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Editorials
sive proteolysis of plasma proteins which converges to the central protein of the complement system called C3. The activation of a C3 convertase (classical or alternative) results in the production of a fragment called C3b which can then initiate different effector pathways: opsoniza- tion, recruitment of inflammatory cells, direct destruction of infectious agents by osmotic lysis, elimination of circu- lating immune complexes and apoptotic cells and modu- lation of specific immune responses.9 C3b can be dissoci- ated into inactive fragments (iC3b, C3dg and then C3d) by means of plasma cofactors (factor I and factor H) or membrane co-factors (CMP, CD35 or CR1). The C3 cleav- age fragments (C3b, iC3b, C3dg and C3d) can interact with different cellular receptors (CR1 or CD35, CR2 or CD21, CR3 or CD11b/CD18, CR4 or CD11c/CD18), thus modulating the response at the surface of the different immune cells: phagocytosis, presentation of the antigen and modulation of specific immune responses.10
As in all activation cascades, a narrow network of circu- lating or membrane proteins is necessary to closely regu- late the different activation pathways. The regulation of the alternative pathway is ensured by factor H which plays a central role in discriminating self from non-self.11 It controls the initiation of the C3bBb complex (alterna- tive C3 convertase) by competing with factor B for C3b binding and accelerates the dissociation of the alternative C3 convertase.
Evidence for altered alternative complement pathway activity in the sera of SCD patients was reported in 1976 by Koethe and collaborators.12 In 1985, Chudwin and collabo- rators showed that 89% of SCD patients’ sera had elevated concentrations of C3b derivatives indicative of increased alternative pathway activation.13 In 1993, Wang and collab- orators showed that altered membrane phospholipid expo- sure of RBC is a critical element of alternative complement pathway activation in SCD patients.14 Very recently, it was shown that cell-free heme and heme-containing microvesi- cles resulting from intravascular hemolysis activate com- plement in SCD.15 In addition, activation of the comple- ment is suspected to be involved in the delayed hemolytic transfusion reaction in SCD, a suspicion recently supported by good outcomes following injections of an anti-C5 mon- oclonal antibody (eculizumab).16
In this issue of Haematologica, Lombardi and collabora- tors investigated the activation of the alternative comple- ment pathway as a potential contributor to increased RBC adhesion in SCD patients at steady state and during vaso- occlusive crises.17 First, they confirmed complement acti- vation in vivo by showing increased serum levels of com- plement activation fragment C5a in SCD patients as well as microvascular deposition of another activation marker, C5b-9, in small vessels of skin biopsies from patients but not from healthy subjects. Investigating blood cells, they found higher numbers of RBC carrying C3d-derived opsonins in SCD patients than in healthy subjects, indica- tive of alternative complement pathway activation occur- ring directly on sickle RBC. This was associated with higher proportions of RBC exposing phosphatidylserine at their surface, as previously reported.14 The authors hypothesized that C3 fragments deposited on the RBC surface may serve as adhesive sites driving abnormal adhesion of sickle RBC to the endothelial wall. They
explored this hypothesis by performing ex vivo adhesion assays under dynamic conditions, in which they found the expected higher levels of adhesion of sickle RBC on tumor necrosis factor-a-activated endothelial cells as compared to control RBC. Pre-incubating RBC with factor H, a soluble regulator of alternative complement pathway activation that circulates in the plasma and binds to C3b/iC3b on self cells, inhibited sickle RBC adhesion in a dose-dependent manner reaching control levels at high concentrations (Figure 1). This was the first evidence that opsonins of the alternative complement pathway, deposited on the surface of sickle RBC, may play a critical role in mediating these cells’ abnormal adhesion to the endothelial wall. The authors tested the inhibitory poten- tial of two factor H fragments and concluded that the fac- tor H 19-20 fragment was sufficient to inhibit sickle RBC adhesion. Finally, using blocking antibodies, the authors showed data suggesting the involvement of P-selectin and Mac-1 in sickle RBC adhesion on the endothelial cell side.
Once activated, the complement pathways play an important role in the induction of tissue lesions, such as recruitment of inflammatory cells (neutrophils, mono- cytes, macrophages and activated lymphocytes), activa- tion of endothelial cells and platelets, and secretion of pro-inflammatory cytokines. Such dysfunctions are fre- quent in many pathological situations, including autoim- mune diseases,18 ischemia-reperfusion syndrome and sep- tic shock,19 making the complement system a potential therapeutic target in these pathologies.20 The study by Lombardi and collaborators reveals a new role for com- plement activation in the pathogenesis of SCD, particular- ly in the adhesive process underlying vaso-occlusive crises.17 It paves the way for future clinical studies in which modulators of the alternative complement path- way, including factor H-based inhibitors, could be tested as potential new therapeutic options in this pathology.
References
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2. Kaul DK, Fabry ME, Nagel RL. Microvascular sites and characteristics of sickle cell adhesion to vascular endothelium in shear flow condi- tions: pathophysiological implications. Proc Natl Acad Sci U S A. 1989;86(9):3356-3360.
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11. Medjeral-Thomas N, Pickering MC. The complement factor H-relat- ed proteins. Immunol Rev. 2016;274(1):191-201.
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haematologica | 2019; 104(5)