| Content Provider |
World Health Organization (WHO)-Global Index Medicus |
| Author |
Anliker, Markus Lambris, John D. Schmidt, Christoph Q. Höchsmann, Britta Schrezenmeier, Hubert Barlow, Paul N. Simmet, Thomas Ricklin, Daniel Harder, Markus J. Huber-Lang, Markus |
| Description |
Author Affiliation: Harder MJ ( Institute of Pharmacology of Natural Products and Clinical Pharmacology, Ulm University, 89081 Ulm, Germany); Anliker M ( Institute of Transfusion Medicine, University of Ulm, 89081 Ulm, Germany); Höchsmann B ( Institute of Transfusion Medicine, University of Ulm, 89081 Ulm, Germany); Simmet T ( Institute of Pharmacology of Natural Products and Clinical Pharmacology, Ulm University, 89081 Ulm, Germany); Huber-Lang M ( Department of Traumatology, Center of Surgery, University of Ulm, 89081 Ulm, Germany); Schrezenmeier H ( Institute of Transfusion Medicine, University of Ulm, 89081 Ulm, Germany); Ricklin D ( Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19102); Lambris JD ( Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19102); Barlow PN ( School of Chemistry, University of Edinburgh, Edinburgh EH9 3JJ, United Kingdom); Schmidt CQ ( Institute of Pharmacology of Natural Products and Clinical Pharmacology, Ulm University, 89081 Ulm, Germany) |
| Abstract |
The serum proteins factor H (FH), consisting of 20 complement control protein modules (CCPs), and its splice product FH-like protein 1 (FHL-1; consisting of CCPs 1-7) are major regulators of the alternative pathway (AP) of complement activation. The engineered version of FH, miniFH, contains only the N- and C-terminal portions of FH linked by an optimized peptide and shows â ¼ 10-fold higher ex vivo potency. We explored the hypothesis that regulatory potency is enhanced by unmasking of a ligand-binding site in the C-terminal CCPs 19-20 that is cryptic in full-length native FH. Therefore, we produced an FH variant lacking the central domains 10-15 (FHΔ10-15). To explore how avidity affects regulatory strength, we generated a duplicated version of miniFH, termed midiFH. We compared activities of FHΔ10-15 and midiFH to miniFH, FH, and FHL-1. Relative to FH, FHΔ10-15 exhibited an altered binding profile toward C3 activation products and a 5-fold-enhanced complement regulation on a paroxysmal nocturnal hemoglobinuria patient's erythrocytes. Contrary to dogma, FHL-1 and FH exhibited equal regulatory activity, suggesting that the role of FHL-1 in AP regulation has been underestimated. Unexpectedly, a substantially increased avidity for complement opsonins, as seen in midiFH, did not potentiate the inhibitory potential on host cells. In conclusion, comparisons of engineered and native FH-based regulators have identified features that determine high AP regulatory activity on host cells. Unrestricted availability of FH CCPs 19-20 and an optimal spatial orientation between the N- and C-terminal FH regions are key. |
| ISSN |
00221767 |
| e-ISSN |
15506606 |
| Journal |
The Journal of Immunology |
| Issue Number |
2 |
| Volume Number |
196 |
| Language |
English |
| Publisher |
The American Association of Immunologists |
| Publisher Date |
2016-01-15 |
| Publisher Place |
United States |
| Access Restriction |
Open |
| Subject Keyword |
Complement C3b Inactivator Proteins Immunology Complement Factor H Complement Inactivating Agents Pharmacology Complement Pathway, Alternative Recombinant Proteins Amino Acid Sequence Chemistry Chemical Synthesis Electrophoresis, Polyacrylamide Gel Enzyme-linked Immunosorbent Assay Flow Cytometry Molecular Sequence Data Polymerase Chain Reaction Protein Binding Comparative Study Research Support, N.i.h., Extramural Research Support, Non-u.s. Gov't Discipline Immunology |
| Content Type |
Text |
| Resource Type |
Article |
| Subject |
Immunology and Allergy Immunology |
