What information and the extent of information research participants need in informed consent forms: a multi-country survey.

BACKGROUND: The use of lengthy, detailed, and complex informed consent forms (ICFs) is of paramount concern in biomedical research as it may not truly promote the rights and interests of research participants. The extent of information in ICFs has been the subject of debates for decades; however, no clear guidance is given. Thus, the objective of this study was to determine the perspectives of research participants about the type and extent of information they need when they are invited to participate in biomedical research. METHODS: This multi-center, cross-sectional, descriptive survey was conducted at 54 study sites in seven Asia-Pacific countries. A modified Likert-scale questionnaire was used to determine the importance of each element in the ICF among research participants of a biomedical study, with an anchored rating scale from 1 (not important) to 5 (very important). RESULTS: Of the 2484 questionnaires distributed, 2113 (85.1%) were returned. The majority of respondents considered most elements required in the ICF to be 'moderately important' to 'very important' for their decision making (mean score, ranging from 3.58 to 4.47). Major foreseeable risk, direct benefit, and common adverse effects of the intervention were considered to be of most concerned elements in the ICF (mean score = 4.47, 4.47, and 4.45, respectively). CONCLUSIONS: Research participants would like to be informed of the ICF elements required by ethical guidelines and regulations; however, the importance of each element varied, e.g., risk and benefit associated with research participants were considered to be more important than the general nature or technical details of research. Using a participant-oriented approach by providing more details of the participant-interested elements while avoiding unnecessarily lengthy details of other less important elements would enhance the quality of the ICF.

Modulation of CD4+ and CD8+ T Cell Function and Cytokine Responses in Strongyloides stercoralis Infection by Interleukin-27 (IL-27) and IL-37.

Strongyloides stercoralis infection is associated with diminished antigen-specific Th1- and Th17-associated responses and enhanced Th2-associated responses. Interleukin-27 (IL-27) and IL-37 are two known anti-inflammatory cytokines that are highly expressed in S. stercoralis infection. We therefore wanted to examine the role of IL-27 and IL-37 in regulating CD4+ and CD8+ T cell responses in S. stercoralis infection. To this end, we examined the frequency of Th1/Tc1, Th2/Tc2, Th9/Tc9, Th17/Tc17, and Th22/Tc22 cells in 15 S. stercoralis-infected individuals and 10 uninfected individuals stimulated with parasite antigen following IL-27 or IL-37 neutralization. We also examined the production of prototypical type 1, type 2, type 9, type 17, and type 22 cytokines in the whole-blood supernatants. Our data reveal that IL-27 or IL-37 neutralization resulted in significantly enhanced frequencies of Th1/Tc1, Th2/Tc2, Th17/Tc17, Th9, and Th22 cells with parasite antigen stimulation. There was no induction of any T cell response in uninfected individuals following parasite antigen stimulation and IL-27 or IL-37 neutralization. Moreover, we also observed increased production of gamma interferon (IFN-γ), IL-5, IL-9, IL-17, and IL-22 and decreased production of IL-10 following IL-27 and IL-37 neutralization and parasite antigen stimulation in whole-blood cultures. Thus, we demonstrate that IL-27 and IL-37 limit the induction of particular T cell subsets along with cytokine responses in S. stercoralis infections, which suggest the importance of IL-27 and IL-37 in immune modulation in a chronic helminth infection.

Anthelmintic Therapy Modifies the Systemic and Mycobacterial Antigen-Stimulated Cytokine Profile in Helminth-Latent Mycobacterium tuberculosis Coinfection.

Helminth infections are known to modulate cytokine responses in latent tuberculosis (LTB). However, very few studies have examined whether this modulation is reversible upon anthelmintic therapy. We measured the systemic and mycobacterial (TB) antigen-stimulated levels of type 1, type 2, type 17, and regulatory cytokines in individuals with LTB and with or without coexistent Strongyloides stercoralis infection before and after anthelmintic therapy. Our data reveal that individuals with LTB and coexistent S. stercoralis infection have significantly lower levels of systemic and TB antigen-stimulated type 1 (gamma interferon [IFN-γ], tumor necrosis factor alpha [TNF-α], and interleukin-2 [IL-2]) and type 17 (IL-17A and/or IL-17F) cytokines and significantly higher levels of systemic but not TB antigen-stimulated type 2 (IL-4 and IL-5) and regulatory (transforming growth factor beta [TGF-ß]) cytokines. Anthelmintic therapy resulted in significantly increased systemic levels of type 1 and/or type 17 cytokines and in significantly decreased systemic levels of type 2 and regulatory (IL-10 and TGF-ß) cytokines. In addition, anthelmintic therapy resulted in significantly increased TB antigen-stimulated levels of type 1 cytokines only. Our data therefore confirm that the modulation of systemic and TB antigen-stimulated cytokine responses in S. stercoralis-LTB coinfection is reversible (for the most part) by anthelmintic treatment.

