Browsing by Author "Ronacher, Katharina"

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    Changes in host immune–endocrine relationships during tuberculosis treatment in patients with cured and failed treatment outcomes
    (Frontiers Media, 2017) Kleynhans, Leanie; Ruzive, Sheena; Ehlers, Lizaan; Thiart, Lani; Chegou, Novel N.; Conradie, Magda; Kriel, Magdalena; Kim Stanley; Van Der Spuy, Gian D.; Kidd, Martin; Van Helden; Walzl, Gerhard; Ronacher, Katharina
    A bidirectional communication between the immune and endocrine systems exists and facilitates optimum responses in the host during infections. This is in part achieved through changes in secretion patterns of hypothalamic hormones induced by inflammatory cytokines. The aim of this study was to elucidate the immune–endocrine alterations during tuberculosis (TB) treatment in patients with cured and failed TB treatment outcomes. Blood samples were collected from 27 cured and 10 failed patients and hormone as well as cytokine concentrations quantified at baseline, week 4, and month 6 of TB treatment. Hormone profiles of the two treatment outcome groups were different from each other prior to as well as during TB treatment. Treatment response effects were observed for cortisol, estradiol, T3, T4 ghrelin, leptin, amylin, adiponectin, and dehydroepiandrosterone (DHEA). Trends suggest that T4, amylin, and DHEA concentrations were different between treatment outcomes, although these did not reach statistical significance. Relationships between endocrine and inflammatory markers and the biological pathways involved differed between cured and failed treatment patients. These results highlight the complex interaction between the endocrine and immune system during active TB disease and throughout treatment and suggest that endocrine markers in conjunction with inflammatory markers may be useful in predicting unfavorable treatment outcomes.
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    Diabetes mellitus among pulmonary tuberculosis patients from 4 tuberculosis-endemic countries : the TANDEM study
    (Oxford University Press, 2019-04) Ugarte-Gil, Cesar; Alisjahbana, Bachti; Ronacher, Katharina; Lelia Riza, Anca; Koesoemadinata, Raspati C.; Malherbe, Stephanus T.; Cioboata, Ramona; Llontop, Juan Carlos; Kleynhans, Leanie; Lopez, Sonia; Santoso, Prayudi; Marius, Ciontea; Villaizan, Katerine; Ruslami, Rovina; Walzl, Gerhard; Panduru, Nicolae Mircea; Dockrell, Hazel M.; Hill, Philip C.; Allister, Susan Mc; Pearson, Fiona; Moore, David A. J.; Critchley, Julia A.; van Crevel, Reinout
    Background Diabetes mellitus (DM) increases active tuberculosis (TB) risk and worsens TB outcomes, jeopardizing TB control especially in TB-endemic countries with rising DM prevalence rates. We assessed DM status and clinical correlates in TB patients across settings in Indonesia, Peru, Romania, and South Africa. Methods Age-adjusted DM prevalence was estimated using laboratory glycated hemoglobin (HbA1c) or fasting plasma glucose in TB patients. Detailed and standardized sociodemographic, anthropometric, and clinical measurements were made. Characteristics of TB patients with or without DM were compared using multilevel mixed-effect regression models with robust standard errors. Results Of 2185 TB patients (median age 36.6 years, 61.2% male, 3.8% human immunodeficiency virus–infected), 12.5% (267/2128) had DM, one third of whom were newly diagnosed. Age-standardized DM prevalence ranged from 10.9% (South Africa) to 19.7% (Indonesia). Median HbA1c in TB–DM patients ranged from 7.4% (Romania) to 11.3% (Indonesia). Compared to those without DM, TB–DM patients were older and had a higher body mass index (BMI) (P value < .05). Compared to those with newly diagnosed DM, TB patients with diagnosed DM had higher BMI and HbA1c, less severe TB, and more frequent comorbidities, DM complications, and hypertension (P value < .05). Conclusions We show that DM prevalence and clinical characteristics of TB–DM vary across settings. Diabetes is primarily known but untreated, hyperglycemia is often severe, and many patients with TB–DM have significant cardiovascular disease risk and severe TB. This underlines the need to improve strategies for better clinical management of combined TB and DM.
