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Background: Helminth infections are known to regulate cytokine responses in both pulmonary and latent tuberculosis infection. Whether helminth infections also modulate cytokine responses in extra-pulmonary tuberculosis, specifically tuberculous lymphadenitis (TBL), has not been examined thus far. Methodology: Hence, to determine the cytokine profile in helminth-TBL coinfection, we measured the systemic and mycobacterial (TB)–antigen stimulated levels of Type 1, Type 2, Type 17, regulatory and pro-inflammatory cytokines in TBL individuals coinfected with or without Strongyloides stercoralis (Ss) infection. Significant findings: TBL-Ss+ individuals have significantly higher bacterial burdens in the affected lymph nodes in comparison to TBL-Ss- individuals. TBL-Ss+ individuals exhibit significantly enhanced plasma levels of Type 2 (IL-5 and IL-13), Type 17 (IL-17 and IL-22) and regulatory (IL-10) cytokines in comparison to TBL-Ss- individuals. In contrast, TBL-Ss+ individuals exhibit significantly diminished plasma levels of pro-inflammatory cytokines (IL-1α and GM-CSF) in comparison to TBL-Ss- individuals. TBL-Ss+ individuals also exhibit significantly diminished unstimulated or mycobacterial—antigen stimulated levels of Type 1, Type 17 or IL-1 family cytokines in comparison to TBL-Ss- individuals but no differences in mitogen stimulated cytokine levels. Conclusion: Therefore, our data reveal a profound influence of Ss infection on the bacteriological profile of TBL and suggesting that the underlying modulation of cytokine responses might be a mechanism by which this helminth infection could impart a detrimental effect on the pathogenesis of TBL disease. [ABSTRACT FROM AUTHOR]

B cell activating factor/a proliferation-inducing ligand (BAFF/APRIL) are members of the tumor necrosis factor alpha (TNF) α family of ligands, which are essential for B cell survival, development, and modulation of the immune system. To examine the association of circulating levels of BAFF and APRIL with pulmonary tuberculosis (PTB) and tuberculous lymphadenitis (TBL), we measured the systemic levels of APRIL and BAFF in individuals with PTB, TBL, latent tuberculosis (LTB) and healthy controls (HC). Further, we also examined the pre and post-treatment plasma levels of above-mentioned parameters in PTB and TBL individuals upon completion of anti-TB chemotherapy. Next, the association of these cytokines either with extent of disease, disease severity, bacterial burden in PTB and lymph node culture grade or the lymph node size in TBL was also assessed. Finally, ROC analysis was performed to examine the discrimination capacity of APRIL and BAFF between PTB or TBL with LTB. Our study revealed significantly diminished plasma levels of APRIL in PTB and higher plasma levels of BAFF in both PTB and TBL individuals compared to LTB and HC. Furthermore, we observed a significant increase in APRIL levels in TBL and significantly decreased plasma levels of BAFF in both PTB and TBL after the completion of successful anti-TB treatment. There was no statistically positive relationship between BAFF and APRIL levels and the extent of disease, disease severity and bacterial burden in PTB. In TBL, there was a significant correlation between APRIL (but not BAFF) levels with lymph node culture grades. In contrast, APRIL in PTB and BAFF in TBL were able to clearly discriminate from LTB in ROC analysis. In summary, our results showed altered levels of BAFF/APRIL and their modulation upon chemotherapy, suggesting that these cytokines might be involved in the immune-modulation of TB infection. [ABSTRACT FROM AUTHOR]

