96 results on '"Rajamanickam, Anuradha"'
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52. Undernutrition is associated with perturbations in T cell-, B cell-, monocyte- and dendritic cell- subsets in latent Mycobacterium tuberculosis infection
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Rajamanickam, Anuradha, primary, Munisankar, Saravanan, additional, Dolla, Chandra Kumar, additional, and Babu, Subash, additional
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- 2019
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53. Cytotoxic T-Lymphocyte-Associated Antigen 4 (CTLA-4)- and Programmed Death 1 (PD-1)-Mediated Regulation of Monofunctional and Dual Functional CD4 + and CD8 + T-Cell Responses in a Chronic Helminth Infection
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Rajamanickam, Anuradha, primary, Munisankar, Saravanan, additional, Dolla, Chandrakumar, additional, Nutman, Thomas B., additional, and Babu, Subash, additional
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- 2019
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- View/download PDF
54. High body mass index is associated with heightened systemic and mycobacterial antigen – Specific pro-inflammatory cytokines in latent tuberculosis
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Subash Babu, Paul Kumaran, Yukthi Bhootra, Rajamanickam Anuradha, Saravanan Munisankar, and Chandrakumar Dolla
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Adult ,Male ,0301 basic medicine ,Microbiology (medical) ,Tuberculosis ,Immunology ,Microbiology ,Article ,Body Mass Index ,Proinflammatory cytokine ,Young Adult ,03 medical and health sciences ,Immune system ,Antigen ,Latent Tuberculosis ,medicine ,Humans ,Obesity ,Antigens, Bacterial ,Latent tuberculosis ,biology ,business.industry ,Mycobacterium tuberculosis ,Middle Aged ,medicine.disease ,030104 developmental biology ,Infectious Diseases ,Case-Control Studies ,Mitogen-activated protein kinase ,biology.protein ,Cytokines ,Female ,Tumor necrosis factor alpha ,Inflammation Mediators ,business - Abstract
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 TGFβ). 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 TGFβ. 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, TGFβ 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.
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- 2016
55. Systemic Cytokine Profiles in Strongyloides stercoralis Infection and Alterations following Treatment
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Kui Shen, Yukthi Bhootra, Rajamanickam Anuradha, Saravanan Munisankar, Jeeva Jagannathan, Thomas B. Nutman, Chandrakumar Dolla, Paul Kumaran, and Subash Babu
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Adult ,Male ,0301 basic medicine ,Adolescent ,medicine.medical_treatment ,Immunology ,Biology ,Microbiology ,Strongyloides stercoralis ,Proinflammatory cytokine ,Interferon-gamma ,Young Adult ,03 medical and health sciences ,Immune system ,medicine ,Animals ,Humans ,Interferon gamma ,Interleukin 5 ,Tumor Necrosis Factor-alpha ,Antinematodal Agents ,Middle Aged ,medicine.disease ,biology.organism_classification ,030104 developmental biology ,Infectious Diseases ,Strongyloidiasis ,Cytokine ,Asymptomatic Diseases ,Cytokines ,Female ,Parasitology ,Tumor necrosis factor alpha ,Interleukin-5 ,Fungal and Parasitic Infections ,medicine.drug - Abstract
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-1β [IL-1β]) 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 β [TGF-β]). 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-1β) and decreased levels of anti-inflammatory (IL-4, IL-5, IL-9, IL-10, IL-13, IL-27, IL-37, and TGF-β) 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.
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- 2016
56. Malnutrition is associated with diminished baseline and mycobacterial antigen – stimulated chemokine responses in latent tuberculosis infection
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Rajamanickam Anuradha, Subash Babu, Nathella Pavan Kumar, Yukthi Bhootra, Chandrakumar Dolla, and Saravanan Munisankar
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0301 basic medicine ,Microbiology (medical) ,Adult ,Male ,CCL1 ,Article ,Body Mass Index ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Latent Tuberculosis ,parasitic diseases ,Medicine ,CXCL10 ,Humans ,CXCL11 ,CCL11 ,Diminution ,Antigens, Bacterial ,Latent tuberculosis ,business.industry ,Malnutrition ,Mycobacterium tuberculosis ,respiratory system ,Middle Aged ,medicine.disease ,bacterial infections and mycoses ,CXCL2 ,030104 developmental biology ,Infectious Diseases ,Case-Control Studies ,Immunology ,Immunologic Techniques ,CXCL9 ,Female ,Chemokines ,Mitogens ,business ,Interferon-gamma Release Tests ,030215 immunology - Abstract
Summary Objectives Previous studies have demonstrated a diminution in the baseline and mycobacterial antigen – specific cytokines in low body mass index (LBMI) individuals with latent tuberculosis infection (LTBI). We hypothesized that LBMI might be also associated with alteration in the baseline and antigen – stimulated levels of chemokines in LTBI. Methods To test this hypothesis, we examined baseline, TB-antigen and mitogen stimulated levels of chemokines in these individuals and compared them with those with LTBI and normal BMI (NBMI). Results LBMI with LTBI is characterized by diminished baseline levels of CCL1, CCL4, CCL11, CXCL1, CXCL9, CXCL10 and CXCL11 in comparison to NBMI with LTBI. Similarly, LTBI with LBMI is also characterized by diminished TB-antigen stimulated levels of CCL1, CCL2, CCL3, CCL4, CCL11, CXCL1, CXCL2, CXCL9, CXCL10 and CXCL11. In contrast, there were no significant differences in the mitogen stimulated chemokine levels between the groups. Finally, there was a significant positive correlation between BMI and CCL1, CCL4, CCL11, CXCL11, CXCL2, CXCL9 and CXCL11 levels in LTBI individuals. Conclusions Therefore, our data reveal that LTBI subjects with low BMI are characterized by diminished levels of a variety of important chemokines, providing a novel biological mechanism for the increased risk of developing active TB.
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- 2018
57. Coexistent Helminth Infection–Mediated Modulation of Chemokine Responses in Latent Tuberculosis
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Rajamanickam, Anuradha, primary, Munisankar, Saravanan, additional, Bhootra, Yukthi, additional, Dolla, Chandra Kumar, additional, Nutman, Thomas B., additional, and Babu, Subash, additional
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- 2019
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58. Modulation of CD4 + and CD8 + T Cell Function and Cytokine Responses in Strongyloides stercoralis Infection by Interleukin-27 (IL-27) and IL-37
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Thomas B. Nutman, Subash Babu, Rajamanickam Anuradha, Saravanan Munisankar, Yukthi Bhootra, Chandrakumar Dolla, and Paul Kumaran
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0301 basic medicine ,biology ,medicine.medical_treatment ,T cell ,Immunology ,biology.organism_classification ,Microbiology ,Neutralization ,Strongyloides stercoralis ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Infectious Diseases ,Cytokine ,medicine.anatomical_structure ,Antigen ,medicine ,Cytotoxic T cell ,Parasitology ,Interleukin 27 ,CD8 ,030215 immunology - Abstract
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.
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- 2017
59. Metabolic Consequences of Concomitant Strongyloides stercoralis Infection in Patients With Type 2 Diabetes Mellitus
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Rajamanickam, Anuradha, primary, Munisankar, Saravanan, additional, Bhootra, Yukthi, additional, Dolla, Chandrakumar, additional, Thiruvengadam, Kannan, additional, Nutman, Thomas B, additional, and Babu, Subash, additional
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- 2018
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60. Modulation of CD4+and CD8+T-Cell Function by Interleukin 19 and Interleukin 24 During Filarial Infections
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Saravanan Munisankar, Subash Babu, Chandrakumar Dolla, Rajamanickam Anuradha, Paul Kumaran, and Thomas B. Nutman
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CD4-Positive T-Lymphocytes ,0301 basic medicine ,Interleukins ,Interleukin ,CD8-Positive T-Lymphocytes ,Biology ,Filariasis ,Interleukin-10 ,Interleukin 33 ,Major Articles and Brief Reports ,03 medical and health sciences ,Interleukin 32 ,030104 developmental biology ,Infectious Diseases ,T-Lymphocyte Subsets ,Interleukin 15 ,Immunology ,Interleukin 12 ,Humans ,Immunology and Allergy ,Interleukin 5 ,Interleukin 4 ,Interleukin 3 - Abstract
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.
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- 2015
61. Parasite Antigen-Specific Regulation of Th1, Th2, and Th17 Responses in Strongyloides stercoralis Infection
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Subash Babu, Thomas B. Nutman, Paul Kumaran, Rajamanickam Anuradha, Saravanan Munisankar, and Chandrakumar Dolla
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Adult ,Male ,Adolescent ,T cell ,Immunology ,Stimulation ,Biology ,Article ,Host-Parasite Interactions ,Flow cytometry ,Strongyloides stercoralis ,Young Adult ,Th2 Cells ,Antigen ,Transforming Growth Factor beta ,Antigen specific ,parasitic diseases ,Leukocytes ,medicine ,Animals ,Humans ,Immunology and Allergy ,Parasite hosting ,Cells, Cultured ,medicine.diagnostic_test ,Middle Aged ,Th1 Cells ,Flow Cytometry ,medicine.disease ,biology.organism_classification ,Basophils ,Interleukin-10 ,Eosinophils ,medicine.anatomical_structure ,Strongyloidiasis ,Antigens, Helminth ,Cytokines ,Th17 Cells ,Female - Abstract
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-β. 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.
