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

From the ^* Division of Infectious Diseases, Case Western Reserve University, Cleveland, Ohio 44106-4984; and the 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)-1β 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-1β was higher in subjects of the IL-1β (+3953) A1⁺ haplotype (P = 0.04). The molar ratio of IL-1Ra/IL-1β 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-1β (+3953) A2 alleles. In M. tuberculosis–stimulated peripheral blood mononuclear cells, the addition of IL-4 increased IL-1Ra secretion, whereas interferon increased and IL-10 decreased IL-1β production, indicative of a differential influence on the IL-1Ra/IL-1β 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-1β and IL-1Ra genes did not differ between the groups. However, the proinflammatory IL-1Ra A2^–/IL-1β (+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

Dr. C.L. King (Case Western Reserve University) is thanked for providing DNA samples from Kenya. We are grateful to Drs. P.A. Zimmerman and J.J. Ellner for their critical review of the manuscript. We are grateful to the clinical, microbiological, and secretarial staff of Northwick Park Hospital, particularly Dr. R.A. Wall, Dr. M.G. Harries, Dr. M. Latif, and Miss Dina Shah. Manijeh Phillips and Beverly Hamilton are thanked for technical assistance. Dr. Carlos Moreno of King's College Hospital Medical School, London is thanked for encouraging this project in its early stages.

R.J. Wilkinson is a Wellcome Trust Fellow in Clinical Tropical Medicine. Additional support was provided by the National Institutes of Health (grant AI-18471), to P. Patel by an MSc studentship from Imperial College of Science, Technology and Medicine, and by the Medical Research Council of the United Kingdom.

Abbreviations used: DTH, delayed-type hypersensitivity; PPD, purified protein derivative; rt, room temperature.

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