Complement binding to erythrocytes is associated with macrophage activation and reduced haemoglobin in Plasmodium falciparum malaria

Goka, Bamenla; Kwarko, Harriet; Kurtzhals, Jørgen A. L.; Gyan, Ben; Ofori-Adjei, Eugenia; Ohene, Sally Ann; Hviid, Lars; Akanmori, Bartholomew D.; Neequaye, Janet

doi:10.1016/s0035-9203(01)90036-7

Cited by 40 publications

(36 citation statements)

References 30 publications

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“…The involvement of complement in Plasmodium infections has been widely reported in malaria literature (10, 112, 113) and extensively reviewed elsewhere (114). Different reports have demonstrated that during ma-laria, complement activation is increased (115,116). Thus, it is necessary that the host complement regulatory proteins, molecules that protect normal cells from autologous complement-mediated lysis, are expressed in sufficient levels to control complement activation on the cell surface and thereby maintain physiological homeostasis (117).…”

Section: The Complement System and Malariamentioning

confidence: 99%

Potential Immune Mechanisms Associated with Anemia in Plasmodium vivax Malaria: a Puzzling Question

et al. 2014

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The pathogenesis of malaria is complex, generating a broad spectrum of clinical manifestations. One of the major complications and concerns in malaria is anemia, which is responsible for considerable morbidity in the developing world, especially in children and pregnant women. Despite its enormous health importance, the immunological mechanisms involved in malaria-induced anemia remain incompletely understood. Plasmodium vivax, one of the causative agents of human malaria, is known to induce a strong inflammatory response with a robust production of immune effectors, including cytokines and antibodies. Therefore, it is possible that the extent of the immune response not only may facilitate the parasite killing but also may provoke severe illness, including anemia. In this review, we consider potential immune effectors and their possible involvement in generating this clinical outcome during P. vivax infections.

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Section: The Complement System and Malariamentioning

confidence: 99%

Potential Immune Mechanisms Associated with Anemia in Plasmodium vivax Malaria: a Puzzling Question

et al. 2014

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“…IgG and complement C3 have been detected on erythrocytes from malaria patients with severe anemia. [30][31][32][33] We demonstrate here that RSP2 has features consistent with a key role in the development of anemia. Tagging RSP2-tagged erythrocytes with a cytophilic anti-RSP2 mAb and sera from immune malaria patients triggered phagocytosis by adherent human monocytes, whereas such phagocytosis was less common in the absence of noncytophilic IgG3 (with mAb D10) or nonimmune human sera.…”

Section: Discussionmentioning

confidence: 94%

“…This possibility has been raised before, when the deposition of surface IgG and changes in the surface expression of complement regulatory protein are correlated with severe malarial anemia. 31,32 However, no specific target antigen was identified that could trigger this reaction. Rigidification of the membrane of RSP2-tagged erythrocytes may lead to cell destruction, even in the absence of antibodies.…”

Section: Discussionmentioning

confidence: 99%

Plasmodium falciparum rhoptry protein RSP2 triggers destruction of the erythroid lineage

Layez

Nogueira²,

Combes³

et al. 2005

Blood

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The destruction of erythrocytes and defects in erythropoiesis are among the most frequently observed causes of morbidity in severe Plasmodium falciparum malaria. The molecular mechanisms involved remain unclear, despite extensive investigation. We show here, for the first time, that tagging with the parasite rhoptry protein ring surface protein 2 (RSP2) is not restricted to the surfaces of normal erythrocytes, as previously reported, but that it extends to erythroid precursor cells in the bone marrow of anemic malaria patients. Monoclonal mouse antibodies and human sera from patients with severe anemia, reacting with RSP2-tagged erythrocytes, induced cell destruction by phagocytosis and complement activation in vitro. Our observations reveal a new parasite mechanism implicated in the destruction of normal erythrocytes and probably dyserythropoiesis in malaria patients. These data suggest that the tagging of host cells with RSP2 may trigger anemia in falciparum malaria. IntroductionAnemia is undoubtedly the most common complication of Plasmodium falciparum infection 1,2 and is particularly severe in children and pregnant women living in endemic areas. Anemia is caused partly by the loss of red blood cells, both infected erythrocytes (IEs) and uninfected erythrocytes (UEs), which are destroyed by hemolysis or phagocytosis. 3 Rigidification of the membranes of IEs and UEs during infection may be an important factor in the destruction of these cells during passage through the spleen. 4,5 There seem to be many causes of anemia, and the underlying mechanisms remain elusive.Our recent studies on ring surface protein 2 (RSP2) suggest that this rhoptry molecule occasionally binds to the surface of UEs. 6 RSP2 has been identified as the highly conserved Rap2 gene found in all P falciparum isolates examined to date 7 (Sterkers Y., L. C., da Rocha M., Scheidig C., Lepolard C., Cowman A., G. J., and Scherf A., manuscript in preparation). Experimental evidence indicates that merozoites transfer RSP2 to the surfaces of erythrocytes, probably during aborted invasions, 6 suggesting a possible link to anemia in malaria patients.In this work, we used anti-RSP2 monoclonal antibodies and sera from P falciparum-infected anemia patients to investigate the role of RSP2 in the destruction of red blood cells. By modeling in vitro and ex vivo observations, we show that anti-RSP2 antibodies specifically react with cells of the erythroid lineage tagged with RSP2. We present experimental evidence that the antibody response against RSP2 can induce phagocytosis and complement binding to RSP2-tagged erythrocytes, leading to the destruction of otherwise normal erythrocytes. Finally, we show that merozoites can also label leukemic erythroblasts in vitro and erythroid precursors in the bone marrow of malaria patients with RSP2, possibly leading to erythropoietic dysfunction. Thus, we describe here a novel molecular mechanism of host-parasite interaction that may have severe consequences in malaria patients. Materials and methods Parasites and ce...

