‘‘Homologous restriction’’ in complement lysis: roles of membrane complement regulators

Abstract

The complement system is a powerful bactericidal immune defence with the potential to damage self cells. Protection of self is provided by expression on cells of a battery of membrane regulators that inhibit activation of complement. Roles of complement in the rejection of transplanted organs have long been recognized, and are particularly relevant in xenotransplantation, where hyperacute rejection is complement-driven. Inhibiting complement was therefore considered early in the history of xenografting, and the use of membrane complement regulators to this end was proposed more than two decades ago. For each of the membrane regulators in humans, early studies implied a species-specificity of action, inhibiting human complement but not that from other species. The dogma of species-specificity dictated strategies for inhibiting complement in xenografts and drove the creation of donor transgenic pigs expressing human regulators. Here we critically evaluate the evidence for species-specificity in membrane complement regulators from humans and other animals. We challenge the dogma and show that there is considerable cross-species activity for each of the membrane regulators of complement. Acceptance of the fact that species selectivity is not a limitation will open new avenues for protection of the xenograft from complement damage.

Species Selectivity in Poxviral Complement Regulators Is Dictated by the Charge Reversal in the Central Complement Control Protein Modules

“…Given that poxviral complement regulators help evade host complementmediated neutralization (18)(19)(20), modulate humoral and T cellmediated responses against the virus (21), and serve as virulence determinants (18,22), it is likely that they function in a speciesspecific manner. The phenomenon of species-selective complement regulation or "homologous restriction" is well recognized in mammalian regulators of complement activation (RCA) proteins (23,24), but the molecular basis for it remained elusive (25). In this study, we show that VCP exhibits preference in inhibiting the bovine alternative complement pathway.…”

Retrovirus-Mediated Over-Expression of Decay-Accelerating Factor Rescues Crry-Deficient Erythrocytes from Acute Alternative Pathway Complement Attack

“…Host tissues avoid complement activation and the ensuing inflammation and cytolysis by expressing a number of complement inhibitory proteins on their cell surface (2,3). In humans, these proteins include decay-accelerating factor (DAF), 3 membrane cofactor protein (MCP), complement receptor 1 (CR1) and CD59. DAF inhibits complement activation by preventing the formation and accelerating the decay of C3 and C5 convertases (4,5).…”

The good and evil of complement activation in HIV-1 infection

“…The complement system consists of about 30 soluble and membrane-bound proteins and is activated by three distinct pathways either on the pathogen surface or in the plasma. [1][2][3] The classical pathway is triggered by antigen-bound Ab molecules and is initiated by the binding of the Ab's Fc part to the C1 component. 4 The alternative pathway is a humoral component of the immune system's natural defense against infections and is activated by cleavage of C3 and then C5.…”