Background: CD4+ and CD8+ T cells are central players in immunity to helminth infections. However, the role of T cell subsets in human helminth infections is not well understood. In addition, the common γc cytokines, IL-2, IL-4, IL-7, IL-9 and IL-15 play an important role in the maintenance of these CD4+ and CD8+ T cell subsets. Methods: To examine the major T cell subsets and their association with the common γc cytokines, the absolute numbers of CD4+ and CD8+ naïve, central memory, effector memory and effector cells and the plasma levels of IL-2, IL-4, IL-7, IL-9 and IL-15 were measured in Strongyloides stercoralis (Ss) infected (INF, n = 60), helminth—uninfected (UN, n = 58) and in post treatment INF individuals. Results: Ss infection is characterized by significantly increased absolute numbers of naïve and decreased absolute numbers of central and effector memory CD4+ T cells in comparison to UN individuals. No significant difference in the numbers of CD8+ T cell subsets was observed between the groups. The numbers of naïve cells and central memory CD4+ T cells were significantly reversed after anthelmintic treatment. Circulating levels of IL-2, IL-7 and IL-15 were significantly diminished, whereas the levels of IL-4 and IL-9 were significantly increased in INF compared to UN individuals. Following anthelminthic treatment, IL-2, IL-7 and IL-15 levels were significantly increased, while IL-4 and IL-9 levels were significantly decreased. Our data also showed a significant positive correlation between the levels of IL-7 and the numbers of central and effector memory CD4+ T cells. Conclusion: Ss infection is characterized by alterations in the absolute numbers of CD4+ T cell subsets and altered levels of common γc cytokines IL-2, IL-4, IL-7, IL-9 and IL-15; alterations which are partially reversed after anthelmintic treatment. [ABSTRACT FROM AUTHOR]

Background: The association of antimicrobial peptides (AMPs) with tuberculosis—diabetes comorbidity (PTB-DM) is not well understood. Methods: To study the association of AMPs with PTB-DM, we examined the systemic levels of cathelicidin (LL37), human beta defensin– 2 (HBD2), human neutrophil peptides 1–3, (HNP1-3) and granulysin in individuals with either PTB-DM, PTB, latent TB (LTB) or no TB infection (NTB). Results: Circulating levels of cathelicidin and HBD2 were significantly higher and granulysin levels were significantly lower in PTB-DM compared to PTB, LTB or NTB, while the levels of HNP1-3 were significantly higher in PTB-DM compared to LTB or NTB individuals. Moreover, the levels of cathelicidin and/or HBD2 were significantly higher in PTB-DM or PTB individuals with bilateral and cavitary disease and also exhibited a significant positive relationship with bacterial burden. Cathelidin, HBD2 and HNP1-3 levels exhibited a positive relationship with HbA1c and/or fasting blood glucose levels. Finally, anti-tuberculosis therapy resulted in significantly diminished levels of cathelicidin, HBD2, granulysin and significantly enhanced levels of HNP1-3 and granulysin in PTB-DM and/or PTB individuals. Conclusion: Therefore, our data demonstrate that PTB-DM is associated with markedly enhanced levels of AMPs and diminished levels of granulysin. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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). [ABSTRACT FROM AUTHOR]

Background: The immune response to tuberculosis (TB) is T cell dependent. T cells are the major facilitators of protection and effector functions with CD4+ T cells being the most important players, followed by CD8+ T cells. The common γ-chain cytokines IL-2, IL-7, IL-15, and IL-21 play a vital role in peripheral T cell growth and survival. However, the role of common γ-chain cytokines in pulmonary TB (PTB) is poorly understood. Aim and methods: To examine the association of circulating common γ-chain cytokines with TB disease or infection, we examined the systemic levels of IL-2, IL-7, IL-15, and IL-21 in individuals with PTB, latent TB (LTB) or no TB infection (NTB). We also examined the levels of these cytokines in PTB individuals before and after anti-tuberculosis treatment. Results: Circulating levels of IL-2, IL-7 and IL-21 were significantly diminished in PTB compared to LTB or NTB individuals. Moreover, TB antigen stimulated whole blood also exhibited diminished levels of common γ-chain cytokines in PTB compared to LTB or NTB individuals. The plasma levels of common γ-chain cytokines exhibited no significant association with the severity or extent of TB disease or with bacterial burdens. However, upon standard anti-TB treatment, both the systemic as well as the TB antigen stimulated levels of IL-2, IL-7 and IL-21 were significantly increased in PTB individuals. Conclusion: Therefore our data demonstrate that diminished levels of common γ-chain cytokines are a common characteristic of PTB and potentially highlight the importance of boosting these responses to improve treatment outcomes. [ABSTRACT FROM AUTHOR]