Coincident diabetes mellitus modulates Th1-, Th2-, and Th17-cell responses in latent tuberculosis in an IL-10- and TGF-ß-dependent manner.

Type 2 diabetes mellitus (DM) is a risk factor for the development of active tuberculosis (TB), although its role in the TB-induced responses in latent TB (LTB) is not well understood. Since Th1, Th2, and Th17 responses are important in immunity to LTB, we postulated that coincident DM could alter the function of these CD4(+) T-cell subsets. To this end, we examined mycobacteria-induced immune responses in the whole blood of individuals with LTB-DM and compared them with responses of individuals without DM (LTB-NDM). T-cell responses from LTB-DM are characterized by diminished frequencies of mono- and dual-functional CD4(+) Th1, Th2, and Th17 cells at baseline and following stimulation with mycobacterial antigens-purified protein derivative, early secreted antigen-6, and culture filtrate protein-10. This modulation was at least partially dependent on IL-10 and TGF-ß, since neutralization of either cytokine resulted in significantly increased frequencies of Th1 and Th2 cells but not Th17 cells in LTB-DM but not LTB individuals. LTB-DM is therefore characterized by diminished frequencies of Th1, Th2, and Th17 cells, indicating that DM alters the immune response in latent TB leading to a suboptimal induction of protective CD4(+) T-cell responses, thereby providing a potential mechanism for increased susceptibility to active disease.

Parasite Antigen-Specific Regulation of Th1, Th2, and Th17 Responses in Strongyloides stercoralis Infection.

Chronic helminth infections are known to be associated with modulation of Ag-specific CD4(+) T responses. However, the role of CD4(+) T cell responses in human infection with Strongyloides stercoralis is not well defined. To examine the role of CD4(+) T cells expressing Th1, Th2, and Th17 cytokines in strongyloidiasis, we compared the frequency (Fo) of these subsets in infected (INF) individuals with Fo in S. stercoralis-uninfected (UN) individuals. INF individuals exhibited a significant decrease in the spontaneous and Ag-specific Fo of both monofunctional and dual-functional Th1 cells compared with UN. Similarly, INF individuals also exhibited significantly decreased Fo of monofunctional and dual-functional Th17 cells upon Ag stimulation compared with UN. In contrast, both the spontaneous and the Ag-induced Fo of monofunctional and dual-functional Th2 cells was significantly increased in INF compared with UN individuals. This differential T cell response was predominantly Ag specific because it was abrogated upon control Ag or mitogen stimulation. The regulation of Th1, Th2, and Th17 cells was predominantly dependent on IL-10, whereas the regulation of Th2, but not Th1 or Th17, cells was also dependent on TGF-ß. In addition, treatment of S. stercoralis infection significantly increased the Ag-specific Fo of Th1 and Th17 cells and decreased the Fo of Th2 cells in INF individuals. Thus, S. stercoralis infection is characterized by a parasite Ag-dependent regulation of monofunctional and dual-functional Th1, Th2, and Th17 cells, a regulation also reversible by antihelminthic treatment.

Impaired Cytokine but Enhanced Cytotoxic Marker Expression in Mycobacterium tuberculosis-Induced CD8+ T Cells in Individuals With Type 2 Diabetes and Latent Mycobacterium tuberculosis Infection.

