Abstract 116: Detrimental Role of Toll-Like Receptor 4 in Cardiovirus-Induced Myocarditis

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Fumitaka Sato ◽  
Seiichi Omura ◽  
Nicholas E Martinez ◽  
Eiichiro Kawai ◽  
Ganta V Chaitanya ◽  
...  
Keyword(s):  
Immune Responses ◽  
Acute Phase ◽  
Viral Entry ◽  
Viral Myocarditis ◽  
Chronic Phase ◽  
Enzyme Linked Immunosorbent Assay ◽  
Tlr4 Ligand ◽  
Ifn Γ ◽  
Deficient Mice

Picornavirus infections have been known as a leading cause of viral myocarditis in humans. Theiler’s murine encephalomyelitis virus (TMEV) belongs to the genus Cardiovirus, the family Picornaviridae and was reported to cause inflammation in the heart in one manuscript, while its pathomechanism is unclear. In viral myocarditis, viral replication in the heart and/or immune responses against virus as well as heart-antigen (autoimmunity) can contribute to the pathogenesis. Toll-like receptors (TLRs) are pattern recognition receptors (PRRs) that are important for recognizing pathogens as well as triggering innate immunity. Among TLRs, TLR4 has been demonstrated to play important roles in virus-mediated pathology: 1) TLR4 can contribute to viral entry in some viruses, 2) TLR4 may mediate tissue damage by anti-virus immune responses (immunopathology), 3) high levels of TLR4 expression were observed in the heart of patients with dilated cardiomyopathy following acute viral myocarditis, and 4) some viruses can bind to lipopolysaccharide (LPS), which is a TLR4 ligand. To determine the role of TLR4 in TMEV-induced myocarditis, we infected male C3H/HeJ (TLR4-deficient) and C3H/HeNtac (control TLR4+) mice with the DA strain of TMEV. We harvested the hearts and spleens on days 6 and 7 (acute phase) or days 63 and 64 (chronic phase) post-infection. Cardiac pathology was evaluated by hematoxylin and eosin staining and production of pro-inflammatory cytokines, interleukin (IL)-17A and interferon (IFN)-γ, from spleen cells was measured by an enzyme-linked immunosorbent assay (ELISA). In both mice, mild myocarditis was observed during the acute phase of TMEV infection. During the chronic phase, both mice developed severe pathology in the heart, including basophilic degeneration and calcification. However, the incidence of myocarditis was higher in control mice than TLR4-deficient mice. IL-17A and IFN-γ production was higher in control mice than in TLR4-deficient mice (control vs. TLR4-deficient mice, acute phase: IL-17A, 196 vs. 146 pg/ml; IFN-γ, 72 vs. 39 ng/ml; chronic phase: IL-17A, 290 vs. 229 pg/ml; IFN- γ, 142 vs. 88 ng/ml). These results suggest that TLR4 may be detrimental in TMEV-induced myocarditis by increasing pro-inflammatory cytokine production.

Abstract 039: Natural Killer T Cells Play Protective Roles in Cardiovirus-Induced Myocarditis by Inducing Anti-Viral and Regulatory Cytokines

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Fumitaka Sato ◽  
Seiichi Omura ◽  
Nicholas E Martinez ◽  
Eiichiro Kawai ◽  
Sadie F Pearson ◽  
...  
Keyword(s):  
Natural Killer ◽  
Acute Phase ◽  
Viral Myocarditis ◽  
Chronic Phase ◽  
Nkt Cells ◽  
Viral Clearance ◽  
Left Ventricular Ejection ◽  
Ifn Γ ◽  
Anti Inflammatory ◽  
Natural Killer T

