Journal
JOURNAL OF IMMUNOLOGY
Volume 176, Issue 2, Pages 1090-1097Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.176.2.1090
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- NHLBI NIH HHS [HL67471, HL59838] Funding Source: Medline
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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 beta 57-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 beta 57-Asp or HLA-DQ beta 57-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 1357-Asp alleles. The presence of HLA-DQ 1357-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 beta 57-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.
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