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REL and BHLHE40 Variants Are Associated with IL-12 and IL-10 Responses and Tuberculosis Risk

Shah, JA; Warr, AJ; Graustein, AD; Saha, A; Dunstan, SJ; Thuong, NTT; Thwaites, GE; ... Hawn, TR; + view all (2022) REL and BHLHE40 Variants Are Associated with IL-12 and IL-10 Responses and Tuberculosis Risk. The Journal of Immunology , 208 (6) pp. 1352-1361. 10.4049/jimmunol.2100671.

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Abstract

The major human genes regulating Mycobacterium tuberculosis-induced immune responses and tuberculosis (TB) susceptibility are poorly understood. Although IL-12 and IL-10 are critical for TB pathogenesis, the genetic factors that regulate their expression in humans are unknown. CNBP, REL, and BHLHE40 are master regulators of IL-12 and IL-10 signaling. We hypothesized that common variants in CNBP, REL, and BHLHE40 were associated with IL-12 and IL-10 production from dendritic cells, and that these variants also influence adaptive immune responses to bacillus Calmette-Guérin (BCG) vaccination and TB susceptibility. We characterized the association between common variants in CNBP, REL, and BHLHE40, innate immune responses in dendritic cells and monocyte-derived macrophages, BCG-specific T cell responses, and susceptibility to pediatric and adult TB in human populations. BHLHE40 single-nucleotide polymorphism (SNP) rs4496464 was associated with increased BHLHE40 expression in monocyte-derived macrophages and increased IL-10 from peripheral blood dendritic cells and monocyte-derived macrophages after LPS and TB whole-cell lysate stimulation. SNP BHLHE40 rs11130215, in linkage disequilibrium with rs4496464, was associated with increased BCG-specific IL-2+CD4+ T cell responses and decreased risk for pediatric TB in South Africa. SNPs REL rs842634 and rs842618 were associated with increased IL-12 production from dendritic cells, and SNP REL rs842618 was associated with increased risk for TB meningitis. In summary, we found that genetic variations in REL and BHLHE40 are associated with IL-12 and IL-10 cytokine responses and TB clinical outcomes. Common human genetic regulation of well-defined intermediate cellular traits provides insights into mechanisms of TB pathogenesis.

Type: Article
Title: REL and BHLHE40 Variants Are Associated with IL-12 and IL-10 Responses and Tuberculosis Risk
Location: United States
DOI: 10.4049/jimmunol.2100671
Publisher version: https://doi.org/10.4049/jimmunol.2100671
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Science & Technology, Life Sciences & Biomedicine, Immunology, GENOME-WIDE ASSOCIATION, MYCOBACTERIUM-TUBERCULOSIS, GENETIC ARCHITECTURE, SUSCEPTIBILITY LOCI, CYTOKINE EXPRESSION, IMMUNE-RESPONSES, POLYMORPHISMS, PROTECTION, RESISTANCE, DISEASES
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Infection and Immunity
URI: https://discovery.ucl.ac.uk/id/eprint/10171015
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