Picornavirus infections have been known as a leading cause of viral myocarditis in humans. Theiler’s murine encephalomyelitis virus (TMEV) belongs to the genus Cardiovirus, the family Picornaviridae, and can cause myocarditis in susceptible mice. In viral myocarditis, viral replication in the heart and/or immune responses against virus as well as cardiac antigens (autoimmunity) can contribute to the pathogenesis. Natural killer T (NKT) cells can play a regulatory role in viral infections by producing anti-viral and anti-inflammatory cytokines; interferon (IFN)-γ can contribute to either viral clearance or tissue damage (immunopathology), while anti-inflammatory interleukin (IL)-10 has been suggested to regulate viral clearance or immunopathology. To determine the role of NKT cells in TMEV-induced myocarditis, we infected wild-type (WT) and NKT knockout (NKT KO, Jα18 KO) mice with TMEV. Myocarditis was monitored by echocardiography using the Vevo 770 system. During the acute (day 7) or chronic phase (day 60) of TMEV infection, cardiac pathology was evaluated by hematoxylin and eosin staining, and production of cytokines, including IFN-γ and IL-10, from spleen cells was measured by enzyme-linked immunosorbent assays. During the acute phase, the levels of left ventricular ejection fraction were significantly lower in NKT KO mice than in WT mice. Immunologically, NKT KO mice had lower levels of IFN-γ production than WT mice [IFN-γ (pg/ml): WT, 768 ± 533; NKT KO, 293 ± 190]. During the chronic phase, high intensity cardiac lesions were observed by echocardiography in NKT KO mice, but not in WT mice. Histologically, NKT KO mice developed moderate inflammation with basophilic degeneration and calcification in the heart, while WT mice had only mild inflammation in the heart. Immunologically, NKT KO mice had lower levels of IL-10 production compared with WT mice [IL-10 (pg/ml): WT, 1771 ± 381; NKT KO, 1199 ± 160]. These results suggest that NKT cells play a protective role in viral myocarditis by producing IFN-γ and IL-10, which contribute to viral clearance during the acute phase and the suppression of immunopathology during the chronic phase of disease, respectively.

scholarly journals Role of Interleukin-4 (IL-4), IL-12, and Gamma Interferon in Primary and Vaccine-Primed Immune Responses to Friend Retrovirus Infection

2001 ◽  
Vol 75 (2) ◽  
pp. 654-660 ◽  
Author(s):  
Ulf Dittmer ◽  
Karin E. Peterson ◽  
Ron Messer ◽  
Ingunn M. Stromnes ◽  
Brent Race ◽  
...  
Keyword(s):  
Immune Responses ◽  
Gamma Interferon ◽  
Immunoglobulin M ◽  
Friend Virus ◽  
T Helper ◽  
Friend Retrovirus ◽  
Ifn Γ ◽  
Deficient Mice ◽  
Helper Type

ABSTRACT The immunological resistance of a host to viral infections may be strongly influenced by cytokines such as interleukin-12 (IL-12) and gamma interferon (IFN-γ), which promote T helper type 1 responses, and IL-4, which promotes T helper type 2 responses. We studied the role of these cytokines during primary and secondary immune responses against Friend retrovirus infections in mice. IL-4- and IL-12-deficient mice were comparable to wild-type B6 mice in the ability to control acute and persistent Friend virus infections. In contrast, more than one-third of the IFN-γ-deficient mice were unable to maintain long-term control of Friend virus and developed gross splenomegaly with high virus loads. Immunization with a live attenuated vaccine virus prior to challenge protected all three types of cytokine-deficient mice from viremia and high levels of spleen virus despite the finding that the vaccinated IFN-γ-deficient mice were unable to class switch from immunoglobulin M (IgM) to IgG virus-neutralizing antibodies. The results indicate that IFN-γ plays an important role during primary immune responses against Friend virus but is dispensable during vaccine-primed secondary responses.

scholarly journals Cytokines and T-Lymphocute count in patients in the acute and chronic phases of Bartonella bacilliformis infection in an endemic area in peru: a pilot study

2011 ◽  
Vol 53 (3) ◽  
pp. 149-154 ◽  
Author(s):  
Erick Huarcaya ◽  
Ivan Best ◽  
Juan Rodriguez-Tafur ◽  
Ciro Maguiña ◽  
Nelson Solórzano ◽  
...  
Keyword(s):  
Pilot Study ◽  
Acute Phase ◽  
Chronic Phase ◽  
Peripheral Tolerance ◽  
Bartonella Bacilliformis ◽  
Cross Sectional ◽  
Bacillary Angiomatosis ◽  
Cd8 T Lymphocyte ◽  
Ifn Γ ◽  
Anti Inflammatory Cytokine

Human Bartonellosis has an acute phase characterized by fever and hemolytic anemia, and a chronic phase with bacillary angiomatosis-like lesions. This cross-sectional pilot study evaluated the immunology patterns using pre- and post-treatment samples in patients with Human Bartonellosis. Patients between five and 60 years of age, from endemic areas in Peru, in the acute or chronic phases were included. In patients in the acute phase of Bartonellosis a state of immune peripheral tolerance should be established for persistence of the infection. Our findings were that elevation of the anti-inflammatory cytokine IL-10 and numeric abnormalities of CD4+ and CD8+ T-Lymphocyte counts correlated significantly with an unfavorable immune state. During the chronic phase, the elevated levels of IFN-γ and IL-4 observed in our series correlated with previous findings of endothelial invasion of B. henselae in animal models.

