Polymorphisms and Lack of or Aberrant Expression of HLA Class I and II May Influence Antigen Presentation in Classical Hodgkin Lymphoma.

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In a previously performed population-based genetic screening analysis we found that polymorphisms in the HLA class I region are specifically associated with EBV-positive classical Hodgkin lymphoma(cHL)(Diepstra et al., Lancet 2005; 365:2216). We now studied the expression of HLA class I and HLA class II in this population (n=450) by immunohistochemistry. HLA-B/C, HLA-G, beta-2-microglobulin and HLA-DP/DQ/DR staining was performed on formalin fixed paraffin embedded tissue sections, and HLA-DM and HLA-DO staining on frozen sections. Hodgkin-Reed Sternberg (HRS) cells showed cell surface expression of HLA class I in 37.5% (159/424) of cHL tumors and expression was observed predominantly in EBV-positive cases (73%; 103/141). Expression of HLA-G, a molecule known to enable evasion from natural killer cell responses, was found in 67% of the cases and was associated with absence of MHC class I and EBV. Only 58% of cHL cases showed HLA class II positive staining in more than 50% of the HRS cells (224/387). The non-classical HLA class II protein HLA-DM, essential for the loading of HLA class II with antigenic peptides was reduced or absent in HRS cells in 7 out of 10 HLA class II positive cases, whereas HLA-DO, the natural repressor of HLA-DM, was not or minimally expressed. Impaired expression of HLA-DM may prevent presentation of antigens at the level of individual HRS cells. Reanalysis of the genotyping data revealed an association of HLA class I positive cases with the known susceptibility polymorphisms in the HLA class I region. However, this association was stronger for the EBV-positive cases than for the HLA class I positive cases. Within the group of EBV-positive cHL patients, the same predisposing alleles were present in both HLA class I negative and positive cases, suggesting that the negative cases probably did express HLA class I during early pathogenesis. Finally, in cases with HLA class II expression on the HRS cells, a genetic association with the HLA class II region was found. These changes may influence (EBV) antigen presentation by HRS cells in cHL.