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Trop Med Int Health. Clin Diagn Lab Immuno. CAS Google Scholar. Nat Immunol. Download references. You can also search for this author in PubMed Google Scholar. Correspondence to Bryan Greenhouse. LG performed a comprehensive review of the primary literature and drafted the manuscript.
SP, PJR and BG reviewed and identified additional primary literature, directed the organization of the manuscript and edited the manuscript. All authors read and approved the final version of the manuscript. Reprints and Permissions. Gong, L. Biochemical and immunological mechanisms by which sickle cell trait protects against malaria. Malar J 12, Download citation. Received : 09 April Accepted : 31 August Clinical experience has shown that, not surprisingly, this combination is highly dangerous.
Of special note is the fact that normally the spleen plays an important role in filtering and removing parasitized red cells: but patients with SCA regularly have an impaired splenic function: often to the extent of functional asplenia, and sometimes the functional asplenia evolves to anatomical atrophy of the spleen from multiple infarcts so-called auto-splenectomy.
In an era of evidence-based medicine it is still not uncommon that hypothetical propositions are stated as facts. By contrast, it is quite remarkable that the protective effect of the Hb S gene against malaria is still portrayed as a hypothesis when it is, in fact, one of the best documented examples in the human species of balanced polymorphism, in which the severe disease of homozygotes SS or SCA is balanced by the advantage of AS heterozygotes.
Malaria and sickle cell anaemia are still major challenges to infectious disease medicine and to haematology respectively, and both are also major public health problems. One might have hoped that what we have learnt about the of advantage of AS heterozygotes with respect to malaria would enable us to protect from malaria mortality other people as well. That this has not yet happened is disappointing but perhaps not surprising, because the key is sickling of red cells, and this is a unique phenomenon.
It cannot be a straightforward task to mimic sickling by a pharmacological approach in subjects who do not have Hb S, and in a way that would act selectively only on parasitized red cells.
We can still hope that human imagination will evolve novel approaches that can match the power of mutation and selection in biological evolution.
In the meantime SCA remains a source of great suffering to patients, especially in those developing countries where the numbers are staggering see Table 1. It is urgent that more is done in order to offer to these patients a better way of life: this ought to include optimal management of pain, often hydroxyurea and, especially in Africa, 34 protection against the potentially fatal threat of P falciparum malaria.
If, as doctors, we have a professional obligation towards all of our patients, for those with SCA we have an added human obligation, if we consider that they carry the genetic burden that has helped human populations to survive in malaria-endemic regions of the world.
I am taking this opportunity to thank all patients with sickle cell anemia from whom I have learnt about the disease through their Hospital and Clinic visits in Ibadan, London, New York and Firenze. Competing interests: The author has declared that no competing interests exist. National Center for Biotechnology Information , U. Mediterr J Hematol Infect Dis. Published online Oct 3. Lucio Luzzatto. Author information Article notes Copyright and License information Disclaimer.
Correspondence to: Prof. Lucio Luzzatto, Istituto Toscano Tumori. Via Taddeo Alderotti 26N, , Firenze. E-mail: ti. Received Aug 31; Accepted Sep 1. Copyright notice. This article has been cited by other articles in PMC. Abstract Sickle cell anaemia is a major chapter within haemolytic anaemias; at the same time, its epidemiology is a remarkable signature of the past and present world distribution of Plasmodium falciparum malaria.
Balanced Polymorphism Many fundamental experiments in genetics have been carried out in micro-organisms, and biological selection is a good example. Table 1 Theoretical and real life examples in the epidemiology of the sickle cell trait and of sickle cell anaemia.
Open in a separate window. Figure 1. Table 2 Protective mechanisms against malaria deployed by polymorphic genes expressed in red cells.
Basic Mechanisms Example Comments References 1. Impaired intra- erythrocytic growth P fal in Hb CC red cells Haemoglobin C interferes with ability of parasite to remodel host cell cytoskeleton 25 ; 37 ; 38 3.
Enhanced removal of parasitized red cells Hb AS red cells sickle preferentially when they are P fal infected Suicidal infection 39 : parasitised sickled cells are phagocytosed see Fig. Probably applies also to parasitized G6PD deficient red cells 16 ; 40 ; Figure 2. Conclusion In an era of evidence-based medicine it is still not uncommon that hypothetical propositions are stated as facts.
Acknowledgement I am taking this opportunity to thank all patients with sickle cell anemia from whom I have learnt about the disease through their Hospital and Clinic visits in Ibadan, London, New York and Firenze. Footnotes Competing interests: The author has declared that no competing interests exist. References 1. Sickle cell anemia, a molecular disease.
Ingram VM. A specific chemical difference between the globins of normal human and sickle cell anaemia haemoglobin. Muirhead H, Perutz MF. Structure of Haemoglobin. Perutz MF, Lehmann H. Molecular pathology of human hemoglobin. Crystal structure of sickle-cel deoxyhemoglobin at 5 resolution. Journal of Molecular Biology. Polymorphism of DNA sequence adjacent to human beta-globin structural gene: relationship to sickle mutation.
Haldane JBS. The causes of evolution. Disease and evolution. Ricerca Sci. Lopez-Revilla R, Bastarrachea F. SCT came from places where malaria is the main cause of death, so anything that provides protection has a good chance of being passed on. However, in places where malaria is not a threat, having SCT is not helpful. It leads to sickle cell disease, which lowers life expectancy and causes major health problems.
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What is malaria? What are the symptoms of malaria? How are malaria and sickle cell disease connected? Compared to those with normal hemoglobin and malaria, people with SCT and malaria: 1, Have lower hospital admissions Have milder cases of malaria Have lower rates of blood transfusions Are less likely to die from malaria Are less likely to get bacteremia blood infection How does sickle cell trait protect against malaria?
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