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-1 on Tuberculosis

By 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)-1 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-1 was higher in subjects of the IL-1 (+3953) A1⁺ haplotype (P = 0.04). The molar ratio of IL-1Ra/IL-1 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-1 (+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-1 production, indicative of a differential influence on the IL-1Ra/IL-1 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-1 and IL-1Ra genes did not differ between the groups. However, the proinflammatory IL-1Ra A2/IL-1 (+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.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

• Fernando, S. L., Saunders, B. M., Sluyter, R., Skarratt, K. K., Goldberg, H., Marks, G. B., Wiley, J. S., Britton, W. J. (2007). A Polymorphism in the P2X7 Gene Increases Susceptibility to Extrapulmonary Tuberculosis. Am. J. Respir. Crit. Care Med. 175: 360-366 [Abstract] [Full Text]  
• Newton, S. M., Smith, R. J., Wilkinson, K. A., Nicol, M. P., Garton, N. J., Staples, K. J., Stewart, G. R., Wain, J. R., Martineau, A. R., Fandrich, S., Smallie, T., Foxwell, B., Al-Obaidi, A., Shafi, J., Rajakumar, K., Kampmann, B., Andrew, P. W., Ziegler-Heitbrock, L., Barer, M. R., Wilkinson, R. J. (2006). A deletion defining a common Asian lineage of Mycobacterium tuberculosis associates with immune subversion. Proc. Natl. Acad. Sci. USA 103: 15594-15598 [Abstract] [Full Text]  
• Nambu, A., Nakae, S., Iwakura, Y. (2006). IL-1{beta}, but not IL-1{alpha}, is required for antigen-specific T cell activation and the induction of local inflammation in the delayed-type hypersensitivity responses. Int Immunol 18: 701-712 [Abstract] [Full Text]  
• Wang, Z. C., Hill, J. A., Yunis, E. J., Xiao, L., Anderson, D. J. (2006). Maternal CD46H*2 and IL1B-511*1 homozygosity in T helper 1-type immunity to trophoblast antigens in recurrent pregnancy loss. Hum Reprod 21: 818-822 [Abstract] [Full Text]  
• Delgado, J. C., Baena, A., Thim, S., Goldfeld, A. E. (2006). Aspartic Acid Homozygosity at Codon 57 of HLA-DQ {beta} Is Associated with Susceptibility to Pulmonary Tuberculosis in Cambodia. J. Immunol. 176: 1090-1097 [Abstract] [Full Text]  
• Elkington, P. T. G., Emerson, J. E., Lopez-Pascua, L. D. C., O'Kane, C. M., Horncastle, D. E., Boyle, J. J., Friedland, J. S. (2005). Mycobacterium tuberculosis Up-Regulates Matrix Metalloproteinase-1 Secretion from Human Airway Epithelial Cells via a p38 MAPK Switch. J. Immunol. 175: 5333-5340 [Abstract] [Full Text]  
• Stewart, G. R., Wilkinson, K. A., Newton, S. M., Sullivan, S. M., Neyrolles, O., Wain, J. R., Patel, J., Pool, K.-L., Young, D. B., Wilkinson, R. J. (2005). Effect of Deletion or Overexpression of the 19-Kilodalton Lipoprotein Rv3763 on the Innate Response to Mycobacterium tuberculosis. Infect. Immun. 73: 6831-6837 [Abstract] [Full Text]  
• Awomoyi, A. A., Charurat, M., Marchant, A., Miller, E. N., Blackwell, J. M., McAdam, K. P.W.J., Newport, M. J. (2005). Polymorphism in IL1B: IL1B--511 association with tuberculosis and decreased lipopolysaccharide-induced IL-1{beta} in IFN-{gamma} primed ex-vivo whole blood assay. Innate Immunity 11: 281-286 [Abstract]  
• Wilkinson, K. A., Stewart, G. R., Newton, S. M., Vordermeier, H. M., Wain, J. R., Murphy, H. N., Horner, K., Young, D. B., Wilkinson, R. J. (2005). Infection Biology of a Novel {alpha}-Crystallin of Mycobacterium tuberculosis: Acr2. J. Immunol. 174: 4237-4243 [Abstract] [Full Text]  
• Dorman, S. E., Hatem, C. L., Tyagi, S., Aird, K., Lopez-Molina, J., Pitt, M. L. M., Zook, B. C., Dannenberg, A. M. Jr., Bishai, W. R., Manabe, Y. C. (2004). Susceptibility to Tuberculosis: Clues from Studies with Inbred and Outbred New Zealand White Rabbits. Infect. Immun. 72: 1700-1705 [Abstract] [Full Text]  
• Price, N. M., Gilman, R. H., Uddin, J., Recavarren, S., Friedland, J. S. (2003). Unopposed Matrix Metalloproteinase-9 Expression in Human Tuberculous Granuloma and the Role of TNF-{alpha}-Dependent Monocyte Networks. J. Immunol. 171: 5579-5586 [Abstract] [Full Text]  
