| Abstract |
The Human Leukocyte Antigen (HLA) region on the short arm of chromosome 6
includes the classical HLA genes and in addition HLA-related and non-HLA
related genes. The majority of the genes located in this region are
directly or indirectly involved in the immune response. The polymorphic
HLA molecules, encoded by the HLA genes, bind endogenous and exogenous
peptides. Stable bound peptides are recognized by CD4+ and CD8+ T-cells,
which elicit a humoral or cytotoxic immune response to pathogens. The
immunological function of HLA molecules in transplantation has been widely
studied. The role of HLA in autoimmune disease and cancer however is less
obvious. In head and neck squamous cell carcinoma (HNSCC) aberrant HLA
expression patterns have been observed on primary tumour cells and lymph
node metastases, suggesting an aberrant immune response. Whether the
aberrant expression resides in the HLA genes themselves or is as a result
of other genes within the HLA region is poorly understood. This thesis
describes how the HLA region on the short arm of chromosome 6 is
associated with the pathogenesis of HNSCC. Associations with particular
HLA-B alleles and HLA-B-DRB1 haplotypes were identified. However, since
few patients carried these alleles and haplotype, this could not be the
primary risk factor for the pathogenesis of HNSCC. The MICA gene is in
linkage disequilibrium with HLA-B and involved in the innate and adaptive
immune system. Allelic polymorphism for the MICA gene was evaluated with a
refined method for determination of MICA allele polymorphism based upon
the combination of nucleotide polymorphisms in exons 2, 3 and 4 and repeat
polymorphism in exon 5. No differences in MICA allelic polymorphism were
identified between patients and controls. Repeat length polymorphism,
present in the MICA transmembrane region and encoded by exon 5, revealed a
significant decrease in the frequency for the MICA-A9 repeat in the
patients. Analysis of MICA protein expression indicated that the majority
of tumours expressed MICA. The expression of MICA was not correlated with
the length of the repeat present in the transmembrane region. To evaluate
the role of non-HLA related genes, located within the HLA region and which
confer susceptibility to HNSCC, disease-associated regions were defined
using microsatellite analysis in pooled DNA analysis. Microsatellite
analysis revealed three associated regions, one in the class I region and
two in the class II region. From the associated regions 18 genes were
selected and evaluated for their RNA expression in tumour tissue compared
to surrounding healthy tissue. MICA RNA expression was significantly
increased in tumour tissue while a significant decrease in RNA expression
was observed for hydroxysteroid (17-beta) dehydrogenase 8 (HSD17B8) in
tumour tissue. For retinoid X receptor beta (RXRbeta) and NOTCH4 a
decreased, but non-significant, RNA expression in tumour tissue was
observed. These results show that apart from HLA genes also other genes in
the HLA region are associated with the pathogenesis of HNSCC.
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