In this study, we developed a mouse model of type 2 diabetes mellitus (T2DM) using streptozotocin and nicotinamide and identified factors that increase susceptibility of T2DM mice to infection by Mycobacterium tuberculosis (Mtb). All Mtb-infected T2DM mice and 40% of uninfected T2DM mice died within 10 months, whereas all control mice survived. In Mtb-infected mice, T2DM increased the bacterial burden and pro- and anti-inflammatory cytokine and chemokine production in the lungs relative to those in uninfected T2DM mice and infected control mice. Levels of IL-6 also increased. Anti-IL-6 monoclonal antibody treatment of Mtb-infected acute- and chronic-T2DM mice increased survival (to 100%) and reduced pro- and anti-inflammatory cytokine expression. CD11c+ cells were the major source of IL-6 in Mtb-infected T2DM mice. Pulmonary natural killer (NK) cells in Mtb-infected T2DM mice further increased IL-6 production by autologous CD11c+ cells through their activating receptors. Anti-NK1.1 antibody treatment of Mtb-infected acute-T2DM mice increased survival and reduced pro- and anti-inflammatory cytokine expression. Furthermore, IL-6 increased inflammatory cytokine production by T lymphocytes in pulmonary tuberculosis patients with T2DM. Overall, the results suggest that NK-CD11c+ cell interactions increase IL-6 production, which in turn drives the pathological immune response and mortality associated with Mtb infection in diabetic mice. [ABSTRACT FROM AUTHOR]

Background: Th9 cells are a subset of CD4+ T cells that express the protoypical cytokine, IL-9. Th9 cells are known to effect protective immunity in animal models of intestinal helminth infections. However, the role of Th9 cells in human intestinal helminth infections has never been examined. Methodology: To examine the role of Th9 cells in Strongyloidis stercoralis (Ss), a common intestinal helminth infection, we compared the frequency of Th9 expressing IL-9 either singly (mono-functional) or co-expressing IL-4 or IL-10 (dual-functional) in Ss-infected individuals (INF) to frequencies in uninfected (UN) individuals. Principal Findings: INF individuals exhibited a significant increase in the spontaneously expressed and/or antigen specific frequencies of both mono- and dual-functional Th9 cells as well as Th2 cells expressing IL-9 compared to UN. The differences in Th9 induction between INF and UN individuals was predominantly antigen-specific as the differences were no longer seen following control antigen or mitogen stimulation. In addition, the increased frequency of Th9 cells in response to parasite antigens was dependent on IL-10 and TGFx since neutralization of either of these cytokines resulted in diminished Th9 frequencies. Finally, following successful treatment of Ss infection, the frequencies of antigen-specific Th9 cells diminished in INF individuals, suggesting a role for the Th9 response in active Ss infection. Moreover, IL-9 levels in whole blood culture supernatants following Ss antigen stimulation were higher in INF compared to UN individuals. Conclusion: Thus, Ss infection is characterized by an IL-10- and TGFβ dependent expansion of Th9 cells, an expansion found to reversible by anti-helmintic treatment. [ABSTRACT FROM AUTHOR]

Background: Angiogenesis and lymphangiogenesis are classical features of granuloma formation in pulmonary tuberculosis (PTB). In addition, the angiogenic factor—VEGF-A is a known biomarker for PTB. Aims/Methodology: To examine the association of circulating angiogenic factors with PTB, we examined the systemic levels of VEGF-A, VEGF-C, VEGF-D, VEGF-R1, VEGF-R2 and VEGF-R3in individuals with PTB, latent TB (LTB) or no TB infection (NTB). Results: Circulating levels of VEGF-A, VEGF-C andVEGF-R2 were significantly higher in PTB compared to LTB or NTB individuals. Moreover, the levels of VEGF-A, VEGF-C and VEGF-R2 were significantly higher in PTB with bilateral and/or cavitary disease. The levels of these factors also exhibited a significant positive relationship with bacterial burdens in PTB. ROC analysis revealed VEGF-A and VEGF-R2 as markers distinguishing PTB from LTB or NTB. Finally, the circulating levels of all the angiogenic factors examined were significantly reduced following successful chemotherapy. Conclusion: Therefore, our data demonstrate that PTB is associated with elevated levels of circulating angiogenic factors, possibly reflecting vascular and endothelial dysfunction. In addition, some of these circulating angiogenic factors could prove useful as biomarkers to monitor disease severity, bacterial burden and therapeutic responses. [ABSTRACT FROM AUTHOR]

