Cell surface complement regulatory functions of factor H are essential for the survival of normal and paroxysmal nocturnal hemoglobinuric (PNH) red blood cells (53.2)

Abstract

Abstract The complement system uses a complex set of cell-bound and plasma regulators to protect host cells from complement-mediated cytolysis. Although PNH red blood cells (RBCs) are partially (type II) or completely (type III) deficient in GPI-linked complement regulatory molecules CD59 and CD55, they are not rapidly lysed by complement. For instance, the in vivo lifespan of PNH III RBCs is 6–60 days, and is close to that of normal cells for PNH II RBCs. The plasma regulator factor H (fH) plays a key role in complement homeostasis. Here we show that a recombinant protein consisting of its two C-terminal domains (rH19-20) blocks its cell surface complement regulatory functions without affecting fluid phase control of soluble C3b. Also, addition of rH19-20 to normal human serum leads to moderate complement-mediated lysis of normal human RBCs, which possess membrane-bound complement regulators, and to aggressive lysis of PNH II and III cells. In agreement with this, the inhibition of CD59 or CD55 on normal RBCs results in their aggressive lysis only when combined with the loss of fH cell surface control. Taken together, the results highlight the importance of the cell surface protective functions of fH compared to other complement regulatory proteins and indicate that fH is essential for the 6–60 day survival of PNH RBCs, with possible implications in diagnosis and treatment. Research support NIH DK35081.