Classical Hodgkin lymphoma: population based studies on HLA and EBV

Classical HL is a hematological malignancy in which immunological interactions are crucially involved. The neoplastic HRS cells use a variety of strategies to evade immune reactions, but also shape the immune response to their own benefit. Antigen presentation may be involved in both of these mechanisms. The significance of antigen presentation is supported by an inherited susceptibility to cHL that has been associated with HLA class I and HLA class II alleles and haplotypes (the sequence of alleles on one chromosome; chapter 2). Because antigenic peptides derived from latent EBV proteins elicit EBV specific immune responses in most individuals, differences in the function of antigen presentation can be expected when comparing EBV positive with EBV negative CHL patients. In this thesis aspects of antigen presentation in cHL are explored with an emphasis on HLA associated genetic susceptibility, HLA protein expression and EBV. The studies were performed in a population based approach, including 418 cHL patients diagnosed between 1987 and 2000 in the northern region of the Netherlands. In chapter three the clinicopathologic characteristics of this population are described as well as the impact of tumour EBV status on prognosis. Chapter four describes a genotyping study in which the entire HLA region of 200 cHL patients was screened with microsatellite markers. One association was found in the HLA class I region and this association was specific for EBV positive cHL patients. Subsequent genetic fine-screening of the associated HLA class I region with single nucleotide polymorphisms (SNPs) was performed to identify susceptibility loci for EBV positive cHL. This indicated a possible involvement of the HLA-A gene. In chapter five the HLA-A gene was examined for polymorphisms that might affect the presentation of EBV derived antigenic peptides. Chapter six describes expression of HLA class I proteins on HRS cells in diagnostic lymph node biopsies. Cells that lack cell surface HLA class I proteins are threatened by cytotoxic NK cell responses. Cytotoxic NK and CTL responses can he inhibited by a HLA class I related molecule, called HLA-G. Therefore, protein expression of HLA-G by HRS cells was investigated. In chapter seven the expression of HLA class II protein on HRS cells was related to genotyping data and clinical outcome.