Background: Lipopolysaccharide (LPS)/Endotoxin is hypothesized to play an important role in chronic inflammation associated with Type-1 diabetes (T1DM) and its complications. Endotoxin core antibodies (EndoCAb), LPS binding protein (LBP) and soluble CD14 (sCD14) act as modulators of LPS induced activation of innate immune system in vivo. For the present study we estimated the levels of LPS and its translocation markers in T1DM subjects with and without microvascular complications (MVC) and correlate them with clinical parameters of T1DM and serum inflammatory cytokine levels (TNF-α, IL-6, IL-1β and GM-CSF). Methods: A total of 197 subjects (64 normal glucose tolerance (NGT) subjects, 97 T1DM subjects without MVC and 36 with MVC) were included in this study and the levels of serum LPS, its translocation markers and cytokines measured by immunoassays. Results: Compared to NGT, T1DM subjects (both with and without MVC) had significantly higher levels of LPS, reduced levels of LBP and EndoCAb along with significant increase in the levels of IL-1β, IL-6, TNF-α and GM-CSF (p<0.05). No significant change was seen in the levels of these biomarkers between T1DM subjects with and without MVC. Conclusions: Decreased levels of EndoCAb and LBP suggest sustained endotoxin activity in T1DM subjects even before the onset of microvascular complications. [ABSTRACT FROM AUTHOR]

Monocyte dysfunction by filarial antigens has been a major mechanism underlying immune evasion following hyporesponsiveness during patent lymphatic filariasis. Recent studies have initiated a paradigm shift to comprehend the immunological interactions of Wolbachia and its antigens in inflammation, apoptosis, lymphocyte anergy, etc. Here we showed that recombinant Wolbachia heat shock protein 60 (rWmhsp60) interacts with TLR-4 and induces apoptosis in monocytes of endemic normal but not in chronic patients. Higher levels of reactive oxygen species (ROS) induced after TLR-4 stimulation resulted in loss of mitochondrial membrane potential and caspase cascade activation, which are the plausible reason for apoptosis. Furthermore, release in ROS owing to TLR-4 signaling resulted in the activation of NF-κB p65 nuclear translocation which leads to inflammation and apoptosis via TNF receptor pathway following the increase in IL-6 and TNF-α level. Here for the first time, we report that in addition to apoptosis, rWmhsp60 antigen in filarial pathogenesis also induces molecular senescence in monocytes. Targeting TLR-4, therefore, presents a promising candidate for treating rWmhsp60-induced apoptosis and senescence. Strikingly, induction of autophagy by rapamycin detains TLR-4 in late endosomes and subverts TLR-4-rWmhsp60 interaction, thus protecting TLR-4–mediated apoptosis and senescence. Furthermore, rapamycin-induced monocytes were unresponsive to rWmhsp60, and activated lymphocytes following PHA stimulation. This study demonstrates that autophagy mediates the degradation of TLR-4 signaling and protects monocytes from rWmhsp60 induced apoptosis and senescence. [ABSTRACT FROM AUTHOR]