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- 2015
62. Modulation of CD4
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Rajamanickam, Anuradha, Saravanan, Munisankar, Yukthi, Bhootra, Chandrakumar, Dolla, Paul, Kumaran, Thomas B, Nutman, and Subash, Babu
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Interleukin-13 ,Interleukins ,Interleukin-17 ,Primary Cell Culture ,Interleukin-9 ,CD8-Positive T-Lymphocytes ,Th1 Cells ,Antibodies, Neutralizing ,Interferon-gamma ,Th2 Cells ,Gene Expression Regulation ,Antigens, Helminth ,Case-Control Studies ,Chronic Disease ,Host-Pathogen Interactions ,Strongyloidiasis ,Animals ,Th17 Cells ,Interleukin-4 ,Interleukin-5 ,Fungal and Parasitic Infections ,Strongyloides stercoralis ,Interleukin-1 ,Signal Transduction - Abstract
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.
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- 2017
63. Anthelmintic Therapy Modifies the Systemic and Mycobacterial Antigen-Stimulated Cytokine Profile in Helminth-Latent Mycobacterium tuberculosis Coinfection
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Saravanan Munisankar, Chandrakumar Dolla, Subash Babu, Paul Kumaran, Yukthi Bhootra, Rajamanickam Anuradha, and Thomas B. Nutman
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0301 basic medicine ,Adult ,Male ,Tuberculosis ,medicine.medical_treatment ,Immunology ,Helminthiasis ,Microbiology ,Strongyloides stercoralis ,Host-Parasite Interactions ,Mycobacterium tuberculosis ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Latent Tuberculosis ,Helminths ,medicine ,Animals ,Humans ,Anthelmintic ,Anthelmintics ,Antigens, Bacterial ,biology ,Latent tuberculosis ,Coinfection ,Middle Aged ,biology.organism_classification ,medicine.disease ,030104 developmental biology ,Infectious Diseases ,Cytokine ,Host-Pathogen Interactions ,Cytokines ,Parasitology ,Tumor necrosis factor alpha ,Female ,Fungal and Parasitic Infections ,030215 immunology ,medicine.drug - Abstract
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-β]) 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-β) 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.
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- 2017
64. Modulation of Mycobacterium tuberculosis-specific humoral immune responses is associated with Strongyloides stercoralis co-infection
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Saravanan Munisankar, Yukthi Bhootra, Thomas B. Nutman, Paul Kumaran, Subash Babu, Rajamanickam Anuradha, and Chandrakumar Dolla
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0301 basic medicine ,Male ,Bacterial Diseases ,B Cells ,Physiology ,Biochemistry ,White Blood Cells ,Animal Cells ,Immune Physiology ,B-Cell Activating Factor ,Medicine and Health Sciences ,Immune Response ,Immune System Proteins ,biology ,Latent tuberculosis ,Coinfection ,lcsh:Public aspects of medicine ,Middle Aged ,Antibodies, Bacterial ,3. Good health ,Actinobacteria ,medicine.anatomical_structure ,Infectious Diseases ,Helminth Infections ,Strongyloidiasis ,Cytokines ,Female ,Antibody ,Cellular Types ,Research Article ,Adult ,lcsh:Arctic medicine. Tropical medicine ,lcsh:RC955-962 ,T cell ,Immune Cells ,Tumor Necrosis Factor Ligand Superfamily Member 13 ,Immunology ,B-Lymphocyte Subsets ,India ,Antibodies ,Strongyloides stercoralis ,Mycobacterium tuberculosis ,03 medical and health sciences ,Young Adult ,Immune system ,Latent Tuberculosis ,medicine ,Parasitic Diseases ,Animals ,Humans ,Tuberculosis ,B-cell activating factor ,Antibody-Producing Cells ,B cell ,Blood Cells ,Bacteria ,Public Health, Environmental and Occupational Health ,Organisms ,Biology and Life Sciences ,Proteins ,lcsh:RA1-1270 ,Cell Biology ,biology.organism_classification ,medicine.disease ,bacterial infections and mycoses ,Memory B cells ,Tropical Diseases ,Virology ,Immunity, Humoral ,030104 developmental biology ,Immunoglobulin M ,Immunoglobulin G ,Co-Infections ,biology.protein - Abstract
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)., Author summary Helminth infections and tuberculosis are two of the major health care problems worldwide and share a great deal of geographical overlap. Moreover, helminth infections are known to induce immune responses that are antagonistic to the protective immune responses elicited by Mycobacterium tuberculosis. Having previously demonstrated that helminth infections can profoundly alter protective T cell responses needed to control tuberculosis infection, we examined how Strongyloides stercoralis (Ss) infection influences B cell responses in latent tuberculosis infection (LTBI) in the context of co-infection and showed the Ss infection is associated with dramatic alterations in mycobacterial-specific IgG and IgM responses and levels of B cells and their growth factors BAFF and APRIL. These alterations in B cell responses could have implications for vaccine-induced immune responses to tuberculosis in helminth—endemic countries.
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- 2017
65. Th2/1 Hybrid Cells Occurring in Murine and Human Strongyloidiasis Share Effector Functions of Th1 Cells
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Bock, Cristin N., Babu, Subash, Breloer, Minka, Rajamanickam, Anuradha, Boothra, Yukhti, Brunn, Marie-Luise, Kühl, Anja A., Merle, Roswitha, Löhning, Max, Hartmann, Susanne, and Rausch, Sebastian
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th2 ,IFN-gamma ,nematode ,Strongyloides ,Th2/1 ,T-bet ,GATA-3 ,Microbiology ,cytokines ,Hybrid ,co-expression - Abstract
Infections by the soil-transmitted threadworm Strongyloides stercoralis affect 50-100 million people worldwide, predominantly in tropic and sub-tropic regions. Here we assessed the T helper cell phenotypes in threadworm-infected patients and experimental murine infections with focus on CD4+ T cells co- expressing markers of Th2 and Th1 differentiation. We show that mice infected with the close relative S. ratti generate strong Th2 responses characterized by the expansion of CD4+ GATA-3+ cells expressing IL-4/-5/-13 in blood, spleen, gut-draining lymph nodes, lung and gut tissue. In addition to conventional Th2 cells, significantly increased frequencies of GATA-3+T-bet+ Th2/1-hybrid cells were detected in all organs and co-expressed Th2- and Th1-cytokines at intermediate levels. Assessing the phenotype of blood-derived CD4+ T cells from South Indian patients infected with S. stercoralis and local uninfected control donors we found that GATA-3 expressing Th2 cells were significantly increased in the patient cohort, coinciding with elevated eosinophil and IgE/IgG4 levels. A fraction of IL-4+CD4+ T cells simultaneously expressed IFN-γ hence displaying a Th2/1 hybrid phenotype. In accordance with murine Th2/1 cells, human Th2/1 cells expressed intermediate levels of Th2 cytokines. Contrasting their murine counterparts, human Th2/1 hybrids were marked by high levels of IFN-γ and rather low GATA-3 expression. Assessing the effector function of murine Th2/1 cells in vitro we found that Th2/1 cells were qualified for driving the classical activation of macrophages. Furthermore, Th2/1 cells shared innate, cytokine-driven effector functions with Th1 cells. Hence, the key findings of our study are that T helper cells with combined characteristics of Th2 and Th1 cells are integral to immune responses of helminth-infected mice, but also occur in helminth-infected humans and we suggest that Th2/1 cells are poised for the instruction of balanced immune responses during nematode infections.
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- 2017
66. Elevated Systemic and Parasite—Antigen Stimulated Levels of Type III IFNs in a Chronic Helminth Infection and Reversal Following Anthelmintic Treatment
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Rajamanickam, Anuradha, primary, Munisankar, Saravanan, additional, Bhootra, Yukthi, additional, Dolla, Chandrakumar, additional, Nutman, Thomas B., additional, and Babu, Subash, additional
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- 2018
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67. Altered levels of memory T cell subsets and common γc cytokines in Strongyloides stercoralis infection and partial reversal following anthelmintic treatment
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Rajamanickam, Anuradha, primary, Munisankar, Saravanan, additional, Bhootra, Yukti, additional, Dolla, Chandra Kumar, additional, Thiruvengadam, Kannan, additional, Nutman, Thomas B., additional, and Babu, Subash, additional
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- 2018
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68. Elevated Systemic Levels of Eosinophil, Neutrophil, and Mast Cell Granular Proteins in Strongyloides Stercoralis Infection that Diminish following Treatment
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Rajamanickam, Anuradha, primary, Munisankar, Saravanan, additional, Bhootra, Yukthi, additional, Dolla, Chandra Kumar, additional, Nutman, Thomas B., additional, and Babu, Subash, additional
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- 2018
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69. IL-4–, TGF-β–, and IL-1–Dependent Expansion of Parasite Antigen-Specific Th9 Cells Is Associated with Clinical Pathology in Human Lymphatic Filariasis
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Parakkal Jovvian George, Paul Kumaran, Rajamanickam Anuradha, Subash Babu, Thomas B. Nutman, Luke Elizabeth Hanna, and Vedachalam Chandrasekaran
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CD4-Positive T-Lymphocytes ,T cell ,Immunology ,Interleukin-9 ,Enzyme-Linked Immunosorbent Assay ,Biology ,Article ,Interleukin-10 ,Interleukin 21 ,Elephantiasis, Filarial ,medicine.anatomical_structure ,Antigen ,T-Lymphocyte Subsets ,Transforming Growth Factor beta ,Interleukin 12 ,medicine ,Humans ,Immunology and Allergy ,Cytotoxic T cell ,Interleukin-4 ,IL-2 receptor ,Interleukin 4 ,Interleukin-1 ,Interleukin 3 - Abstract
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-β, 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.
