Abstract
Plasmodium falciparum is responsible for the deaths of hundreds of thousands of children every year. Most of these deaths are the result of complications such as severe malarial anemia (SMA). There are now considerable data that suggest that complement plays a role in the development of anemia during malaria infection by opsonization of uninfected erythrocytes with C3 fragments which can lead to phagocytosis of erythrocytes. The increased susceptibility to complement deposition of erythrocytes seems to be related to the loss of complement regulatory proteins, in particular CR1, and to age-related decreases in their expression in young children. Further, there is evidence that malaria treatment exacerbates complement activation and may lead to increased opsonization of uninfected erythrocytes. The evidence suggests that complement is an attractive target for adjunctive therapy during the treatment of SMA. Genetic studies have not revealed any strong associations between CR1 polymorphisms and severe malarial anemia. Further genetic association studies between polymorphisms of the complement genes and susceptibility to SMA are needed to identify additional potential therapeutic targets.
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Adam C, Geniteau M, Gougerot-Pocidalo M, Verroust P, Lebras J, Gibert C, Morel-Maroger L (1981) Cryoglobulins, circulating immune complexes, and complement activation in cerebral malaria. Infect Immun 31(2):530–535
Barrett-Connor E (1967) Plasmodium vivax malaria dn Coombs positive anemia. Am J Trop Med Hyg 16(6):699–703
Biswas S, Saxena QB, Roy A (1990) The natural occurrence of circulating antibodies in populations of endemic malarious areas. Indian J Malariol 27(3):139–148
Boldt AB, Luty A, Grobusch MP, Dietz K, Dzeing A, Kombila M, Kremsner PG, Kun JF (2006) Association of a new mannose-binding lectin variant with severe malaria in Gabonese children. Genes Immun 7(5):393–400
Cockburn IA, Mackinnon MJ, O’Donnell A, Allen SJ, Moulds JM, Baisor M, Bockarie M, Reeder JC, Rowe JA (2004) A human complement receptor 1 polymorphism that reduces Plasmodium falciparum rosetting confers protection against severe malaria. Proc Natl Acad Sci U S A 101(1):272–277
Cooper NR, Fogel BJ (1966) Complement in acute experimental malaria. II. Alterations in the components of complement. Mil Med 131(9):1180–1190
Covas DT, de Oliveira FS, Rodrigues ES, Abe-Sandes K, Silva WA Jr, Fontes AM (2007) Knops blood group haplotypes among distinct Brazilian populations. Transfusion 47(1):147–153
Dasari P, Fries A, Heber SD, Salama A, Blau IW, Lingelbach K, Bhakdi SC, Udomsangpetch R, Torzewski M, Reiss K, Bhakdi S (2014) Malarial anemia: digestive vacuole of Plasmodium falciparum mediates complement deposition on bystander cells to provoke hemophagocytosis. Med Microbiol Immunol 203(6):383–393
Demirag B, Sozer C (1956) Hemolytic anemia following malaria. Ann Paediatr 186(2):86–89
Dulaney AD (1947) Complement activity of human serum with especial reference to malaria. Fed Proc 6(1):425
Dulaney AD, Priest JB, Almeda ML, Parker B (1948) The complement content of human sera with especial reference to malaria. J Clin Invest 27(3 Pt 1):320–326
Ermini L, Wilson IJ, Goodship TH, Sheerin NS (2012) Complement polymorphisms: geographical distribution and relevance to disease. Immunobiology 217(2):265–271
Facer CA (1980) Direct Coombs antiglobulin reactions in Gambian children with Plasmodium falciparum malaria. II. Specificity of erythrocyte-bound IgG. Clin Exp Immunol 39(2):279–288
Facer CA, Bray RS, Brown J (1979) Direct Coombs antiglobulin reactions in Gambian children with Plasmodium falciparum malaria. I. Incidence and class specificity. Clin Exp Immunol 35(1):119–127
Fernandez-Arias C, Lopez JP, Hernandez-Perez JN, Bautista-Ojeda MD, Branch O, Rodriguez A (2013) Malaria inhibits surface expression of complement receptor 1 in monocytes/macrophages, causing decreased immune complex internalization. J Immunol 190(7):3363–3372
Fogel BJ, Von Doenhoff AE Jr, Cooper NR, Fife EH Jr (1966) Complement in acute experimental malaria. I. Total hemolytic activity. Mil Med 131(9):1173–1179
