Abstract
Ph.D.
Heat shock proteins (HSP) (in particular hsp70) are increasingly synthesised
during and following exposure to stressful insults, playing an important role in
protection and adaptation. Protective effects of HSP concerning infection and
immunity include self/non-self discrimination, enhancement of the immune
response, immune protection, thermotolerance and cytoprotection from
inflammatory mediators (reactive oxygen species and cytokines). Considering
the general protective role of hsp70 and its specific immunological functions,
including antigen processing and presentation, variation in hsp 70 genes may
contribute towards differential coping with stress and disease susceptibility. In
humans, three members of the hsp70 gene family, hspl0-1, hsp70-2 and
hsp70-hom, were mapped to the MHC class Ill region approximately 280 kbp
centromeric to the TNFa gene and 92 kbp telomeric to the C2 gene.
Polymorphisms in MHC-Iocalized hsp70 genes have been implicated in
susceptibility to a number of diseases, independently or in combination with
class II polymorphisms due to linkage disequilibrium (LD). MHC alleles are most
often associated with immunosuppressive diseases. Tuberculosis (TB) has a
strong immunological basis, involving cell-mediated immunity with human
leukocyte antigen (HLA) variants implicated in its susceptibility/resistance. In the
light of the above, the role of hsp70 polymorphism in TB susceptibility, alone or
in combination with MHC class II alleles, was investigated through the following
objectives:
1) Typing of hsp70 gene polymorphism (hsp70-1, hsp70-2 and hsp70-hom) in
controls and TB cases from the Cape Coloured population of South Africa
2) Comparison between Cape Coloureds and Caucasoid populations with
regard to hsp70 allele and genotype distribution
3) Studying linkage disequilibrium between members of MHC class II (HLADRB1)
and Ill (hsp70) alleles in the Cape Coloureds
4) Simulation of MHC class II and Ill haplotypes in this particular population
Hsp70 polymorphism was studied in controls (n=106) and TB cases (n=107)
from the complex hybrid Cape Coloured population inhabiting the Western
Cape region of South Africa - a population showing increased susceptibility to
TB. PCR-RFLP and PAGE analysis were used to determine the hsp70 allele
frequencies and genotype distribution of the individuals studied, while linkage
disequilibrium between MHC class II and Ill, and within class Ill alleles, was
investigated using the software "Graphical Overview of Linkage Disequilibruim"
(GOLD). Haplotypes comprising MHC class II and Ill alleles were simulated
using the software PHASE.