Volume 74, Issue 4
  • ISSN: 0002-9637
  • E-ISSN: 1476-1645


The high frequencies of both α+ thalassemia and the sickle cell trait (hemoglobin AS [HbAS]) found in many tropical populations are thought to reflect selection pressure from malaria. For HbAS, but not for α+ thalassemia, protection appears to be mediated by the enhanced phagocytic clearance of ring-infected erythrocytes. We have investigated the genotype-specific distributions of peripheral blood leukocyte populations in two groups of children living on the coast of Kenya: a group of healthy parasite-negative children sampled at cross-sectional survey during a period of low malaria transmission, and a group of children attending the hospital with acute malaria. We report distinctive distributions of peripheral blood myeloid dendritic cells and monocytes in children with α+ thalassemia and HbAS during healthy periods and disease, and suggest ways in which these might relate to the mechanisms of protection afforded by these conditions.


Article metrics loading...

Loading full text...

Full text loading...



  1. Banchereau J, Briere F, Caux C, Davoust J, Lebecque S, Liu Y-J, Pulendran B, Palucka K, 2000. Immunobiology of dendritic cells. Annu Rev Immunol 18 : 767–811.
  2. Facchetti F, Vermi W, Mason D, Colonna M, 2003. The plasmacytoid monocyte/interferon producing cells. Virchows Arch 443 : 703–717.
  3. Seixas E, Cross C, Quin S, Langhorne J, 2001. Direct activation of dendritic cells by the malaria parasite, Plasmodium chabaudi chabaudi. Eur J Immunol 31 : 2970–2978.
  4. Perry JA, Rush A, Wilson RJ, Olver CS, Avery AC, 2004. Dendritic cells from malaria-infected mice are fully functional APC. J Immunol 172 : 475–482.
  5. Leisewitz AL, Rockett KA, Gumede B, Jones M, Urban B, Kwiatkowski DP, 2004. Response of the splenic dendritic cell population to malaria infection. Infect Immun 72 : 4233–4239.
  6. Pichyangkul S, Yongvanitchit K, Kumarb U, Hemmi H, Akira S, Krieg AM, Heppner DG, Stewart VA, Hasegawa H, Looareesuwan S, Shanks GD, Miller RS, 2004. Malaria blood stage parasites activate human plasmacytoid dendritic cells and murine dendritic cells through a Toll-like receptor 9-dependent pathway. J Immunol 172 : 4926–4933.
  7. Krishnegowda G, Hajjar AM, Zhu J, Douglass EJ, Uematsu S, Akira S, Woods AS, Gowda DC, 2005. Induction of proinflammatory responses in macrophages by the glycosylphosphatidylinositols of Plasmodium falciparum: cell signaling receptors, glycosylphosphatidylinositol (GPI) structural requirement, and regulation of GPI activity. J Biol Chem 280 : 8606–8616.
  8. Urban BC, Ferguson DJ, Pain A, Willcox N, Plebanski M, Austyn JM, Roberts DJ, 1999. Plasmodium falciparum-infected erythrocytes modulate the maturation of dendritic cells. Nature 400 : 73–77.
  9. Urban BC, Mwangi T, Ross A, Kinyanjui S, Mosobo M, Kai O, Lowe B, Marsh K, Roberts DJ, 2001. Peripheral blood dendritic cells in children with acute Plasmodium falciparum malaria. Blood 98 : 2859–2861.
  10. Nyakeriga AM, Troye-Blomberg M, Chemtai AK, Marsh K, Williams TN, 2004. Malaria and nutritional status in children living on the coast of Kenya. Am J Clin Nutr 80 : 1604–1610.
  11. Friedman MJ, 1978. Erythrocytic mechanism of sickle cell resistance to malaria. Proc Natl Acad Sci USA 75 : 1994–1997.
  12. Pasvol G, Weatherall DJ, Wilson RJ, 1978. Cellular mechanism for the protective effect of haemoglobin S against P. falciparum malaria. Nature 274 : 701–703.
  13. Ayi K, Turrini F, Piga A, Arese P, 2004. Enhanced phagocytosis of ring-parasitized mutant erythrocytes: a common mechanism that may explain protection against falciparum malaria in sickle trait and beta-thalassemia trait. Blood 104 : 3364–3371.
