Co-factor-independent phosphoglycerate mutase of Leishmania donovani modulates macrophage signalling and promotes T-cell repertoires bearing epitopes for both MHC-I and MHC-II

Parasitology ◽  
2017 ◽  
Vol 145 (3) ◽  
pp. 292-306 ◽  
Author(s):  
MANISH K. SINGH ◽  
FAUZIA JAMAL ◽  
AMIT K. DUBEY ◽  
PUSHKAR SHIVAM ◽  
SARITA KUMARI ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
T Cell ◽  
Leishmania Donovani ◽  
Mononuclear Cells ◽  
Interleukin 1 ◽  
T Cell Subsets ◽  
Phosphoglycerate Mutase ◽  
Mhc I ◽  
Tumour Growth Factor ◽  
Oxide Synthase

SUMMARYImmunoactivation depends upon the antigen potential to modulate T-cell repertoires. The present study has enumerated the effect of 61 kDa recombinant Leishmania donovani co-factor-independent phosphoglycerate mutase (rLd-iPGAM) on mononuclear cells of healthy and treated visceral leishmaniasis subjects as well as on THP-1 cell line. rLd-iPGAM stimulation induced higher expression of interleukin-1β (IL-1β) in the phagocytic cell, its receptor and CD69 on T-cell subsets. These cellular activations resulted in upregulation of host-protective cytokines IL-2, IL-12, IL-17, tumour necrosis factor-α and interferon-γ, and downregulation of IL-4, IL-10 and tumour growth factor-β. This immune polarization was also evidenced by upregulation of nuclear factor-κ light-chain enhancer of activated B cells p50 and regulated expression of suppressor of mother against decapentaplegic protein-4. rLd-iPGAM stimulation also promoted lymphocyte proliferation and boosted the leishmaniacidal activity of macrophages by upregulating reactive oxygen species. It also induced 1·8-fold higher release of nitric oxide (NO) by promoting the transcription of inducible nitric oxide synthase gene. Besides, in silico analysis suggested the presence of major histocompatibility complex class I and II restricted epitopes, which can proficiently trigger CD8+ and CD4+ cells, respectively. This study reports rLd-iPGAM as an effective immunoprophylactic agent, which can be used in future vaccine design.

scholarly journals Inducible Nitric Oxide Synthase Is Not Essential for Control of Trypanosoma cruzi Infection in Mice

2004 ◽  
Vol 72 (7) ◽  
pp. 4081-4089 ◽  
Author(s):  
Kara L. Cummings ◽  
Rick L. Tarleton
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Trypanosoma Cruzi ◽  
Inducible Nitric Oxide Synthase ◽  
Interleukin 1 ◽  
Mouse Strains ◽  
Wild Type ◽  
Necrosis Factor Alpha ◽  
Oxide Synthase ◽  
Inducible Nitric Oxide

ABSTRACT Immune control of many intracellular pathogens, including Trypanosoma cruzi, is reported to be dependent on the production of nitric oxide. In this study, we show that mice deficient in inducible nitric oxide synthase (iNOS or NOS2) exhibit resistance to T. cruzi infection that is comparable to that of wild-type mice. This is the case for two iNOS-deficient mouse strains, Nos2tm1Lau and Nos2 N5, infected with the Brazil or Tulahuen strain of T. cruzi. In all cases, blood parasitemia, tissue parasite load, and survival rates are similar between wild-type and iNOS-deficient mice. In contrast, both wild-type and Nos2tm1Lau mice died within 32 days postinfection when treated with the nitric oxide synthase inhibitor aminoguanidine. Increased transcription of NOS1 or NOS3 is not found in iNOS-knockout (KO) mice, indicating that the absence of nitric oxide production through iNOS is not compensated for by increased production of other NOS isoforms. However, Nos2tm1Lau mice exhibit enhanced expression of tumor necrosis factor alpha, interleukin-1, and macrophage inflammatory protein 1α compared to that of wild-type mice, and these alterations may in part compensate for the lack of iNOS. These results clearly show that iNOS is not required for control of T. cruzi infection in mice.

