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

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.

CD30 co-stimulation drives differentiation of protective T cells during Mycobacterium tuberculosis infection

“…Expression of several immune genes by granuloma T cells positively correlated with bacterial loads. BHLHE40 is a transcription factor that has previously been observed in granuloma T cells in Mtb-infected macaques ( Gideon et al, 2022 ), and variants of this gene have been associated with TB risk in humans ( Shah et al, 2022 ). In mice, BHLHE40 has been shown to be a central regulator in the production of pro- versus anti-inflammatory T cells, as it promotes IFNγ while simultaneously inhibiting IL-10 production ( Yu et al, 2018 ).…”

Risk Genetic Variants (IL-10) for Osteoporosis in Han Population from Northwest China

“…This determines that IL-10 has important and broad clinical application prospects in autoimmune and gene therapy of inflammatory diseases. In recent years, a correlation between IL-10 genetic polymorphism and various disease risks has been reported, including tuberculosis, 21 periodontitis, 22 and bacterial sepsis. 23 In addition, the correlation between IL-10 genetic polymorphism and bone mineral density and OP risk has also been reported in many populations, including South Korea, 19 Turkey, 16 Taiwan, 18 and Chinese postmenopausal women.…”

Resistance and Susceptibility Immune Factors at Play during Mycobacterium tuberculosis Infection of Macrophages

“…An SNP in IL-17 that resulted in decreased IL-17A production upon stimulation was associated with TB susceptibility in a Chinese Han population [ 176 ]. Interestingly, a study that examined the master regulators of IL-12 and IL-10 signaling found that variants resulting in the increased production of IL-12 were associated with susceptibility to TB but an SNP that resulted in increased IL-10 production was associated with decreased pediatric TB [ 177 ]. In conclusion, variations in cytokine responses resulting from their genetic polymorphisms can lead to the enhanced or decreased control of TB infection, although it is important to note that too much of a cytokine can also be as detrimental as too little.…”