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- 2013
70. Modulation of Mycobacterial-Specific Th1 and Th17 Cells in Latent Tuberculosis by Coincident Hookworm Infection
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Vedachalam Chandrasekaran, Parakkal Jovvian George, Paramasivam Paul Kumaran, Rajamanickam Anuradha, Thomas B. Nutman, and Subash Babu
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Adult ,Ancylostomatoidea ,Male ,Tuberculosis ,T cell ,Immunology ,Stimulation ,Article ,Mycobacterium tuberculosis ,Feces ,Hookworm Infections ,Young Adult ,Th2 Cells ,Immune system ,Latent Tuberculosis ,parasitic diseases ,medicine ,Animals ,Humans ,Immunology and Allergy ,Hookworm infection ,Aged ,biology ,Latent tuberculosis ,Middle Aged ,Th1 Cells ,medicine.disease ,biology.organism_classification ,medicine.anatomical_structure ,Th17 Cells ,Female - Abstract
Hookworm infections and tuberculosis (TB) are coendemic in many parts of the world. It has been suggested that infection with helminth parasites could suppress the predominant Th1 (IFN-γ–mediated) response needed to control Mycobacterium tuberculosis infection and enhance susceptibility to infection and/or disease. To determine the role of coincident hookworm infection on responses at steady-state and on M. tuberculosis–specific immune responses in latent TB (LTB), we examined the cellular responses in individuals with LTB with or without concomitant hookworm infection. By analyzing the expression of Th1, Th2, and Th17 subsets of CD4+ T cells, we were able to demonstrate that the presence of coincident hookworm infection significantly diminished both spontaneously expressed and M. tuberculosis–specific mono- and dual-functional Th1 and Th17 cells. Hookworm infection, in contrast, was associated with expanded frequencies of mono- and dual-functional Th2 cells at both steady-state and upon Ag stimulation. This differential induction of CD4+ T cell subsets was abrogated upon mitogen stimulation. Additionally, coincident hookworm infection was associated with increased adaptive T regulatory cells but not natural regulatory T cells in LTB. Finally, the CD4+ T cell cytokine expression pattern was also associated with alterations in the systemic levels of Th1 and Th2 cytokines. Thus, coincident hookworm infection exerts a profound inhibitory effect on protective Th1 and Th17 responses in LTB and may predispose toward the development of active tuberculosis in humans.
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- 2013
71. Coexistent Malnutrition Is Associated with Perturbations in Systemic and Antigen-Specific Cytokine Responses in Latent Tuberculosis Infection
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Subash Babu, Chandrakumar Dolla, Saravanan Munisankar, Yukthi Bhootra, Rajamanickam Anuradha, Paul Kumaran, and Nathalla Pavan Kumar
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0301 basic medicine ,Microbiology (medical) ,Adult ,Male ,Adolescent ,medicine.medical_treatment ,Clinical Biochemistry ,Immunology ,Proinflammatory cytokine ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Antigen ,Latent Tuberculosis ,medicine ,Immunology and Allergy ,Humans ,030212 general & internal medicine ,Risk factor ,Antigens, Bacterial ,biology ,Latent tuberculosis ,business.industry ,Malnutrition ,Transforming growth factor beta ,Mycobacterium tuberculosis ,Middle Aged ,medicine.disease ,030104 developmental biology ,Cytokine ,biology.protein ,Cytokines ,Tumor necrosis factor alpha ,Female ,Clinical Immunology ,business ,Transforming growth factor - Abstract
Malnutrition, as defined by low body mass index (BMI), is a major risk factor for the development of active tuberculosis (TB), although the biological basis underlying this susceptibility remains poorly characterized. To verify whether malnutrition affects the systemic and antigen-specific cytokine levels in individuals with latent TB (LTB), we examined circulating and TB antigen-stimulated levels of cytokines in individuals with LTB and low BMI (LBMI) and compared them with those in individuals with LTB and normal BMI (NBMI). Coexistent LBMI with LTB was characterized by diminished circulating levels of type 1 (gamma interferon [IFN-γ] and tumor necrosis factor alpha [TNF-α]), type 2 (interleukin-4 [IL-4]), type 17 (IL-22), and other proinflammatory (IL-1α, IL-1β, and IL-6) cytokines but elevated levels of other type 2 (IL-5 and IL-13) and regulatory (IL-10 and transforming growth factor beta [TGF-β]) cytokines. In addition, LBMI with LTB was associated with diminished TB antigen-induced IFN-γ, TNF-α, IL-6, IL-1α, and IL-1β levels. Finally, there was a significant positive correlation between BMI values and TNF-α and IL-1β levels and a significant negative correlation between BMI values and IL-2, IL-10, and TGF-β levels in individuals with LTB. Therefore, our data reveal that latent TB with a coexistent low BMI is characterized by diminished protective cytokine responses and heightened regulatory cytokine responses, providing a potential biological mechanism for the increased risk of developing active TB.
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- 2016
72. IL-10- and TGFβ-mediated Th9 Responses in a Human Helminth Infection
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Saravanan Munisankar, Subash Babu, Jeeva Jagannathan, Paul Kumaran, Rajamanickam Anuradha, Chandrakumar Dolla, Yukthi Bhootra, and Thomas B. Nutman
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0301 basic medicine ,Adult ,Male ,lcsh:Arctic medicine. Tropical medicine ,Adolescent ,lcsh:RC955-962 ,medicine.medical_treatment ,Albendazole ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,T-Lymphocyte Subsets ,Transforming Growth Factor beta ,parasitic diseases ,medicine ,Helminths ,Humans ,Regulation of gene expression ,Gastrointestinal tract ,Ivermectin ,biology ,Antiparasitic Agents ,lcsh:Public aspects of medicine ,Public Health, Environmental and Occupational Health ,lcsh:RA1-1270 ,Transforming growth factor beta ,Middle Aged ,medicine.disease ,Antiparasitic agent ,Interleukin-10 ,Interleukin 10 ,030104 developmental biology ,Infectious Diseases ,Cytokine ,Strongyloidiasis ,Gene Expression Regulation ,Case-Control Studies ,Immunology ,biology.protein ,Female ,030215 immunology ,Research Article - Abstract
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., Author Summary Strongyloides stercoralis is a common intestinal parasite affecting about 50–100 million people worldwide. It is characterized by a complex lifecycle involving both free- living and parasitic stages and the clinical manifestations range from asymptomatic infection to multi-organ failure. It has the propensity to cause disseminated disease and death in immunocompromised individuals. Therefore, an in depth understanding of the immune responses to this helminth parasite is warranted. However, what we know about the immunity to this infection is mostly derived from animal studies. Th9 cells are a subset of CD4+ T cells producing the cytokine—IL-9. Since Th9 cells are increasingly recognized as being important in immunity to intestinal infection with helminths, we examined the induction and regulation Th9 cell responses to Ss infection utilizing infected and uninfected individuals from an endemic area in India. We show that Ss infection is characterized by profound alterations in the Th9 compartment and that this response is mainly regulated by the cytokines—IL-10 and TGFβ. In addition, we also demonstrate that active infection is a pre-requisite for this regulation and anti-Ss treatment can dampen enhanced Th9 responses.
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- 2016
73. Toll-Like Receptor- and Filarial Antigen-Mediated, Mitogen-Activated Protein Kinase- and NF-κB-Dependent Regulation of Angiogenic Growth Factors in Filarial Lymphatic Pathology
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V. Kumaraswami, Subash Babu, P. Jovvian George, Rajamanickam Anuradha, Thomas B. Nutman, and N. Pavan Kumar
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Adult ,Male ,MAPK/ERK pathway ,Pathology ,medicine.medical_specialty ,Adolescent ,medicine.medical_treatment ,Immunology ,Inflammation ,Biology ,Microbiology ,Young Adult ,Elephantiasis, Filarial ,medicine ,Humans ,Angiogenic Proteins ,Aged ,Lymphatic Vessels ,Toll-like receptor ,Neovascularization, Pathologic ,Growth factor ,Toll-Like Receptors ,NF-kappa B ,Middle Aged ,Lymphangiogenesis ,TLR2 ,Vascular endothelial growth factor A ,Infectious Diseases ,Lymphatic system ,Antigens, Helminth ,Female ,Parasitology ,Fungal and Parasitic Infections ,Mitogen-Activated Protein Kinases ,medicine.symptom - Abstract
Filarial lymphatic pathology is of multifactorial origin, with inflammation, lymphangiogenesis, and innate immune responses all playing important roles. The role of Toll-like receptors (TLRs) in the development of filarial pathology is well characterized. Similarly, the association of pathology with elevated levels of plasma angiogenic factors has also been documented. To examine the association between TLR function and the development of lymphangiogenesis in filarial infections, we examined TLR- and filarial antigen-induced expression and production of various angiogenic growth factors. We demonstrate that TLR ligands (specifically TLR2, -3, and -5 ligands) induce significantly increased expression/production of vascular endothelial growth factor A (VEGF-A) and angiopoietin-1 (Ang-1) in the peripheral blood mononuclear cells of individuals with lymphatic pathology (CP individuals) compared to that in cells of asymptomatic infected (INF) individuals. Similarly, filarial antigens induce significantly enhanced production of VEGF-C in CP compared with INF individuals. TLR2-mediated enhancement of angiogenic growth factor production in CP individuals was shown to be dependent on mitogen-activated protein kinase (MAPK) and NF-κB signaling, as pharmacologic inhibition of either extracellular signal-regulated kinase 1/2 (ERK1/2), p38 MAPK, or NF-κB signaling resulted in significantly diminished production of VEGF-A and Ang-1. Our data therefore strongly suggest an important association between TLR signaling and lymphangiogenesis in the development of pathology in human lymphatic filariasis.
