Crawley, Esther Madeleine; (2000) The role of interleukin 10 in children with juvenile idiopathic arthritis. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

This thesis investigates the function of the IL-10 5' flanking region haplotypes and the association of these haplotypes in children with Juvenile Idiopathic Arthritis (JIA). We have shown that children with extended oligoarticular JIA are less likely to have a genotype containing the ATA haplotype than children with oligoarticular JIA (p<0.05, OR = 1.9,95% Cl: 1 to 3.5). The ATA haplotype is associated with lower reporter gene expression in transfection studies (Crawley, 1999c). The ATA/ATA genotype was shown to be associated with lower IL-10 production using whole blood culture in controls (p<0.02). This is consistent with the observation that mean IL-10 production was lower in the parents of those with extended oligoarticular disease when compared to the parents of children with oligoarticular disease (p=0.03, 95% Cl 88 to 2016). A similar effect was seen in asthma where those with severe asthma were less likely to have ATA containing genotypes than controls (p=0.04, OR1.57, Cl: 1.01 to 2). We did not show a difference in genotype distribution between patients with SLE and controls. The transmission disequilibrium test (TDT) demonstrated an increase in transmission of the ATA haplotype to patients with oligoarticular onset JIA (p=0.05). There was also increased transmission of both the ACC and the ATA haplotype to patients with uveitis (p=0.014 for each transmission). Strong linkage disequilibrium was demonstrated (p<0.0005) between these haplotypes and a microsatellite at -1000 in the IL-10 5' flanking region which has previously been shown to be associated with rheumatoid arthritis and systemic lupus erythematosus. Treatment of patients with methylprednisolone was associated with large changes in ex vivo stimulated IL-10 production which was strongly correlated with the change in ESR (correlation coefficient 0.922, p<0.01). To investigate whether the IL-10 5' flanking region haplotypes affected transcription, THP-1 cells were transfected with IL-10 luciferase DNA reporter constructs. Overall, reporter gene expression was higher with the GCC than the ATA construct when the THP-1 cells were transfected using Effectene Liposomes (median fold difference 1.71, range 1.12 to 5.49).

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