Type 2 diabetes mellitus (DM) is a risk factor for tuberculosis among individuals with latent Mycobacterium tuberculosis infection. To explore the influence of DM on CD8(+) T-cell responses during latent M. tuberculosis infection, we estimated the cytokine and cytotoxic marker expression pattern in individuals with latent M. tuberculosis infection with DM and those with latent M. tuberculosis infection without DM. Among individuals with latent M. tuberculosis infection, those with DM had diminished frequencies of CD8(+) T-helper type 1 (Th1), Th2, and Th17 cells following stimulation by M. tuberculosis antigen and enhanced frequencies of CD8(+) T cells expressing cytotoxic markers, compared with those without DM. Thus, our results suggest that coincident DM modulates CD8(+) T-cell function during latent M. tuberculosis infection.

Modulation of CD4+ and CD8+ T-Cell Function by Interleukin 19 and Interleukin 24 During Filarial Infections.

Interleukin 19 (IL-19) and interleukin 24 (IL-24) are cytokines that are highly expressed in filarial infections. To study the role of IL-19 and IL-24 in regulating T-cell responses, we examined the frequency of T-helper type 1 (Th1)/Tc1, Th2/Tc2, Th9/Tc9, Th17/Tc17, Th22/Tc22, and Tr1 cells in 26 filariae-infected individuals stimulated with filarial antigen following IL-19 or IL-24 neutralization. IL-19 or IL-24 neutralization resulted in significantly enhanced frequencies of Th1/Tc1 and/or Th17/Tc17 cells and significantly reduced frequencies of Th2/Tc2, Tr1, and/or Th9/Tc9 cells. Thus, we demonstrate that IL-19 and IL-24 are associated with the modulation of T-cell responses in filarial infections.

Systemic Cytokine Profiles in Strongyloides stercoralis Infection and Alterations following Treatment.

Strongyloides stercoralis is a soil-transmitted helminth organism that infects ~50 to 100 million people worldwide. Despite its widespread prevalence, very little is known about the immune response that characterizes human S. stercoralis infection. To study the systemic cytokine profile characteristic of Strongyloides infection, we measured the circulating levels of a large panel of pro- and anti-inflammatory cytokines in asymptomatic, infected individuals (n = 32) and compared them to those in uninfected, controls (n = 24). Infected individuals exhibited significantly lower circulating levels of proinflammatory cytokines (gamma interferon [IFN-γ], tumor necrosis factor alpha [TNF-α], and interleukin-1ß [IL-1ß]) and significantly higher levels of anti-inflammatory cytokines (IL-4, IL-5, IL-9, IL-10, IL-13, IL-27, IL-37, and transforming growth factor ß [TGF-ß]). Moreover, treatment of Strongyloides infection resulted in a significant reversal of the cytokine profile, with increased levels of proinflammatory (IFN-γ, TNF-α, IL-2, IL-17A, IL-17F, IL-22, IL-23, and IL-1ß) and decreased levels of anti-inflammatory (IL-4, IL-5, IL-9, IL-10, IL-13, IL-27, IL-37, and TGF-ß) cytokines following treatment. Thus, S. stercoralis infection is characterized by alterations in the levels of systemic cytokines, reflecting major alterations in the underlying immune response to this chronic helminth infection.

Type 2 diabetes mellitus coincident with pulmonary or latent tuberculosis results in modulation of adipocytokines.

Type 2 diabetes mellitus (T2DM) is recognized as major risk factor for the progress of active pulmonary tuberculosis (PTB), although the mechanistic link between diabetes and tuberculosis remains poorly characterized. Moreover, the influence of poorly controlled diabetes on the baseline levels of adipocytokines in the context of tuberculosis has not been explored in detail. To characterize the influence of coexistent DM on adipocytokine levels in pulmonary or latent TB (LTB), we examined circulating levels of adipocytokines in the plasma of individuals with PTB-DM or LTB-DM and compared them with those without DM (PTB or LTB). PTB-DM or LTB-DM is characterized by diminished circulating levels of adiponectin and adipsin and/or heightened circulating levels of leptin, visfatin and PAI-1. In addition, adiponectin and adipsin exhibit a significant negative correlation, whereas leptin, visfatin and PAI-1 display a significant positive correlation with HbA1C levels and random blood glucose levels. Therefore, our data reveal that PTB-DM or LTB-DM is characterized by alterations in the systemic levels of adipocytokines, indicating that altered adipose tissue inflammation underlying Type 2 diabetes potentially contributes to pathogenesis of TB disease.

Profiling leucocyte subsets in tuberculosis-diabetes co-morbidity.

