title: The DBY gene codes for an HLA-DQ5-restricted human male-specific minor histocompatibility antigen involved in graft-versus-host disease.
abstract: Graft rejection or graft-versus-host (GVH) disease after HLA-identical stem cell transplantation is the result of recognition of minor histocompatibility antigens (mHags) by immunocompetent T lymphocytes from recipient or donor origin, respectively. Cytolytic T lymphocyte (CTL) clones can be isolated during graft rejection and GVH disease to identify mHags and their corresponding genes. Thus far, all human mHags identified appeared to be HLA class I-restricted. Here, we report the characterization of the first human HLA class II-restricted sex-linked mHag involved in GVH disease. Previously, we isolated an HLA-DQ5-restricted CD4(+) CTL clone from a male patient with chronic myeloid leukemia who developed acute GVH disease grade III-IV after transplantation of HLA genotypically identical female stem cells. Using a panel of female HLA-DQ5(+) EBV cells that we stably transfected with Y chromosome-specific genes, we determined that the HLA class II male-specific mHag (H-Y) was encoded by the Y chromosome-specific gene DBY. The H-Y epitope was localized in the DBY protein using female HLA-DQ5(+) peripheral blood mononuclear cells loaded with DBY protein fragments. The minimal peptide sequence leading to maximal recognition by the specific HLA-DQ5-restricted CTL clone was characterized as the 12-amino acid sequence HIENFSDIDMGE. Although the epitope differed by 3 amino acids from its X-homolog DBX, only 2 polymorphisms were shown to be essential for recognition by the CTL clone.
authors.affiliation: Department of Hematology, Leiden University Medical Center, The Netherlands. m.h.j.vogt@lumc.nl
authors.forename: Mario H J
authors.initials: MH
authors.lastname: Vogt
authors.forename: Joost W
authors.initials: JW
authors.lastname: van den Muijsenberg
authors.forename: Els
authors.initials: E
authors.lastname: Goulmy
authors.forename: Eric
authors.initials: E
authors.lastname: Spierings
authors.forename: Petra
authors.initials: P
authors.lastname: Kluck
authors.forename: Michel G
authors.initials: MG
authors.lastname: Kester
authors.forename: Ronald A
authors.initials: RA
authors.lastname: van Soest
authors.forename: Jan W
authors.initials: JW
authors.lastname: Drijfhout
authors.forename: Roel
authors.initials: R
authors.lastname: Willemze
authors.forename: J H Frederik
authors.initials: JH
authors.lastname: Falkenburg
mesh_terms: D000595:Amino Acid Sequence; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D053487:DEAD-box RNA Helicases; D018604:Epitope Mapping; D000939:Epitopes / Q000032:analysis / Q000235:genetics / Q000276:immunology; D005260:Female; D008040:Genetic Linkage; D006086:Graft vs Host Disease / Q000276:immunology*; D006683:HLA-DQ Antigens / Q000276:immunology*; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology; D006801:Humans; D008297:Male; D015778:Minor Histocompatibility Antigens / Q000235:genetics / Q000276:immunology*; D009842:Oligopeptides / Q000138:chemical synthesis / Q000276:immunology; D011506:Proteins / Q000235:genetics / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014998:Y Chromosome
chemical_list: D000939:Epitopes; D006683:HLA-DQ Antigens; C410042:HLA-DQ5 antigen; D000949:Histocompatibility Antigens Class II; D015778:Minor Histocompatibility Antigens; D009842:Oligopeptides; D011506:Proteins; C492034:DDX3Y protein, human; D053487:DEAD-box RNA Helicases