  14. Aidoo M, Terlouw DJ, Kolczak MS, McElroy PD, ter Kuile FO, Kariuki S, Nahlen BL, Lal AA, Udhayakumar V, 2002. Protective effects of the sickle cell gene against malaria morbidity and mortality. Lancet 359 : 1311–1312.
  15. Williams TN, Mwangi TW, Wambua S, Alexander ND, Kortok M, Snow RW, Marsh K, 2005. Sickle cell trait and the risk of Plasmodium falciparum malaria and other childhood diseases. J Infect Dis 192 : 178–186.
  16. Allen SJ, O’Donnell A, Alexander ND, Alpers MP, Peto TE, Clegg JB, Weatherall DJ, 1997. alpha+-Thalassemia protects children against disease caused by other infections as well as malaria. Proc Natl Acad Sci USA 94 : 14736–14741.
  17. Williams TN, Wambua S, Uyoga S, Macharia A, Mwacharo JK, Newton CR, Maitland K, 2005. Both heterozygous and homozygous alpha+ thalassemias protect against severe and fatal Plasmodium falciparum malaria on the coast of Kenya. Blood 106 : 368–371.
  18. Mockenhaupt FP, Ehrhardt S, Gellert S, Otchwemah RN, Dietz E, Anemana SD, Bienzle U, 2004. Alpha(+)-thalassemia protects African children from severe malaria. Blood 104 : 2003–2006.
  19. Williams TN, Maitland K, Bennett S, Ganczakowski M, Peto TE, Newbold CI, Bowden DK, Weatherall DJ, Clegg JB, 1996. High incidence of malaria in alpha-thalassaemic children. Nature 383 : 522–525.
  20. Le Hesran JY, Personne I, Personne P, Fievet N, Dubois B, Beyeme M, Boudin C, Cot M, Deloron P, 1999. Longitudinal study of Plasmodium falciparum infection and immune responses in infants with or without the sickle cell trait. Int J Epidemiol 28 : 793–798.
  21. Marsh K, Otoo L, Hayes RJ, Carson DC, Greenwood BM, 1989. Antibodies to blood stage antigens of Plasmodium falciparum in rural Gambians and their relation to protection against infection. Trans R Soc Trop Med Hyg 83 : 293–303.
  22. Williams TN, Mwangi TW, Roberts DJ, Alexander ND, Weatherall DJ, Wambua S, Kortok M, Snow RW, Marsh K, 2005. An immune basis for malaria protection by the sickle cell trait. PLoS Med 2 : e128.
  23. Cabrera G, Cot M, Migot-Nabias F, Kremsner PG, Deloron P, Luty AJ, 2005. The sickle cell trait is associated with enhanced immunoglobulin G antibody responses to Plasmodium falciparum variant surface antigens. J Infect Dis 191 : 1631–1638.
  24. Luzzi GA, Merry AH, Newbold CI, Marsh K, Pasvol G, Weatherall DJ, 1991. Surface antigen expression on Plasmodium falciparum-infected erythrocytes is modified in alpha- and beta-thalassemia. J Exp Med 173 : 785–791.
  25. Williams TN, Weatherall DJ, Newbold CI, 2002. The membrane characteristics of Plasmodium falciparum-infected and -uninfected heterozygous alpha(0)thalassaemic erythrocytes. Br J Haematol 118 : 663–670.
  26. Williams TN, Mwangi TW, Wambua S, Peto TE, Weatherall DJ, Gupta S, Recker M, Penman BS, Uyoga S, Macharia A, Mwacharo JK, Snow RW, Marsh K, 2005. Negative epistasis between the malaria-protective effects of α+-thalassaemia and the sickle cell trait. Nat Genet 37 : 1253–1257.
  27. Dzionek A, Fuchs A, Schmidt P, Cremer S, Zysk M, Miltenyi S, Buck DW, Schmitz J, 2000. BDCA-2, BDCA-3, and BDCA-4: three markers for distinct subsets of dendritic cells in human peripheral blood. J Immunol 165 : 6037–6046.
  28. Rees DC, Williams TN, Maitland K, Clegg JB, Weatherall DJ, 1998. Alpha thalassaemia is associated with increased soluble transferrin receptor levels. Br J Haematol 103 : 365–369.
  29. Hagendorens MM, Ebo DG, Schuerwegh AJ, Huybrechs A, van Bever HP, Bridts CH, de Clerck LS, Stevens WJ, 2003. Differences in circulating dendritic cell subtypes in cord blood and peripheral blood of healthy and allergic children. Clin Exp Allergy 33 : 633–639.