The immune system plays an important role in the pathogenesis of pulmonary tuberculosis-type 2 diabetes mellitus (PTB-DM) co-morbidity. However, the phenotypic profile of leucocyte subsets at homeostasis in individuals with active or latent tuberculosis (LTB) with coincident diabetes is not known. To characterize the influence of diabetes on leucocyte phenotypes in PTB or LTB, we examined the frequency (Fo ) of leucocyte subsets in individuals with TB with (PTB-DM) or without (PTB) diabetes; individuals with latent TB with (LTB-DM) or without (LTB) diabetes and non-TB-infected individuals with (NTB-DM) or without (NTB) diabetes. Coincident DM is characterized by significantly lower Fo of effector memory CD4(+) T cells in LTB individuals. In contrast, DM is characterized by significantly lower Fo of effector memory CD8(+) T cells and significantly higher Fo of central memory CD8(+) T cells in PTB individuals. Coincident DM resulted in significantly higher Fo of classical memory B cells in PTB and significantly higher Fo of activated memory and atypical B cells in LTB individuals. Coincident DM resulted in significantly lower Fo of classical and intermediate monocytes in PTB, LTB and NTB individuals. Finally, DM resulted in significantly lower Fo of myeloid and plasmacytoid dendritic cells in PTB, LTB and NTB individuals. Our data reveal that coincident diabetes alters the cellular subset distribution of T cells, B cells, dendritic cells and monocytes in both individuals with active TB and those with latent TB, thus potentially impacting the pathogenesis of this co-morbid condition.

IL-4-, TGF-ß-, and IL-1-dependent expansion of parasite antigen-specific Th9 cells is associated with clinical pathology in human lymphatic filariasis.

Th9 cells are a subset of CD4(+) T cells, shown to be important in allergy, autoimmunity, and antitumor responses; however, their role in human infectious diseases has not been explored in detail. We identified a population of IL-9 and IL-10 coexpressing cells (lacking IL-4 expression) in normal individuals. These cells respond to antigenic and mitogenic stimulation, but are distinct from IL-9(+) Th2 cells. We also demonstrate that these Th9 cells exhibit Ag-specific expansion in a chronic helminth infection (lymphatic filariasis). Comparison of Th9 responses reveals that individuals with pathology associated with filarial infection exhibit significantly expanded frequencies of filarial Ag-induced Th9 cells, but not of IL9(+)Th2 cells in comparison with filarial-infected individuals without associated disease. Moreover, the per cell production of IL-9 is significantly higher in Th9 cells compared with IL9(+)Th2 cells, indicating that the Th9 cells are the predominant CD4(+) T cell subset producing IL-9 in the context of human infection. This expansion was reflected in elevated Ag-stimulated IL-9 cytokine levels in whole blood culture supernatants. Finally, the frequencies of Th9 cells correlated positively with the severity of lymphedema (and presumed inflammation) in filarial-diseased individuals. This expansion of Th9 cells was dependent on IL-4, TGF-ß, and IL-1 in vitro. We have therefore identified an important human CD4(+) T cell subpopulation coexpressing IL-9 and IL-10, but not IL-4, the expansion of which is associated with disease in chronic lymphatic filariasis and could potentially have an important role in the pathogenesis of other inflammatory disorders.

Diminished systemic and antigen-specific type 1, type 17, and other proinflammatory cytokines in diabetic and prediabetic individuals with latent Mycobacterium tuberculosis infection.

BACKGROUND: Diabetes mellitus type 2 (DM) is known to be a major risk factor for the development of active tuberculosis, although its influence on latent Mycobacterium tuberculosis infection (hereafter, "latent infection") remains poorly characterized. METHODS: We examined circulating plasma cytokine levels in individuals with latent infection with DM or pre-DM (ie, intermediate hyperglycemia) and compared them to levels in patients with latent infection and normal glycemic control. RESULTS: In persons with DM or pre-DM, latent infection is characterized by diminished circulating levels of type 1 (interferon γ, interleukin 2, and tumor necrosis factor α) and type 17 (interleukin 17F) cytokines. This was associated with decreased systemic levels of other proinflammatory cytokines (interleukin 1ß and interleukin 18) and the antiinflammatory cytokine interleukin 10 but not with decreased systemic levels of type 2 cytokines. Moreover, latently infected individuals with DM had diminished levels of spontaneous and M. tuberculosis antigen-specific levels of type 1 and type 17 cytokines when antigen-stimulated whole blood was examined. Finally, there was no significant correlation between the levels of any of the cytokines measured (with the exception of interleukin 22) with hemoglobin A1c levels. CONCLUSIONS: Our data reveal that latent infection in the presence of DM or pre-DM, is characterized by diminished production of cytokines, implicated in the control of M. tuberculosis activation, allowing for a potential immunological mechanism that could account for the increased risk of active tuberculosis in latently infected individuals with DM.

