Biomarkers on patient T cells diagnose active tuberculosis and monitor treatment response

Adékambi, Toïdi; Ibegbu, Chris; Cagle, Stephanie; Kalokhe, Ameeta S.; Wang, Yun F.; Hu, Yi‐Juan; Day, Cheryl L.; Ray, Susan M.; Rengarajan, Jyothi

doi:10.1172/jci83279

Cited by 29 publications

(31 citation statements)

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“…We first compared the activation profile of IFN-g 1 Mtbspecific CD4 1 T cells between the four groups ( Figure 1A). As previously shown (5), in HIV-uninfected persons, HLA-DR, Ki67, and CD38 expression on IFN-g 1 Mtb-specific CD4 1 T cells was significantly higher in aTB participants than in those with LTBI ( Figure 1B). Interestingly, although HLA-DR expression on Mtb-specific CD4 1 T cells in the LTBI/HIV 1 group (median, 41.7%; IQR, 25.7-54.6%) was significantly higher than in the LTBI/HIV 2 group (median, 13.7%; IQR, 8.9-27.5%), HLA-DR expression on these cells was significantly further increased in HIV-infected individuals with aTB (median, 84%; IQR, 73.7-87.9%) ( Figure 1B).…”

supporting

confidence: 78%

Activation Profile of Mycobacterium tuberculosis–Specific CD4⁺ T Cells Reflects Disease Activity Irrespective of HIV Status

Wilkinson

Oni

Gideon

et al. 2016

Am J Respir Crit Care Med

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The diagnosis of pulmonary tuberculosis in HIV-infected individuals is particularly challenging as HIV-induced alterations of the immune system lead to reduced cavitation, limiting the sensitivity of sputum-based assays (1). Thus, alternate markers are needed to distinguish between latent tuberculosis infection (LTBI) and active tuberculosis (aTB) in this high-risk group. Several attributes of Mycobacterium tuberculosis (Mtb)-specific CD4 1 T cells have been shown to efficiently delineate LTBI and aTB in HIV-uninfected individuals, including their polyfunctional or memory profiles (2-4). Moreover, Adekambi and colleagues recently demonstrated that the activation profile of Mtb-specific CD4 1 T cells accurately discriminates between LTBI and aTB (5). As chronic HIV infection is characterized by persistent systemic immune activation (6), it is plausible that these blood-based markers may not be relevant for HIV-infected individuals. We, therefore, compared the potential of the activation and polyfunctional profiles of Mtb-specific CD4 1 T cells to distinguish between LTBI and aTB in HIV-uninfected and HIV-infected individuals. We analyzed 76 participants divided in four groups according to their TB and HIV status: LTBI/HIV 2 (n = 17; median age, 22 yr; 47% female), aTB/HIV 2 (n = 17; median age, 27 yr; 29% female), LTBI/HIV 1 (n = 21; median age, 29 yr; 67% female; median CD4 count, 316 cells/mm 3 ; interquartile range [IQR], 231-543 cells/mm 3), and aTB/HIV 1 (n = 21; median age, 35 yr; 57% female; CD4 count, 250 cells/mm 3 ; IQR, 155-295 cells/mm 3). LTBI was defined as tuberculin skin test positive, IFN-g release assay positive, sputum culture negative, and normal chest X-ray. aTB was diagnosed on the basis of symptoms suggestive of tuberculosis and Mtb-positive smear and/or sputum culture, as previously described (7). All HIV-infected participants were antiretroviral therapy-naive. The University of Cape Town ethics committee approved the study, and written consent was obtained from participants. Cryopreserved peripheral blood mononuclear cells were stimulated for 16 hours with early secretory antigenic target-6 (ESAT-6)/culture filtrate protein-10 (CFP-10) peptide pool, and intracellular staining, using a live/dead marker and antibodies toward CD3, CD4, CD8, human leukocyte antigen-DR (HLA-DR), Ki67, CD38, IFN-g, tumor necrosis factor (TNF)-a, and IL-2, was performed. Positive ESAT-6/CFP-10 responses (defined as twice the

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supporting

confidence: 78%

Activation Profile of Mycobacterium tuberculosis–Specific CD4⁺ T Cells Reflects Disease Activity Irrespective of HIV Status

Wilkinson

Oni

Gideon

et al. 2016

Am J Respir Crit Care Med

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“…The presence of interleukin-2 (IL-2) cytokine-secreting CD4 ϩ T cells has been shown to correlate with bacterial burden and clinical disease (78,79). People with active TB disease also have a more activated and proapoptotic phenotype of antigen-specific CD4 ϩ T cells than people with LTBI (80,81). Th17-type CD4 ϩ T cell responses may be associated with a lower risk of progression to TB (67).…”