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- 2012
74. Filarial Lymphatic Pathology Reflects Augmented Toll-Like Receptor-Mediated, Mitogen-Activated Protein Kinase-Mediated Proinflammatory Cytokine Production
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P. Jovvian George, Subash Babu, Thomas B. Nutman, Rajamanickam Anuradha, N. Pavan Kumar, and V. Kumaraswami
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Adult ,Male ,MAPK/ERK pathway ,Pathology ,medicine.medical_specialty ,medicine.medical_treatment ,p38 mitogen-activated protein kinases ,Immunology ,Mitogen-activated protein kinase kinase ,Biology ,Microbiology ,Proinflammatory cytokine ,Lymphatic System ,Young Adult ,Elephantiasis, Filarial ,medicine ,Humans ,Aged ,Inflammation ,Mitogen-Activated Protein Kinase Kinases ,Toll-like receptor ,Toll-Like Receptors ,Middle Aged ,TLR2 ,Infectious Diseases ,Cytokine ,Lymphatic system ,Gene Expression Regulation ,Cytokines ,Female ,Parasitology ,Fungal and Parasitic Infections - Abstract
Lymphatic filariasis can be associated with the development of serious pathology in the form of lymphedema, hydrocele, and elephantiasis in a subset of infected patients. Toll-like receptors (TLRs) are thought to play a major role in the development of filarial pathology. To elucidate the role of TLRs in the development of lymphatic pathology, we examined cytokine responses to different Toll ligands in patients with chronic lymphatic pathology (CP), infected patients with subclinical pathology (INF), and uninfected, endemic-normal (EN) individuals. TLR2, -7, and -9 ligands induced significantly elevated production of Th1 and other proinflammatory cytokines in CP patients in comparison to both INF and EN patients. TLR adaptor expression was not significantly different among the groups; however, both TLR2 and TLR9 ligands induced significantly higher levels of phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and p38 mitogen-activated protein (MAP) kinases (MAPK) as well as increased activation of NF-κB in CP individuals. Pharmacologic inhibition of both ERK1/2 and p38 MAP kinase pathways resulted in significantly diminished production of proinflammatory cytokines in CP individuals. Our data, therefore, strongly suggest an important role for TLR2- and TLR9-mediated proinflammatory cytokine induction and activation of both the MAPK and NF-κB pathways in the development of pathology in human lymphatic filariasis.
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- 2011
75. Th2/1 Hybrid Cells Occurring in Murine and Human Strongyloidiasis Share Effector Functions of Th1 Cells
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Bock, Cristin N., primary, Babu, Subash, additional, Breloer, Minka, additional, Rajamanickam, Anuradha, additional, Boothra, Yukhti, additional, Brunn, Marie-Luise, additional, Kühl, Anja A., additional, Merle, Roswitha, additional, Löhning, Max, additional, Hartmann, Susanne, additional, and Rausch, Sebastian, additional
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- 2017
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76. Microbial Translocation Associated with an Acute-Phase Response and Elevations in MMP-1, HO-1, and Proinflammatory Cytokines in Strongyloides stercoralis Infection
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Rajamanickam, Anuradha, primary, Munisankar, Saravanan, additional, Bhootra, Yukthi, additional, Dolla, Chandrakumar, additional, Nutman, Thomas B., additional, and Babu, Subash, additional
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- 2017
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77. Metabolic Consequences of Concomitant Strongyloides stercoralis Infection in Patients With Type 2 Diabetes Mellitus.
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Rajamanickam, Anuradha, Munisankar, Saravanan, Bhootra, Yukthi, Dolla, Chandrakumar, Thiruvengadam, Kannan, Nutman, Thomas B, and Babu, Subash
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BLOOD sugar analysis , *TYPE 2 diabetes prevention , *TYPE 2 diabetes risk factors , *ANTHELMINTICS , *AGE distribution , *CYTOKINES , *GLUCAGON , *GLYCOSYLATED hemoglobin , *HELMINTHIASIS , *INFLAMMATION , *INSULIN , *KIDNEY function tests , *MULTIVARIATE analysis , *PROTEOLYTIC enzymes , *SEX distribution , *SOILS , *T cells , *BODY mass index , *TREATMENT effectiveness , *ADIPOKINES , *GLYCEMIC control , *THERAPEUTICS - Abstract
Background Human and animal studies have demonstrated that helminth infections are associated with a decreased prevalence of type 2 diabetes mellitus (T2DM). However, very little is known about their biochemical and immunological interactions. Methods To assess the relationship between a soil-transmitted helminth, Strongyloides stercoralis (Ss), and T2DM, we examined analytes associated with glycemic control, metabolic processes, and T-cell–driven inflammation at the time of Ss diagnosis and 6 months after definitive anthelmintic treatment. We measured plasma levels of hemoglobin A1c, glucose, insulin, glucagon, adipocytokines, and T-helper (TH) 1-, 2-, and 17- associated cytokines in patients with T2DM with (INF group) or without (UN group) Ss infection. In INF individuals, we again assessed the levels of these analytes 6 months following anthelmintic treatment. Results Compared to UN individuals, INF individuals exhibited significantly diminished levels of insulin and glucagon that increased significantly following therapy. Similarly, INF individuals exhibited significantly diminished levels of adiponectin and adipsin that reversed following therapy. INF individuals also exhibited significantly decreased levels of the TH1- and TH17- associated cytokines in comparison to UN individuals; again, anthelmintic therapy augmented these levels. As expected, INF individuals had elevated levels of TH2-associated and regulatory cytokines that normalized following definitive therapy. Multivariate analysis revealed that these changes were independent of age, sex, body mass index, and liver and renal function. Conclusions Strongyloides stercoralis infection is associated with a significant modulation of glycemic, hormonal, and cytokine parameters in T2DM and its reversal following anthelmintic therapy. Hence, Ss infection has a protective effect on diabetes-related parameters. [ABSTRACT FROM AUTHOR]
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- 2019
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78. Interleukin-10- and transforming growth factor β-independent regulation of CD8⁺ T cells expressing type 1 and type 2 cytokines in human lymphatic filariasis
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Thomas B. Nutman, Subash Babu, Paul Kumaran, Parakkal Jovvian George, and Rajamanickam Anuradha
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Microbiology (medical) ,Adult ,CD4-Positive T-Lymphocytes ,Clinical Biochemistry ,Immunology ,Biology ,CD8-Positive T-Lymphocytes ,Interleukin 21 ,Immune system ,Elephantiasis, Filarial ,Th2 Cells ,Antigen ,Transforming Growth Factor beta ,Immunology and Allergy ,Cytotoxic T cell ,Humans ,Aged ,Middle Aged ,Th1 Cells ,Interleukin-10 ,Interleukin 10 ,Lymphatic system ,Cytokines ,Tumor necrosis factor alpha ,Clinical Immunology ,CD8 - Abstract
Lymphatic filariasis is known to be associated with diminished CD4+Th1 and elevated CD4+Th2 responses to parasite-specific antigens. The roles of cytokine-expressing CD8+T cells in immune responses to filarial infections are not well defined. To study the roles of CD8+T cells expressing type 1, type 2, and type 17 cytokines in filarial infections, we examined the frequencies of these cells in clinically asymptomatic, patently infected (INF) individuals, directlyex vivoand in response to parasite or nonparasite antigens; these frequencies were compared with the results for individuals with filarial lymphedema (i.e., clinical pathology [CP]) and those without active infection or pathology (i.e., endemic normal [EN]). INF individuals exhibited significant decreases in the frequencies of CD8+T cells expressing tumor necrosis factor alpha (TNF-α), gamma interferon (IFN-γ), and interleukin-22 (IL-22) at baseline and/or in response to filarial antigens, compared with CP and EN individuals. In contrast, the same individuals exhibited significant increases in the frequencies of CD8+T cells expressing IL-4, IL-5, IL-9, IL-13, and IL-21, compared with CP and/or EN individuals. Curative treatment resulted in significantly increased frequencies of CD8+T cells expressing IL-2 and significantly decreased frequencies of CD8+T cells expressing type 2 cytokines. Finally, the regulation of these responses appears to be independent of IL-10 and transforming growth factor β (TGF-β), since blockade of IL-10 or TGF-β signaling did not significantly alter the frequencies of type 1 or type 2 cytokine-expressing CD8+T cells. Our findings suggest that alterations in the frequencies of cytokine-expressing CD8+T cells are characteristic features of lymphatic filarial infections.
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- 2014
79. Helminth infections coincident with active pulmonary tuberculosis inhibit mono- and multifunctional CD4+ and CD8+ T cell responses in a process dependent on IL-10
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Rathinam Sridhar, Parakkal Jovvian George, Thomas B. Nutman, Subash Babu, Nathella Pavan Kumar, Vaithilingam V. Banurekha, and Rajamanickam Anuradha
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CD4-Positive T-Lymphocytes ,Bacterial Diseases ,lcsh:Immunologic diseases. Allergy ,Tuberculosis ,medicine.medical_treatment ,T cell ,Immunology ,Helminthiasis ,Biology ,CD8-Positive T-Lymphocytes ,Lymphocyte Activation ,Microbiology ,Immunomodulation ,Interferon-gamma ,Immune system ,Virology ,Helminths ,parasitic diseases ,Genetics ,medicine ,Medicine and Health Sciences ,Parasitic Diseases ,Cytotoxic T cell ,Animals ,Humans ,Molecular Biology ,Tuberculosis, Pulmonary ,Immune Response ,lcsh:QH301-705.5 ,Diminution ,Biology and Life Sciences ,Mycobacterium tuberculosis ,Th1 Cells ,medicine.disease ,Interleukin-10 ,Interleukin 10 ,Cytokine ,medicine.anatomical_structure ,Infectious Diseases ,lcsh:Biology (General) ,Helminth Infections ,Cytokines ,Th17 Cells ,Parasitology ,lcsh:RC581-607 ,CD8 ,Research Article - Abstract
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., Author Summary While it has long been recognized that helminth infections alter the pathophysiology of allergic and autoimmune disease, data suggest that helminth infections also exert an important immunological effect on concomitant infections and vaccine responses. In particular, helminth coinfection can modulate the severity, pathogenesis and transmission of other infectious diseases. In this study, we examine the mechanism by which helminth infections modulate the immunological responses to tuberculosis antigens in individuals with active pulmonary tuberculosis. Our data suggest that two different helminth infections, with different life cycles, tissue localization and modes of transmission essentially exert very similar effects on the adaptive immune response to tuberculosis antigens in pulmonary tuberculosis. This includes a compromised induction of protective cytokine-expressing T cells as well as inhibitory effects on systemic cytokines that are potentially protective in tuberculosis. The strength of this study lies in the fact that this is the first study to demonstrate that two different helminth infections essentially impair cytokine responses in a similar manner in pulmonary tuberculosis.