Operational Challenges in Conducting a Subnational TB Prevalence Survey in India: Lessons Learned for Resource-Limited, High-Burden Settings.

Estimating the burden of TB at the subnational level is critical to planning and prioritizing resources for TB control activities according to the local epidemiological situation. We report the experiences and operational challenges of implementing a TB prevalence survey at the subnational level in India. Information was collected from research reports that gathered data from periodic meetings, informal discussions with study teams, letters of communication, and various site visit reports. During the implementation of the survey, several challenges were encountered, including frequent turnover in human resources, lack of survey participation and community engagement, breakdown of X-ray machines, laboratory issues that delayed sputum sample testing, delays in X-ray reading, and network and Internet connectivity issues that impeded data management. To help ensure the survey was implemented in a timely manner, we developed several solutions, including planning ahead to anticipate challenges, ensuring timely communication, having a high commitment from all stakeholders, having strong team motivation, providing repetitive hands-on training, and involving local leaders to increase community engagement. This experience may help future states and countries that plan to conduct TB prevalence surveys to address these anticipated challenges and develop alternative strategies well in advance.

Multi-Dimensionality Immunophenotyping Analyses of MAIT Cells Expressing Th1/Th17 Cytokines and Cytotoxic Markers in Latent Tuberculosis Diabetes Comorbidity.

Mucosal-associated invariant T (MAIT) cells are innate like, and play a major role in restricting disease caused by Mycobacterium tuberculosis (Mtb) disease before the activation of antigen-specific T cells. Additionally, the potential link and synergistic function between diabetes mellitus (DM) and tuberculosis (TB) has been recognized for a long time. However, the role of MAIT cells in latent TB (LTB) DM or pre-DM (PDM) and non-DM (NDM) comorbidities is not known. Hence, we examined the frequencies (represented as geometric means, GM) of unstimulated (UNS), mycobacterial (purified protein derivative (PPD) and whole-cell lysate (WCL)), and positive control (phorbol myristate acetate (P)/ionomycin (I)) antigen stimulated MAIT cells expressing Th1 (IFNγ, TNFα, and IL-2), Th17 (IL-17A, IL-17F, and IL-22), and cytotoxic (perforin (PFN), granzyme (GZE B), and granulysin (GNLSN)) markers in LTB comorbidities by uniform manifold approximation (UMAP) and flow cytometry. We also performed a correlation analysis of Th1/Th17 cytokines and cytotoxic markers with HbA1c, TST, and BMI, and diverse hematological and biochemical parameters. The UMAP analysis demonstrated that the percentage of MAIT cells was higher; T helper (Th)1 cytokine and cytotoxic (PFN) markers expressions were different in LTB-DM and PDM individuals in comparison to the LTB-NDM group on UMAP. Similarly, no significant difference was observed in the geometric means (GM) of MAIT cells expressing Th1, Th17, and cytotoxic markers between the study population under UNS conditions. In mycobacterial antigen stimulation, the GM of Th1 (IFNγ (PPD and WCL), TNFα (PPD and WCL), and IL-2 (PPD)), and Th17 (IL-17A, IL-17F, and IL-22 (PPD and/or WCL)) cytokines were significantly elevated and cytotoxic markers (PFN, GZE B, and GNLSN (PPD and WCL)) were significantly reduced in the LTB-DM and/or PDM group compared to the LTB-NDM group. Some of the Th1/Th17 cytokines and cytotoxic markers were significantly correlated with the parameters analyzed. Overall, we found that different Th1 cytokines and cytotoxic marker population clusters and increased Th1 and Th17 (IL-17A, IL-22) cytokines and diminished cytotoxic markers expressing MAIT cells are associated with LTB-PDM and DM comorbidities.

