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Complement pathway gene activation and rising circulating immune complexes characterize early disease in HIV-associated tuberculosis

Esmail, H; Lai, RP; Lesosky, M; Wilkinson, KA; Graham, CM; Horswell, S; Coussens, AK; ... Wilkinson, RJ; + view all (2018) Complement pathway gene activation and rising circulating immune complexes characterize early disease in HIV-associated tuberculosis. Proceedings of the National Academy of Sciences of the United States of America , 115 (5) E964-E973. 10.1073/pnas.1711853115. Green open access

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Abstract

The transition between latent and active tuberculosis (TB) occurs before symptom onset. Better understanding of the early events in subclinical disease will facilitate the development of diagnostics and interventions that improve TB control. This is particularly relevant in the context of HIV-1 coinfection where progression of TB is more likely. In a recent study using [18F]-fluoro-2-deoxy-D-glucose positron emission/computed tomography (FDG-PET/CT) on 35 asymptomatic, HIV-1–infected adults, we identified 10 participants with radiographic evidence of subclinical disease, significantly more likely to progress than the 25 participants without. To gain insight into the biological events in early disease, we performed blood-based whole genome transcriptomic analysis on these participants and 15 active patients with TB. We found transcripts representing the classical complement pathway and Fcγ receptor 1 overabundant from subclinical stages of disease. Levels of circulating immune (antibody/antigen) complexes also increased in subclinical disease and were highly correlated with C1q transcript abundance. To validate our findings, we analyzed transcriptomic data from a publicly available dataset where samples were available in the 2 y before TB disease presentation. Transcripts representing the classical complement pathway and Fcγ receptor 1 were also differentially expressed in the 12 mo before disease presentation. Our results indicate that levels of antibody/antigen complexes increase early in disease, associated with increased gene expression of C1q and Fcγ receptors that bind them. Understanding the role this plays in disease progression may facilitate development of interventions that prevent this, leading to a more favorable outcome and may also be important to diagnostic development.

Type: Article
Title: Complement pathway gene activation and rising circulating immune complexes characterize early disease in HIV-associated tuberculosis
Open access status: An open access version is available from UCL Discovery
DOI: 10.1073/pnas.1711853115
Publisher version: https://doi.org/10.1073/pnas.1711853115
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: tuberculosis, HIV, complement, immune complex, incipient disease
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 Population Health Sciences > Inst of Clinical Trials and Methodology
URI: https://discovery.ucl.ac.uk/id/eprint/10074314
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