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- 2014
80. Human monocyte subsets at homeostasis and their perturbation in numbers and function in filarial infection
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Rajamanickam Anuradha, Rachel N. Cotton, Roshanak Tolouei Semnani, Sundar Ganesan, Vanessa Moore, Subash Babu, Renee McDonald-Fleming, Sasisekhar Bennuru, and Thomas B. Nutman
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Adult ,Lipopolysaccharides ,Male ,Chemokine ,medicine.medical_treatment ,T cell ,CD14 ,Immunology ,CD16 ,Microbiology ,Monocytes ,Interferon-gamma ,Young Adult ,Antigen ,Cell Movement ,medicine ,Animals ,Homeostasis ,Humans ,Interleukin 4 ,Brugia malayi ,Cells, Cultured ,Host Response and Inflammation ,biology ,Monocyte ,Middle Aged ,Cell biology ,Filariasis ,Infectious Diseases ,Cytokine ,medicine.anatomical_structure ,Case-Control Studies ,biology.protein ,Parasitology ,Female ,Interleukin-4 ,Gerbillinae - Abstract
To characterize the function and plasticity of the major human circulating monocyte populations and to explore their role in systemic helminth infection, highly purified (by flow-based sorting) human monocyte subsets (CD14 hi /CD16 neg [classical], CD14 + or hi /CD16 med [intermediate], and CD14 neg /CD16 hi [nonclassical]) were examined at homeostasis and after activation. Among these three subsets the classical and intermediate subsets were found to be the major sources of inflammatory and regulatory cytokines, as well as cytokines/chemokines associated with alternative activation, whereas the nonclassical and classical populations demonstrated an ability to transmigrate through endothelial monolayers. Moreover, it was primarily the classical subset that was the most efficient in promoting autologous T cell proliferation. The distribution of these subsets changed in the context of a systemic helminth ( Wuchereria bancrofti ) infection such that patent infection altered the frequency and distribution of these monocyte subsets with the nonclassical monocytes being expanded (almost 2-fold) in filarial infection. To understand further the filarial/monocyte interface, in vitro modeling demonstrated that the classical subset internalized filarial antigens more efficiently than the other two subsets but that the parasite-driven regulatory cytokine interleukin-10 was exclusively coming from the intermediate subset. Our data suggest that monocyte subsets have a differential function at homeostasis and in response to helminth parasites.
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- 2014
81. Interleukin 1 (IL-1)- and IL-23-Mediated Expansion of Filarial Antigen-Specific Th17 and Th22 Cells in Filarial Lymphedema
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Vedachalam Chandrasekaran, Paul Kumaran, Subash Babu, P. Jovvian George, Rajamanickam Anuradha, and Thomas B. Nutman
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Microbiology (medical) ,Clinical Biochemistry ,Immunology ,Interleukin-23 ,Brugia malayi ,Pathogenesis ,Elephantiasis, Filarial ,Antigen ,T-Lymphocyte Subsets ,Transforming Growth Factor beta ,Interleukin 23 ,Immunology and Allergy ,Animals ,Humans ,Wuchereria bancrofti ,biology ,Interleukin ,Transforming growth factor beta ,biology.organism_classification ,Lymphatic system ,biology.protein ,Th17 Cells ,Clinical Immunology ,Ex vivo ,Interleukin-1 - Abstract
Lymphatic filarial disease is known to be associated with elevated Th1 responses and normal or diminished Th2 responses to parasite-specific antigens. The roles of Th17 cells and the recently described Th22 cells have not been examined in detail in either filarial infection itself or in filarial disease (e.g., lymphedema and elephantiasis). To explore the roles of Th17 and Th22 cells and their subsets, we examined the frequencies of these cells in individuals with filarial lymphedema (chronic pathology [CP]), in clinically asymptomatic infected (INF) individuals, and in uninfected (UN) individualsex vivoand in response to parasite and nonparasite antigens. Those with disease (CP) had significantly expanded frequencies of Th17 and Th22 cells, compared with either INF or UN individuals, at baseline (ex vivo) and in response to parasite antigens. This antigen-driven expansion of Th17 and Th22 cells was dependent on interleukin 1 (IL-1), IL-23, and, to lesser extent, transforming growth factor β (TGF-β), as blockade of any of these cytokines resulted in significantly diminished frequencies of Th17 and Th22 cells. Our findings, therefore, suggest that filarial parasite-driven expansion of Th17 and Th22 cells is associated with the pathogenesis of filarial infections and disease.
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- 2014
82. Expansion of parasite-specific CD4+ and CD8+ T cells expressing IL-10 superfamily cytokine members and their regulation in human lymphatic filariasis
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Parakkal Jovvian George, Thomas B. Nutman, Vedachalam Chandrasekaran, Luke Elizabeth Hanna, Paul Kumaran, Subash Babu, and Rajamanickam Anuradha
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Adult ,CD4-Positive T-Lymphocytes ,Male ,lcsh:Arctic medicine. Tropical medicine ,lcsh:RC955-962 ,medicine.medical_treatment ,T cell ,Immunology ,Biology ,CD8-Positive T-Lymphocytes ,Immunomodulation ,Interleukin 21 ,Young Adult ,Immune system ,Elephantiasis, Filarial ,Antigen ,medicine ,Medicine and Health Sciences ,Parasitic Diseases ,Cytotoxic T cell ,Animals ,Humans ,Immune Response ,Aged ,Interleukins ,lcsh:Public aspects of medicine ,Public Health, Environmental and Occupational Health ,Biology and Life Sciences ,lcsh:RA1-1270 ,Middle Aged ,Filariasis ,Interleukin 10 ,Cytokine ,medicine.anatomical_structure ,Infectious Diseases ,Helminth Infections ,Female ,Clinical Immunology ,CD8 ,Research Article - Abstract
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., Author Summary Lymphatic filariasis afflicts over 120 million people worldwide. While the infection is mostly clinically asymptomatic, approximately 40 million people suffer from overt, morbid clinical pathology, characterized by swelling of the scrotal area and lower limbs (hydrocele and lymphedema). Host immunologic factors that influence the pathogenesis of disease in these individuals are not completely understood. CD4+ and CD8+ T cells are known to play a role in promoting pathogenesis through the secretion of pro-inflammatory cytokines, while IL-10 is known to play an important role in dampening inflammation. IL-10 belongs to a family of cytokines that include IL-19, IL-24 and IL-26, known as the IL-10 superfamily. We investigated whether these cytokines have a function similar to IL-10 in individuals with asymptomatic infection and no clinical pathology and those with overt, clinical pathology. We first identify that CD4+ and CD8+ T cells produce these cytokines. We next identify a significant association of IL-19 and IL-24 secreting T cells with asymptomatic infection. IL-26 secreting T cells, in contrast, appear to be significantly associated with the presence of lymphatic pathology in filarial infection. Therefore, we have uncovered a potentially new regulatory pathway involving the IL-10 superfamily cytokines in filarial infections.