HALOTHANE INHIBITS INTERLEUKIN-1 β-STIMULATED INDUCTION OF NITRIC OXIDE SYNTHASE IN VASCULAR SMOOTH MUSCLE

1994 ◽  
Vol 81 (SUPPLEMENT) ◽  
pp. A681
Author(s):  
H. Maeda ◽  
M. Yamamoto ◽  
K. Mizumoto ◽  
T. Yosbiyama ◽  
Y. Hatano
Keyword(s):  
Nitric Oxide ◽  
Smooth Muscle ◽  
Nitric Oxide Synthase ◽  
Vascular Smooth Muscle ◽  
Interleukin 1 ◽  
Oxide Synthase

scholarly journals Effects of Immunomodulatory Substances on Phagocytosis of A by Human Microglia

2010 ◽  
Vol 2010 ◽  
pp. 1-18 ◽  
Author(s):  
Erik Hjorth ◽  
Dan Frenkel ◽  
Howard Weiner ◽  
Marianne Schultzberg
Keyword(s):  
Nitric Oxide ◽  
Membrane Protein ◽  
Inducible Nitric Oxide Synthase ◽  
Inflammatory Markers ◽  
Interleukin 1 ◽  
Type I ◽  
Human Microglia ◽  
Amyloid A ◽  
Oxide Synthase ◽  
Inducible Nitric Oxide

Glial activation and increased inflammation characterize neuropathology in Alzheimer's disease (AD). The aim was to develop a model for studying phagocytosis of -amyloid (A) peptide by human microglia and to test effects thereupon by immunomodulatory substances. Human CHME3 microglia showed intracellular A colocalized with lysosome-associated membrane protein-2, indicating phagocytosis. This was increased by interferon-, and to a lesser degree with Protollin, a proteosome-based adjuvant. Secretion of brain-derived neurotrophic factor (BDNF) was decreased by A and by interferon- and interleukin-1. These cytokines, but not A, stimulated interleukin-6 release. Microglia which phagocytosed A exhibited a higher degree of expression of interleukin-1 receptor type I and inducible nitric oxide synthase. In conclusion, we show that human microglia are able to phagocytose A and that this is associated with expression of inflammatory markers. A and interferon- decreased BDNF secretion suggesting a new neuropathological role for A and the inflammation accompanying AD.

scholarly journals Conditional deletion of cytokine receptor chains reveals that IL-7 and IL-15 specify CD8 cytotoxic lineage fate in the thymus

2012 ◽  
Vol 209 (12) ◽  
pp. 2263-2276 ◽  
Author(s):  
Tom M. McCaughtry ◽  
Ruth Etzensperger ◽  
Amala Alag ◽  
Xuguang Tai ◽  
Sema Kurtulus ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Conditional Knockout ◽  
Cytokine Receptor ◽  
T Cell Subsets ◽  
Cytotoxic T Cell ◽  
Lineage Specification ◽  
Class I Mhc ◽  
Mhc I

The thymus generates T cells with diverse specificities and functions. To assess the contribution of cytokine receptors to the differentiation of T cell subsets in the thymus, we constructed conditional knockout mice in which IL-7Rα or common cytokine receptor γ chain (γc) genes were deleted in thymocytes just before positive selection. We found that γc expression was required to signal the differentiation of MHC class I (MHC-I)–specific thymocytes into CD8+ cytotoxic lineage T cells and into invariant natural killer T cells but did not signal the differentiation of MHC class II (MHC-II)–specific thymocytes into CD4+ T cells, even into regulatory Foxp3+CD4+ T cells which require γc signals for survival. Importantly, IL-7 and IL-15 were identified as the cytokines responsible for CD8+ cytotoxic T cell lineage specification in vivo. Additionally, we found that small numbers of aberrant CD8+ T cells expressing Runx3d could arise without γc signaling, but these cells were developmentally arrested before expressing cytotoxic lineage genes. Thus, γc-transduced cytokine signals are required for cytotoxic lineage specification in the thymus and for inducing the differentiation of MHC-I–selected thymocytes into functionally mature T cells.

