Relationship between interleukin 10 responses, endemic burkitt's lymphoma and toll-like receptor 9 polymorphisms among children in a malaria holoendemic area

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dc.contributor.authorMulama, Kandira Hughes David
dc.date.accessioned2011-12-06T06:43:43Z
dc.date.available2011-12-06T06:43:43Z
dc.date.issued2011-12-06
dc.descriptionThe RC 643.M8en_US
dc.description.abstractEndemic Burkitt's lymphoma (eBL), the most common childhood cancer in equatorial Africa is associated with exposure to holoendemic Plasmodium falcipar um malaria and infantile infection with Epstein-Barr virus (EBV). The mechanisms by which these two infectious pathogens interact to increase the risk of tumorigenesis are however unknown. It has recently been reported that P. falciparum may stimulate EBV latently infected B cells via Toll-like receptor 9 (TLR9). Toll-like receptor 9, a pattern recognition receptor, is central to the recognition of double stranded microbial unmethylated CpG motifs and promotes the secretion of proinflammatory cytokines. Polymorphisms in TLR9 have been associated with increased susceptibility to human diseases due to altered immune responses. This receptor contains 20 single nucleotide polymorphisms (SNPs) that may modulate immune responses to CpG motifs. The frequencies of the four most common TLR9 SNPs (-1486, -1174, 1174 and 2848) among children residing in two regions of western Kenya with differential malaria transmission patterns and their association with eBL is principally undefined. As such, TLR9 genotypes were determined in children diagnosed with eBL admitted at Nyanza Provincial General Hospital (n=23), from a malaria holoendemic region (n = 30) and from a region of unstable malaria transmission (n = 29). Alongside these study population, 19 adult controls were recruited. The study further investigated the functional role of TLR9 polymorphisms in the expression of interleukin-10 (IL-10) upon TLR9 ligand (CpG ODN) stimulation ex vivo in these four study populations. TLR9 genotypes were determined by multiplex Ligation Detection Reaction (LDR). The IL-10 level was determined by use of Enzyme Linked Immunosorbent Assay (ELISA). The proportion of B cells was determined by flow cytometry. Results revealed that IL-10 levels significantly varied according to the degree of malaria exposure and TLR9 genotypes at low cell concentration (p < 0.05, ANOVA). There was significant difference in expression of CD3, CD 19 and CD45 (p=0.002, 0.008 and 0.011 respectively) between the three groups. Results further showed that children with eBL had an inverse correlation with mean IL-10 level and age suggesting that decreases in IL-10 may allow a milieu permissive for eBL tumorigenesis after increases in EBV viral loads (p< 0.05). It also revealed that there was no significant variation in the frequencies of TLR9 SNPs across the three study groups. Although there was no significantly increased risk of developing eBL with any particular TLR9 allele, (p > 0.05, OR; 0.61, 95 % Cl, 1-14 for all the alleles), those who had the rare allele within the promoter region of the gene had low IL-10 response, while those with both alleles in the post promoter region of the gene increased the responsiveness to CpG ODNs. Allelic frequencies at position +1174 in eBL children though not significant were uniquely different from children in malaria endemic and low transmission areas. This study highlights the fact that apart from environmental factors, genetic factors and indeed polymorphisms in TLR9 could be playing a significant role in the aetiology of endemic Burkitt's lymphoma by controlling the intensity of IL-10 response. Findings from this study have implications on the use of CpG ODNs in vaccine production as adjuvants especially in paediatric populations that are co-infected with P. falciparum and EBV. Future studies are warranted to investigate how malaria infections influence innate immune responses to EBV as a putative mechanism in eBL lympen_US
dc.description.sponsorshipKenyatta Universityen_US
dc.identifier.urihttp://ir-library.ku.ac.ke/handle/123456789/1894
dc.language.isoenen_US
dc.subjectBurkitt's lymphoma//Leukemia//Malaria--Immunological aspects//Interlukinsen_US
dc.titleRelationship between interleukin 10 responses, endemic burkitt's lymphoma and toll-like receptor 9 polymorphisms among children in a malaria holoendemic areaen_US
dc.typeThesisen_US
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