Gandhi M, Singh A, Dev V, Adak T, Dashd AP, Joshi H (2009) Role of CR1 Knops polymorphism in the pathophysiology of malaria: Indian scenario. J Vector Borne Dis 46(4):288–294
Ghiran I, Barbashov SF, Klickstein LB, Tas SW, Jensenius JC, Nicholson-Weller A (2000) Complement receptor 1/CD35 is a receptor for mannan-binding lectin. J Exp Med 192(12):1797–1808
Goka BQ, Kwarko H, Kurtzhals JA, Gyan B, Ofori-Adjei E, Ohene SA, Hviid L, Akanmori BD, Neequaye J (2001) Complement binding to erythrocytes is associated with macrophage activation and reduced haemoglobin in Plasmodium falciparum malaria. Trans R Soc Trop Med Hyg 95(5):545–549
Greenwood BM, Brueton MJ (1974) Complement activation in children with acute malaria. Clin Exp Immunol 18(2):267–272
Greenwood BM, Stratton D, Williamson WA, Mohammed I (1978) A study of the role of immunological factors in the pathogenesis of the anaemia of acute malaria. Trans R Soc Trop Med Hyg 72(4):378–385
Gupta N, Sehgal R, Mahajan RC, Banerjee AK, Ganguly NK (1988) Role of immune complexes in cerebral malaria. Pathology 20(4):373–376
Gwamaka M, Fried M, Domingo G, Duffy PE (2011) Early and extensive CD55 loss from red blood cells supports a causal role in malarial anaemia. Malar J 10:386
Hansson HH, Kurtzhals JA, Goka BQ, Rodriques OP, Nkrumah FN, Theander TG, Bygbjerg IC, Alifrangis M (2013) Human genetic polymorphisms in the Knops blood group are not associated with a protective advantage against Plasmodium falciparum malaria in Southern Ghana. Malar J 12:400
Herrera AH, Xiang L, Martin SG, Lewis J, Wilson JG (1998) Analysis of complement receptor type 1 (CR1) expression on erythrocytes and of CR1 allelic markers in Caucasian and African American populations. Clin Immunol Immunopathol 87(2):176–183
Holmberg V, Schuster F, Dietz E, Sagarriga Visconti JC, Anemana SD, Bienzle U, Mockenhaupt FP (2008) Mannose-binding lectin variant associated with severe malaria in young African children. Microbes Infect 10(4):342–348
Houba V, Lambert PH, Voller A, Soyanwo MA (1976) Clinical and experimental investigation of immune complexes in malaria. Clin Immunol Immunopathol 6(1):1–12
Jakeman GN, Saul A, Hogarth WL, Collins WE (1999) Anaemia of acute malaria infections in non-immune patients primarily results from destruction of uninfected erythrocytes. Parasitology 119:127–133
Jhaveri KN, Ghosh K, Mohanty D, Parmar BD, Surati RR, Camoens HM, Joshi SH, Iyer YS, Desai A, Badakere SS (1997) Autoantibodies, immunoglobulins, complement and circulating immune complexes in acute malaria. Natl Med J India 10(1):5–7
Klickstein LB, Barbashov SF, Liu T, Jack RM, Nicholson-Weller A (1997) Complement receptor type 1 (CR1, CD35) is a receptor for C1q. Immunity 7(3):345–355
Krych-Goldberg M, Atkinson JP (2001) Structure-function relationships of complement receptor type 1. Immunol Rev 180:112–122
Looareesuwan S, Merry AH, Phillips RE, Pleehachinda R, Wattanagoon Y, Ho M, Charoenlarp P, Warrell DA, Weatherall DJ (1987) Reduced erythrocyte survival following clearance of malarial parasitaemia in Thai patients. Br J Haematol 67(4):473–478
Luty AJ, Kun JF, Kremsner PG (1998) Mannose-binding lectin plasma levels and gene polymorphisms in Plasmodium falciparum malaria. J Infect Dis 178(4):1221–1224
Lutz HU, Bussolino F, Flepp R, Fasler S, Stammler P, Kazatchkine MD, Arese P (1987) Naturally occurring anti-band-3 antibodies and complement together mediate phagocytosis of oxidatively stressed human erythrocytes. Proc Natl Acad Sci U S A 84(21):7368–7372
Lutz HU, Stammler P, Fasler S (1990) How naturally occurring anti-band 3 antibodies stimulate C3b deposition to senescent and oxidatively stressed red blood cells. Biomed Biochim Acta 49(2–3):S224–S229
Mahajan RC, Narain K, Mahanta J (2011) Anaemia & expression levels of CD35, CD55 & CD59 on red blood cells in Plasmodium falciparum malaria patients from India. Indian J Med Res 133:662–664
Mastellos DC, Yancopoulou D, Kokkinos P, Huber-Lang M, Hajishengallis G, Biglarnia AR, Lupu F, Nilsson B, Risitano AM, Ricklin D, Lambris JD (2015) Compstatin: a C3-targeted complement inhibitor reaching its prime for bedside intervention. Eur J Clin Investig 45(4):423–440