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    Effect of standard tuberculosis treatment on plasma cytokine levels in patients with active pulmonary tuberculosis
    (Public Library of Science, 2012-05-14) Riou, Catherine; Peixoto, Blas Perez; Roberts, Lindi; Ronacher, Katharina; Walzl, Gerhard; Manca, Claudia; Rustomjee, Roxana; Mthiyane, Thuli; Fallows, Dorothy; Gray, Clive M.; Kaplan, Gilla
    Background: Sputum Mycobacterium tuberculosis (Mtb) culture is commonly used to assess response to antibiotic treatment in individuals with pulmonary tuberculosis (TB). Such techniques are constrained by the slow growth rate of Mtb, and more sensitive methods to monitor Mtb clearance are needed. The goal of this study was to evaluate changes in plasma cytokines in patients undergoing treatment for TB as a means of identifying candidate host markers associated with microbiologic response to therapy. Methods: Twenty-four plasma cytokines/chemokines were measured in 42 individuals diagnosed with active pulmonary TB, 52% were HIV co-infected. Individuals, undergoing a 26-week standard TB treatment, were followed longitudinally over 18 months and measurements were associated with HIV status and rates of sputum culture conversion. Results: Plasma concentrations of interferon-inducible protein-10 (IP-10) and vascular endothelial growth factor (VEGF) were significantly reduced upon TB treatment, regardless of HIV status. By the end of treatment, IP-10 concentrations were significantly lower in HIV negative individuals when compared to HIV-positive individuals (p = 0.02). Moreover, in HIV negative patients, plasma VEGF concentrations, measured as early as 2-weeks post TB treatment initiation, positively correlated with the time of sputum conversion (p = 0.0017). No significant changes were observed in other studied immune mediators. Conclusions: These data suggest that VEGF plasma concentration, measured during early TB treatment, could represent a surrogate marker to monitor sputum culture conversion in HIV uninfected individuals.
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    The functional response of B cells to antigenic stimulation : a preliminary report of latent tuberculosis
    (Public Library of Science, 2016-04) Du Plessis, Willem J.; Kleynhans, Leanie; Du Plessis, Nelita; Stanley, Kim; Malherbe, Stephanus T.; Maasdorp, Elizna; Ronacher, Katharina; Chegou, Novel N.; Walzl, Gerhard; Loxton, Andre G.
    Mycobacterium tuberculosis (M.tb) remains a successful pathogen, causing tuberculosis disease numbers to constantly increase. Although great progress has been made in delineating the disease, the host-pathogen interaction is incompletely described. B cells have shown to function as both effectors and regulators of immunity via non-humoral methods in both innate and adaptive immune settings. Here we assessed specific B cell functional interaction following stimulation with a broad range of antigens within the LTBI milieu. Our results indicate that B cells readily produce pro- and anti-inflammatory cytokines (including IL-1β, IL-10, IL-17, IL-21 and TNF-α) in response to stimulation. TLR4 and TLR9 based stimulations achieved the greatest secreted cytokine-production response and BCG stimulation displayed a clear preference for inducing IL-1β production. We also show that the cytokines produced by B cells are implicated strongly in cell-mediated communication and that plasma (memory) B cells (CD19+CD27+CD138+) is the subset with the greatest contribution to cytokine production. Collectively our data provides insight into B cell responses, where they are implicated in and quantifies responses from specific B cell phenotypes. These findings warrant further functional B cell research with a focus on specific B cell phenotypes under conditions of active TB disease to further our knowledge about the contribution of various cell subsets which could have implications for future vaccine development or refined B cell orientated treatment in the health setting.
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    IL-22 : an underestimated player in natural resistance to tuberculosis?
    (Frontiers Media, 2018) Ronacher, Katharina; Sinha, Roma; Cestari, Michelle
    ENGLISH ABSTRACT: Approximately 10% of individuals latently infected with Mycobacterium tuberculosis (Mtb) develop active tuberculosis (TB) during their lifetime. Although it is well recognized that T-helper 1 immune responses are crucial for containing latent TB infection, the full array of host factors conferring protective immunity from TB progression are not completely understood. IL-22 is produced by cells of the innate and adaptive immune system including innate lymphoid cells, and natural killer cells as well as T lymphocytes (Th1, Th17, and Th22) and binds to its cognate receptor, the IL-22R1, which is expressed on non-hematopoietic cells such as lung epithelial cells. However, recent studies suggest that Mtb induces expression of the IL-22R1 on infected macrophages and multiple studies have indicated a protective role of IL-22 in respiratory tract infections. Reduced concentrations of circulating IL-22 in active TB compared to latent TB and decreased percentages of Mtb-specific IL-22 producing T cells in TB patients compared to controls designate this cytokine as a key player in TB immunology. More recently, it has been shown that in type 2 diabetes (T2D) and TB co-morbidity serum IL-22 concentrations are further reduced compared to TB patients without co-morbidities. However, whether a causative link between low IL-22 and increased susceptibility to TB and disease severity of TB exists remains to be established. This review summarizes the contribution of IL-22, a potentially under-appreciated key player in natural resistance to TB, at the interface between the immune response to Mtb and the lung epithelium.
