Critical Role of the C-Terminal Domains of Factor H in Regulating Complement Activation at Cell Surfaces

• Published in: Journal of Immunology 2006-11, Vol.177 (9), p.6308-6316
• Main Authors: Ferreira, Viviana P, Herbert, Andrew P, Hocking, Henry G, Barlow, Paul N, Pangburn, Michael K
• Format: Article
• Language: English
• Subjects: Animals; Binding Sites; Binding, Competitive; Complement Activation; Complement C3b - metabolism; Complement Factor H - genetics; Complement Factor H - metabolism; Erythrocyte Membrane - immunology; Erythrocytes - immunology; Hemolysis - immunology; Humans; Protein Structure, Tertiary - genetics; Protein Structure, Tertiary - physiology; Recombinant Proteins - genetics; Recombinant Proteins - metabolism
• ISSN: 0022-1767; 1550-6606; 1365-2567
• DOI: 10.4049/jimmunol.177.9.6308

The plasma protein factor H primarily controls the activation of the alternative pathway of complement. The C-terminal of factor H is known to be involved in protection of host cells from complement attack. In the present study, we show that domains 19-20 alone are capable of discriminating between host-like and complement-activating cells. Furthermore, although factor H possesses three binding sites for C3b, binding to cell-bound C3b can be almost completely inhibited by the single site located in domains 19-20. All of the regulatory activities of factor H are expressed by the N-terminal four domains, but these activities toward cell-bound C3b are inhibited by isolated recombinant domains 19-20 (rH 19-20). Direct competition with the N-terminal site is unlikely to explain this because regulation of fluid phase C3b is unaffected by domains 19-20. Finally, we show that addition of isolated rH 19-20 to normal human serum leads to aggressive complement-mediated lysis of normally nonactivating sheep erythrocytes and moderate lysis of human erythrocytes, which possess membrane-bound regulators of complement. Taken together, the results highlight the importance of the cell surface protective functions exhibited by factor H compared with other complement regulatory proteins. The results may also explain why atypical hemolytic uremic syndrome patients with mutations affecting domains 19-20 can maintain complement homeostasis in plasma while their complement system attacks erythrocytes, platelets, endothelial cells, and kidney tissue.