Factor H interferes with the adhesion of sickle red cells to vascular endothelium: a novel disease-modulating molecule

Abstract

Sickle cell disease is an autosomal recessive genetic red cell disorder with a worldwide distribution. Growing evidence suggests a possible involvement of complement activation in the severity of clinical complications of sickle cell disease. In this study we found activation of the alternative complement pathway with microvascular deposition of C5b-9 on skin biopsies from patients with sickle cell disease. There was also deposition of C3b on sickle red cell membranes, which is promoted locally by the exposure of phosphatidylserine. In addition, we showed for the first time a peculiar “stop-and-go” motion of sickle cell red blood cells on tumor factor-α–activated vascular endothelial surfaces. Using the C3b/iC3b binding plasma protein factor Has an inhibitor of C3b cell-cell interactions, we found that factor H and its domains 19-20 prevent the adhesion of sickle red cells to the endothelium, normalizing speed transition times of red cells. We documented that factor H acts by preventing the adhesion of sickle red cells to P-selectin and/or the Mac-1 receptor (CD11b/CD18), supporting the activation of the alternative pathway of complement as an additional mechanism in the pathogenesis of acute sickle cell related vaso-occlusive crises. Our data provide a rationale for further investigation of the potential contribution of factor H and other modulators of the alternative complement pathway with potential implications for the treatment of sickle cell disease.

Complement activation in sickle cell disease: Dependence on cell density, hemolysis and modulation by hydroxyurea therapy

“…Hemolysis‐derived products or anti‐endothelial antibodies present in the serum could explain this activation. This complement over activation is concordant with the complement‐mediated cytotoxicity from SCD patients' sera (modified Ham's test), the enhanced C3 deposits on ECs exposed to SCD RBC microvesicles, and the endothelial C3 deposits in tissues of SCD mice and biopsies of patients . This over activation is indeed at least in part heme‐dependent since it was inhibited by the heme scavenger hemopexin.…”

“…Taken together, recent mouse models and data from patients suggest that complement plays a key role in the SCD disease process and is a potential therapeutic target . The HU treatment resulted in prevention of complement activation on blood cells.…”

“…This cascade is a first line of defense against pathogens, but it induces host tissue damage when inappropriately over activated . Clinical observations have shown markers of complement activation in the circulation of SCD patients and increased levels of surface‐bound C3 fragments on RBCs . Mouse models have demonstrated that complement plays a key role in vaso‐occlusion and tissue injury, since complement blockade at the level of C5 or C5aR1 had a protective effect .…”

The Red Blood Cell—Inflammation Vicious Circle in Sickle Cell Disease

“…Increased soluble C5b-9 levels have been reported in SCD patients (53,54). Vercellotti et al (55) demonstrated increased C3 activation fragments and C5b-9 in the kidneys, lungs and liver of sickle cell mice, compared to control mice, and Lombardi et al (56) found increased microvascular deposition of C5b-9 on skin biopsies in SCD patients. Increased alternative pathway Bb fragments have also been reported in the plasma of both sickle cell mice and sickle cell patients (55,57).…”

“…The infusion of recombinant C5a has been shown to cause blood stasis and inflammation in the liver of sickle cell mice (through NF-κB activation and increased expression of TLR4 and several adhesion molecules), but this response was reversed by an anti-C5a receptor IgG (55). The increased externalization of phosphatidylethanolamine and phosphatidylserine at the membrane of sickle RBCs is also suspected to induce complement activation with increased C3 and C3b binding (56,57). A very recent work investigated the role of heme on complement activation in the context of SCD (58).…”