Influence of polymorphism in the genes for the interleukin (IL)-1 receptorantagonist and IL-1 beta on tuberculosis

Several lines of evidence suggest that host genetic factors controlling the immune response influence infection by Mycobacterium tuberculosis. The pro inflammatory cytokine interleukin (IL)-1 beta and its antagonist, IL-1Ra (I L-1 receptor agonist), are strongly induced by M tuberculosis and are encod ed by polymorphic genes. The induction of both IL-1Ra mRNA and secreted pro tein by M. tuberculosis in IL-1Ra allele Aa-positive (IL-1Ra A2(+)) healthy subjects was 1.9-fold higher than in IL-1Ra A2(-) subjects. The M. tubercu losis-induced expression of mRNA for IL-IP was higher in subjects of the IL -1 beta (+3953) Al+ haplotype (P = 0.04). The molar ratio of IL-1Ra/IL-1 be ta induced by M tuberculosis was markedly higher in IL-1Ra A2(+) individual s (P < 0.05), with minor overlap between the groups, reflecting linkage bet ween the IL-1Ra A2 and IL-1 beta (+3953) A2 alleles. In M. tuberculosis-sti mulated peripheral blood mononuclear cells, the addition of IL-4 increased IL-1Ra secretion, whereas interferon gamma increased and IL-10 decreased IL -1 beta production, indicative of a differential influence on the IL-1Ra/IL -1 beta ratio by cytokines. In a study of 114 healthy purified protein deri vative-reactive subjects and 89 patients with tuberculosis, the frequency o f allelic variants at two positions (-511 and +3953) in the IL-1 beta and I L-1Ra genes did not differ between the groups. However, the proinflammatory IL-1Ra A2(-)/IL-1 beta (+3953) Al+ haplotype was unevenly distributed, bei ng more common in patients with tuberculous pleurisy (92%) in comparison wi th healthy M.. tuberculosis-sensitized control subjects or patients with ot her disease forms (57%, P = 0.028 and 56%, P = 0.024, respectively). Furthe rmore, the IL-1Ra A2(+) haplotype was associated with a reduced Mantoux res ponse 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.