Reduced red blood cell surface level of Factor H as a mechanism underlying paroxysmal nocturnal hemoglobinuria

The absence of the cell-surface complement inhibitors CD55 and CD59 is considered the mechanism underlying the complement-mediated destruction of affected red blood cells (RBCs) in paroxysmal nocturnal hemoglobinuria (PNH) patients, but Factor H (FH), a fluid-phase complement inhibitor, has also been proposed to be involved. However, the status of FH on the PNH patient RBC surface is unclear and its precise role in PNH pathogenesis remains to be further defined. In this study, we identified significantly lower levels of surface-bound FH on the affected CD59− RBCs than on the unaffected CD59+ RBCs. Although this reduction in surface-bound FH on PNH RBCs was accompanied by decreased surface sialic acid levels, the enzymatic removal of sialic acids from these RBCs did not significantly affect the levels of surface-bound FH. We further observed higher surface levels of FH on the C3b/iC3b/C3dhigh RBCs than on C3b/iC3b/C3dlow RBCs within the affected PNH RBCs of patients treated with eculizumab. Finally, we determined that enhanced surface levels of FH on CD55/CD59-deficient RBCs from mice and PNH patients protected against complement-mediated hemolysis. Taken together, our results suggest that a reduced surface level of FH is another important mechanism underlying the pathogenesis of PNH.