scholarly journals Gamma Interferon Produced by Antigen-Specific CD4+ T Cells Regulates the Mucosal Immune Responses to Citrobacter rodentium Infection

2010 ◽  
Vol 78 (6) ◽  
pp. 2653-2666 ◽  
Author(s):  
Hideyuki Shiomi ◽  
Atsuhiro Masuda ◽  
Shin Nishiumi ◽  
Masayuki Nishida ◽  
Tetsuya Takagawa ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Responses ◽  
Gamma Interferon ◽  
Immune Defense ◽  
Interleukin 4 ◽  
Mucosal Inflammation ◽  
Citrobacter Rodentium ◽  
Macrophage Phagocytosis ◽  
Ifn Γ ◽  
Deficient Mice

ABSTRACT Citrobacter rodentium, a murine model pathogen for enteropathogenic Escherichia coli, colonizes the surface of intestinal epithelial cells and causes mucosal inflammation. This bacterium is an ideal model for investigating pathogen-host immune interactions in the gut. It is well known that gene transcripts for Th1 cytokines are highly induced in colonic tissue from mice infected with C. rodentium. However, it remains to be seen whether the Th1 or Th2 cytokines produced by antigen-specific CD4+ T cells provide effective regulation of the host immune defense against C. rodentium infection. To investigate the antigen-specific immune responses, C. rodentium expressing ovalbumin (OVA-C. rodentium), a model antigen, was generated and used to define antigen-specific responses under gamma interferon (IFN-γ)-deficient or interleukin-4 (IL-4)-deficient conditions in vivo. The activation of antigen-specific CD4+ T cells and macrophage phagocytosis were evaluated in the presence of IFN-γ or IL-4 in vitro. IFN-γ-deficient mice exhibited a loss of body weight and a higher bacterial concentration in feces during OVA-C. rodentium infection than C57BL/6 (wild type) or IL-4-deficient mice. This occurred through the decreased efficiency of macrophage phagocytosis and the activation of antigen-specific CD4+ T cells. Furthermore, a deficiency in antigen-specific CD4+ T-cell-expressed IFN-γ led to a higher susceptibility to mucosal and gut-derived systemic OVA-C. rodentium infection. These results show that the IFN-γ produced by antigen-specific CD4+ T cells plays an important role in the defense against C. rodentium.

Role of kallikrein-kinin system in pathogenesis of bacterial cell wall-induced inflammation

1991 ◽  
Vol 260 (2) ◽  
pp. G213-G219 ◽  
Author(s):  
R. A. DeLa Cadena ◽  
K. J. Laskin ◽  
R. A. Pixley ◽  
R. B. Sartor ◽  
J. H. Schwab ◽  
...  
Keyword(s):  
Cell Wall ◽  
Acute Phase ◽  
Bacterial Cell ◽  
Chronic Phase ◽  
Bacterial Cell Wall ◽  
Kinin System ◽  
Kallikrein Kinin System ◽  
Bacterial Products

The plasma kallikrein-kinin system is activated in Gram-negative sepsis and typhoid fever, two diseases in which bacterial products have been shown to initiate inflammation. Because a single intraperitoneal injection of bacterial cell wall peptidoglycan-polysaccharide polymers from group A steptococci (PG-APS) into a Lewis rat produces a syndrome of relapsing polyarthritis and anemia, we investigated changes in the role of the kallikrein-kinin system in this model of inflammation. Coagulation studies after injection of PG-APS revealed an immediate and persistent decrease in prekallikrein levels. High-molecular-weight kininogen levels decreased significantly during the acute phase and correlated with the severity of arthritis. Factor XI levels were decreased only during the acute phase. Antithrombin III levels remained unchanged, indicating that neither decreased hepatic synthesis nor disseminated intravascular coagulation caused the decreased plasma contact factors. Plasma T-kininogen (an acute phase protein) was significantly elevated during the chronic phase. PG-APS failed to activate the contact system in vitro. Thus the kallikrein-kinin system plays an important role in this experimental model of inflammation, suggesting that activation of this system may play a role in the pathogenesis of inflammatory bowel disease and rheumatoid arthritis in which bacterial products might be etiologically important.

scholarly journals The Role of Vitamin D and Vitamin D Receptor in Immunity toLeishmania majorInfection

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
James P. Whitcomb ◽  
Mary DeAgostino ◽  
Mark Ballentine ◽  
Jun Fu ◽  
Martin Tenniswood ◽  
...  
Keyword(s):  
Vitamin D ◽  
Immune Responses ◽  
Vitamin D Receptor ◽  
Leishmania Major ◽  
Active Form ◽  
Wild Type ◽  
Vitamin D Signaling ◽  
Deficient Mice ◽  
Th 1