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    Impact of intermediate hyperglycaemia as well as diabetes on immune dysfunction in tuberculosis
    (Oxford University Press, 2020-01) Eckold, Clare; Kumar, Vinod; Weiner, January; Alisjahbana, Bachti; Riza, Anca-Lelia; Ronacher, Katharina; Coronel, Jorge; Kerry-Barnard, Sarah; Malherbe, Stephanus T.; Kleynhans, Leanie; Stanley, Kim; Ruslami, Rovina; Ioana, Mihai; Ugarte-Gil, Cesar; Walzl, Gerhard; van Crevel, Reinout; Wijmenga, Cisca; Critchley, Julia A.; Dockrell, Hazel M.; Cliff, Jacqueline M.
    Background: People with diabetes have an increased risk of developing active tuberculosis (TB) and are more likely to have poor TB-treatment outcomes, which may impact on control of TB as the prevalence of diabetes is increasing worldwide. Blood transcriptomes are altered in patients with active TB relative to healthy individuals. The effects of diabetes and intermediate hyperglycemia (IH) on this transcriptomic signature were investigated to enhance understanding of immunological susceptibility in diabetes-TB comorbidity. Methods: Whole blood samples were collected from active TB patients with diabetes (glycated hemoglobin [HbA1c] ≥6.5%) or IH (HbA1c = 5.7% to <6.5%), TB-only patients, and healthy controls in 4 countries: South Africa, Romania, Indonesia, and Peru. Differential blood gene expression was determined by RNA-seq (n = 249). Results: Diabetes increased the magnitude of gene expression change in the host transcriptome in TB, notably showing an increase in genes associated with innate inflammatory and decrease in adaptive immune responses. Strikingly, patients with IH and TB exhibited blood transcriptomes much more similar to patients with diabetes-TB than to patients with only TB. Both diabetes-TB and IH-TB patients had a decreased type I interferon response relative to TB-only patients. Conclusions: Comorbidity in individuals with both TB and diabetes is associated with altered transcriptomes, with an expected enhanced inflammation in the presence of both conditions, but also reduced type I interferon responses in comorbid patients, suggesting an unexpected uncoupling of the TB transcriptome phenotype. These immunological dysfunctions are also present in individuals with IH, showing that altered immunity to TB may also be present in this group. The TB disease outcomes in individuals with IH diagnosed with TB should be investigated further.
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    Medroxyprogesterone acetate alters mycobacterium bovis BCG-induced cytokine production in peripheral blood mononuclear cells of contraceptive users
    (Public Library of Science, 2011-09-08) Kleynhans, Leanie; Du Plessis, Nelita; Black, Gillian F.; Loxton, Andre G.; Kidd, Martin; Van Helden, Paul D.; Walzl, Gerhard; Ronacher, Katharina
    Most individuals latently infected with Mycobacterium tuberculosis (M.tb) contain the infection by a balance of effector and regulatory immune responses. This balance can be influenced by steroid hormones such as glucocorticoids. The widely used contraceptive medroxyprogesterone acetate (MPA) possesses glucocorticoid activity. We investigated the effect of this hormone on immune responses to BCG in household contacts of active TB patients. Multiplex bead array analysis revealed that MPA demonstrated both glucocorticoid and progestogenic properties at saturating and pharmacological concentrations in peripheral blood mononuclear cells (PBMCs) and suppressed antigen specific cytokine production. Furthermore we showed that PBMCs from women using MPA produced significantly lower levels of IL-1α, IL-12p40, IL-10, IL-13 and G-CSF in response to BCG which corresponded with lower numbers of circulating monocytes observed in these women. Our research study is the first to show that MPA impacts on infections outside the genital tract due to a systemic effect on immune function. Therefore MPA use could alter susceptibility to TB, TB disease severity as well as change the efficacy of new BCG-based vaccines, especially prime-boost vaccine strategies which may be administered to adult or adolescent women in the future. © 2011 Kleynhans et al.