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- 2014
83. Evidence of microbial translocation associated with perturbations in T cell and antigen-presenting cell homeostasis in hookworm infections
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Rajamanickam Anuradha, Thomas B. Nutman, Subash Babu, Palakkal Jovvian George, Nathella Pavan Kumar, and V. Kumaraswami
- Subjects
lcsh:Arctic medicine. Tropical medicine ,lcsh:RC955-962 ,T cell ,T-Lymphocytes ,Immunology ,Antigen-Presenting Cells ,Gastroenterology and Hepatology ,Biology ,Hookworm Infections ,Immune system ,T-Lymphocyte Subsets ,parasitic diseases ,medicine ,Cytotoxic T cell ,Humans ,Lymphocyte Count ,Prospective Studies ,Antigen-presenting cell ,lcsh:Public aspects of medicine ,Public Health, Environmental and Occupational Health ,lcsh:RA1-1270 ,Dendritic cell ,medicine.anatomical_structure ,Infectious Diseases ,Bacterial Translocation ,Medicine ,Clinical Immunology ,Memory T cell ,CD8 ,Research Article - Abstract
Background Microbial translocation (MT) is the process by which microbes or microbial products translocate from the intestine to the systemic circulation. MT is a common cause of systemic immune activation in HIV infection and is associated with reduced frequencies of CD4+ T cells; no data exist, however, on the role of MT in intestinal helminth infections. Methods We measured the plasma levels of MT markers, acute-phase proteins, and pro- and anti - inflammatory cytokines in individuals with or without hookworm infections. We also estimated the absolute counts of CD4+ and CD8+ T cells as well as the frequencies of memory T cell and dendritic cell subsets. Finally, we also measured the levels of all of these parameters in a subset of individuals following treatment of hookworm infection. Results Our data suggest that hookworm infection is characterized by increased levels of markers associated with MT but not acute-phase proteins nor pro-inflammatory cytokines. Hookworm infections were also associated with increased levels of the anti – inflammatory cytokine – IL-10, which was positively correlated with levels of lipopolysaccharide (LPS). In addition, MT was associated with decreased numbers of CD8+ T cells and diminished frequencies of particular dendritic cell subsets. Antihelmintic treatment of hookworm infection resulted in reversal of some of the hematologic and microbiologic alterations. Conclusions Our data provide compelling evidence for MT in a human intestinal helminth infection and its association with perturbations in the T cell and antigen-presenting cell compartments of the immune system. Our data also reveal that at least one dominant counter-regulatory mechanism i.e. increased IL-10 production might potentially protect against systemic immune activation in hookworm infections., Author Summary Hookworm infections affect more than half a billion people worldwide and cause morbidity in the form of intestinal injury and blood loss. Host immunologic factors that influence the pathogenesis of disease in these individuals are not completely understood. Circulating microbial products such as LPS and markers associated with microbial translocation (transfer of microbes or microbial products from the intestine to the circulation) have been shown to play an important role in disease pathogenesis of certain infections like HIV. We have attempted to elucidate the role of the above mentioned factors in disease pathogenesis by comparing the plasma levels of the various markers in a group of hookworm infected and uninfected individuals. We show that circulating levels of microbial translocation markers are elevated in hookworm infected individuals, a potential cause of morbidity in these infections. This is associated with changes in the host immune system, especially in terms of lymphocyte and dendritic cells subsets. However, microbial translocation is not accompanied by increased levels of acute phase proteins or pro-inflammatory cytokines indicating that the parasite has evolved mechanisms to dampen LPS induced inflammation. Thus, our study highlights a novel pathway of pathogenesis in an intestinal helminth infection and improves our understanding of the various factors involved in the complex host-parasite interaction.
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- 2012
84. Altered circulating levels of matrix metalloproteinases and inhibitors associated with elevated type 2 cytokines in lymphatic filarial disease
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V. Kumaraswami, Rajamanickam Anuradha, Jovvian P. George, Subash Babu, Nathella Pavankumar, and Thomas B. Nutman
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Adult ,Male ,lcsh:Arctic medicine. Tropical medicine ,Adolescent ,lcsh:RC955-962 ,Immunology ,Cellular homeostasis ,Inflammation ,Biology ,Matrix metalloproteinase ,Extracellular matrix ,Plasma ,Young Adult ,Elephantiasis, Filarial ,parasitic diseases ,Extracellular ,medicine ,Animals ,Humans ,Subcutaneous fibrosis ,Aged ,lcsh:Public aspects of medicine ,Public Health, Environmental and Occupational Health ,Tissue Inhibitor of Metalloproteinases ,lcsh:RA1-1270 ,Middle Aged ,Matrix Metalloproteinases ,Lymphatic system ,Infectious Diseases ,Medicine ,Cytokines ,Female ,medicine.symptom ,Homeostasis ,Research Article - Abstract
Background Infection with Wuchereria bancrofti can cause severe disease characterized by subcutaneous fibrosis and extracellular matrix remodeling. Matrix metalloproteinases (MMPs) are a family of enzymes governing extracellular remodeling by regulating cellular homeostasis, inflammation, and tissue reorganization, while tissue-inhibitors of metalloproteinases (TIMPs) are endogenous regulators of MMPs. Homeostatic as well as inflammation-induced balance between MMPs and TIMPs is considered critical in mediating tissue pathology. Methods To elucidate the role of MMPs and TIMPs in filarial pathology, we compared the plasma levels of a panel of MMPs, TIMPs, other pro-fibrotic factors, and cytokines in individuals with chronic filarial pathology with (CP Ag+) or without (CP Ag−) active infection to those with clinically asymptomatic infections (INF) and in those without infection (endemic normal [EN]). Markers of pathogenesis were delineated based on comparisons between the two actively infected groups (CP Ag+ compared to INF) and those without active infection (CP Ag− compared to EN). Results and Conclusion Our data reveal that an increase in circulating levels of MMPs and TIMPs is characteristic of the filarial disease process per se and not of active infection; however, filarial disease with active infection is specifically associated with increased ratios of MMP1/TIMP4 and MMP8/TIMP4 as well as with pro-fibrotic cytokines (IL-5, IL-13 and TGF-β). Our data therefore suggest that while filarial lymphatic disease is characterized by a non-specific increase in plasma MMPs and TIMPs, the balance between MMPs and TIMPs is an important factor in regulating tissue pathology during active infection., Author Summary Lymphatic filariasis afflicts over 120 million people worldwide. While the infection is mostly clinically asymptomatic, approximately 40 million people suffer from overt, morbid clinical pathology characterized by swelling of the scrotal area and lower limbs (hydrocele and lymphedema). Host immunologic factors that influence the pathogenesis of disease in these individuals are not completely understood. Matrix metalloproteinases are a family of circulating and tissue proteins that influence the development of tissue fibrosis. They are regulated by another family of proteins called tissue inhibitors of metalloproteinases. The interplay between these proteins governs tissue fibrosis in a variety of conditions. In addition, certain cytokines are known to promote pro-fibrotic events. We have attempted to elucidate the role of the above-mentioned factors in disease pathogenesis by comparing the plasma levels of the various markers in four groups of individuals: chronic pathology individuals with or without active filarial infection; asymptomatic, filaria-infected individuals; and uninfected, endemic normal individuals. We show that altered ratios of the metalloproteinases and their inhibitors—as well as elevated levels of pro-fibrotic cytokines—characterize filarial infection-induced lymphatic pathology.
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- 2012
85. Heightened measures of immune complex and complement function and immune complex-mediated granulocyte activation in human lymphatic filariasis
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Rajamanickam Anuradha, Thomas B. Nutman, Subash Babu, V. Kumaraswami, Prakash Senbagavalli, and Vadakkuppattu D. Ramanathan
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Adult ,Male ,Granulocyte activation ,Antigen-Antibody Complex ,Adolescent ,Enzyme-Linked Immunosorbent Assay ,Granulocyte ,Biology ,Lymphocyte Activation ,Young Adult ,Immune system ,Elephantiasis, Filarial ,Virology ,medicine ,Humans ,Lymphatic filariasis ,Aged ,Complement System Proteins ,Articles ,Middle Aged ,medicine.disease ,Immune complex ,Complement system ,Infectious Diseases ,Lymphatic system ,medicine.anatomical_structure ,Immunology ,Parasitology ,Female ,Granulocytes - Abstract
The presence of circulating immune complexes (CICs) is a characteristic feature of human lymphatic filariasis. However, the role of CICs in modulating granulocyte function and complement functional activity in filarial infection is unknown. The levels of CICs in association with complement activation in clinically asymptomatic, filarial-infected patients (INF); filarial-infected patients with overt lymphatic pathologic changes (CPDT); and uninfected controls (EN) were examined. Significantly increased levels of CICs and enhanced functional efficiency of the classical and mannose-binding lectin pathways of the complement system was observed in INF compared with CPDT and EN. Polyethylene glycol–precipitated CICs from INF and CPDT induced significantly increased granulocyte activation compared with those from EN, determined by the increased production of neutrophil granular proteins and a variety of pro-inflammatory cytokines. Thus, CIC-mediated enhanced granulocyte activation and modulation of complement function are important features of filarial infection and disease.
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- 2011
86. Attenuation of toll-like receptor expression and function in latent tuberculosis by coexistent filarial infection with restoration following antifilarial chemotherapy
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Subash Babu, C. Kolappan, Rajamanickam Anuradha, P G Gopi, Thomas B. Nutman, N. Pavan Kumar, Sajid Q. Bhat, V. Kumaraswami, and Paul Kumaran
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Adult ,Male ,Tuberculosis ,lcsh:Arctic medicine. Tropical medicine ,lcsh:RC955-962 ,Immunology/Immunomodulation ,Infectious Diseases/Bacterial Infections ,Mycobacterium tuberculosis ,Immune system ,Latent Tuberculosis ,Immunology/Immunity to Infections ,Immune Tolerance ,medicine ,Animals ,Humans ,Infectious Diseases/Helminth Infections ,Filarioidea ,Aged ,Toll-like receptor ,biology ,Latent tuberculosis ,lcsh:Public aspects of medicine ,Toll-Like Receptors ,Public Health, Environmental and Occupational Health ,lcsh:RA1-1270 ,Middle Aged ,medicine.disease ,biology.organism_classification ,Virology ,Filariasis ,TLR2 ,Filaricides ,Infectious Diseases ,Immunology ,Coinfection ,Cytokines ,Female ,Research Article - Abstract
Mycobacterium tuberculosis (Mtb) and filarial coinfection is highly prevalent, and the presence of filarial infections may regulate the Toll-like receptor (TLR)-dependent immune response needed to control Mtb infection. By analyzing the baseline and mycobacterial antigen–stimulated expression of TLR1, 2, 4, and 9 (in individuals with latent tuberculosis [TB] with or without filarial infection), we were able to demonstrate that filarial infection, coincident with Mtb, significantly diminishes both baseline and Mtb antigen-specific TLR2 and TLR9 expression. In addition, pro-inflammatory cytokine responses to TLR2 and 9 ligands are significantly diminished in filaria/TB-coinfected individuals. Definitive treatment of lymphatic filariasis significantly restores the pro-inflammatory cytokine responses in individuals with latent TB. Coincident filarial infection exerted a profound inhibitory effect on protective mycobacteria-specific TLR-mediated immune responses in latent tuberculosis and suggests a novel mechanism by which concomitant filarial infections predispose to the development of active tuberculosis in humans., Author Summary Lymphatic filariasis afflicts over 120 million people worldwide, while Mycobacterium tuberculosis infects over 2 billion people worldwide. Almost 90% of infected people harbor latent tuberculosis infection with no clinical manifestations. Toll-like receptors (TLRs), pattern-recognition receptors that are present on host immune cells, constitute an important facet of host immune response initiation against a variety of pathogens. Because lymphatic filariasis and tuberculosis are co-endemic in many parts of the world and because TLR modulation is an important feature of both infections, we examined the effect of coexisting filarial infection on TLR-specific immune responses in latent tuberculosis by comparing cellular immune responses to Toll ligands in individuals with latent tuberculosis with or without concomitant lymphatic filariasis. We first examined modulation of TLRs at the gene expression level and determined that downregulation of TLR2 and 9 is associated with coexisting filarial infection. We then determined that Toll ligand-induced pro-inflammatory cytokine production—which is crucial in host defense against TB—is diminished in the presence of filarial coinfection. Treatment of filarial infection restores cytokine production in individuals with latent TB. Thus, we conclude that coexisting filarial infections might significantly compromise essential immune responses in tuberculosis and that treatment of filarial infections would potentially confer tremendous benefit in combating tuberculosis.
