Identification of HLA-DQalpha and -DRbeta residues associated with susceptibility and protection to epithelial ovarian cancer.
Substantial evidence has been accumulated suggesting that T cells in patients with epithelial ovarian carcinoma (EOC) exhibit an antigen-driven immune response directed against the tumor cells. In the context of human leukocyte antigen (HLA), this suggests its possible involvement in the disease. Therefore, we examined the distribution of the HLA-DRB1*, -DQA1*, and -DQB1* alleles in 47 patients with EOC and 67 healthy Caucasian women. The frequency of D(70) and E(71) polymorphic residues of the DRB1 alleles was significantly reduced in EOC patients versus controls (pD(70)E(71) = 0.009), suggesting a protective role against the disease. The DQalpha residues R(52) and Y(11)R(55) were increased in the patients (p = 0.008 and 0.012, respectively). Because residues 11 and 55 participate in the formation of pocket 1, they may be functionally important amino acid positions that influence disease susceptibility. The frequency of the DQalpha susceptibility epitope (R(52)Y(11)R(55)) among the DRbetaD(70)E(71)-positive EOC patients was increased when compared with DRbetaD(70)E(71)-positive controls (EOC, 100%; control, 52%; p = 0.028). Among individuals without the DQalpha susceptibility epitope, the distribution of DRbetaD(70)E(71)-positive cases was significantly different between EOC patients and controls (EOC, 0%; control, 60%; p = 0.039). Therefore, it appears that the presence of DQalpha susceptibility elements overrides the protective effect of the DRbetaD(70)E(71) epitope and suggests an interactive relationship between DRbeta and DQalpha epitopes that may be of importance for disease susceptibility. Because positions DRbeta 70,71 and DQalpha 52 have been implicated in immunologic diseases, it is likely that besides being critical for T-cell recognition, they may also play a role in T-cell development and acquisition of the T-cell repertoire.
Monos
Dimitri S
DS
Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
Pappas
John
J
Magira
Eleni E
EE
Gaughan
John
J
Aplenc
Richard
R
Sakkas
Lazaros
L
Freedman
Ralph
R
Reveille
John D
JD
Platsoucas
Chris D
CD
D000595:Amino Acid Sequence / Q000235:genetics; D004198:Disease Susceptibility / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology; D005260:Female; D005787:Gene Frequency / Q000235:genetics / Q000276:immunology; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006683:HLA-DQ Antigens / Q000235:genetics* / Q000276:immunology; D059848:HLA-DQ alpha-Chains; D006684:HLA-DR Antigens / Q000235:genetics* / Q000276:immunology; D006650:Histocompatibility Testing; D006801:Humans; D008969:Molecular Sequence Data; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics* / Q000276:immunology; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000276:immunology; D011110:Polymorphism, Genetic / Q000235:genetics / Q000276:immunology
D018984:Epitopes, T-Lymphocyte; D006683:HLA-DQ Antigens; D059848:HLA-DQ alpha-Chains; C069050:HLA-DQA1 antigen; D006684:HLA-DR Antigens