Loss of Red Blood Cell–Complement Regulatory Proteins and Increased Levels of Circulating Immune Complexes Are Associated with Severe Malarial Anemia

Stoute, José A.; Odindo, Alfred; Owuor, Boaz O.; Mibei, Erick; Opollo, Malachi O.; Waitumbi, John N.

doi:10.1086/367712

Cited by 101 publications

(117 citation statements)

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“…Malarial anemia is multifactorial in origin; it results from the combined effects of suppression of erythropoiesis, lysis of infected erythrocytes, and the accelerated destruction of uninfected erythrocytes [21,22]. Although there are no validated predictive models of human falciparum malaria [23], the observation of malaria-associated anemia in New World monkeys with prolonged Plasmodium falciparum parasitemia has led to speculation that malaria vaccines eliciting immunity that controls but does not eliminate parasitemia might themselves increase the risk of anemia in endemic populations [24].…”

Section: Discussionmentioning

confidence: 99%

Phase 1 randomized double-blind safety and immunogenicity trial of Plasmodium falciparum malaria merozoite surface protein FMP1 vaccine, adjuvanted with AS02A, in adults in western Kenya

Stoute

Gombe

Withers

et al. 2007

Vaccine

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randomized double-blind safety and immunogenicity trial of Plasmodium falciparum malaria merozoite surface protein FMP1 vaccine, adjuvanted with AS02A, in adults in western Kenya" (2007 AbstractWe report the first trial of candidate malaria vaccine antigen FMP1, a 42 kDa fragment from the C-terminus of merozoite surface protein-1 (MSP-1) from the 3D7 strain of Plasmodium falciparum, in an endemic area. Forty adult male and female residents of western Kenya were enrolled to receive 3 doses of either FMP1/AS02A or Imovax ® rabies vaccine by intra-deltoid injection on a 0, 1, 2 month schedule. Thirty-seven volunteers received all three immunizations and 38 completed the 12-month evaluation period. Slightly more recipients of the FMP1/AS02A vaccine experienced any instance of pain at 24 h post-immunization than in the Imovax ® group This document is a U.S. government work and is not subject to copyright in the United States. J. A. Stoute et al. / Vaccine 25 (2007) 176-184 177 (95% versus 65%), but otherwise the two vaccines were equally safe and well-tolerated. Baseline antibody levels were high in both groups and were boosted in the FMP1/AS02A group. Longitudinal models revealed a highly significant difference between groups for both the average post-baseline antibody responses to MSP-1 42 (F 1,335 = 13.16; P < 0.001) and the Day 90 responses to MSP-1 42 (F 1,335 = 16.69; P < 0.001). The FMP1/AS02A vaccine is safe and immunogenic in adults and should progress to safety testing in children at greatest risk of malaria. Published by Elsevier Ltd.

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Section: Discussionmentioning

confidence: 99%

Phase 1 randomized double-blind safety and immunogenicity trial of Plasmodium falciparum malaria merozoite surface protein FMP1 vaccine, adjuvanted with AS02A, in adults in western Kenya

Stoute

Gombe

Withers

et al. 2007

Vaccine

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“…Entre los mecanismos que explican la destrucción esplénica prematura de eritrocitos no parasitados, están: el daño de la membrana eritrocitaria causado por la respuesta inflamatoria, por el estrés oxidativo generado por la producción de radicales libres de oxígeno con exposición de fosfatidilserinas y por la disminución de la elasticidad de la membrana (93); el depósito de anticuerpos sobre la membrana del eritrocito que pueden estar dirigidos contra elementos modificados de la pared del glóbulo rojo y actuar como autoanticuerpos, o contra proteínas de estadios asexuales del parásito depositadas sobre la célula durante la ruptura periódica de esquizontes; y la producción de alteraciones en las proteínas reguladoras del complemento sobre la membrana del eritrocito (CR1, DAF) que pueden predisponer al depósito de complejos inmunitarios y complemento sobre el glóbulo rojo y facilitar su destrucción en el bazo (92,95,96).…”

Section: Destrucción De Eritrocitos No Parasitadosunclassified

Pathogenic mechanisms in Plasmodium falciparum malaria

Vásquez

Tobón

2012

biomedica

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Se presentan los mecanismos patogénicos más conocidos en la infección por Plasmodium falciparum durante la fase eritrocitaria y extraeritrocitaria. La obstrucción vascular, explicada por los fenómenos de secuestro de glóbulos rojos parasitados y la formación de rosetas, mediados por diversos ligandos y receptores endoteliales, además de los procesos inflamatorios instaurados ante la presencia del parásito, son aspectos centrales en la patogenia de la malaria que permiten explicar los procesos de disfunción, daño y muerte celular en diferentes órganos. A partir de eventos como la lesión y la destrucción de eritrocitos, hepatocitos y células endoteliales, la pérdida de integridad del endotelio y la activación de promotores de daño celular y de apoptosis, se explican alteraciones como el aumento de la permeabilidad vascular, la hipoxia y el metabolismo anaerobio, que conducen tanto a lesiones localizadas en órganos como cerebro y pulmón, como a un estado de acidosis generalizada y falla multisistémica.Palabras clave: malaria/etiología, Plasmodium falciparum, inflamación. Pathogenic mechanisms in Plasmodium falciparum malariaThe most recognized pathogenic mechanisms of the infection with Plasmodium falciparum, during both the erythrocytic and exo-erithrocytic stages are presented. Vascular obstruction explained by the sequestration of parasitized red blood cells and erythrocyte rosetting, mediated by different endothelial ligands and receptors, in addition to the inflammatory processes induced by the presence of the parasite, are central aspects in the pathogenesis of malaria that explain the processes of damage, dysfunction and cell death in various organs. Alterations such as increased vascular permeability, hypoxia and anaerobic metabolism leading to localized lesions in organs such as brain and lung, as well as to a generalized acidotic state with multisystem failure can be explained by events such as the injury and destruction of erythrocytes, hepatocytes and endothelial cells, the loss of endothelial integrity, and the activation of cell damage and apoptosis promoters.Key words: Malaria/ethiology, Plasmodium falciparum, inflamation.Los signos y síntomas clínicos en la malaria, o paludismo, expresión del daño ocasionado en diversos órganos y sistemas, se exacerban durante el período de multiplicación del parásito en el eritrocito, mientras que el estadio hepático y la presencia de gametocitos tradicionalmente no se han asociado con la sintomatología. La malaria causa lesiones estructurales y alteraciones funcionales y metabólicas, cuya presentación clínica está en función de la edad, el estado inmunitario y las características genéticas del huésped, y por la especie, el genotipo y la virulencia del parásito. Puede conducir a un cuadro clínico grave el cual casi siempre se observa en las infecciones causadas por Plasmodium falciparum. Las complicaciones informadas con mayor frecuencia incluyen anemia grave, malaria cerebral, síndrome de dificultad respiratoria aguda y falla renal (1); en los últimos años se vien...