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    Patients with concurrent tuberculosis and diabetes have a pro-atherogenic plasma lipid profile
    (Elsevier, 2018) Vrieling, Frank; Ronacher, Katharina; Kleynhans, Leanie; Van Den Akker, Erik; Walzl, Gerhard; Ottenhoff, Tom H. M.; Joosten, Simone A.
    Background: Type 2 diabetes mellitus (DM) is a major risk factor for development of tuberculosis (TB), however the underlyingmolecular foundations are unclear. Since lipids play a central role in the development of both DM and TB, lipid metabolism may be important for TB-DM pathophysiology. Methods: A 1H NMR spectroscopy-based platform was used to determine 225 lipid and other metabolic intermediates in plasma samples of healthy controls (n=50) and patients with TB (n=50), DM(n=50) or TB-DM (n = 27). Results: TB patients presented with wasting disease, represented by decreased amino acid levels including histidine and alanine. Conversely, DM patients were dyslipidemic as evidenced by high levels of very lowdensity lipoprotein triglycerides and low high-density lipoprotein cholesterol. TB-DM patients displayed metabolic characteristics of both wasting and dyslipidemia combined with disease interaction-specific increases in phospholipid metabolites (e.g. sphingomyelins) and atherogenic remnant-like lipoprotein particles. Biomarker analysis identified the ratios of phenylalanine/histidine and esterified cholesterol/ sphingomyelin as markers for TB classification regardless of DM-status. Conclusions: TB-DM patients possess a distinctive plasma lipid profile with pro-atherogenic properties. These findings support further research on the benefits of improved blood lipid control in the treatment of TB-DM.
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    Profiling persistent tubercule bacilli from patient sputa during therapy predicts early drug efficacy
    (BioMed Central, 2016-04-07) Honeyborne, Isobella; McHugh, Timothy D.; Kuittinen, Iitu; Cichonska, Anna; Evangelopoulos, Dimitrios; Ronacher, Katharina; Van Helden, Paul D.; Gillespie, Stephen H.; Fernandez-Reyes, Delmiro; Walzl, Gerhard; Rousu, Juho; Butcher, Philip D.; Waddell, Simon J.
    Background: New treatment options are needed to maintain and improve therapy for tuberculosis, which caused the death of 1.5 million people in 2013 despite potential for an 86 % treatment success rate. A greater understanding of Mycobacterium tuberculosis (M.tb) bacilli that persist through drug therapy will aid drug development programs. Predictive biomarkers for treatment efficacy are also a research priority. Methods and Results: Genome-wide transcriptional profiling was used to map the mRNA signatures of M.tb from the sputa of 15 patients before and 3, 7 and 14 days after the start of standard regimen drug treatment. The mRNA profiles of bacilli through the first 2 weeks of therapy reflected drug activity at 3 days with transcriptional signatures at days 7 and 14 consistent with reduced M.tb metabolic activity similar to the profile of pre-chemotherapy bacilli. These results suggest that a pre-existing drug-tolerant M.tb population dominates sputum before and after early drug treatment, and that the mRNA signature at day 3 marks the killing of a drug-sensitive sub-population of bacilli. Modelling patient indices of disease severity with bacterial gene expression patterns demonstrated that both microbiological and clinical parameters were reflected in the divergent M.tb responses and provided evidence that factors such as bacterial load and disease pathology influence the host-pathogen interplay and the phenotypic state of bacilli. Transcriptional signatures were also defined that predicted measures of early treatment success (rate of decline in bacterial load over 3 days, TB test positivity at 2 months, and bacterial load at 2 months). Conclusions: This study defines the transcriptional signature of M.tb bacilli that have been expectorated in sputum after two weeks of drug therapy, characterizing the phenotypic state of bacilli that persist through treatment. We demonstrate that variability in clinical manifestations of disease are detectable in bacterial sputa signatures, and that the changing M.tb mRNA profiles 0–2 weeks into chemotherapy predict the efficacy of treatment 6 weeks later. These observations advocate assaying dynamic bacterial phenotypes through drug therapy as biomarkers for treatment success.
