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Title: Immunogenetic analysis of patients with HTLV-I infection : associations with HLA, cytokine and perforin gene polymorphisms
Author: Rafatpanah Baygi, Houshang
ISNI:       0000 0001 3504 4386
Awarding Body: University of Manchester
Current Institution: University of Manchester
Date of Award: 2003
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Human T lymphotropic virus type (HTLV-I) is associated with HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP) and adult T-cell leukaemia (ATL). Fewer than 2% of HTLV-I-infected individuals develop HAM/TSP. The different outcome of HTLV-I infection may be explained by the existence of viral agents, genetic background or even environmental factors. In the initial part of this study we determined if there was a correlation between cytokine gene polymorphisms, mainly Thl and Th2, in Iranian patients with HAM/TSP, asymptomatic HTLV-I carriers and healthy controls. It was shown that polymorphisms in the TNF-alpha gene promoter at position -308, in TGF-beta1 gene at codons 10_and 25, in IL-10 at positions -1082, -819, -592, in IFN-gamma at position +874, in IL-13 at position +2043 and in IL-4 at position -590 correlates with differential production of these cytokines in vitro. There was a significant difference between HAM/TSP patients and healthy controls in the distribution of IL-10 promoter polymorphisms at position -819 and -592 (p=0.01) and HTLV-I carriers and healthy controls (p=0.02). The frequency of the IL-10 low producer haplotype (ATA) was significantly associated with HAM/TSP compared with healthy controls (p=0.01) and HTLV-I carriers with healthy controls (p=0.02). These data suggest that IL-10 -819 and -592 polymorphisms are associated with HTLV-I infection. However, how this influences HAM/TSP patients and HTLV-I carriers remain unknown. In contrast, we failed to detect any differences in the frequencies of other cytokines between any of the three groups. In this part, we also analysed the influence of HLA class II DRB1 alleles and class I HLA-A2, A-30, CW8 and B54 alleles in all three groups. The frequency of the HLA-DRB1*01 allele was significantly increased in HAM/TSP patients compared with carriers (p=0.03). In contrast, the distribution of HLA-DRB1*014 was higher in HTLV-I carriers compared to HAM/TSP patients (p=0.03). There was also a significant difference in the frequency of HLA-CW8 between HAM/TSP patients and healthy controls (p=0.01). HLA typing suggests that HLA-DRB1*01 and HLA-CW8 are relative risk factors for development to HAM/TSP, whereas possession of the HLA-DRB1*014 allele decreases the risk of HAM/TSP. In this case, the role of other genetic backgrounds should be taken into account. The second part of this study was to define GM-CSF polymorphisms and to seek association between GM-CSF polymorphism and HTLV-I infection. The 5'-flanking region, promoter, exon 1 and 2 and 3'UTR of GM-CSF was screened for detection of polymorphism by SSCP and sequencing. Three novel polymorphisms were found in the 5'-flanking region of GM-CSF at positions -677*A/C, -1440*A/G and -1916*T/C, relative to the translation start site. Mitogenic stimulation of PBMCs from healthy controls showed no correlation between GM-CSF gene polymorphisms and protein level. However, a gel shift assay demonstrated that the -611*A allele binds the transcriptional factor TEF-2 better than the -677*C allele. The frequencies of GM-CSF polymorphisms were the same in all of the HTLV-I groups and controls. In the third part of our study, we screened the promoter and first intron of the perforin gene, as a key factor in elimination of viral-infected cells, to determine novel polymorphisms. A novel polymorphism at position +418 relative to the transcription start site was detected. Results from flow cytometry and Western blotting in non stimulated and stimulated PBMCs showed no association between perforin gene polymorphism and perforin expression. The frequency of the +418*C allele in HAM/TSP patients was significantly increased compared with healthy controls (p=0.015). There was also a difference in the distribution of +418*C allele between HAM/TSP patients and HTLV-I carriers, but this did not reach significant levels (p=0.09). This result suggests that the +418*C allele acts as genetic risk factor for development of HAM/TSP.
Supervisor: Hutchinson, Ian Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Immunology ; Virology