• Murillo, L. S., Land, J. A., Pleijster, J., Bruggeman, C. A., Pena, A. S., Morre, S. A. (2003). Interleukin-1B (IL-1B) and interleukin-1 receptor antagonist (IL-1RN) gene polymorphisms are not associated with tubal pathology and Chlamydia trachomatis-related tubal factor subfertility. Hum Reprod 18: 2309-2314 [Abstract] [Full Text]  
• Lopez-Maderuelo, D., Arnalich, F., Serantes, R., Gonzalez, A., Codoceo, R., Madero, R., Vazquez, J. J., Montiel, C. (2003). Interferon-{gamma} and Interleukin-10 Gene Polymorphisms in Pulmonary Tuberculosis. Am. J. Respir. Crit. Care Med. 167: 970-975 [Abstract] [Full Text]  
• Barton, P. T., Gerber, S., Skupski, D. W., Witkin, S. S. (2003). Interleukin-1 Receptor Antagonist Gene Polymorphism, Vaginal Interleukin-1 Receptor Antagonist Concentrations, and Vaginal Ureaplasma urealyticum Colonization in Pregnant Women. Infect. Immun. 71: 271-274 [Abstract] [Full Text]  
• Karplus, T. M., Jeronimo, S. M. B., Chang, H., Helms, B. K., Burns, T. L., Murray, J. C., Mitchell, A. A., Pugh, E. W., Braz, R. F. S., Bezerra, F. L., Wilson, M. E. (2002). Association between the Tumor Necrosis Factor Locus and the Clinical Outcome of Leishmania chagasi Infection. Infect. Immun. 70: 6919-6925 [Abstract] [Full Text]  
• Griffin, W. S. T., Mrak, R. E. (2002). Interleukin-1 in the genesis and progression of and risk for development of neuronal degeneration in Alzheimer's disease. J. Leukoc. Biol. 72: 233-238 [Abstract] [Full Text]  
• Lipsitch, M., Sousa, A. O. (2002). Historical Intensity of Natural Selection for Resistance to Tuberculosis. Genetics 161: 1599-1607 [Abstract] [Full Text]  
• van Crevel, R., Ottenhoff, T. H. M., van der Meer, J. W. M. (2002). Innate Immunity to Mycobacterium tuberculosis. Clin. Microbiol. Rev. 15: 294-309 [Abstract] [Full Text]  
• Francis, S E, Camp, N J, Burton, A J, Dewberry, R M, Gunn, J, Stephens-Lloyd, A, Cumberland, D C, Gershlick, A, Crossman, D C (2001). Interleukin 1 receptor antagonist gene polymorphism and restenosis after coronary angioplasty. Heart 86: 336-340 [Abstract] [Full Text]  
• Canaday, D. H., Wilkinson, R. J., Li, Q., Harding, C. V., Silver, R. F., Boom, W. H. (2001). CD4+ and CD8+ T Cells Kill Intracellular Mycobacterium tuberculosis by a Perforin and Fas/Fas Ligand-Independent Mechanism. J. Immunol. 167: 2734-2742 [Abstract] [Full Text]  
• VAMVAKOPOULOS, J, MADHOK, R (2001). Interleukin 1 gene polymorphisms. Ann Rheum Dis 60: 718a-719 [Full Text]  
• Marquet, S., Schurr, E. (2001). Genetics of Susceptibility to Infectious Diseases: Tuberculosis and Leprosy as Examples. Drug Metab. Dispos. 29: 479-483 [Full Text]  
• Ghigo, E., Capo, C., Raoult, D., Mege, J.-L. (2001). Interleukin-10 Stimulates Coxiella burnetii Replication in Human Monocytes through Tumor Necrosis Factor Down-Modulation: Role in Microbicidal Defect of Q Fever. Infect. Immun. 69: 2345-2352 [Abstract] [Full Text]  
• Chackerian, A. A., Perera, T. V., Behar, S. M. (2001). Gamma Interferon-Producing CD4+ T Lymphocytes in the Lung Correlate with Resistance to Infection with Mycobacterium tuberculosis. Infect. Immun. 69: 2666-2674 [Abstract] [Full Text]  
• Wilkinson, K. A., Martin, T. D., Reba, S. M., Aung, H., Redline, R. W., Boom, W. H., Toossi, Z., Fulton, S. A. (2000). Latency-Associated Peptide of Transforming Growth Factor beta Enhances Mycobacteriocidal Immunity in the Lung during Mycobacterium bovis BCG Infection in C57BL/6 Mice. Infect. Immun. 68: 6505-6508 [Abstract] [Full Text]  
• Dewberry, R., Holden, H., Crossman, D., Francis, S. (2000). Interleukin-1 Receptor Antagonist Expression in Human Endothelial Cells and Atherosclerosis. Arterioscler. Thromb. Vasc. Bio. 20: 2394-2400 [Abstract] [Full Text]  
• WHYTE, M., HUBBARD, R., MELICONI, R., WHIDBORNE, M., EATON, V., BINGLE, C., TIMMS, J., DUFF, G., FACCHINI, A., PACILLI, A., FABBRI, M., HALL, I., BRITTON, J., JOHNSTON, I., DI GIOVINE, F. (2000). Increased Risk of Fibrosing Alveolitis Associated with Interleukin-1 Receptor Antagonist and Tumor Necrosis Factor-alpha Gene Polymorphisms. Am. J. Respir. Crit. Care Med. 162: 755-758 [Abstract] [Full Text]  
• Opal, S. M., DePalo, V. A. (2000). Anti-Inflammatory Cytokines. Chest 117: 1162-1172 [Abstract] [Full Text]  

Home | Help | Feedback | Subscriptions | Archive | Search

TABLE OF CONTENTS