  30. Vakkila J, Thomson AW, Vettenranta K, Sariola H, Saarinen-Pihkala UM, 2004. Dendritic cell subsets in childhood and in children with cancer: relation to age and disease prognosis. Clin Exp Immunol 135 : 455–461.
  31. 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 USA 101 : 272–277.
  32. Schrier SL, Rachmilewitz E, Mohandas N, 1989. Cellular and membrane properties of alpha and beta thalassemic erythrocytes are different: implication for differences in clinical manifestations. Blood 74 : 2194–2202.
  33. Chehimi J, Campbell DE, Azzoni L, Bacheller D, Papasavvas E, Jerandi G, Mounzer K, Kostman J, Trinchieri G, Montaner LJ, 2002. Persistent decreases in blood plasmacytoid dendritic cell number and function despite effective highly active antiretroviral therapy and increased blood myeloid dendritic cells in HIV-infected individuals. J Immunol 168 : 4796–4801.
  34. Longman RS, Talal AH, Jacobson IM, Rice CM, Albert ML, 2005. Normal functional capacity in circulating myeloid and plasmacytoid dendritic cells in patients with chronic hepatitis C. J Infect Dis 192 : 497–503.
  35. Pichyangkul S, Endy TP, Kalayanarooj S, Nisalak A, Yongvanitchit K, Green S, Rothman AL, Ennis FA, Libraty DH, 2003. A blunted blood plasmacytoid dendritic cell response to an acute systemic viral infection is associated with increased disease severity. J Immunol 171 : 5571–5578.
  36. Hviid L, Theander TG, Abdulhadi NH, Abu-Zeid YA, Bayoumi RA, Jensen JB, 1991. Transient depletion of T cells with high LFA-1 expression from peripheral circulation during acute Plasmodium falciparum malaria. Eur J Immunol 21 : 1249–1253.
  37. Birmingham DJ, Hebert LA, 2001. CR1 and CR1-like: the primate immune adherence receptors. Immunol Rev 180 : 100–111.
  38. Zhu J, Krishnegowda G, Gowda DC, 2005. Induction of proinflammatory responses in macrophages by the glycosylphosphatidylinositols of Plasmodium falciparum: the requirement of extracellular signal-regulated kinase, p38, c-Jun N-terminal kinase and NF-kappaB pathways for the expression of proinflammatory cytokines and nitric oxide. J Biol Chem 280 : 8617–8627.
  39. Coban C, Ishii KJ, Kawai T, Hemmi H, Sato S, Uematsu S, Yamamoto M, Takeuchi O, Itagaki S, Kumar N, Horii T, Akira S, 2005. Toll-like receptor 9 mediates innate immune activation by the malaria pigment hemozoin. J Exp Med 201 : 19–25.
  40. Leadbetter EA, Rifkin IR, Hohlbaum AM, Beaudette BC, Shlomchik MJ, Marshak-Rothstein A, 2002. Chromatin-IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors. Nature 416 : 603–607.
  41. Brittenham G, Lozoff B, Harris JW, Mayson SM, Miller A, Huisman TH, 1979. Sickle cell anemia and trait in southern India: further studies. Am J Hematol 6 : 107–123.
  42. Abu-Zeid YA, Abdulhadi NH, Theander TG, Hviid L, Saeed BO, Jepsen S, Jensen JB, Bayoumi RA, 1992. Seasonal changes in cell mediated immune responses to soluble Plasmodium falciparum antigens in children with haemoglobin AA and haemoglobin AS. Trans R Soc Trop Med Hyg 86 : 20–22.
  43. Abu-Zeid YA, Theander TG, Abdulhadi NH, Hviid L, Saeed BO, Jepsen S, Jensen JB, Bayoumi RA, 1992. Modulation of the cellular immune response during Plasmodium falciparum infections in sickle cell trait individuals. Clin Exp Immunol 88 : 112–118.
  44. Bayoumi RA, Abu-Zeid YA, Abdulhadi NH, Saeed BO, Theander TG, Hviid L, Ghalib HW, Nugud AH, Jepsen S, Jensen JB, 1990. Cell-mediated immune responses to Plasmodium falciparum purified soluble antigens in sickle-cell trait subjects. Immunol Lett 25 : 243–249.

Data & Media loading...

  • Received : 25 Aug 2005
  • Accepted : 06 Dec 2005

Most Cited This Month

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error