Background: The disease course of human immunodeficiency virus (HIV) is often altered by existing or newly acquired coincident infections. Methodology/Principal Findings: To assess the influence of pre-existing Wuchereria bancrofti infection on HIV progression, we performed a case-controlled treatment study of HIV positive individuals with (FIL+) or without (FIL-) W. bancrofti infection. Twenty-eight HIV+/FIL+ and 51 matched HIV+/FIL- subjects were treated with a single dose of diethylcarbamazine and albendazole (DEC/Alb) and followed for a year at regular intervals. Sixteen of the HIV+/FIL+ subjects (54%) and 28 of the HIV+/FIL- controls (57%) were on antiretroviral therapy (ART) during the study. Following treatment, no differences were noted in clinical outcomes between the 2 groups. There also was no significant difference between the groups in the HIV viral load at 12 months as a percentage of baseline viral load (HIV+/FIL+ group had on average 0.97 times the response of the HIV+/FIL- group, 95% CI 0.88, 1.07) between the groups. Furthermore, there were no significant differences found in either the change in viral load at 1, 3, or 6 months or in the change in CD4 count at 3, 6, or 12 months between the 2 groups. Conclusions/Significance: We were unable to find a significant effect of W. bancrofti infection or its treatment on HIV clinical course or surrogate markers of HIV disease progression though we recognized that our study was limited by the smaller than predicted sample size and by the use of ART in half of the patients. Treatment of W. bancrofti coinfection in HIV positive subjects (as is usual in mass drug administration campaigns) did not represent an increased risk to the subjects, and should therefore be considered for PLWHA living in W. bancrofti endemic areas. Trial Registration: ClinicalTrials.gov [ABSTRACT FROM AUTHOR]

Background: Helminth infections are known to modulate innate and adaptive immune responses in active and latent tuberculosis (TB). However, the role of helminth infections in modulating responses associated with inflammation and immune activation (reflecting disease activity and/or severity) in TB is not known. Methodology: We measured markers of inflammation and immune activation in active pulmonary TB individuals (ATB) with co-incidental Strongyloides stercoralis (Ss) infection. These included systemic levels of acute phase proteins, matrix metalloproteinases and their endogenous inhibitors and immune activation markers. As a control, we measured the systemic levels of the same molecules in TB-uninfected individuals (NTB) with or without Ss infection. Principal Findings: Our data confirm that ATB is associated with elevated levels of the various measured molecules when compared to those seen in NTB. Our data also reveal that co-incident Ss infection in ATB individuals is associated with significantly decreased circulating levels of acute phase proteins, matrix metalloproteinases, tissue inhibitors of matrix metalloproteinases as well as the systemic immune activation markers, sCD14 and sCD163. These changes are specific to ATB since they are absent in NTB individuals with Ss infection. Conclusions: Our data therefore reveal a profound effect of Ss infection on the markers associated with TB disease activity and severity and indicate that co-incidental helminth infections might dampen the severity of TB disease. [ABSTRACT FROM AUTHOR]

Background: Cytokines play an important role in the pathogenesis of pulmonary tuberculosis (PTB) - Type 2 diabetes mellitus co-morbidity. However, the cytokine interactions that characterize PTB coincident with pre-diabetes (PDM) are not known. Methods: To identify the influence of coincident PDM on cytokine levels in PTB, we examined circulating levels of a panel of cytokines in the plasma of individuals with TB-PDM and compared them with those without PDM (TB-NDM). Results: TB-PDM is characterized by elevated circulating levels of Type 1 (IFNγ, TNFα and IL-2), Type 17 (IL-17A and IL-17F) and other pro-inflammatory (IL-1β, IFNβ and GM-CSF) cytokines. TB-PDM is also characterized by increased systemic levels of Type 2 (IL-5) and regulatory (IL-10 and TGFβ) cytokines. Moreover, TB antigen stimulated whole blood also showed increased levels of pro-inflammatory (IFNγ, TNFα and IL-1β) cytokines as well. However, the cytokines did not exhibit any significant correlation with HbA1C levels or with bacterial burdens. Conclusion: Our data reveal that pre-diabetes in PTB individuals is characterized by heightened cytokine responsiveness, indicating that a balanced pro and anti - inflammatory cytokine milieu is a feature of pre-diabetes - TB co-morbidity. [ABSTRACT FROM AUTHOR]