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    Quantitative 18F-FDG PET-CT scan characteristics correlate with tuberculosis treatment response
    (SpringerOpen (part of Springer Nature), 2020-02-10) Malherbe, Stephanus T.; Chen, Ray Y.; Dupont, Patrick; Kant, Ilse; Kriel, Magdalena; Loxton, Andre G.; Smith, Bronwyn; Beltran, Caroline G. G.; Van Zyl, Susan; McAnda, Shirely; Abrahams, Charmaine; Maasdorp, Elizna; Doruyter, Alex; Via, Laura E.; Barry, Clifton E.; Alland, David; Richards, Stephanie G.; Ellman, Annare; Peppard, Thomas; Belisle, John; Tromp, Gerard; Ronacher, Katharina; Warwick, James M.; Winter, Jill; Walzl, Gerhard
    Background: There is a growing interest in the use of F-18 FDG PET-CT to monitor tuberculosis (TB) treatment response. Tuberculosis lung lesions are often complex and diffuse, with dynamic changes during treatment and persisting metabolic activity after apparent clinical cure. This poses a challenge in quantifying scan-based markers of burden of disease and disease activity. We used semi-automated, whole lung quantification of lung lesions to analyse serial FDG PET-CT scans from the Catalysis TB Treatment Response Cohort to identify characteristics that best correlated with clinical and microbiological outcomes. Results: Quantified scan metrics were already associated with clinical outcomes at diagnosis and 1 month after treatment, with further improved accuracy to differentiate clinical outcomes after standard treatment duration (month 6). A high cavity volume showed the strongest association with a risk of treatment failure (AUC 0.81 to predict failure at diagnosis), while a suboptimal reduction of the total glycolytic activity in lung lesions during treatment had the strongest association with recurrent disease (AUC 0.8 to predict pooled unfavourable outcomes). During the first year after TB treatment lesion burden reduced; but for many patients, there were continued dynamic changes of individual lesions. Conclusions: Quantification of FDG PET-CT images better characterised TB treatment outcomes than qualitative scan patterns and robustly measured the burden of disease. In future, validated metrics may be used to stratify patients and help evaluate the effectiveness of TB treatment modalities.
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    Quantitative 18F-FDG PET-CT scan characteristics correlate with tuberculosis treatment response
    (SpringerOpen (part of Springer Nature), 2020) Malherbe, Stephanus T.; Chen, Ray Y.; Dupont, Patrick; Kant, Ilse; Kriel, Magdalena; Loxton, Andre G.; Smith, Bronwyn; Beltran, Caroline G. G.; Van Zyl, Susan; McAnda, Shirely; Abrahams, Charmaine; Maasdorp, Elizna; Doruyter, Alex; Via, Laura E.; Barry, Clifton E.; Alland, David; Griffith- Richards, Stephanie; Ellman, Annare; Peppard, Thomas; Belisle, John; Tromp, Gerard; Ronacher, Katharina; Warwick, James M.; Winter, Jill; Walzl, Gerhard
    Background: There is a growing interest in the use of F-18 FDG PET-CT to monitor tuberculosis (TB) treatment response. Tuberculosis lung lesions are often complex and diffuse, with dynamic changes during treatment and persisting metabolic activity after apparent clinical cure. This poses a challenge in quantifying scan-based markers of burden of disease and disease activity. We used semi-automated, whole lung quantification of lung lesions to analyse serial FDG PET-CT scans from the Catalysis TB Treatment Response Cohort to identify characteristics that best correlated with clinical and microbiological outcomes. Results: Quantified scan metrics were already associated with clinical outcomes at diagnosis and 1 month after treatment, with further improved accuracy to differentiate clinical outcomes after standard treatment duration (month 6). A high cavity volume showed the strongest association with a risk of treatment failure (AUC 0.81 to predict failure at diagnosis), while a suboptimal reduction of the total glycolytic activity in lung lesions during treatment had the strongest association with recurrent disease (AUC 0.8 to predict pooled unfavourable outcomes). During the first year after TB treatment lesion burden reduced; but for many patients, there were continued dynamic changes of individual lesions. Conclusions: Quantification of FDG PET-CT images better characterised TB treatment outcomes than qualitative scan patterns and robustly measured the burden of disease. In future, validated metrics may be used to stratify patients and help evaluate the effectiveness of TB treatment modalities.
