A.G. Smith

Comprehensive Analysis of HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 Loci and Squamous Cell Cervical Cancer Risk

Variation in human major histocompatibility genes may influence the risk of squamous cell cervical cancer (SCC) by altering the efficiency of the T-cell-mediated immune response to human papillomavirus (HPV) antigens. We used high-resolution methods to genotype human leukocyte antigen (HLA) class I (A, B, and Cw) and class II (DRB1 and DQB1) loci in 544 women with SCC and 542 controls. Recognizing that HLA molecules are codominantly expressed, we focused on co-occurring alleles. Among 137 allele combinations present at >5% in the case or control groups, 36 were significantly associated with SCC risk. All but one of the 30 combinations that increased risk included DQB1*0301, and 23 included subsets of A*0201-B*4402-Cw*0501-DRB1*0401-DQB1*0301. Another combination, B*4402-DRB1*1101-DQB1*0301, conferred a strong risk of SCC (odds ratio, 10.0; 95% confidence interval, 3.0-33.3). Among the six combinations that conferred a decreased risk of SCC, four included Cw*0701 or DQB1*02. Most multilocus results were similar for SCC that contained HPV16; a notable exception was A*0101-B*0801-Cw*0701-DRB1*0301-DQB1*0201 and its subsets, which were associated with HPV16-positive SCC (odds ratio, 0.5; 95% confidence interval, 0.3-0.9). The main multilocus associations were replicated in studies of cervical adenocarcinoma and vulvar cancer. These data confirm that T helper and cytotoxic T-cell responses are both important cofactors with HPV in cervical cancer etiology and indicate that co-occurring HLA alleles across loci seem to be more important than individual alleles. Thus, certain co-occurring alleles may be markers of disease risk that have clinical value as biomarkers for targeted screening or development of new therapies.

T-cell clones identify three distinct epitopes associated with HLA-Dw14.

Alloreactive T-cell clones were used to study allodeterminants associated with the HLA-DR1, -DR4, and -DRw14 allelic families. Three clones derived by priming against the DR4,Dw14 alloantigen were tested against a panel of HLA-D homozygous B-cell lines and homozygous and heterozygous peripheral blood lymphocytes. Each clone was blocked by monoclonal antibodies specific for HLA-DR, but not HLA-DQ or -DP, molecules, and each showed a unique pattern of allorecognition when tested against the cell panel. Clone 14B appeared to recognize a specific sequence, termed L67-A74, comprised of amino acids in the third hypervariable region of the alpha-helix of the DR beta 1 molecule, and expressed on certain DR1-, DR4-, and DRw14-positive cells. Clone EMO25 recognized the same L67-A74 sequence, but only when expressed on DR4-positive cells, suggesting a role for residues in the first and second hypervariable regions of DR4-positive DR beta 1 molecules in T-cell recognition. Clone EM036 also recognized the L67-A74 sequence, but only when expressed on DR4,Dw14.1-positive cells, implicating residues at positions 57 and 86 of the alpha-helix in T-cell recognition. These results demonstrate the range of specific T-cell responses that are possible against alloepitopes expressed by a single class II allele (Dw14), and are an indication of the diverse regions of the class II molecule that can contribute to allorecognition sites.