Effect of Interactions between Pro-Inflammatory Cytokines And Iron In Malaria-Infected Pregnant Women In ABA, Nigeria.
Journal Title: International Journal of Medical Science and Innovative Research (IJMSIR) - Year 2018, Vol 3, Issue 12
Abstract
Cytokines are agonists and among the inflammatory mediators secreted principally by activated immune cells (1). They induce various transcription factors which in turn determine the fate of cells either for proliferation, differentiation, maturation or death (2). Activation of immune cells could be caused by infectious or non-infectious conditions. Most infections that activate immune cells include malaria and HIV (1,3,4,5) while non-infectious conditions include pregnancy (3,6) and iron-replete states, among others (7,8,9). Functionally, cytokines may be classified as pro and anti-inflammatory molecules1. The pro-inflammatory cytokines promote inflammation and drive immunity to cell mediated response1 while anti-inflammatory cytokines regulate the actions of pro-inflammatory cytokines and drive immunity to humoral response. The pro-inflammatory cytokines include IL1, IL6, TNFα and IFNγ. The pro-inflammatory cytokine enhances the killing of malaria parasites1 and are critical intermediates for clinical manifestations (10,11). In early pregnancy, the pro-inflammatory cytokines are known for immune-survelliance against pathogens (12); however, their upregulation at the materno-foetal interphase may compromise the viability of the foetus (13,14). Pro-inflammatory cytokine levels in pregnancy may be greatly exacerbated by infection with malaria. It is reported that cytokine secretion modulates iron levels (15) while iron chelation increases Th1-mediated immune response in P. falciparum infection (16), an effect that is associated with more efficient clearance of the parasite (17). Increased cytokine levels thus effectively reduce the iron available and consequently, the haemoglobin in circulation. On the other hand, iron is essential in the synthesis of haemoglobin and myoglobin as well as the proper functioning of some enzymes required for proper body metabolism. The body iron is obtained from dietary sources, mostly from meat and dark green vegetables. The dietary iron occurs as haem and non-haem iron; however, non-haem iron is the predominant form. Cereals, vegetables and cooking utensils are the major sources of non-haem iron while meat appears to be the major source of haem iron (18). One of the effects of maternal malaria infection is anaemia. Malaria alone without other adverse events is responsible for up to 26% of anaemia cases in pregnancy (19) in those developing countries in which malaria is endemic. In addition, malaria contributes as much as 23% of the pregnancy-related deaths in these countries (19). However, even without malaria, pregnancy is a state in which there is generally a reduction in the level of maternal haemoglobin as a result of the expanded blood volume caused by the new foetus (20,21,22). The modulation of iron levels in malaria by cytokines during pregnancy should therefore be a cause for concern as this is capable of further depressing the circulating haemoglobin level. One of the ways by which malaria reduces blood haemoglobin is by haemolysis of parasitized red blood cells (23). There is no effective excretory mechanism for iron; however, small amount of iron is lost on daily basis through various routes, even in health. In health, it is lost by desquamation, mostly by sloughing of the enterocytes through the skin and urinary tract (15). Some iron obtained from destruction of effete red cells is however recycled and brought back into the circulation for incorporation into new cells. It is also known that not all erythroblasts develop to maturation; some may die in the marrow and the iron salvaged by the macrophages (23). At the surface of the erythroids and other cells that require iron are transferrin receptors that receive iron from transferrin. Iron then enters the cells by endocytosis and is followed by series of reactions that result in the release of iron in the cytosol (18). The iron in the store could be mobilized to the circulation when it is required. The storage of iron is regulated by hepcidin; the major regulatory hormone and an inflammatory protein (24). Hepcidin binds to its putative receptor ferroportin and the binding determines the retention or the release of iron by the macrophages (9, 25). It is known that reduced iron levels protect the foetus against malaria. Again, low availability of iron in the maternal circulation restricts the amount of iron transferred to the foetus in pregnant women exposed to malaria infection, thus protecting the child against malaria ailments; the consequence may be the eventual development of iron deficiency anaemia when the baby is born. It has been stated that functional iron deficiency may result from high hepcidin concentrations that limits dietary iron absorption (24). Increased hepcidin production by hepatic cells may be induced by excess dietary iron, slowed rate of red blood cell production and inflammation (26). Inflammation is reflected in the raised blood level of C-reactive protein (C-RP). There appears to be a link between malaria, elevated levels of hepcidin and C-RP, since malaria induces inflammation that raises the levels of these biomarkers. In iron deficiency, the amount of iron-sulphur (4Fe- 4S) is relatively low, allowing for effective binding of Iron Regulatory Protein-1 (IRP1) with Iron Regulatory (responsive) Element (IRE) at 3’ downstream unsaturated region of the mRNA. This interaction increases the translation of TfR1mRNA which results in iron uptake. Conversely, the high amount of iron-sulphur in iron-replete states results in low iron uptake. Binding at the 5’ upstream unsaturated region increases the translation of ferritin mRNA resulting in increased iron store (18,23,27,28). Levels of iron in the body could be assessed by evaluating haemoglobin levels, red cell indices and assay of serum ferritin along with evidence of inflammation, infection and liver disease (29). The best combination would be estimations of haemoglobin or haematocrit, serum transferrin receptor and serum ferritin. Such a combination would reflect functional impairment, tissue avidity and iron storage (30). Evaluating C-reactive protein is commonly used to assess infection/ inflammation (1,31). Under regulated conditions, sufficient amount of cytokines and iron are required to enhance immunity. Ironically, interactions between the two molecules may modulate iron and this impairs immunity. This study is therefore aimed at determining the effects of interactions between pro-inflammatory cytokines (IFNγ, TNFα and IL6) and Iron as measured by haemoglobin (Hb), serum transferrin (sTfR) and serum ferritin (SF)] in malaria parasite infected pregnant women. It is with a view to assessing the effect of the relationship between these cytokines and iron on the immune status of the pregnant woman. The findings of this study will provide understanding to one key cause of the impaired immunity of pregnant women with malaria; so that appropriate intervention can ensure successful pregnancy outcome.
Authors and Affiliations
Dr. Ayodele O. Ilesanmi
Keywords
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