scholarly journals Expression of Inducible Nitric Oxide Synthase in Skin Lesions of Patients with American Cutaneous Leishmaniasis

2002 ◽  
Vol 70 (8) ◽  
pp. 4638-4642 ◽  
Author(s):  
Muna Qadoumi ◽  
Inge Becker ◽  
Norbert Donhauser ◽  
Martin Röllinghoff ◽  
Christian Bogdan
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Cutaneous Leishmaniasis ◽  
Leishmania Donovani ◽  
Leishmania Major ◽  
Parasite Burden ◽  
Skin Lesions ◽  
And Function ◽  
Oxide Synthase

ABSTRACT Cytokine-inducible (or type 2) nitric oxide synthase (iNOS) is indispensable for the resolution of Leishmania major or Leishmania donovani infections in mice. In contrast, little is known about the expression and function of iNOS in human leishmaniasis. Here, we show by immunohistological analysis of skin biopsies from Mexican patients with local (LCL) or diffuse (DCL) cutaneous leishmaniasis that the expression of iNOS was most prominent in LCL lesions with small numbers of parasites whereas lesions with a high parasite burden (LCL or DCL) contained considerably fewer iNOS-positive cells. This is the first study to suggest an antileishmanial function of iNOS in human Leishmania infections in vivo.

CD4+ T cells are essential for the development of destructive thyroiditis induced by anti–PD-1 antibody in thyroglobulin-immunized mice

2021 ◽  
Vol 13 (593) ◽  
pp. eabb7495
Author(s):  
Yoshinori Yasuda ◽  
Shintaro Iwama ◽  
Daisuke Sugiyama ◽  
Takayuki Okuji ◽  
Tomoko Kobayashi ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Lymph Nodes ◽  
Mononuclear Cells ◽  
Critical Role ◽  
T Cell Subsets ◽  
Effector Memory ◽  
Histopathological Analysis ◽  
Activated T Cells ◽  
Cervical Lymph Nodes

Immune-related adverse events induced by anti–programmed cell death–1 antibodies (PD-1-Ab), including destructive thyroiditis (thyroid-irAE), are thought to be caused by activated T cells. However, the T cell subsets that are directly responsible for damaging self-organs remain unclear. To clarify which T cell subsets are involved in the development of thyroid-irAE, a mouse model of thyroid-irAE was analyzed. PD-1-Ab administration 2.5 months after immunization with thyroglobulin caused destructive thyroiditis. Thyroiditis was completely prevented by previous depletion of CD4+ T cells and partially prevented by depleting CD8+ T cells. The frequencies of central and effector memory CD4+ T cell subsets and the secretion of interferon-γ after stimulation with thyroglobulin were increased in the cervical lymph nodes of mice with thyroid-irAE compared with controls. Histopathological analysis revealed infiltration of CD4+ T cells expressing granzyme B in thyroid glands and major histocompatibility complex class II expression on thyrocytes in mice with thyroid-irAE. Adoptive transfer of CD4+ T cells from cervical lymph nodes in mice with thyroid-irAE caused destruction of thyroid follicular architecture in the irradiated recipient mice. Flow cytometric analyses showed that the frequencies of central and effector memory CD4+ T cells expressing the cytotoxic marker CD27 were higher in peripheral blood mononuclear cells collected from patients with thyroid-irAE induced by PD-1-Ab versus those without. These data suggest a critical role for cytotoxic memory CD4+ T cells activated by PD-1-Ab in the pathogenesis of thyroid-irAE.

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