Influence of Polymorphism in the Genes for the Interleukin (IL)-1 Receptor Antagonist and IL-1 b on Tuberculosis

Several lines of evidence suggest that host genetic factors controlling the immune response influence infection by Mycobacterium tuberculosis . The proinflammatory cytokine interleukin (IL)-1 b and its antagonist, IL-1Ra (IL-1 receptor agonist), are strongly induced by M . tuberculosis and are encoded by polymorphic genes. The induction of both IL-1Ra mRNA and secreted protein by M . tuberculosis in IL-1Ra allele A2–positive (IL-1Ra A2 1 ) healthy subjects was 1.9-fold higher than in IL-1Ra A2 2 subjects. The M . tuberculosis– induced expression of mRNA for IL-1 b was higher in subjects of the IL-1 b ( 1 3953) A1 1 haplotype ( P 5 0.04). The molar ratio of IL-1Ra/IL-1 b induced by M . tuberculosis was markedly higher in IL-1Ra A2 1 individuals ( P , 0.05), with minor overlap between the groups, reflecting linkage between the IL-1Ra A2 and IL-1 b ( 1 3953) A2 alleles. In M . tuberculosis –stimulated peripheral blood mononuclear cells, the addition of IL-4 increased IL-1Ra secretion, whereas interferon g increased and IL-10 decreased IL-1 b production, indicative of a differential influence on the IL-1Ra/IL-1 b ratio by cytokines. In a study of 114 healthy purified protein derivative–reactive subjects and 89 patients with tuberculosis, the frequency of allelic variants at two positions ( 2 511 and 1 3953) in the IL-1 b and IL-1Ra genes did not differ between the groups. However, the proinflammatory IL-1Ra A2 2 /IL-1 b ( 1 3953) A1 1 haplotype was unevenly distributed, being more common in patients with tuberculous pleurisy (92%) in comparison with healthy M . tuberculosis –sensitized control subjects or patients with other disease forms (57%, P 5 0.028 and 56%, P 5 0.024, respectively). Furthermore, the IL-1Ra A2 1 haplotype was associated with a reduced Mantoux response to purified protein derivative of M . tuberculosis : 60% of tuberculin-nonreactive patients were of this type. Thus, the polymorphism at the IL-1 locus influences the cytokine response and may be a determinant of delayed-type hypersensitivity and disease expression in human tuberculosis.