title: Aspartic acid homozygosity at codon 57 of HLA-DQ beta is associated with susceptibility to pulmonary tuberculosis in Cambodia.
abstract: After infection with Mycobacterium tuberculosis, clinical disease usually remains latent, contained by the host immune response. Although polymorphisms of HLA loci have been hypothesized to play a major role in the breakdown of latency, a functional link has not been established. Molecular-based HLA-typing methods were used to test the association of sets of HLA alleles encoding an aspartic acid at codon 57 of the HLA-DQ beta-chain (HLA-DQ beta57-Asp) with susceptibility to tuberculosis in a cohort of 436 pulmonary tuberculosis patients and 107 healthy controls from Cambodia. HLA class II null cells were transduced with HLA-DQ beta57-Asp or HLA-DQ beta57-Ala and evaluated for their ability to bind peptides from two immunogenic M. tuberculosis specific proteins, ESAT-6 and CFP-10. In this study, we report a highly significant association between progressive pulmonary tuberculosis and homozygosity for HLA-DQ beta57-Asp alleles. The presence of HLA-DQ beta57-Asp resulted in a significantly reduced ability to bind a peptide from the central region of the ESAT-6 protein. Furthermore, when this peptide was presented by an HLA-DQ beta57-Asp allele, Ag-specific IFN-gamma production from CD4+ T cells from tuberculosis patients was significantly less than when this peptide was presented by an HLA-DQ-beta allele encoding an alanine at codon 57. Multiple genetic loci and ethnic-specific factors are likely involved in the human immune response to tuberculosis. The data presented here provide a functional explanation for a highly significant association between an HLA polymorphism and tuberculosis in a highly characterized group of patients with susceptibility to progressive tuberculosis infection in Cambodia.
authors.affiliation: CBR Institute for Biomedical Research, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Julio C
authors.initials: JC
authors.lastname: Delgado
authors.forename: Andres
authors.initials: A
authors.lastname: Baena
authors.forename: Sok
authors.initials: S
authors.lastname: Thim
authors.forename: Anne E
authors.initials: AE
authors.lastname: Goldfeld
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D017951:Antigen Presentation; D000942:Antigens, Bacterial / Q000378:metabolism; D001224:Aspartic Acid / Q000235:genetics; D001426:Bacterial Proteins / Q000276:immunology / Q000378:metabolism; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002160:Cambodia; D016022:Case-Control Studies; D002460:Cell Line; D003062:Codon / Q000235:genetics; D015331:Cohort Studies; D004247:DNA / Q000235:genetics; D005260:Female; D006683:HLA-DQ Antigens / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D059866:HLA-DQ beta-Chains; D006720:Homozygote; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009169:Mycobacterium tuberculosis / Q000276:immunology / Q000472:pathogenicity; D011110:Polymorphism, Genetic; D011487:Protein Conformation; D014161:Transduction, Genetic; D014397:Tuberculosis, Pulmonary / Q000235:genetics* / Q000276:immunology*
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D003062:Codon; D006683:HLA-DQ Antigens; D059866:HLA-DQ beta-Chains; C057615:HLA-DQbeta antigen; D001224:Aspartic Acid; D007371:Interferon-gamma; D004247:DNA