Hematin Promotes Complement Alternative Pathway-Mediated Deposition of C3 Activation Fragments on Human Erythrocytes: Potential Implications for the Pathogenesis of Anemia in Malaria

Abstract

Childhood malaria caused by Plasmodium falciparum is often characterized by severe anemia at low parasite burdens; the mechanism(s) responsible for this pathology remain to be defined. We have reported, based on clinical observations and in vitro models, that complement control proteins on erythrocytes such as CR1, the immune adherence receptor specific for C3b, may be reduced in childhood malaria, suggesting a possible role for complement in erythrocyte destruction. Intravascular lysis of iE by P. falciparum leads to release of erythrocyte breakdown products such as hemoglobin and hematin, which have inflammatory properties. In the present article, we demonstrate that in serum and in anticoagulated whole blood, moderate concentrations of hematin activate the alternative pathway of complement and promote deposition of C3 activation and breakdown products on erythrocytes. The degree of C3 fragment deposition is directly correlated with erythrocyte CR1 levels, and erythrocytes opsonized with large amounts of C3dg form rosettes with Raji cells, which express CR2, the C3dg receptor which is expressed on several types of B cells in the spleen. Thus, the reaction mediated by hematin promotes opsonization and possible clearance of the youngest (highest CR1) erythrocytes. A mAb specific for C3b, previously demonstrated to inhibit the alternative pathway of complement, completely blocks the C3 fragment deposition reaction. Use of this mAb in nonhuman primate models of malaria may provide insight into mechanisms of erythrocyte destruction and thus aid in the development of targeted therapies based on inhibiting the alternative pathway of complement.

Complement activation by heme as a secondary hit for atypical hemolytic uremic syndrome

“…First, we found that the presence of heme in NHS is sufficient to trigger fluid phase complement AP activation with release of anaphylotoxins C3a and C5a, as well as sC5b9, in agreement with previous reports. 13,30 Heme has a dual role in complement, activating AP but inhibiting the binding of C1q to its ligands. 23 We investigated the mechanism of AP complement activation and showed that it results from the interaction of heme with the C3 molecule, which favors C3 homophilic interactions and leads to the formation of an active AP C3/C5 convertase.…”

“…13,14 Complement AP activation has also been reported during the acute phase of other hemolytic disorders, such as sickle-cell disease, 15 b thalassemia major, 16 and thrombotic thrombocytopenic purpura, 17 but the participation of hemoglobin or its breakdown products in complement activation has not been investigated.…”

Complement inhibitors to treat IgM-mediated autoimmune hemolysis

“…So via complement activation, free heme may perpetuate the development of anemia in patients with extravascular hemolysis. 38,39 In contrast, a negative effect of free heme on C1q binding to IgG and IgM has been described. 40,41 It was mentioned that classical pathway activation can be modulated by released heme by inhibiting the binding of C1q to its ligands.…”

Hemin-induced suicidal erythrocyte death

“…A variety of disorders may lead to formation of hemin, which in turn may drive erythrocytes into cell death [29,39,48,49,59,61,70]. On the other hand, hemin has been proven useful in the treatment of acute porphyria [62,63].…”