ß2-glycoprotein I, the major target in antiphospholipid syndrome, is a special human complement regulator.

The human plasma protein ß(2)-glycoprotein I (ß(2)-GPI) is the major target of autoantibodies associated with antiphospholipid syndrome. However, the biologic function of this abundant protein is still unclear. Here we identify ß(2)-GPI as a complement regulator. ß(2)-GPI circulates in the plasma in an inactive circular form. On surface binding, such as to apoptotic cells, ß(2)-GPI changes conformation to an elongated form that acquires C3/C3b binding activities. ß(2)-GPI apparently changes conformation of C3, so that the regulator factor H attaches and induces subsequent degradation by the protease factor I. ß(2)-GPI also mediates further cleavage of C3/C3b compared with factor H alone. Our data provide important insights into innate immune regulation by plasma protein ß(2)-GPI, which may be exploited in the prevention and therapy of autoimmune disease antiphospholipid syndrome.

The yeast Candida albicans evades human complement attack by secretion of aspartic proteases.

Candida albicans, which represents one of the most important human pathogenic yeasts, is directly attacked by the host innate immune system upon infection. However this pathogen has developed multiple strategies to escape host immune defense. Here, we show that C. albicans secreted proteases interfere and inactivate host innate immune effector components, such as complement proteins. Secreted aspartic proteases (Saps) in the culture supernatant of C. albicans cells and also recombinant Sap1, Sap2 and Sap3 degrade host complement components C3b, C4b and C5 and also inhibit terminal complement complex (TCC) formation. This proteolytic activity is specific to the three recombinant and wild type Sap proteins. The triple knock out C. albicans strain Delta sap1-3 and also the non-pathogenic yeast S. cerevisiae lack such degrading activities. The complement inhibitory role of Sap1, Sap2 and Sap3 was confirmed in hemolysis assays with rabbit erythrocytes and normal human plasma. Secretion of complement degrading proteases provides a highly efficient complement defense response of this human pathogenic yeast that acts after the immediate acquisition of host complement regulators to the cell surface.

Factor H-related protein 1 (CFHR-1) inhibits complement C5 convertase activity and terminal complex formation.

Homozygous deletion of a 84-kb genomic fragment in human chromosome 1 that encompasses the CFHR1 and CFHR3 genes represents a risk factor for hemolytic uremic syndrome (HUS) but has a protective effect in age-related macular degeneration (AMD). Here we identify CFHR1 as a novel inhibitor of the complement pathway that blocks C5 convertase activity and interferes with C5b surface deposition and MAC formation. This activity is distinct from complement factor H, and apparently factor H and CFHR1 control complement activation in a sequential manner. As both proteins bind to the same or similar sites at the cellular surfaces, the gain of CFHR1 activity presumably is at the expense of CFH-mediated function (inhibition of the C3 convertase). In HUS, the absence of CFHR1 may result in reduced inhibition of terminal complex formation and in reduced protection of endothelial cells upon complement attack. These findings provide new insights into complement regulation on the cell surface and biosurfaces and likely define the role of CFHR1 in human diseases.