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

Shah, Javeed A, Warr, Alex J, Graustein, Andrew D, Saha, Aparajita, Dunstan, Sarah J, Thuong, Nguyen T T, Thwaites, Guy E, Caws, Maxine ORCID: https://orcid.org/0000-0002-9109-350X, Thai, Phan V K, Bang, Nguyen D, Chau, Tran T H, Khor, Chiea Chuen, Li, Zheng, Hibberd, Martin, Chang, Xuling, Nguyen, Felicia K, Hernandez, Carlo A, Jones, Madison A, Sassetti, Christopher M, Fitzgerald, Katherine A, Musvosvi, Munyaradzi, Gela, Anele, Hanekom, Willem A, Hatherill, Mark, Scriba, Thomas J and Hawn, Thomas R (2022) 'REL and BHLHE40 Variants Are Associated with IL-12 and IL-10 Responses and Tuberculosis Risk.'. The Journal of Immunology, Vol 208, Issue 6, pp. 1352-1361.

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Abstract

The major human genes regulating -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 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. [Abstract copyright: Copyright © 2022 by The American Association of Immunologists, Inc.]

Item Type:	Article
Subjects:	QU Biochemistry > Cells and Genetics > QU 350 Cellular structures QW Microbiology and Immunology > Reference Works. General Immunology > QW 520 Research (General) WF Respiratory System > Tuberculosis > WF 200 Tuberculosis (General)
Faculty: Department:	Clinical Sciences & International Health > Clinical Sciences Department
Digital Object Identifer (DOI):	https://doi.org/10.4049/jimmunol.2100671
SWORD Depositor:	JISC Pubrouter
Depositing User:	JISC Pubrouter
Date Deposited:	07 Jul 2022 12:42
Last Modified:	23 Aug 2023 14:16
URI:	https://archive.lstmed.ac.uk/id/eprint/20091

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