C3b:Plasma Protein Complexes During Complement Activation. Functional Significance and Possible Implications in C3 Glomerulopathies | |
| dcterms.type | Dissertation | |
