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E-mail: WASSIM EL NEMER - wassim.el-nemer@inserm.fr doi:10.3324/haematol.2018.214668
Sickle cell disease (SCD) is an autosomal recessive disor- der caused by a point mutation in the β globin gene that substitutes glutamic acid (GAG) at position 6 of the protein into valine (GTG).1 The resulting mutated hemoglo- bin (HbS) polymerizes under hypoxic conditions driving sickling of red blood cells (RBC). Sickling and dehydration alter the shape of the RBC, decreasing their deformability and increasing their rigidity, which results in significant intravascular hemolysis. These alterations affect blood rhe- ology and microcirculatory flow as well as blood and endothelial cell functions because of the release of hemoglo- bin and subsequent free heme in the circulation. In addition to chronic hemolysis and related complications, patients with SCD experience frequent vaso-occlusive crises that are painful episodes caused by obstruction of micro-capillaries, believed to be initiated by abnormally adherent RBC or neu- trophils reducing the luminal section of the capillaries with subsequent blockage by rigid, deformed RBC.2,3 Hemolysis and vaso-occlusive crises are critical components of the chronic inflammatory state reported in SCD,4,5 which in turn is responsible for several cellular dysfunctions including acti- vation of neutrophils that contributes to vaso-occlusive crises in a vicious feedback loop.
SCD is a multisystem disease that has been explored for decades. Despite significant efforts to date and recent advances showing a role for neutrophils in vaso-occlusive crises, the pathogenesis of SCD, in terms of the sequence of molecular events underlying the disease, remains only par- tially understood. Hemolysis and chronic inflammation are features common to SCD and other pathologies in which complement activation has been reported, such as atypical hemolytic uremic syndromes and paroxysmal nocturnal hemoglobinuria.
The complement system is one of the oldest defense mechanisms against infections during evolution.6 It is com- posed of the classical, alternative and lectin pathways that can be activated by specific chemical components. Activation of the classical pathway is initiated by the attach- ment of the first protein of the complement, C1q, to one of its ligands, the most important being the CH2 domain of the IgG Fc fragment and the CH4 domain of IgM. This activa- tion leads to the cleavage of the C4 component present in plasma into a small C4a fragment and a large C4b fragment that binds covalently to the target surface and subsequently forms the C4bC2a complex, called the “classical C3 conver- tase” because of its ability to cleave C3.7 The lectin pathway is activated by the carbohydrate structure of microorgan- isms. The recognition protein is MBL (mannan-binding lectin) and is associated with serine proteases called MASP- 1, -2 or -3. Once activated, MASP acquire the ability to cleave C4 and C2 proteins thus forming the classical C3 con- vertase C4b2a. The alternative pathway is activated by bac- terial products, such as lipopolysaccharides, viruses, and infected, transformed or apoptotic cells; it leads to the for- mation of the “alternative C3 convertase”. It is initiated by the association of soluble C3b with factor B allowing this lat- ter to be cleaved by a serine protease circulating in active form in the plasma, factor D, producing the Ba and Bb frag- ments. While Ba is excluded from the complex, Bb remains associated with C3b to form the C3bBb complex, named the “alternative C3 convertase”, capable of catalyzing the cleav- age of C3 to C3b, like the C4b2a complex. Activation of the alternative pathway is capable of self-amplification, which is very important for the recognition and elimination of pathogens in the absence of specific antibodies.8
Activation of one of the three pathways leads to succes-
Figure 1. Anti-adhesive role of factor H in sickle cell disease. Activation of the alternative complement pathway in sickle cell disease drives accumula- tion of C3 cleavage fragments, iC3b in this figure, on the sur- face of red blood cells trigger- ing their abnormal adhesion to endothelial cells. Factor H binds iC3b and inhibits adhe- sion of sickle red blood cells to the vascular wall.
EDITORIALS
Factor H: a novel modulator in sickle cell disease
Wassim El Nemer1,2,3 and Bérengère Koehl1,2,3,4
1Biologie Intégrée du Globule Rouge UMR_S1134, Inserm, Univ. Paris Diderot, Sorbonne Paris Cité, Univ. de la Réunion, Univ. des Antilles; 2Institut National de la Transfusion Sanguine, F-75015; 3Laboratoire d’Excellence GR-Ex and 4Hematology Unit, Sickle Cell Disease Center, Robert Debré Hospital, AP-HP, Paris, France
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