Influence of Polymorphism in the Genes for the Interleukin (IL)-1 Receptor Antagonist and IL-1β on Tuberculosis
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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 γ 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.
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Human polymorphisms of IL-1 genes are associated with susceptibility to tuberculosis.
“and human polymorphisms of IL-1 genes were associated with susceptibility to tuberculosis (99).”
From Macrophage defense mechanisms against intracellular bacteria (2015) · cites this paper as [99]
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- Authors
- Wilkinson, R. J., Patel, P., Llewelyn, M., Hirsch, C. S., Pasvol, G., Snounou, G., Davidson, R. N., & Toossi, Z.
- Affiliations
- Northwick Park Hospital (GB)
- Corresponding author
- Toossi, Zahra
- Venue
- The Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 1999-06-21
- Volume
- 189
- Issue
- 12
- Pages
- 1863-1874
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC2192963
- OpenAlex
- W2156995597
- Cited by
- 295
- References
- 58
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 7 · 2023: 3 · 2022: 3 · 2021: 3 · 2020: 8 · 2019: 4 · 2018: 9 · 2017: 7 · 2016: 6 · 2015: 11 · 2014: 9 · 2013: 10 · 2012: 9
- FWCI
- 14.57
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Experimental Medicine (publishedVersion)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Spiral (Imperial College London) (submittedVersion)
- Sussex Research Online (University of Sussex) (submittedVersion)
- Funders
- Wellcome Trust
- Imperial College London
- National Institutes of Health
- Medical Research Council
- National Institute of Allergy and Infectious Diseases (AI-18471)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Tuberculosis Research and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- interleukin-1 receptor antagonist, IL-1β, genetic polymorphism, host genetic susceptibility, Mycobacterium tuberculosis, pleural tuberculosis, tuberculin skin test
- MeSH terms
- Cell Division, Genotype, Haplotypes, Humans, Hypersensitivity, Delayed, Interleukin-1, Leukocytes, Mycobacterium tuberculosis, Polymorphism, Genetic, RNA, Messenger, Sialoglycoproteins, Tuberculin, Tuberculosis, Interleukin-4, Interleukin-6, Interleukin-10, Receptors, Interleukin-1, Interleukin 1 Receptor Antagonist Protein
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