Background: Circulating T follicular helper (Tfh) cells represent a distinct subset of CD4+ T cells and are important in immunity to infections. Although they have been shown to play a role in experimental models of tuberculosis infection, their role in human tuberculosis remains unexplored. Aims/Methodology: To determine the distribution of circulating Tfh cells in human TB, we measured the frequencies of Tfh cells ex vivo and following TB - antigen or polyclonal stimulation in pulmonary TB (PTB; n = 30) and latent TB (LTB; n = 20) individuals, using the markers CXCR5, PD-1 and ICOS. Results: We found that both ex vivo and TB - antigen induced frequencies of Tfh cell subsets was significantly lower in PTB compared to LTB individuals. Similarly, antigen induced frequencies of Tfh cells expressing IL-21 was also significantly lower in PTB individuals and this was reflected in diminished circulating levels of IL-21 and IFNγ. This was not accompanied by diminished frequencies of activated or memory B cell subsets. Finally, the diminution in frequency of Tfh cells in PTB individuals was dependent on IL-10, CTLA-4 and PD-L1 in vitro. Conclusions: Thus, PTB is characterized by adiminution in the frequency of Tfh cell subsets. [ABSTRACT FROM AUTHOR]

Tissue invasive helminth infections and tuberculosis (TB) are co-endemic in many parts of the world and can trigger immune responses that might antagonize each other. We have previously shown that helminth infections modulate the Th1 and Th17 responses to mycobacterial-antigens in latent TB. To determine whether helminth infections modulate antigen-specific and non-specific immune responses in active pulmonary TB, we examined CD4+ and CD8+ T cell responses as well as the systemic (plasma) cytokine levels in individuals with pulmonary TB with or without two distinct helminth infections—Wuchereria bancrofti and Strongyloides stercoralis infection. By analyzing the frequencies of Th1 and Th17 CD4+ and CD8+ T cells and their component subsets (including multifunctional cells), we report a significant diminution in the mycobacterial–specific frequencies of mono- and multi–functional CD4+ Th1 and (to a lesser extent) Th17 cells when concomitant filarial or Strongyloides infection occurs. The impairment in CD4+ and CD8+ T cell cytokine responses was antigen-specific as polyclonal activated T cell frequencies were equivalent irrespective of helminth infection status. This diminution in T cell responses was also reflected in diminished circulating levels of Th1 (IFN-γ, TNF-α and IL-2)- and Th17 (IL-17A and IL-17F)-associated cytokines. Finally, we demonstrate that for the filarial co-infections at least, this diminished frequency of multifunctional CD4+ T cell responses was partially dependent on IL-10 as IL-10 blockade significantly increased the frequencies of CD4+ Th1 cells. Thus, co-existent helminth infection is associated with an IL-10 mediated (for filarial infection) profound inhibition of antigen-specific CD4+ T cell responses as well as protective systemic cytokine responses in active pulmonary TB. [ABSTRACT FROM AUTHOR]

Background: Lymphatic filariasis (LF) is known to be associated with an increased production of IL-10. The role of the other IL-10 family members in the pathogenesis of infection and/or disease is not known. Methodology/Principal Findings: We examined the expression patterns of IL-10 family members – IL-19, IL-24 and IL-26 in LF. We demonstrate that both CD4+ and CD8+ T cells express IL-19, IL-24 and IL-26 and that the frequency of CD4+ T cells expressing IL-19 and IL-24 (as well as IL-10) is significantly increased at baseline and following filarial antigen stimulation in patients with LF in comparison to individuals with filarial lymphedema and uninfected individuals. This CD4+ T cell expression pattern was associated with increased production of IL-19 and IL-24 by filarial – antigen stimulated PBMC. Moreover, the frequency of CD4+ and CD8+ T cells expressing IL-26 was significantly increased following filarial antigen stimulation in filarial lymphedema individuals. Interestingly, IL-10 blockade resulted in diminished frequencies of IL-19+ and IL-24+ T cells, whereas the addition of recombinant IL-10 resulted in significantly increased frequency of IL-19+ and IL-24+ T cells as well as significantly up regulated IL-19 and IL-24 gene expression, suggesting that IL-10 regulates IL-19 and IL-24 expression in T cells. In addition, IL-1β and IL-23 blockade also induced a diminution in the frequency of IL-19+ and IL-24+ T cells, indicating a novel role for these cytokines in the induction of IL-19 and IL-24 expressing T cells. Finally, elimination of infection resulted in significantly decreased frequencies of antigen – specific CD4+ T cells expressing IL-10, IL-19 and IL-24. Conclusions: Our findings, therefore, suggest that IL-19 and IL-24 are associated with the regulation of immune responses in active filarial infection and potentially with protection against development of pathology, while IL-26 is predominantly associated with pathology in LF. [ABSTRACT FROM AUTHOR]

