title: Influence of polymorphism in the genes for the interleukin (IL)-1 receptor antagonist and IL-1beta on tuberculosis.
abstract: Several lines of evidence suggest that host genetic factors controlling the immune response influence infection by Mycobacterium tuberculosis. The proinflammatory cytokine interleukin (IL)-1beta 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(+)) healthy subjects was 1.9-fold higher than in IL-1Ra A2(-) subjects. The M. tuberculosis-induced expression of mRNA for IL-1beta was higher in subjects of the IL-1beta (+3953) A1(+) haplotype (P = 0.04). The molar ratio of IL-1Ra/IL-1beta induced by M. tuberculosis was markedly higher in IL-1Ra A2(+) individuals (P < 0.05), with minor overlap between the groups, reflecting linkage between the IL-1Ra A2 and IL-1beta (+3953) A2 alleles. In M. tuberculosis-stimulated peripheral blood mononuclear cells, the addition of IL-4 increased IL-1Ra secretion, whereas interferon gamma increased and IL-10 decreased IL-1beta production, indicative of a differential influence on the IL-1Ra/IL-1beta 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 (-511 and +3953) in the IL-1beta and IL-1Ra genes did not differ between the groups. However, the proinflammatory IL-1Ra A2(-)/IL-1beta (+3953) A1(+) 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 = 0.028 and 56%, P = 0. 024, respectively). Furthermore, the IL-1Ra A2(+) 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.
authors.affiliation: Division of Infectious Diseases, Case Western Reserve University, Cleveland, Ohio 44106-4984, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: Wilkinson
authors.forename: P
authors.initials: P
authors.lastname: Patel
authors.forename: M
authors.initials: M
authors.lastname: Llewelyn
authors.forename: C S
authors.initials: CS
authors.lastname: Hirsch
authors.forename: G
authors.initials: G
authors.lastname: Pasvol
authors.forename: G
authors.initials: G
authors.lastname: Snounou
authors.forename: R N
authors.initials: RN
authors.lastname: Davidson
authors.forename: Z
authors.initials: Z
authors.lastname: Toossi
mesh_terms: D002455:Cell Division / Q000235:genetics / Q000276:immunology; D005838:Genotype; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000235:genetics / Q000276:immunology; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000235:genetics*; D016753:Interleukin-10 / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D007962:Leukocytes / Q000276:immunology / Q000378:metabolism; D009169:Mycobacterium tuberculosis / Q000235:genetics / Q000276:immunology*; D011110:Polymorphism, Genetic; D012333:RNA, Messenger / Q000235:genetics; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors*; D012795:Sialoglycoproteins / Q000235:genetics*; D014373:Tuberculin / Q000276:immunology; D014376:Tuberculosis / Q000235:genetics / Q000276:immunology
chemical_list: C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D015850:Interleukin-6; D012333:RNA, Messenger; D017472:Receptors, Interleukin-1; D012795:Sialoglycoproteins; D014373:Tuberculin; D016753:Interleukin-10; D015847:Interleukin-4