- Published
- 2009
87. Levels of Complement Components in Children With Acute COVID-19 or Multisystem Inflammatory Syndrome.
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Rajamanickam, Anuradha, Nathella, Pavan Kumar, Venkataraman, Aishwarya, Dasan, Bindu, Putlibai, Sulochana, Ahamed, Shaik Fayaz, Selvaraj, Nandhini, Sadasivam, Kalaimaran, Sundaram, Balasubramanian, Nutman, Thomas B., and Babu, Subash
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- 2023
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88. Rubella serosurveys at three Aravind Eye Hospitals in Tamil Nadu, India
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Perumalsamy, Vijayalakshmi, Rajamanickam, Anuradha, Karthik, Prakash, Kalpana, Narendran, Meenakshi, Ravindran, Lalitha, Prajna, David, Brown, and Susan E, Robertson
- Subjects
Adult ,Cross Infection ,Adolescent ,Vaccination ,virus diseases ,India ,Antibodies, Viral ,Hospitals, Special ,Personnel, Hospital ,Seroepidemiologic Studies ,Immunoglobulin G ,Humans ,Female ,Rubella Vaccine ,Disease Susceptibility ,Prospective Studies ,Rubella virus ,Rubella ,Research Article - Abstract
OBJECTIVE: To determine the susceptibility of female eye hospital staff to rubella infection and the potential risk for hospital-based rubella outbreaks. METHODS: A prospective cohort study on the seroprevalence of rubella IgG antibodies was conducted at three large eye hospitals in Coimbatore, Madurai and Tirunelveli, Tamil Nadu, India, where young children with eye abnormalities attributable to congenital rubella are treated. A total of 1000 female hospital employees aged 18-40 years agreed to participate and gave written informed consent. FINDINGS: The proportions of rubella-seronegative women were: 11.7% at Coimbatore, with a 95% confidence interval (CI) of 8.1-16.5; 15% at Madurai (95% CI = 12.3-18.1), and 20.8 at Tirunelveli (95% CI = 14.7-28.6). For the entire cohort the proportion seronegative was significantly higher among married women (21.5%) than among single women (14.0%) (P = 0.02). Rates of seronegativity were highest among physicians and lowest among housekeepers. All 150 seronegative women in the study sample accepted a dose of rubella vaccine. CONCLUSION: These are the first rubella serosurveys to have been reported from eye hospitals in any country. The relatively high rate of susceptibility indicated a risk of a rubella outbreak, and this was reduced by vaccinating all seronegative women. A policy has been established at all three hospitals for the provision of rubella vaccine to new employees. Other hospitals, especially eye hospitals and hospitals in countries without routine rubella immunization, should consider the rubella susceptibility of staff and the risk of hospital-based rubella outbreaks.
- Published
- 2004
89. Parasite-Antigen Driven Expansion of IL-5− and IL-5+ Th2 Human Subpopulations in Lymphatic Filariasis and Their Differential Dependence on IL-10 and TGFβ
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Vedachalam Chandrasekaran, Paul Kumaran, Luke E. Hanna, Parakkal Jovvian George, Subash Babu, Rajamanickam Anuradha, and Thomas B. Nutman
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Adult ,Male ,Allergy ,Immune Cells ,Immunology ,RC955-962 ,Helminth Infection ,Biology ,Immunoglobulin E ,Young Adult ,Elephantiasis, Filarial ,Th2 Cells ,Immune system ,Antigen ,T-Lymphocyte Subsets ,Transforming Growth Factor beta ,Arctic medicine. Tropical medicine ,Parasitic Diseases ,medicine ,Animals ,Humans ,Immune Response ,Interleukin 5 ,Aged ,T Cells ,Public Health, Environmental and Occupational Health ,Transforming growth factor beta ,Middle Aged ,Eosinophil ,medicine.disease ,Filariasis ,Interleukin-10 ,Interleukin 10 ,Infectious Diseases ,medicine.anatomical_structure ,Antigens, Helminth ,biology.protein ,Medicine ,Female ,Interleukin-5 ,Public aspects of medicine ,RA1-1270 ,Research Article - Abstract
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., Author Summary Th2 cells are CD4+ T cells that produce a unique set of cytokines - IL-4, IL-5 and IL-13. Th2 cells are commonly associated with allergies, asthma and helminth infections. A common helminth infection that infects over 120 million people worldwide is lymphatic filarial infection caused by filarial parasites. We show here data that filarial infection is associated with the expansion of two types of Th2 cells, one which produces IL-4 and IL-13 alone without IL-5 and the other which produces all three cytokines. Interestingly, while the former subset is associated with the levels of antibodies - IgG4 and IgE; the latter is associated with the presence of eosinophilia in filarial infected individuals. In addition, these subsets appear to be modulated differently by the immunoregulatory cytokines - IL-10 and TGFβ. Therefore, our study highlights a novel regulation of Th2 cells and suggests that the Th2 compartment is quite heterogeneous in phenotype with possible functional consequences.
- Published
- 2014
90. Circulating Microbial Products and Acute Phase Proteins as Markers of Pathogenesis in Lymphatic Filarial Disease
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V. Kumaraswami, Rajamanickam Anuradha, Thomas B. Nutman, N. Pavan Kumar, Subash Babu, Michael P. Fay, and P. Jovvian George
- Subjects
Adult ,Lipopolysaccharides ,Male ,lcsh:Immunologic diseases. Allergy ,Lipopolysaccharide ,Immunology ,Inflammation ,Microbiology ,Proinflammatory cytokine ,Pathogenesis ,Young Adult ,chemistry.chemical_compound ,Elephantiasis, Filarial ,Virology ,Genetics ,medicine ,Humans ,lcsh:QH301-705.5 ,Molecular Biology ,Lymphatic filariasis ,Membrane Glycoproteins ,biology ,Haptoglobin ,Acute-phase protein ,Middle Aged ,medicine.disease ,Infectious Diseases ,Lymphatic system ,lcsh:Biology (General) ,chemistry ,biology.protein ,Cytokines ,Medicine ,Female ,Clinical Immunology ,Parasitology ,medicine.symptom ,Carrier Proteins ,lcsh:RC581-607 ,Biomarkers ,Acute-Phase Proteins ,Research Article - Abstract
Lymphatic filariasis can be associated with development of serious pathology in the form of lymphedema, hydrocele, and elephantiasis in a subset of infected patients. Dysregulated host inflammatory responses leading to systemic immune activation are thought to play a central role in filarial disease pathogenesis. We measured the plasma levels of microbial translocation markers, acute phase proteins, and inflammatory cytokines in individuals with chronic filarial pathology with (CP Ag+) or without (CP Ag−) active infection; with clinically asymptomatic infections (INF); and in those without infection (endemic normal [EN]). Comparisons between the two actively infected groups (CP Ag+ compared to INF) and those without active infection (CP Ag− compared to EN) were used preliminarily to identify markers of pathogenesis. Thereafter, we tested for group effects among all the four groups using linear models on the log transformed responses of the markers. Our data suggest that circulating levels of microbial translocation products (lipopolysaccharide and LPS-binding protein), acute phase proteins (haptoglobin and serum amyloid protein-A), and inflammatory cytokines (IL-1β, IL-12, and TNF-α) are associated with pathogenesis of disease in lymphatic filarial infection and implicate an important role for circulating microbial products and acute phase proteins., Author Summary Lymphatic filariasis afflicts over 120 million people worldwide. While the infection is mostly clinically asymptomatic, approximately 40 million people suffer from overt, morbid clinical pathology, characterized by swelling of the scrotal area and lower limbs (hydrocele and lymphedema). Host immunologic factors that influence the pathogenesis of disease in these individuals are not completely understood. Circulating microbial products such as LPS and markers associated with microbial translocation have been shown to play an important role in disease pathogenesis of certain infections like HIV. Similarly, proteins associated with the acute phase response and related cytokines also play an important role in pathogenesis. We have attempted to elucidate the role of the above mentioned factors in disease pathogenesis by comparing the plasma levels of the various markers in four groups of individuals: chronic pathology individuals with or without active filarial infection, asymptomatic, filarial infected individuals and uninfected, endemic normal individuals. We show that circulating levels of LPS, acute phase proteins and certain cytokines are significantly elevated in filarial disease with active infection but not in the other groups indicating that filarial infection induced increased production of these factors correlated with the development of filarial lymphatic pathology.
