The Journal of Experimental Medicine
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J. Exp. Med., Volume 189, Number 12, June 21, 1999 1863-1874

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

By Robert J. Wilkinson,*Dagger Punita Patel,Dagger Martin Llewelyn,Dagger Christina S. Hirsch,* Geoffrey Pasvol,Dagger Georges Snounou,Dagger Robert N. Davidson,Dagger and Zahra Toossi*

From the * Division of Infectious Diseases, Case Western Reserve University, Cleveland, Ohio 44106-4984; and the Dagger  Wellcome Center for Clinical Tropical Medicine, Imperial College School of Medicine, Northwick Park Hospital, Harrow HA1 3UJ, United Kingdom

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.

Key words: interleukin 1 receptor;  tuberculosis;  susceptibility, disease;  hypersensitivity, delayed;  granuloma


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