Section: Immune Correlates Of Incipient and Subclinical Tuberculosismentioning

confidence: 99%

Incipient and Subclinical Tuberculosis: a Clinical Review of Early Stages and Progression of Infection

et al. 2018

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SUMMARYTuberculosis (TB) is the leading infectious cause of mortality worldwide, due in part to a limited understanding of its clinical pathogenic spectrum of infection and disease. Historically, scientific research, diagnostic testing, and drug treatment have focused on addressing one of two disease states: latent TB infection or active TB disease. Recent research has clearly demonstrated that human TB infection, from latent infection to active disease, exists within a continuous spectrum of metabolic bacterial activity and antagonistic immunological responses. This revised understanding leads us to propose two additional clinical states: incipient and subclinical TB. The recognition of incipient and subclinical TB, which helps divide latent and active TB along the clinical disease spectrum, provides opportunities for the development of diagnostic and therapeutic interventions to prevent progression to active TB disease and transmission of TB bacilli. In this report, we review the current understanding of the pathogenesis, immunology, clinical epidemiology, diagnosis, treatment, and prevention of both incipient and subclinical TB, two emerging clinical states of an ancient bacterium.

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“…However, the attenuated T cell response to ESAT‐6 stimulation in M. africanum infected individuals has been shown to affect the interpretation of IGRA results . In addition, a number of studies have reported that activated T cell markers and soluble cytokines can be used as reliable biomarker for monitoring the anti‐TB treatment response. It has been shown that the production of 27 proinflammatory and regulatory cytokines in response to ESAT‐6/CFP‐10 stimulation was not significantly different between M. africanum and Mtb‐infected patients pre‐treatment.…”

Section: Translational Implications Of Mtbc Lineage Associated Variatmentioning

confidence: 99%

Immunological consequences of strain variation within the Mycobacterium tuberculosis complex

et al. 2017

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In 2015, there were an estimated 10.4 million new cases of tuberculosis (TB) globally, making it one of the leading causes of death due to an infectious disease. TB is caused by members of the Mycobacterium tuberculosis complex (MTBC), with human disease resulting from infection by M. tuberculosis sensu stricto and M. africanum. Recent progress in genotyping techniques, in particular the increasing availability of whole genome sequence data, has revealed previously under appreciated levels of genetic diversity within the MTBC. Several studies have shown that this genetic diversity may translate into differences in TB transmission, clinical manifestations of disease, and host immune responses. This suggests the existence of MTBC genotype‐dependent host–pathogen interactions which may influence the outcome of infection and progression of disease. In this review, we highlight the studies demonstrating differences in innate and adaptive immunological outcomes consequent on MTBC genetic diversity, and discuss how these differences in immune response might influence the development of TB vaccines, diagnostics and new therapies.

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Biomarkers on patient T cells diagnose active tuberculosis and monitor treatment response

Abstract: A r t i c l e A m e n d m e n t s 3 7 2 3

Cited by 29 publications

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Activation Profile of Mycobacterium tuberculosis–Specific CD4⁺ T Cells Reflects Disease Activity Irrespective of HIV Status

Activation Profile of Mycobacterium tuberculosis–Specific CD4⁺ T Cells Reflects Disease Activity Irrespective of HIV Status

Incipient and Subclinical Tuberculosis: a Clinical Review of Early Stages and Progression of Infection

Immunological consequences of strain variation within the Mycobacterium tuberculosis complex

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Biomarkers on patient T cells diagnose active tuberculosis and monitor treatment response

Abstract: A r t i c l e A m e n d m e n t s 3 7 2 3

Cited by 29 publications

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Activation Profile of Mycobacterium tuberculosis–Specific CD4+ T Cells Reflects Disease Activity Irrespective of HIV Status

Activation Profile of Mycobacterium tuberculosis–Specific CD4+ T Cells Reflects Disease Activity Irrespective of HIV Status

Incipient and Subclinical Tuberculosis: a Clinical Review of Early Stages and Progression of Infection

Immunological consequences of strain variation within the Mycobacterium tuberculosis complex

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Activation Profile of Mycobacterium tuberculosis–Specific CD4⁺ T Cells Reflects Disease Activity Irrespective of HIV Status

Activation Profile of Mycobacterium tuberculosis–Specific CD4⁺ T Cells Reflects Disease Activity Irrespective of HIV Status