Background: Filarial (and other helminth) infections are known to modulate mycobacteria-specific pro-inflammatory cytokine responses necessary for maintaining latency in tuberculosis (TB). We sought to address whether helminth co-infection alters progression to active pulmonary TB in a co-endemic area of South India. Methods/Principal Findings: Incidence of active pulmonary TB was assessed in 5096 subjects from five villages among helminth-infected (hel+) and –uninfected (hel−) groups. Baseline stool examinations, circulating filarial antigen, and tuberculin skin testing (PPD) were performed along with chest radiographs, sputum microscopy, and culture. During three follow-up visits each 2.5 years, patients were assessed using PPD tests and questionnaires and—for those with potential symptoms of TB—sputum microscopy and culture. Of the 5096 subjects, 1923 were found to be hel+ and 3173 were hel−. Follow up interval stool examination could not be performed. In each group, 21 developed active TB over the course of the study. After adjusting for sex, age, BCG vaccination status, and PPD positivity, no difference was seen in active TB incidence between hel+ and hel− groups either at baseline (relative risk (RR) 1.60; 95% confidence interval (CI): 0.69, 3.71, P = 0·27), or when followed prospectively (RR 1.24; 95% CI: 0.48, 3.18, P = 0·66). Conclusions/Significance: Our findings suggest that, despite the immunomodulatory effects of helminth infection, baseline co-morbid infection with these parasites had little effect on the clinical progression from latent to active pulmonary TB. [ABSTRACT FROM AUTHOR]

Background: Two different Th2 subsets have been defined recently on the basis of IL-5 expression – an IL-5+Th2 subset and an IL-5−Th2 subset in the setting of allergy. However, the role of these newly described CD4+ T cells subpopulations has not been explored in other contexts. Methods: To study the role of the Th2 subpopulation in a chronic, tissue invasive parasitic infection (lymphatic filariasis), we examined the frequency of IL-5+IL-4+IL-13+ CD4+ T cells and IL-5−IL-4 IL-13+ CD4+ T cells in asymptomatic, infected individuals (INF) and compared them to frequencies (Fo) in filarial-uninfected (UN) individuals and to those with filarial lymphedema (CP). Results: INF individuals exhibited a significant increase in the spontaneously expressed and antigen-induced Fo of both Th2 subpopulations compared to the UN and CP. Interestingly, there was a positive correlation between the Fo of IL-5+Th2 cells and the absolute eosinophil and neutrophil counts; in addition there was a positive correlation between the frequency of the CD4+IL-5−Th2 subpopulation and the levels of parasite antigen – specific IgE and IgG4 in INF individuals. Moreover, blockade of IL-10 and/or TGFβ demonstrated that each of these 2 regulatory cytokines exert opposite effects on the different Th2 subsets. Finally, in those INF individuals cured of infection by anti-filarial therapy, there was a significantly decreased Fo of both Th2 subsets. Conclusions: Our findings suggest that both IL-5+ and IL-5−Th2 cells play an important role in the regulation of immune responses in filarial infection and that these two Th2 subpopulations may be regulated by different cytokine-receptor mediated processes. [ABSTRACT FROM AUTHOR]

