Editors' ChoiceTuberculosis

Too Much of a Good Thing: Finding an IL1B Polymorphism That Increases Tuberculosis Susceptibility

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Science Translational Medicine  29 Oct 2014:
Vol. 6, Issue 260, pp. 260ec187
DOI: 10.1126/scitranslmed.aaa1237

Tuberculosis (TB) is a chronic bacterial disease caused by Mycobacterium tuberculosis (Mtb) that kills ~1.4 million people every year. A portion of Mtb-infected people develop active disease, characterized by a progressive inflammatory pathology of the lung. Proinflammatory cytokines, such as interleukin-1 β (IL-1β), play an important role in promoting initial resistance to Mtb infection. However, uncontrolled IL-1β production must be avoided to prevent chronic tissue damage. It remains unknown whether exaggerated IL-1β is detrimental during chronic Mtb infection and by which molecular mechanisms IL-1β affects the progressive inflammatory pathology in the lung during Mtb infection.

Zhang et al. sought to determine naturally occurring polymorphisms in the human IL1B promoter region that could influence the outcome of human TB and to examine the molecular consequences involved in these events. Although a number of single nucleotide polymorphisms (SNPs) in the IL1B gene have been identified and associated with Mtb susceptibility, a definite role of IL1B SNPs remains to be determined. The authors performed a number of correlative analyses between SNPs, production of IL-1β, neutrophil recruitment, bacterial killing, and severity of the disease. They found three SNPs located within the known IL1B promoter region: -31 T>C (rs1143627), -511 G>A (rs16944), and -1473 G>C (rs1143623). The authors identified that the polymorphism rs1143627T correlates with high-IL-1β, but not IL1 receptor antagonist-expressing monocytes, which was associated with increased risk of active tuberculosis and poor clinical outcome. The authors then found that single base change in the IL1B promoter increased the synergistic activity of the transcription factors C/EBPβ and PU.1 that increases IL-1β expression in monocytes and PBMC. Surprisingly, the rs1143627T allele does not impair the antimycobacterial adaptive immune response but promotes neutrophil infiltration to the lung of infected patients. Taken together, these results indicated that the rs1143627T allele is associated with more severe pulmonary TB and the expression of extrapulmonary disease.

In summary, individuals carrying the high–IL-1β–producing rs1143627T allele are more prone to develop active TB, to have severe pathology in the lung, and to harbor extrapulmonary lesions by increasing neutrophil recruitment and actions.

G. Zhang et al., Allele-specific induction of IL-1β expression by C/EBPβ and PU.1 contributes to increased tuberculosis susceptibility. PLoS Pathog. 10.1371/journal.ppat.1004426 (2014). [Full Text]

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