Vitamin D signaling modulates a variety of immune responses. Here, we assessed the role of vitamin D in immunity to experimental leishmaniasis infection in vitamin D receptor-deficient mice (VDRKO). We observed that VDRKO mice on a genetically resistant background have decreasedLeishmania major-induced lesion development compared to wild-type (WT) mice; additionally, parasite loads in infected dermis were significantly lower at the height of infection. Enzymatic depletion of the active form of vitamin D mimics the ablation of VDR resulting in an increased resistance toL. major. Conversely, VDRKO or vitamin D-deficient mice on the susceptible Th2-biased background had no change in susceptibility. These studies indicate vitamin D deficiency, either through the ablation of VDR or elimination of its ligand, 1,25D3, leads to an increase resistance toL. majorinfection but only in a host that is predisposed for Th-1 immune responses.

scholarly journals Correlation of Cellular Immune Responses with Protection against Culture-Confirmed Influenza Virus in Young Children

2008 ◽  
Vol 15 (7) ◽  
pp. 1042-1053 ◽  
Author(s):  
Bruce D. Forrest ◽  
Michael W. Pride ◽  
Andrew J. Dunning ◽  
Maria Rosario Z. Capeding ◽  
Tawee Chotpitayasunondh ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Young Children ◽  
Immune Responses ◽  
Virus Vaccine ◽  
Elispot Assay ◽  
Influenza Virus Vaccine ◽  
The Philippines ◽  
Influenza Viruses ◽  
Ifn Γ

ABSTRACT The highly sensitive gamma interferon (IFN-γ) enzyme-linked immunosorbent spot (ELISPOT) assay permits the investigation of the role of cell-mediated immunity (CMI) in the protection of young children against influenza. Preliminary studies of young children confirmed that the IFN-γ ELISPOT assay was a more sensitive measure of influenza memory immune responses than serum antibody and that among seronegative children aged 6 to <36 months, an intranasal dose of 107 fluorescent focus units (FFU) of a live attenuated influenza virus vaccine (CAIV-T) elicited substantial CMI responses. A commercial inactivated influenza virus vaccine elicited CMI responses only in children with some previous exposure to related influenza viruses as determined by detectable antibody levels prevaccination. The role of CMI in actual protection against community-acquired, culture-confirmed clinical influenza by CAIV-T was investigated in a large randomized, double-blind, placebo-controlled dose-ranging efficacy trial with 2,172 children aged 6 to <36 months in the Philippines and Thailand. The estimated protection curve indicated that the majority of infants and young children with ≥100 spot-forming cells/106 peripheral blood mononuclear cells were protected against clinical influenza, establishing a possible target level of CMI for future influenza vaccine development. The ELISPOT assay for IFN-γ is a sensitive and reproducible measure of CMI and memory immune responses and contributes to establishing requirements for the future development of vaccines against influenza, especially those used for children.

scholarly journals Potential Role of the Chemokine Macrophage Inflammatory Protein 1α in Human and Experimental Schistosomiasis

2005 ◽  
Vol 73 (4) ◽  
pp. 2515-2523 ◽  
Author(s):  
Adriano L. S. Souza ◽  
Ester Roffê ◽  
Vanessa Pinho ◽  
Danielle G. Souza ◽  
Adriana F. Silva ◽  
...  
Keyword(s):  
Potential Role ◽  
Severe Disease ◽  
Experimental Studies ◽  
Interleukin 4 ◽  
Enzyme Linked Immunosorbent Assay ◽  
Inflammatory Protein ◽  
Macrophage Inflammatory Protein ◽  
Deficient Mice

ABSTRACT In human schistosomiasis, the concentrations of the chemokine macrophage inflammatory protein 1α (MIP-1α/CCL3) is greater in the plasma of patients with clinical hepatosplenic disease. The objective of the present study was to confirm the ability of CCL3 to detect severe disease in patients classified by ultrasonography (US) and to evaluate the potential role of CCL3 in Schistosoma mansoni-infected mice. CCL3 was measured by enzyme-linked immunosorbent assay in the plasma of S. mansoni-infected patients. CCL3-deficient mice were infected with 25 cercariae, and various inflammatory and infectious indices were evaluated. The concentration of CCL3 was higher in the plasma of S. mansoni-infected than noninfected patients. Moreover, CCL3 was greater in those with US-defined hepatosplenic than with the intestinal form of the disease. In CCL3-deficient mice, the size of the granuloma and the liver eosinophil peroxidase activity and collagen content were diminished compared to wild-type mice. In CCL3-deficient mice, the worm burden after 14 weeks of infection, but not after 9 weeks, was consistently smaller. The in vitro response of mesenteric lymph node cells to antigen stimulation was characterized by lower levels of interleukin-4 (IL-4) and IL-10. CCL3 is a marker of disease severity in infected humans, and experimental studies in mice suggest that CCL3 may be a causative factor in the development of severe schistosomiasis.