Mayilyan KR (2012) Complement genetics, deficiencies, and disease associations. Protein Cell 3(7):487–496
Mibei EK, Orago AS, Stoute JA (2005) Immune complex levels in children with severe Plasmodium falciparum malaria. Am J Trop Med Hyg 72(5):593–599
Mibei EK, Otieno WO, Orago AS, Stoute JA (2008) Distinct pattern of class and subclass antibodies in immune complexes of children with cerebral malaria and severe malarial anaemia. Parasite Immunol 31(2):61–63
Moulds JM, Nickells MW, Moulds JJ, Brown MC, Atkinson JP (1991) The C3b/C4b receptor is recognized by the Knops, McCoy, Swain-langley, and York blood group antisera. J Exp Med 173(5):1159–1163
Moulds JM, Reveille JD, Arnett FC (1996) Structural polymorphisms of complement receptor 1 (CR1) in systemic lupus erythematosus (SLE) patients and normal controls of three ethnic groups. Clin Exp Immunol 105(2):302–305
Moulds JM, Kassambara L, Middleton JJ, Baby M, Sagara I, Guindo A, Coulibaly S, Yalcouye D, Diallo DA, Miller L, Doumbo O (2000) Identification of complement receptor one (CR1) polymorphisms in west Africa. Genes Immun 1(5):325–329
Moulds JM, Zimmerman PA, Doumbo OK, Kassambara L, Sagara I, Diallo DA, Atkinson JP, Krych-Goldberg M, Hauhart RE, Hourcade DE, McNamara DT, Birmingham DJ, Rowe JA, Moulds JJ, Miller LH (2001) Molecular identification of Knops blood group polymorphisms found in long homologous region D of complement receptor 1. Blood 97(9):2879–2885
Moulds JM, Thomas BJ, Doumbo O, Diallo DA, Lyke KE, Plowe CV, Rowe JA, Birmingham DJ (2004) Identification of the Kna/Knb polymorphism and a method for Knops genotyping. Transfusion 44(2):164–169
Nagayasu E, Ito M, Akaki M, Nakano Y, Kimura M, Looareesuwan S, Aikawa M (2001) CR1 density polymorphism on erythrocytes of falciparum malaria patients in Thailand. Am J Trop Med Hyg 64(1–2):1–5
Nyakoe NK, Taylor RP, Makumi JN, Waitumbi JN (2009) Complement consumption in children with Plasmodium falciparum malaria. Malar J 8:7
Odhiambo CO, Otieno W, Adhiambo C, Odera MM, Stoute JA (2008) Increased deposition of C3b on red cells with low CR1 and CD55 in a malaria-endemic region of western Kenya: implications for the development of severe anemia. BMC Med 6:23
Opi DH, Uyoga S, Orori EN, Williams TN, Rowe JA (2016) Red blood cell complement receptor one level varies with Knops blood group, alpha(+)thalassaemia and age among Kenyan children. Genes Immun 17(3):171–178
Owuor BO, Odhiambo CO, Otieno WO, Adhiambo C, Makawiti DW, Stoute JA (2007) Reduced immune complex binding capacity and increased complement susceptibility of red cells from children with severe malaria-associated anemia. Mol Med 14(3–4):89–97
Pawluczkowycz AW, Lindorfer MA, Waitumbi JN, Taylor RP (2007) Hematin promotes complement alternative pathway-mediated deposition of C3 activation fragments on human erythrocytes: potential implications for the pathogenesis of anemia in malaria. J Immunol 179(8):5543–5552
Phanuphak P, Hanvanich M, Sakulramrung R, Moollaor P, Sitprija V, Phanthumkosol D (1985) Complement changes in falciparum malaria infection. Clin Exp Immunol 59(3):571–576
Price RN, Simpson JA, Nosten F, Luxemburger C, Hkirjaroen L, ter Kuile F, Chongsuphajaisiddhi T, White NJ (2001) Factors contributing to anemia after uncomplicated falciparum malaria. Am J Trop Med Hyg 65(5):614–622
Rao N, Ferguson DJ, Lee SF, Telen MJ (1991) Identification of human erythrocyte blood group antigens on the C3b/C4b receptor. J Immunol 146(10):3502–3507
Reinagel ML, Gezen M, Ferguson PJ, Kuhn S, Martin EN, Taylor RP (1997) The primate erythrocyte complement receptor (CR1) as a privileged site: binding of immunoglobulin G to erythrocyte CR1 does not target erythrocytes for phagocytosis. Blood 89(3):1068–1077
Reyburn H, Mbatia R, Drakeley C, Bruce J, Carneiro I, Olomi R, Cox J, Nkya WM, Lemnge M, Greenwood BM, Riley EM (2005) Association of transmission intensity and age with clinical manifestations and case fatality of severe Plasmodium falciparum malaria. JAMA 293(12):1461–1470
Roestenberg M, McCall M, Mollnes TE, van DM, Sprong T, Klasen I, Hermsen CC, Sauerwein RW, van der Ven A (2007) Complement activation in experimental human malaria infection. Trans R Soc Trop Med Hyg 101(7):643–649