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“…Red cells are able to bind C3b-bearing ICs via CR1 and carry them to the liver and spleen where they are removed from circulation (10,11). Consequently, complement regulatory proteins may play an important role in protecting red cells from complement-mediated destruction as a result of IC formation and complement activation that occur during malaria infection (12)(13)(14)(15).…”

Section: Introductionmentioning

confidence: 99%

“…Online address: http://www.molmed.org doi: 10.2119/2007-00093. Owuor result of IC formation and complement activation that occur during malaria infection (12)(13)(14)(15).We have shown that red cells of children with SMA have decreased levels of CR1 and CD55 (14,16,17). We hypothesized that these changes could translate into a decreased functional capacity to bind ICs and prevent complement deposition, which could result in their increased rate of destruction.…”

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confidence: 99%

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Reduced Immune Complex Binding Capacity and Increased Complement Susceptibility of Red Cells from Children with Severe Malaria-Associated Anemia

Owuor

Odhiambo

Otieno

et al. 2008

Mol Med

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Plasmodium falciparum malaria causes 1-2 million deaths per year. Most deaths occur as a result of complications such as severe anemia and cerebral malaria (CM) (coma). Red cells of children with severe malaria-associated anemia (SMA) have acquired deficiencies in the complement regulatory proteins complement receptor 1 (CR1, CD35) and decay accelerating factor (DAF, CD55). We investigated whether these deficiencies affect the ability of erythrocytes to bind immune complexes (ICs) and regulate complement activation. We recruited 75 children with SMA (Hb ≤ 6 g/dL) from the holoendemic malaria region of the Lake Victoria basin, western Kenya, and 74 age-and gender-matched uncomplicated malaria controls. In addition, we recruited 32 children with CM and 52 age-and gender-matched controls. Deficiencies in red cell CR1 and CD55 in children with SMA were accompanied by a marked decline in IC binding capacity and increased C3b deposition in vivo and ex vivo. Importantly, these changes were specific because they were not seen in red cells of children with CM or their controls. These data suggest that the declines in red cell CR1 and CD55 seen in children with SMA are of physiologic significance and may predispose erythrocytes to complement-mediated damage and phagocytosis in vivo. Online address: http://www.molmed.org doi: 10.2119/2007-00093. Owuor result of IC formation and complement activation that occur during malaria infection (12)(13)(14)(15).We have shown that red cells of children with SMA have decreased levels of CR1 and CD55 (14,16,17). We hypothesized that these changes could translate into a decreased functional capacity to bind ICs and prevent complement deposition, which could result in their increased rate of destruction. To test our hypothesis we carried out a case-control study in children with SMA and age and gender-matched symptomatic uncomplicated malaria controls and determined their levels of erythrocyte CR1 and CD55, their erythrocyte IC binding capacity, and the susceptibility of their red cells to complement deposition in vivo and ex vivo. As an additional comparison group, we recruited children with cerebral malaria (CM) and age-and gender-matched symptomatic uncomplicated malaria controls. MATERIALS AND METHODS Study Design and PopulationsParticipants were recruited under a human use protocol approved by the Human Use Research Committee, the Walter Reed Army Institute of Research, and the National Ethics Review Committee of the Kenya Medical Research Institute. Informed consent was obtained from all parents or guardians. The study had a matched case-control design. SMA cases, defined as children with asexual P. falciparum parasitemia by Giemsastained thick and thin blood smear and Hb ≤ 6 g/dL, were recruited from the pediatric ward of the Nyanza Provincial General Hospital (NPGH), Kisumu, Kenya, where malaria is holoendemic. Because CM is uncommon in this area, CM cases were recruited from the pediatric ward of the Kisii District Hospital (KDH), as well as from the NPGH. KDH is located in t...

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Loss of Red Blood Cell–Complement Regulatory Proteins and Increased Levels of Circulating Immune Complexes Are Associated with Severe Malarial Anemia

Cited by 101 publications

References 13 publications

Phase 1 randomized double-blind safety and immunogenicity trial of Plasmodium falciparum malaria merozoite surface protein FMP1 vaccine, adjuvanted with AS02A, in adults in western Kenya

Phase 1 randomized double-blind safety and immunogenicity trial of Plasmodium falciparum malaria merozoite surface protein FMP1 vaccine, adjuvanted with AS02A, in adults in western Kenya

Pathogenic mechanisms in Plasmodium falciparum malaria

Reduced Immune Complex Binding Capacity and Increased Complement Susceptibility of Red Cells from Children with Severe Malaria-Associated Anemia

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