期刊
JOURNAL OF IMMUNOLOGY
卷 196, 期 2, 页码 866-876出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1501919
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资金
- Deutsche Forschungsgesellschaft [SCHM 3018/2-1]
- National Institutes of Health [AI030040, AI068730]
- European Community's Seventh Framework Programme Grant [602699]
- Biotechnology and Biological Sciences Research Council [BB/L024403/1, BB/I007946/1] Funding Source: researchfish
- BBSRC [BB/L024403/1, BB/I007946/1] Funding Source: UKRI
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 similar to 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 (FH Delta 10-15). To explore how avidity affects regulatory strength, we generated a duplicated version of miniFH, termed midiFH. We compared activities of FH Delta 10-15 and midiFH to miniFH, FH, and FHL-1. Relative to FH, FH Delta 10-15 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.
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