scholarly journals Aberrant Contraction of Antigen-Specific CD4 T Cells after Infection in the Absence of Gamma Interferon or Its Receptor

2006 ◽  
Vol 74 (11) ◽  
pp. 6252-6263 ◽  
Author(s):  
Jodie S. Haring ◽  
John T. Harty
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Interleukin 2 ◽  
Gamma Interferon ◽  
Model Systems ◽  
Important Regulator ◽  
Ifn Γ ◽  
And Function ◽  
Deficient Mice

ABSTRACT Several lines of evidence from different model systems suggest that gamma interferon (IFN-γ) is an important regulator of T-cell contraction after antigen (Ag)-driven expansion. To specifically investigate the role of IFN-γ in regulating the contraction of Ag-specific CD4 T cells, we infected IFN-γ−/− and IFN-γR1−/− mice with attenuated Listeria monocytogenes and monitored the numbers of Ag-specific CD4 T cells during the expansion, contraction, and memory phases of the immune response to infection. In the absence of IFN-γ or the ligand-binding portion of its receptor, Ag-specific CD4 T cells exhibited normal expansion in numbers, but in both strains of deficient mice there was very little decrease in the number of Ag-specific CD4 T cells even at time points later than day 90 after infection. This significant delay in contraction was not due to prolonged infection, since mice treated with antibiotics to conclusively eliminate infection exhibited the same defect in contraction. In addition to altering the number of Ag-specific CD4 T cells, the absence of IFN-γ signaling also changed the phenotype of cells generated after infection. IFN-γR1−/− Ag-specific CD4 T cells reacquired expression of CD127 more quickly than wild-type cells, and more IFN-γR1−/− CD4 T cells were capable of producing both IFN-γ and interleukin 2 following Ag stimulation. From these data we conclude that IFN-γ regulates the contraction, phenotype, and function of Ag-specific CD4 T cells generated after infection.

scholarly journals Role of Interferon-Gamma (Ifn-γ) in Immune Response Regulation in Hiv-1 and Hiv-1 + Mycobacterium Tuberculosis (Tb) Infected Patients / Interferona-gamma (Ifn-γ) Loma Imūnās Atbildes Regulēšanā Pacientiem Ar HIV-1 un HIV-1 + mycobacterium Tuberculosis

2016 ◽  
Vol 70 (4) ◽  
pp. 211-214
Author(s):  
Inga Januškevica ◽  
Baiba Rozentāle ◽  
Elvīra Hagina ◽  
Jeīena Eglīte ◽  
Tatjana Kolupajeva ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Viral Load ◽  
University Hospital ◽  
Enzyme Linked Immunosorbent Assay ◽  
Cell Counts ◽  
Cd4 Cell Counts ◽  
Ifn Γ ◽  
Cd4 Cell ◽  
Hiv 1

Abstract The aim of this research was to investigate the role of IFN-γ in interaction between IL-10, IL-18, IL-1b, CD4 cell counts and HIV-1 RNA viral load in the development of HIV-1 in patients co-infected with Mycobacterium tuberculosis (TB). The study was conducted by Rīga East Clinical University Hospital with data from the HIV-1 register, in collaboration with the RSU Joint Laboratory of Clinical Immunology and Immunogenetics. 200 HIV-1 infected patients and 184 HIV-1 with TB co-infection patients divided in four groups were included in the study. IFN-γ, IL-10, IL-18, IL-1b levels were measured in serum with commercially enzyme-linked immunosorbent assay (ELISA Vector-Best Corporation, Novosibirsk, Russia). CD4 cell counts were measured by flow Partec IVD cytometry (USA). HIV-1 RNA quantification was performed using the COBAS AmpliPrep/COBAS Taqman HIV-1 Test (Germany). All groups were compared with each another. IFN-γ production was significantly lower, and IL-10 and CD4 cell counts were significantly higher, in HIV-1 patients without TB compared with the other groups. The group with HIV-1 and TB had significantly elevated IL-18 production. HIV patients with primary TB had significantly elevated IFN-γ production and HIV-1 RNA viral load and significantly lower IL-10 production.

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