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    A semi-automatic technique to quantify complex tuberculous lung lesions on 18F-fluorodeoxyglucose positron emission tomography/computerised tomography images
    (Springer Open, 2018-06-25) Malherbe, Stephanus T.; Dupont, Patrick; Kant, Ilse; Ahlers, Petri; Kriel, Magdalena; Loxton, Andre G.; Chen, Ray Y.; Via, Laura E.; Thienemann, Friedrich; Wilkinson, Robert J; Barry, Clifton E.; Griffith-Richards, Stephanie; Ellman, Annare; Ronacher, Katharina; Winter, Jill; Walzl, Gerhard; Warwick, James M.
    Background: There is a growing interest in the use of 18F-FDG PET-CT to monitor tuberculosis (TB) treatment response. However, TB causes complex and widespread pathology, which is challenging to segment and quantify in a reproducible manner. To address this, we developed a technique to standardise uptake (Z-score), segment and quantify tuberculous lung lesions on PET and CT concurrently, in order to track changes over time. We used open source tools and created a MATLAB script. The technique was optimised on a training set of five pulmonary tuberculosis (PTB) cases after standard TB therapy and 15 control patients with lesion-free lungs. Results: We compared the proposed method to a fixed threshold (SUV > 1) and manual segmentation by two readers and piloted the technique successfully on scans of five control patients and five PTB cases (four cured and one failed treatment case), at diagnosis and after 1 and 6 months of treatment. There was a better correlation between the Z-score-based segmentation and manual segmentation than SUV > 1 and manual segmentation in terms of overall spatial overlap (measured in Dice similarity coefficient) and specificity (1 minus false positive volume fraction). However, SUV > 1 segmentation appeared more sensitive. Both the Z-score and SUV > 1 showed very low variability when measuring change over time. In addition, total glycolytic activity, calculated using segmentation by Z-score and lesion-to-background ratio, correlated well with traditional total glycolytic activity calculations. The technique quantified various PET and CT parameters, including the total glycolytic activity index, metabolic lesion volume, lesion volumes at different CT densities and combined PET and CT parameters. The quantified metrics showed a marked decrease in the cured cases, with changes already apparent at month one, but remained largely unchanged in the failed treatment case. Conclusions: Our technique is promising to segment and quantify the lung scans of pulmonary tuberculosis patients in a semi-automatic manner, appropriate for measuring treatment response. Further validation is required in larger cohorts.
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    Successful TB treatment induces B-cells expressing FASL and IL5RA mRNA
    (Impact Journals, 2016-09) Van Rensburg, Ilana C.; Wagman, Chandre; Stanley, Kim; Beltran, Caroline; Ronacher, Katharina; Walzl, Gerhard; Loxton, Andre G.
    ENGLISH ABSTRACT: Activated B-cells increase T-cell behaviour during autoimmune disease and other infections by means of cytokine production and antigen-presentation. Functional studies in experimental autoimmune encephalomyelitis (EAE) indicate that B-cell deficiencies, and a lack of IL10 and IL35 leads to a poor prognosis. We hypothesised that B-cells play a role during tuberculosis. We evaluated B-cell mRNA expression using real-time PCR from healthy community controls, individuals with other lung diseases and newly diagnosed untreated pulmonary TB patients at three different time points (diagnosis, month 2 and 6 of treatment). We show that FASLG, IL5RA, CD38 and IL4 expression was lower in B-cells from TB cases compared to healthy controls. The changes in expression levels of CD38 may be due to a reduced activation of B-cells from TB cases at diagnosis. By month 2 of treatment, there was a significant increase in the expression of APRIL and IL5RA in TB cases. Furthermore, after 6 months of treatment, APRIL, FASLG, IL5RA and CD19 were upregulated in B-cells from TB cases. The increase in the expression of APRIL and CD19 suggests that there may be restored activation of B-cells following anti-TB treatment. The upregulation of FASLG and IL5RA indicates that B-cells expressing regulatory genes may play an important role in the protective immunity against M.tb infection. Our results show that increased activation of B-cells is present following successful TB treatment, and that the expression of FASLG and IL5RA could potentially be utilised as a signature to monitor treatment response.