- Published
- 2012
91. Effect of BCG vaccination on proinflammatory responses in elderly individuals.
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Kumar, Nathella Pavan, Padmapriyadarsini, Chandrasekaran, Rajamanickam, Anuradha, Marinaik, Shrinivasa B., Nancy, Arul, Padmanaban, Srinivasan, Akbar, Nabila, Murhekar, Manoj, and Babu, Subash
- Subjects
- *
COVID-19 , *BCG vaccines , *OLDER people , *HAPTOGLOBINS , *MEDICAL personnel , *MEDICAL research , *RESPIRATORY infections - Abstract
The article presents a coronavirus research report on effect of Bacillus Calmette-Guérin (BCG) vaccination on proinflammatory responses in elderly individuals. Topics include demonstrates the immunomodulatory properties of BCG vaccination and suggests its potential utility in nonspecific vaccination of COVID-19 by down-modulating pathogenic inflammatory responses; and Plasma levels of the aforementioned parameters were significantly lower in vaccinated individuals.
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- 2021
- Full Text
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92. Cytotoxic T-Lymphocyte-Associated Antigen 4 (CTLA-4)- and Programmed Death 1 (PD-1)-Mediated Regulation of Monofunctional and Dual Functional CD4+and CD8+T-Cell Responses in a Chronic Helminth Infection
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Rajamanickam, Anuradha, Munisankar, Saravanan, Dolla, Chandrakumar, Nutman, Thomas B., and Babu, Subash
- Abstract
Chronic helminth infections are known to be associated with the modulation of antigen-specific T-cell responses. Strongyloides stercoralisinfection is characterized by the downmodulation of antigen-specific Th1 and Th17 responses and the upregulation of Th2 and Th9 responses. Immune homeostasis is partially maintained by negative regulators of T-cell activation, cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed death 1 (PD-1), which dampen effector responses during chronic infections.
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- 2019
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93. Microbial Translocation Associated with an Acute-Phase Response and Elevations in MMP-1, HO-1, and Proinflammatory Cytokines in Strongyloides stercoralisInfection
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Rajamanickam, Anuradha, Munisankar, Saravanan, Bhootra, Yukthi, Dolla, Chandrakumar, Nutman, Thomas B., and Babu, Subash
- Abstract
ABSTRACTMicrobial translocation, characterized by elevated levels of lipopolysaccharide (LPS) and related markers, is a common occurrence in HIV and some parasitic infections. This is usually associated with extensive inflammation and immune activation. To examine the occurrence of microbial translocation and the associated inflammatory response in asymptomatic Strongyloides stercoralisinfection, we measured the plasma levels of LPS and other microbial translocation markers, acute-phase proteins, inflammatory markers, and proinflammatory cytokines in individuals with (infected [INF]) or without (uninfected [UN]) S. stercoralisinfections. Finally, we also measured the levels of all of these markers in INF individuals following treatment of S. stercoralisinfection. We show that INF individuals exhibit significantly higher plasma levels of microbial translocation markers (LPS, soluble CD14 [sCD14], intestinal fatty acid-binding protein [iFABP], and endotoxin core IgG antibody [EndoCAb]), acute-phase proteins (α-2 macroglobulin [α-2M], C-reactive protein [CRP], haptoglobin, and serum amyloid protein A [SAA]), inflammatory markers (matrix metalloproteinase 1 [MMP-1] and heme oxygenase 1 [HO-1]), and proinflammatory cytokines (interleukin-6 [IL-6], IL-8, monocyte chemoattractant protein 1 [MCP-1], and IL-1β) than do UN individuals. INF individuals exhibit significantly decreased levels of tissue inhibitor of metalloproteinases 4 (TIMP-4). Following treatment of S. stercoralisinfection, the elevated levels of microbial translocation markers, acute-phase proteins, and inflammatory markers were all diminished. Our data thus show that S. stercoralisinfection is characterized by microbial translocation and accompanying increases in levels of acute-phase proteins and markers of inflammation and provide data to suggest that microbial translocation is a feature of asymptomatic S. stercoralisinfection and is associated with an inflammatory response.
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- 2016
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94. Plasma Immune Biomarkers Predictive of Progression to Active Tuberculosis in Household Contacts of TB Patients.
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Rajamanickam A, Ann Daniel E, Dasan B, Thiruvengadam K, Chandrasekaran P, Gaikwad S, Pattabiraman S, Bhanu B, Sivaprakasam A, Kulkarni V, Karyakarte R, Paradkar M, Shivakumar SVBY, Mave V, Gupta A, Hanna LE, and Babu S
- Abstract
Background: The progression from Mycobacterium tuberculosis infection to active tuberculosis (TB) disease varies among individuals, and identifying biomarkers to predict progression is crucial for guiding interventions. In this study, we aimed to determine plasma immune biomarker profiles in healthy household contacts of index pulmonary TB (PTB) patients who either progressed to TB or remained as non-progressors., Methods: A cohort of household contacts of adults with PTB was enrolled, consisting of 15 contacts who progressed to TB disease and 15 non-progressors. Plasma samples were collected at baseline, 4 months, and 12 months to identify predictive TB progression markers., Results: Our findings revealed that individuals in the progressor group exhibited significantly decreased levels of IFNγ, IL-2, TNFα, IL1α, IL1β, IL-17A, and IL-1Ra at baseline, months 4 and 12. In contrast, the progressor group displayed significantly elevated levels of IFNα, IFNβ, IL-6, IL-12, GM-CSF, IL-10, IL-33, CCL2, CCL11, CXCL8, CXCL10, CX3CL1, VEGF, Granzyme-B and PDL-1 compared to the non-progressor group at baseline, months 4 and 12. ROC analysis identified IFNγ, GM-CSF, IL-1Ra, CCL2 and CXCL10 as the most promising predictive markers, with an AUC of ≥90. Furthermore, combinatorial analysis demonstrated that GM-CSF, CXCL10 and IL-1Ra, when used in combination, exhibited high accuracy in predicting progression to active TB disease., Conclusions: Our study suggests that a specific set of plasma biomarkers GM-CSF, CXCL10 and IL-1Ra, can effectively identify household contacts at significant risk of developing TB disease. These findings have important implications for early intervention and preventive strategies in TB-endemic regions., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2024.)
- Published
- 2024
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95. Characterization of memory T cell subsets and common γ-chain cytokines in convalescent COVID-19 individuals.
- Author
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Rajamanickam A, Pavan Kumar N, Pandiaraj AN, Selvaraj N, Munisankar S, Renji RM, Venkataramani V, Murhekar M, Thangaraj JWV, Muthusamy SK, Chethrapilly Purushothaman GK, Bhatnagar T, Ponnaiah M, Ramasamy S, Velusamy S, and Babu S
- Subjects
- CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Convalescence, Humans, Immunologic Memory immunology, Interleukin-15 blood, Interleukin-2 blood, Interleukin-7 blood, RNA, Viral, SARS-CoV-2, T-Lymphocyte Subsets immunology, COVID-19 blood, COVID-19 immunology, Cytokines blood, Memory T Cells immunology
- Abstract
T cells are thought to be an important correlates of protection against SARS-CoV2 infection. However, the composition of T cell subsets in convalescent individuals of SARS-CoV2 infection has not been well studied. The authors determined the lymphocyte absolute counts, the frequency of memory T cell subsets, and the plasma levels of common γ-chain in 7 groups of COVID-19 individuals, based on days since RT-PCR confirmation of SARS-CoV-2 infection. The data show that both absolute counts and frequencies of lymphocytes as well as, the frequencies of CD4
+ central and effector memory cells increased, and the frequencies of CD4+ naïve T cells, transitional memory, stem cell memory T cells, and regulatory cells decreased from Days 15-30 to Days 61-90 and plateaued thereafter. In addition, the frequencies of CD8+ central memory, effector, and terminal effector memory T cells increased, and the frequencies of CD8+ naïve cells, transitional memory, and stem cell memory T cells decreased from Days 15-30 to Days 61-90 and plateaued thereafter. The plasma levels of IL-2, IL-7, IL-15, and IL-21-common γc cytokines started decreasing from Days 15-30 till Days 151-180. Severe COVID-19 patients exhibit decreased levels of lymphocyte counts and frequencies, higher frequencies of naïve cells, regulatory T cells, lower frequencies of central memory, effector memory, and stem cell memory, and elevated plasma levels of IL-2, IL-7, IL-15, and IL-21. Finally, there was a significant correlation between memory T cell subsets and common γc cytokines. Thus, the study provides evidence of alterations in lymphocyte counts, memory T cell subset frequencies, and common γ-chain cytokines in convalescent COVID-19 individuals., (© 2022 The Authors. Journal of Leukocyte Biology published by Wiley Periodicals LLC on behalf of Society for Leukocyte Biology.)- Published
- 2022
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96. Determining the Frequencies of Th9 Cells from Whole Blood.
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Rajamanickam A and Babu S
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- CD4-Positive T-Lymphocytes metabolism, Cytokines metabolism, Humans, Interleukin-4 metabolism, T-Lymphocyte Subsets metabolism, T-Lymphocytes, Helper-Inducer metabolism, Transforming Growth Factor beta metabolism, Interleukin-9 metabolism
- Abstract
Th9 cells are a subset of CD4+ T cells producing the cytokine, IL-9. Th9 cells are increasingly recognized as being important player in allergy, autoimmunity, and antitumor responses. The polarization and expansion of Th9 cells requires the cytokines IL-4, TGF-β. In this chapter, we described the protocol for measuring Th9 frequencies using whole blood.
- Published
- 2017
- Full Text
- View/download PDF
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