Age-specific prevalence of TB infection among household contacts of pulmonary TB: Is it time for TB preventive therapy?

BACKGROUND: Household contacts (HHCs) of TB patients are at high risk of developing evidence of latent TB infection (LTBI) and active disease from the index patient. We estimated the age-specific prevalence of LTBI and the force of infection (FI), as a measure of recent transmission, among HHCs of active TB patients. METHODS: A cross-sectional analysis of HHCs of pulmonary TB patients enrolled in a prospective study, 'CTRIUMPh', was conducted at two sites in India. LTBI was defined as either a positive tuberculin skin test (induration ≥5 mm) or QuantiFERON-Gold in tube test (value ≥0.35 IU/ml) and was stratified by age. FI, which is a measure of recent transmission of infection and calculated using changes in age-specific prevalence rates at specific ages, was calculated. Factors associated with LTBI were determined by logistic regression models. RESULTS: Of 1020 HHCs of 441 adult pulmonary TB cases, there were 566 (55%) females and 289 (28%) children aged ≤15 y. While screening for the study 3% of HHC were diagnosed with active TB. LTBI prevalence among HHCs of pulmonary TB was 47% at <6 y, 53% between 6-14 y and 78% between 15-45 y. FI increased significantly with age, from 0.4 to 1.15 in the HHCs cohort (p=0.05). CONCLUSION: This study observed an increased prevalence of LTBI and FI among older children and young adults recently exposed to infectious TB in the household. In addition to awareness of coughing etiquette and general hygiene, expanding access to TB preventive therapy to all HHCs, including older children, may be beneficial to achieve TB elimination by 2035.

Modulation of iron status biomarkers in tuberculosis-diabetes co-morbidity.

Tuberculosis (TB) and diabetes mellitus (DM) remain vital disease burdens in developing countries and the dual burden of DM and TB clearly signifies a growing global public health concern. While modulation of iron status biomarkers in TB is well described, very little is known about the association of these markers with TB-DM. To examine the association of circulating iron status biomarkers in TB disease, we examined the systemic levels of ferritin, hepcidin, soluble transferrin receptor (sTfR), transferrin, apotransferrin and hemopexin in pulmonary TB (PTB) individuals with DM (PTB-DM), without DM (PTB) and those with diabetes only (DM). Circulating levels of ferritin and hepcidin were significantly enhanced in PTB-DM and PTB compared to the DM group. On the other hand, the circulating levels of transferrin and apotransferrin were significantly diminished in PTB-DM and PTB compared to the DM group. The levels of ferritin and hepcidin exhibited a significant positive relationship with HbA1c, whereas apotransferrin exhibited negative relationship with HbA1c in PTB-DM and PTB. ROC analysis revealed that ferritin, hepcidin and transferrin are markers that can distinguish PTB-DM from DM individuals. Our results suggest that some of these circulating iron status markers could prove useful as biomarkers to monitor disease severity.

Prediabetes is associated with the modulation of antigen-specific Th1/Tc1 and Th17/Tc17 responses in latent Mycobacterium tuberculosis infection.

Type 2 diabetes mellitus (DM) is associated with the down modulation of Th1, Th2 and Th17 responses in latent Mycobacterium tuberculosis infection but the role of prediabetes (PDM) in this setting is not well understood. To examine the role of CD4+ and CD8+ T cell cytokines in latent tuberculosis (LTB) with coincident PDM, we studied the baseline, mycobacterial, control antigen and mitogen-stimulated T cell cytokine responses in LTB individuals with (LTB-PDM; n = 20) or without (LTB-NDM; n = 20) concomitant prediabetes. LTB-PDM is characterized by diminished frequencies of mono-and dual-functional CD4+ Th1 and Th17 cells and mono-functional Th2 cells at baseline and/or following mycobacterial-antigen stimulation in comparison to LTB-NDM. LTB-PDM is also characterized by diminished frequencies of mono-functional CD8+ Tc1, Tc2 and Tc17 cells at baseline and/or following mycobacterial-antigen stimulation in comparison to LTB-NDM. LTB-PDM is therefore characterized by diminished frequencies of antigen-specific Th1/Tc1 and Th17/Tc17 cells, indicating that PDM is associated with alterations of the immune response in latent TB associated with compromised CD4+ and CD8+ T cell function.

