Archives

  • 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-06
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • Biomarkers characteristics that can be objectively measured

    2018-10-23

    Biomarkers (characteristics that can be objectively measured as indicators of a pathogenic process) (Biomarkers Definitions Working Group, 2001) have the potential to contribute significantly in the battle against Mtb. The vast majority of Mtb-infected individuals remain healthy, suggesting that immune responses in individuals that control latent infection with Mtb throughout their lifetime differ from responses in those who develop TB within the first years following infection (Weiner and Kaufmann, 2014; Schuetz et al., 2011). If true, correlates of TB progression should be identifiable, and these could be valuable in early identification of individuals at risk of developing – and transmitting – TB (Ottenhoff et al., 2012a). Furthermore, in low incidence countries biomarkers predictive of TB progression would be useful in selecting high-risk individuals for preventive therapy or regular screening. Examples are individuals with known or frequent exposure, such as contacts of infectious pulmonary TB patients or drug users. Likewise, TB-HIV co-infected individuals have an increased risk of progression to TB, reactivation of latent TB infection (LTBI) and TB related mortality (Nunn et al., 2005). Determination of such biomarkers could be embedded in existing programs in the Netherlands, in which HIV-infected individuals are actively screened for TB. Several studies have identified host gene 7-Nitroindazole patterns in the blood from patients with pulmonary TB that differ from patterns in latently infected individuals or patients with other inflammatory conditions (Berry et al., 2010; Maertzdorf et al., 2011a,b, 2012; Ottenhoff et al., 2012b; Cliff et al., 2013). Individual studies have mostly pointed towards type I interferon (IFN) signaling components as key markers of pulmonary TB, however, analysis of combined data indicated that besides type I IFN signaling also myeloid cell activation, general inflammation and B cell related markers are important players during TB (Joosten et al., 2013). To date no studies have identified biomarkers that can predict disease development well before the onset of clinical symptoms, and thus before the onset of contagious disease. The aim of this study was to explore whether biomarkers exist that may predict clinical TB. We used peripheral blood mononuclear cell (PBMC) samples of HIV-infected drug users, participating in a unique cohort, the Amsterdam Cohort Study (ACS), which undertook regular blood sampling and storage over several decades, independent from TB symptoms or diagnosis and thus allowed retrospective selection of samples prior to TB diagnosis.
    Materials & Methods
    Results
    Discussion The combination of IL13 and AIRE expressions appeared to classify cases versus controls with the highest discriminatory power among our gene sets. The majority of case samples expressing IL13 had been obtained 190–250days prior to TB diagnosis, suggesting that these combined markers are able to identify individuals that will progress to TB disease within 8months prior to diagnosis. Screening for such markers could allow early identification and subsequent treatment of individuals at high risk of developing disease, such as homeless, drug users, recent TST converters following contact in low endemic areas or HIV-infected individuals. Identification before the development of contagious TB would help in limiting transmission of infection, and, early treatment of cases could reduce morbidity and minimize complications. IL13 was expressed in about half of the cases up to 250days prior to diagnosis. Since it cannot be formally excluded that the other eight cases were not yet infected with Mtb (all >140days prior to diagnosis) and therefore did not show specific gene expression patterns, we focussed on the IL13 expressing cases to obtain more insights into the pathophysiology of TB. Restricting analysis to the 15 controls and the IL13+ cases identified 50 genes that were significantly differently expressed between IL13+ cases and controls. Interestingly, many of these differentially expressed genes belong to the type I IFN signature that previous studies have consistently reported to discriminate patients with pulmonary TB at the moment of diagnosis from healthy controls (Berry et al., 2010; Maertzdorf et al., 2011a,b, 2012; Ottenhoff et al., 2012b; Cliff et al., 2013). Identifying a similar pattern up to 8months before TB diagnosis strengthens our findings that it is possible to predict TB months before diagnosis and that genes identified here play a role in the development of TB. This was further supported by the high number of genes that remained significantly associated with subsequent TB disease development after multiple testing correction, indicating that selected genes could be strong predictors for TB development with increasing sample sizes.