Background: Tuberculosis (TB) is associated with oxidative stress and the induction of host anti-oxidants to counteract this response. Heme oxygenase-1 (HO-1) is a critical promoter of cytoprotection in diverse disease models including mycobacterial infection. Nevertheless, the pattern of expression of HO-1 in human tuberculosis has not been studied. Here, we examine expression of HO-1 in M. tuberculosis-exposed and -infected individuals and test its ability to distinguish active from latent and successfully treated TB cases. In addition, we assess correlations between plasma levels of HO-1 and cytokines closely associated with the immunopathogenesis of TB. Methods: Cross-sectional and longitudinal analyses of levels of HO-1, acute phase proteins and pro-inflammatory cytokines were performed in plasma samples from individuals with active pulmonary, extra-pulmonary or latent TB infection and healthy controls as part of a prospective cohort study in South India. Results: Systemic levels of HO-1 were dramatically increased in individuals with active pulmonary and extra-pulmonary tuberculosis and particularly those with bilateral lung lesions and elevated bacillary loads in sputum. HO-1 levels effectively discriminated active from latent tuberculosis with higher predictive values than either C-reactive protein or serum amyloid protein. Moreover, there was a marked reduction in HO-1 levels in active TB cases following anti-tuberculous therapy but not in those who failed treatment. Pulmonary TB patients displaying the highest concentrations of HO-1 in plasma exhibited significantly elevated plasma levels of interleukin (IL)-10, interferon (IFN)-γ and IL-17 and diminished levels of tumor necrosis factor (TNF)-α. Conclusion: These findings establish HO-1 levels as a potentially useful parameter for distinguishing active from latent or treated pulmonary tuberculosis, that is superior in this respect to the measurement of other acute inflammatory proteins. [ABSTRACT FROM AUTHOR]

Background: Although Type 1 cytokine responses are considered protective in pulmonary tuberculosis (PTB), their role as well as those of Type 2, 17 and immunoregulatory cytokines in tuberculous lymphadenitis (TBL) and latent tuberculosis (LTB) have not been well studied. Aim and Methods: To identify cytokine responses associated with pulmonary tuberculosis (TB), TB lymphadenitits and latent TB, we examined mycobacterial antigen-specific immune responses of PTB, TBL and LTB individuals. More specifically, we examined ESAT-6 and CFP-10 induced Type 1, Type 2 and Type 17 cytokine production and their regulation using multiplex ELISA. Results: PTB individuals exhibited a significantly lower baseline as well as antigen-specific production of Type 1 (IFNγ, TNFα and IL-2); Type 2 (IL-4) and Type 17 (IL-17A and IL-17F) cytokines in comparison to both TBL and LTB individuals. TBL individuals exhibited significantly lower antigen-specific IFNγ responses alone in comparison to LTB individuals. Although, IL-10 levels were not significantly higher, neutralization of IL-10 during antigen stimulation resulted in significantly enhanced production of IFNγ, IL-4 and IL-17A in PTB individuals, indicating that IL-10 mediates (at least partially) the suppression of cytokine responses in PTB. Conclusion: Pulmonary TB is characterized by an IL-10 dependent antigen-specific suppression of Type 1, Type 2 and Type 17 cytokines, reflecting an important association of these cytokines in the pathogenesis of active TB. [ABSTRACT FROM AUTHOR]

Background: Th1 and Th17 responses are known to play an important role in immunity to pulmonary tuberculosis (PTB), although little is known about their role in extrapulmonary forms of tuberculosis (TB). Methods: To identify the role of Th1, Th17, and Th22 cells in multi-focal TB lymphadenitis (TBL), we examined mycobacteria–specific immune responses in the whole blood of individuals with PTB (n = 20) and compared them with those with TBL (n = 25). Results: Elevated frequencies of CD4+ T cells expressing IFN- γ, TNF-α, and IL-2 were present in individuals with TBL compared with those with PTB at baseline and in response to ESAT-6 and CFP-10. Similarly, increased frequencies of CD4+ T cells expressing IL-17A, IL-17F, and IFN-γ were also present in individuals with TBL at baseline and following ESAT-6 and CFP-10 stimulation although no significant difference in frequency of Th22 cells was observed. Finally, frequencies of Th1 (but not Th17) cells exhibited a significantly negative correlation with natural regulatory T cell frequencies at baseline. Conclusions: Multi-focal TB lymphadenitis is therefore characterized by elevated frequencies of Th1 and Th17 cells, indicating that Th1 and Th17 responses in TB disease are probably correlates of disease severity rather than of protective immunity. [ABSTRACT FROM AUTHOR]