Modulation of Mycobacterium tuberculosis-specific humoral immune responses is associated with Strongyloides stercoralis co-infection.

BACKGROUND / OBJECTIVES: Helminth infections are known to influence T cell responses in latent tuberculosis (LTBI). Whether helminth infections also modulate B cell responses in helminth-tuberculosis co-infection is not known. METHODS: We assessed Mycobacterium tuberculosis (Mtb)-antigen specific IgM and IgG levels, circulating levels of the B cell growth factors, BAFF and APRIL and the absolute numbers of the various B cell subsets in individuals with LTBI, LTBI with coincident Strongyloides stercoralis (Ss) infection (LTBI/Ss) and in those with Ss infection alone (Ss). We also measured the above-mentioned parameters in the LTBI-Ss group after anthelmintic therapy. RESULTS: Our data reveal that LTBI-Ss exhibit significantly diminished levels of Mtb-specific IgM and IgG, BAFF and APRIL levels in comparison to those with LTBI. Similarly, those with LTBI-Ss had significantly diminished numbers of all B cell subsets (naïve, immature, classical memory, activated memory, atypical memory and plasma cells) compared to those with LTBI. There was a positive correlation between Mtb-antigen specific IgM and IgG levels and BAFF and APRIL levels that were in turn related to the numbers of activated memory B cells, atypical memory B cells and plasma cells. Finally, anthelmintic treatment resulted in significantly increased levels of Mtb-antigen specific IgM and IgG levels and the numbers of each of the B cell subsets. CONCLUSIONS: Our data, therefore, reveal that Ss infection is associated with significant modulation of Mtb-specific antibody responses, the levels of B cell growth factors and the numbers of B cells (and their component subsets).

Coincident filarial, intestinal helminth, and mycobacterial infection: helminths fail to influence tuberculin reactivity, but BCG influences hookworm prevalence.

The prevalence of helminth and tuberculosis infections is high in South India, whereas Bacille-Calmette-Guerin (BCG) vaccine efficacy is low. Our aim was to determine whether concurrent helminth infection alters the ability to mount a delayed-type hypersensitivity response to tuberculin. In a cross-sectional study in southern India, individuals 6-65 years of age were screened for intestinal helminths, circulating filarial antigenemia, tuberculin reactivity, active tuberculosis, and history of BCG vaccination; 54% were purified protein derivative (PPD) positive, 32% had intestinal helminth infection, 9% were circulating filarial antigen positive, and 0.5% had culture-confirmed active tuberculosis. Only age and BCG vaccination were significantly associated with PPD reactivity; however, BCG vaccination was associated with a lower prevalence of hookworm infection relative to those without prior BCG vaccination. Neither intestinal helminth infection nor filarial infection was associated with diminished frequencies of PPD positivity. Our findings suggest that preceding helminth infection does not influence significantly the delayed-type hypersensitivity response to tuberculin.

High body mass index is associated with heightened systemic and mycobacterial antigen - Specific pro-inflammatory cytokines in latent tuberculosis.

High body mass index (HBMI) has been shown to be protective against active tuberculosis (TB), although the biological mechanism underlying this protection is poorly understood. The immunological association between HBMI and latent TB has never been examined. In order to study the association of HBMI with latent TB, we examined the circulating and TB- antigen or mitogen stimulated levels of a large panel of cytokines in individuals with latent TB (LTB) and high or normal body mass index (HBMI or NBMI). HBMI is characterized by heightened circulating levels of pro-inflammatory (IFNγ, TNFα, IL-22, IL-1α, IL-12 and GM-CSF) cytokines but decreased circulating levels of anti-inflammatory cytokines (IL-4, IL-5 and TGFß). This systemic cytokine profile is associated with elevated TB-antigen and mitogen stimulated levels of IFNγ, TNFα, IL-2 and IL-1α and diminished levels of IL-10 and TGFß. In addition, we also observed a positive correlation between the circulating levels of IFNγ, TNFα, IL-22, IL-1α with BMI and a negative correlation between the circulating levels of IL-10, TGFß and BMI. Our data, therefore, suggest the modulation of protective and regulatory cytokines might underlie the protective effect of HBMI against the development of active TB.