B in TB: B Cells as Mediators of Clinically Relevant Immune Responses in Tuberculosis

Rao, Martin; Valentini, Davide; Poiret, Thomas; Dodoo, Ernest; Parida, Shreemanta K.; Zumla, Alimuddin; Brighenti, Susanna; Maeurer, Markus

doi:10.1093/cid/civ614

Cited by 62 publications

(49 citation statements)

References 66 publications

(99 reference statements)

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“…19 Historically, B-cells were not considered to be an important component in TB immunopathogenesis, however there is growing evidence to suggest that B-cells mediate protection through antigen presentation, cytokine production, and antibody production via interactions with T-cells. 20,21 Ultimately, we rely on measuring the T-cell mediated immune responses as an indication of TB infection, through the IFN-γ release assays (IGRAs) and the tuberculin skin test (TST).…”

Section: Pathogenesismentioning

confidence: 99%

Tuberculosis in Children

Thomas

2017

Pediatric Clinics of North America

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Synopsis Mycobacterium tuberculosis is the leading cause of death worldwide from a single bacterial pathogen. World Health Organization (WHO) estimates that annually, 1 million children have TB disease and many more harbor a latent form of infection. However, accurate estimates are hindered by under-recognition and challenges in diagnosis; to date, an accurate diagnostic test to confirm TB in children does not exist. TB treatment is lengthy, but outcomes are generally favorable with timely initiation. As we move toward the End TB Strategy, there is an urgent need for improved diagnostics and treatment to prevent the unnecessary morbidity and mortality from TB in children.

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Section: Pathogenesismentioning

confidence: 99%

Tuberculosis in Children

Thomas

2017

Pediatric Clinics of North America

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“…Current research findings have signified the importance of B-cells during M.tb infection, in which absence or impaired function of this immune cell type has been associated with poor disease prognosis (Achkar et al, 2015; Bénard et al, 2018; Du Plessis et al, 2016a, 2016b; Rao et al, 2015). For decades, the primary function of B-cells was considered to be antibody secretion, forming part of the adaptive humoral response (Abbas et al, 2014; Zabriskie, 2009).…”

Section: Discussionmentioning

confidence: 99%

Immunoglobulin profile and B-cell frequencies are altered with changes in the cellular micro-environment independent of the stimulation conditions

Moore

Leisching

Snyders

et al. 2019

Preprint

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19 B-cells are essential in the defense against Mycobacterium tuberculosis. Studies on isolated cells 20 may not accurately reflect the responses that occur in vivo due to the presence of other cells. This 21 study elucidated the influence of microenvironment complexity on B-cell polarisation and function 22 in the context of TB disease. B-cell function was tested in whole blood, PBMC's and as isolated 23 cells. The different fractions were stimulated and the B-cell phenotype and immunoglobulin profiles 24 analysed. The immunoglobulin profile and killer B-cell frequencies varied for each of the 25 investigated sample types, while in an isolated cellular environment, secretion of immunoglobulin 26 isotypes IgA, IgG2 and IgG3 was hampered. The differences in the immunoglobulin profile 27 highlight the importance of cell-cell communication for B-cell activation. In contrast, increased 28 frequencies of killer B-cells were observed following cellular isolation, suggesting a biased shift in 29 augmented immune response in vitro. This suggests that humoral B-cell function and development 30 was impaired likely due to a lack of co-stimulatory signals from other cell types. Thus, B-cell 31 function should ideally be studied in a PBMC or whole blood fraction. 32 33 42 et al., 2010b; Carter, Rosser and Mauri, 2012a), and the presence and activation of these cell 43 types may contribute significantly to the function of a cell type of interest, through directing the 44 mounting immune response. As such, absence of these cells during isolated cell studies may 109 limitations involved in comparing plasma supernatants to culture supernatants, only differences 110 between PBMCs and isolated B-cells were considered. Here, significant decreases in the observed 111 concentration of all immunoglobulin isotypes were observed for isolated B-cell culture supernatants 112 compared to those of PBMC samples. 113Additionally, the effects of QFN status and stimulation condition on immunoglobulin profiles were 114 investigated. We investigated whether or not M.tb-exposed (QFN positive) individuals with immune 115 memory would respond differently to M.tb challenge compared to QFN negative individuals. In all 116 instances, QFN status was found to have no effect on the relative abundance of the various 117 immunoglobulin isotypes (Fig. 2B). To conclude, the impact of stimulation condition on 118 immunoglobulin profiles were investigated to determine the effect of M.tb infection on B-cell 119 performance. For the majority of immunoglobulin isotypes, stimulation with different antigens had 120 no effect on the measured immunoglobulin abundance (Fig. 2C). However, a significant decrease 121 in IgA levels were observed following TLR9 stimulation for all sample types compared to 122 unstimulated controls (p=0.0038) and H37Rv stimulated (p=0.0292) samples. Conversely, an 123 increase in IgG3 levels were observed following TLR9 stimulation for all sample types compared to 124 unstimulated controls (p=0.0482). 125 126 B-cells isolation results in decr...

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“…Our work suggests that the ALS assay could serve as a diagnostic and response-predictive biomarker among adults by harnessing B-cell stimulation to gauge TB disease activity. There is growing evidence to suggest that B-cells mediate protection for TB through antigen presentation, cytokine production, and antibody production via interactions with cell mediated immunity [22–25]. When immunologic biomarkers are dependent on T-cell immunity, as is the case for the currently available tuberculin skin test and interferon-γ release assays, concern is raised about reduced performance among populations with concomitant HIV co-infection or other immunocompromising conditions [26].…”

Section: Discussionmentioning

confidence: 99%

Evaluation of the Antibody in Lymphocyte Supernatant Assay to Detect Active Tuberculosis

Sariko¹,

Anderson²,

Mujaga³

et al. 2017

PLoS ONE

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BackgroundWe aimed to evaluate the antibody in lymphocyte supernatant (ALS) assay as a biomarker to diagnose tuberculosis among adults from Tanzania with and without HIV.MethodsAdults admitted with suspicion for tuberculosis had sputa obtained for GeneXpert MTB/RIF, acid-fast bacilli smear and mycobacterial culture; blood was obtained prior to treatment initiation and after 4 weeks. Adults hospitalized with non-infectious conditions served as controls. Peripheral blood mononuclear cells were cultured unstimulated for 72 hours. Anti-mycobacterial antibodies were measured from culture supernatants by ELISA, using BCG vaccine as the coating antigen. Median ALS responses were compared between cases and controls at baseline and between cases over time.ResultsOf 97 TB cases, 85 were microbiologically confirmed and 12 were clinically diagnosed. Median ALS responses from TB cases (0.366 OD from confirmed cases and 0.285 from clinical cases) were higher compared to controls (0.085, p<0.001). ALS responses did not differ based on HIV status, CD4 count or sputum smear status. Over time, the median ALS values declined significantly (0.357 at baseline; 0.198 after 4-weeks, p<0.001).ConclusionsRobust ALS responses were mounted by patients with TB regardless of HIV status, CD4 count, or low sputum bacillary burden, potentially conferring a unique niche for this immunologic biomarker for TB.

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B in TB: B Cells as Mediators of Clinically Relevant Immune Responses in Tuberculosis

Cited by 62 publications

References 66 publications

Tuberculosis in Children

Tuberculosis in Children

Immunoglobulin profile and B-cell frequencies are altered with changes in the cellular micro-environment independent of the stimulation conditions

Evaluation of the Antibody in Lymphocyte Supernatant Assay to Detect Active Tuberculosis

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