Rowe JA, Raza A, Diallo DA, Baby M, Poudiougo B, Coulibaly D, Cockburn IA, Middleton J, Lyke KE, Plowe CV, Doumbo OK, Moulds JM (2002) Erythrocyte CR1 expression level does not correlate with a HindIII restriction fragment length polymorphism in Africans; implications for studies on malaria susceptibility. Genes Immun 3(8):497–500
Stoute JA (2005) Complement-regulatory proteins in severe malaria: too little or too much of a good thing? Trends Parasitol 21(5):218–223
Stoute JA, Odindo AO, Owuor BO, Mibei EK, Opollo MO, Waitumbi JN (2003) Loss of red blood cell-complement regulatory proteins and increased levels of circulating immune complexes are associated with severe malarial anemia. J Infect Dis 187(3):522–525
Teeranaipong P, Ohashi J, Patarapotikul J, Kimura R, Nuchnoi P, Hananantachai H, Naka I, Putaporntip C, Jongwutiwes S, Tokunaga K (2008) A functional single-nucleotide polymorphism in the CR1 promoter region contributes to protection against cerebral malaria. J Infect Dis 198(12):1880–1891
Tettey R, Ayeh-Kumi P, Tettey P, Adjei GO, Asmah RH, Dodoo D (2015) Severity of malaria in relation to a complement receptor 1 polymorphism: a case-control study. Pathog Glob Health 109(5):247–252
Thathy V, Moulds JM, Guyah B, Otieno W, Stoute JA (2005) Complement receptor 1 polymorphisms associated with resistance to severe malaria in Kenya. Malar J 4:54
Thomas BN, Diallo DA, Noumsi GT, Moulds JM (2012) Circulating immune complex levels are associated with disease severity and seasonality in children with malaria from Mali. Biomark Insights 7:81–86
Tyagi P, Biswas S (1999) Naturally occurring plasmodia-specific circulating immune complexes in individuals of malaria endemic areas in India. Indian J Malariol 36(1–2):12–18
Van DS, Holers VM, Lublin DM, Atkinson JP (1987) The polymorphism of the C3b/C4b receptor in the normal population and in patients with systemic lupus erythematosus. Clin Exp Immunol 68(3):570–579
Waitumbi JN, Opollo MO, Muga RO, Misore AO, Stoute JA (2000) Red cell surface changes and erythrophagocytosis in children with severe Plasmodium falciparum anemia. Blood 95(4):1481–1486
Waitumbi JN, Donvito B, Kisserli A, Cohen JH, Stoute JA (2004) Age-related changes in red blood cell complement regulatory proteins and susceptibility to severe malaria. J Infect Dis 190(6):1183–1191
Wenisch C, Spitzauer S, Florris-Linau K, Rumpold H, Vannaphan S, Parschalk B, Graninger W, Looareesuwan S (1997) Complement activation in severe Plasmodium falciparum malaria. Clin Immunol Immunopathol 85(2):166–171
WHO (2000) Severe falciparum malaria. World Health Organization, Communicable Diseases Cluster. Trans R Soc Trop Med Hyg 94(Suppl 1):S1–S90
Wilson JG, Murphy EE, Wong WW, Klickstein LB, Weis JH, Fearon DT (1986) Identification of a restriction fragment length polymorphism by a CR1 cDNA that correlates with the number of CR1 on erythrocytes. J Exp Med 164(1):50–59
Wong WW, Cahill JM, Rosen MD, Kennedy CA, Bonaccio ET, Morris MJ, Wilson JG, Klickstein LB, Fearon DT (1989) Structure of the human CR1 gene. Molecular basis of the structural and quantitative polymorphisms and identification of a new CR1-like allele. J Exp Med 169(3):847–863
World Health Organization (2016) World Malaria Report 2016. World Health Organization
Xiang L, Rundles JR, Hamilton DR, Wilson JG (1999) Quantitative alleles of CR1: coding sequence analysis and comparison of haplotypes in two ethnic groups. J Immunol 163(9):4939–4945
Zimmerman PA, Fitness J, Moulds JM, McNamara DT, Kasehagen LJ, Rowe JA, Hill AV (2003) CR1 Knops blood group alleles are not associated with severe malaria in the Gambia. Genes Immun 4(5):368–373
Zoutendyk A, GEAR J (1951) Auto-antibodies in the pathogenesis of disease; a preliminary study of auto-sensitization of red cells in various diseases. S Afr Med J 25(37):665–668
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Stoute, J.A. (2018). Role of Complement in Severe Malarial Anemia. In: Stoute, J. (eds) Complement Activation in Malaria Immunity and Pathogenesis. Springer, Cham. https://doi.org/10.1007/978-3-319-77258-5_3
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