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“…[19][20][21][22][23][24][25] In addition, in patients with paroxysmal nocturnal hemoglobinuria (PNH) syndrome, the observed intravascular hemolysis is due to increased sensitivity of RBCs to autologous complement-mediated lysis. 26,27 It is generally believed that the lack of CD59, which inhibits the assembly of the membrane-attack complex C5b-C9 by interacting with C8 and C9, 28,29 is most likely responsible for the increased sensitivity of PNH RBCs and platelets to complement.…”

Section: Author Manuscriptmentioning

confidence: 99%

“…7 Complement-mediated intravascular and extravascular destruction of RBCs has been implicated as a contributing cause of anemia associated with sickle cell disease (SCD) [8][9][10][11][12][13][14][15][16][17][18] and in severe malarial infection. [19][20][21][22][23][24][25] In addition, in patients with paroxysmal nocturnal hemoglobinuria (PNH) syndrome, the observed intravascular hemolysis is due to increased sensitivity of RBCs to autologous complement-mediated lysis. 26,27 It is generally believed that the lack of CD59, which inhibits the assembly of the membrane-attack complex C5b-C9 by interacting with C8 and C9, 28,29 is most likely responsible for the increased sensitivity of PNH RBCs and platelets to complement.…”

Section: The Complement System In Transfusion Medicinementioning

confidence: 99%

Development of complement therapeutics for inhibition of immune‐mediated red cell destruction

Yazdanbakhsh

2005

Transfusion

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A major objective of my National Blood Foundation (NBF)-funded proposal was to produce recombinant soluble forms of a complement regulatory protein called complement receptor 1 (CR1) that carries the Knops blood group system antigens to perform antibody neutralization studies. By generating these recombinant proteins, we were able to inhibit several Knops antibodies in patient serum samples, thereby demonstrating their usefulness for clinical use. Interestingly, the recombinant CR1 proteins generated through NBF funding were also found to strongly reduce complement-mediated red cell destruction in a mouse hemolytic transfusion model. In this review, I will outline our NBF-funded studies, give an overview of recent advances from our group and others in the development of complement therapeutics, and highlight their potential use in the transfusion medicine setting. THE COMPLEMENT SYSTEM IN TRANSFUSION MEDICINEThe complement system is an important part of the innate immune system that responds to challenges by microorganisms before an adaptive response has developed. 1 It is also an important regulator of B-cell, and possibly T-cell, immunity. 2 In addition to its essential role in immune defense, the complement system contributes to tissue damage in many clinical conditions, including ischemia-reperfusion injuries after myocardial infarction, and in patients undergoing cardiopulmonary bypass. 3,4 In the transfusion medicine setting, complement-mediated red cell (RBC) destruction plays a critical role, being involved in both intravascular and extravascular hemolysis. 5 Generally, in the presence of a potent, complement-binding antibody and large numbers of closely situated RBC antigens, complement activation can proceed to completion, resulting in intravascular hemolysis, which can be fatal. 6 The majority of blood group antibodies (including both allo-and autoantibodies) that can fix complement, however, only activate complement up to the C3 stage but do not go on to act as hemolysins. Although antibody-coated RBCs can be destroyed extravascularly without complement activation, RBC removal by tissue macrophages in the spleen and liver is enhanced considerably when C3 is present on RBCs in addition to immunoglobulin G (IgG). Indeed, as many as 50 percent of patients with autoimmune hemolytic anemia have both IgG and complement on their RBCs. 7Address reprint requests to: Karina Yazdanbakhsh, PhD, Complement Biology, New York Blood Center, 310, E 67th Street, New York, NY 10021; kyazdanbakhsh@nybloodcenter.org. HHS Public Access Author Manuscript Author ManuscriptAuthor Manuscript Author ManuscriptComplement-mediated intravascular and extravascular destruction of RBCs has been implicated as a contributing cause of anemia associated with sickle cell disease (SCD) [8][9][10][11][12][13][14][15][16][17][18] and in severe malarial infection. [19][20][21][22][23][24][25] In addition, in patients with paroxysmal nocturnal hemoglobinuria (PNH) syndrome, the observed intravascular hemolysis is due to increased sen...

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Complement binding to erythrocytes is associated with macrophage activation and reduced haemoglobin in Plasmodium falciparum malaria

Cited by 40 publications

References 30 publications

Potential Immune Mechanisms Associated with Anemia in Plasmodium vivax Malaria: a Puzzling Question

Potential Immune Mechanisms Associated with Anemia in Plasmodium vivax Malaria: a Puzzling Question

Plasmodium falciparum rhoptry protein RSP2 triggers destruction of the erythroid lineage

Development of complement therapeutics for inhibition of immune‐mediated red cell destruction

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