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Tuberculosis Study Leads to Potential Immune Markers for Active Disease

NEW YORK – Investigators in the UK, Peru, and Italy have identified immune-related expression patterns that appear to distinguish active tuberculosis from latent Mycobacterium tuberculosis infections or TB cases that have been resolved.

"The distinctions that tip the balance between protective and pathogenic immune responses remain a fundamental question in tuberculosis research," first and corresponding author Gabriele Pollara, a medical microbiology researcher at the University College London, and his colleagues wrote in Science Translational Medicine on Wednesday. "This knowledge is expected to inform rational vaccine design by identifying correlates of disease protection."

Reasoning that immune responses to standard tuberculin skin test challenges might help in uncovering active TB-associated molecular features, the team did RNA sequencing on tuberculin skin test site biopsy samples from four dozen HIV-negative individuals diagnosed with pulmonary TB and from 191 HIV-negative individuals with latent TB, comparing expression profiles with those found following a control injection with saline.

"We used in vivo transcriptional responses at the site of [tuberculin skin tests] to deconvolute differential cellular infiltration and functional cytokine activity, identifying in active TB the enrichment of molecular change associated with immunopathology," the authors explained.

The expression profiling pointed to higher-than-usual levels of several cytokines in the active TB cases, including the interleukin IL-17A cytokine, as well as other gene expression shifts linked to T helper 17 cell representation. Those expression shifts corresponded with other features implicated in TB pathogenesis, the researchers noted, particularly pronounced recruitment of neutrophil immune cells and enhanced expression of the matrix metalloproteinase enzyme.

In contrast, the team noted that the skin expression patterns became more similar to those in control samples after successful TB treatment.

"Together, our data implicate IL-17A immune responses as drivers of tissue immunopathology in TB," the authors reported. "We propose that therapeutic targeting of these responses as an adjunct to antimicrobial therapy in active TB offers strategies to ameliorate tissue damage and further reduce transmission of infection by promoting immune homeostasis."

The investigators went on to validate these and other findings using array-based expression profiling on samples from additional active and latent TB cases, along with individuals classified as being cured of TB. They also did a series of follow-up transcriptome, cytokine staining, and other experiments on peripheral blood mononuclear cells, identifying a rise in interleukins such as IL-1-beta and IL-6 in mycobacteria-stimulated monocytes.

"The availability of therapies that block IL-17A/F cytokine pathways, or upstream signals such as the IL-1-apha/beta and IL-6 axes, offers invaluable opportunities to transition from proof-of-concept pre-clinical studies to first-in-human experiments," the authors concluded. "These studies are needed to establish the functional interaction between these cytokines and their causal role in the pathogenesis of human TB as a prelude to clinical trials for therapeutic benefit."

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