scholarly journals Aberrant type 1 immunity drives susceptibility to mucosal fungal infections

Science ◽  
2021 ◽  
Vol 371 (6526) ◽  
pp. eaay5731
Author(s):  
Timothy J. Break ◽  
Vasileios Oikonomou ◽  
Nicolas Dutzan ◽  
Jigar V. Desai ◽  
Marc Swidergall ◽  
...  
Keyword(s):  
Fungal Infection ◽  
Fungal Infections ◽  
Interferon Γ ◽  
Janus Kinase ◽  
Mucosal Inflammation ◽  
Systemic Fungal Infection ◽  
Monogenic Disorders ◽  
Infection Susceptibility ◽  
Ifn Γ

Human monogenic disorders have revealed the critical contribution of type 17 responses in mucosal fungal surveillance. We unexpectedly found that in certain settings, enhanced type 1 immunity rather than defective type 17 responses can promote mucosal fungal infection susceptibility. Notably, in mice and humans with AIRE deficiency, an autoimmune disease characterized by selective susceptibility to mucosal but not systemic fungal infection, mucosal type 17 responses are intact while type 1 responses are exacerbated. These responses promote aberrant interferon-γ (IFN-γ)– and signal transducer and activator of transcription 1 (STAT1)–dependent epithelial barrier defects as well as mucosal fungal infection susceptibility. Concordantly, genetic and pharmacologic inhibition of IFN-γ or Janus kinase (JAK)–STAT signaling ameliorates mucosal fungal disease. Thus, we identify aberrant T cell–dependent, type 1 mucosal inflammation as a critical tissue-specific pathogenic mechanism that promotes mucosal fungal infection susceptibility in mice and humans.

scholarly journals Role of Vitamin D in Premature Atherosclerosis in Adolescents Type 1 Diabetes through Transforming Growth Factor-β1, Interferon-γ, Interleukin-10, and Interleukin-17

2020 ◽  
Vol 8 (B) ◽  
pp. 738-746
Author(s):  
Haryudi Aji Cahyono ◽  
Wisnu Barlianto ◽  
Dian Handayani ◽  
Handono Kalim
Keyword(s):  
Vitamin D ◽  
Type 1 Diabetes ◽  
Transforming Growth Factor ◽  
Interleukin 10 ◽  
Interferon Γ ◽  
Transforming Growth Factor Β1 ◽  
Premature Atherosclerosis ◽  
Ifn Γ ◽  
Tgf Β1

BACKGROUND: Cardiovascular disease (CVD) is one the cause of mortality in patients with type 1 diabetes (T1D). The development of CVD is mainly triggered by atherosclerosis, which is associated with the inflammatory process. AIM: The current study was aimed to investigate the association of Vitamin D level and premature atherosclerosis in adolescents with T1D, mainly through the regulation of various cytokines (interferon-γ [IFN-γ], IL-17, interleukin-10 [IL-10], and transforming growth factor-β1 [TGF-β1]). METHODS: This study was designed as a cross-sectional study involving 40 T1D and 40 healthy control who came to the outpatient clinic, Saiful Anwar Hospital, Malang, Indonesia, within the study period (January 2019-July 2019). RESULTS: Our data demonstrated that the IFN-γ and IL-17 levels were significantly higher (p < 0.001), whereas the TGF-β1 and IL-10 levels were significantly lower (p < 0.001) in T1D group compared with control. Furthermore, T1D also has higher carotid intima-media thickness (cIMT) value and lower flow-mediated dilatation (FMD) value compared to the control group (p < 0.001). Level of 25(OH)D3 was strongly associated with reduced cIMT and elevated FMD (p < 0.005). The direct effect of 25(OH)D3 on cIMT and FMD was higher than the indirect effect of Vitamin D through TGF-β1, IL-10, IL-17, and IFN-γ. The cutoff value of 25(OH)D3 levels for the risk of atherosclerosis was 12.8 ng/dL (sensitivity 85.7% and specificity 86.7%). CONCLUSION: The level of Vitamin D in the T1D group was significantly lower than those in healthy children and Vitamin D deficiency substantially influences the formation of premature atherosclerosis.

scholarly journals Itraconazole Oral Solution for Primary Prophylaxis of Fungal Infections in Patients with Hematological Malignancy and Profound Neutropenia: a Randomized, Double-Blind, Double-Placebo, Multicenter Trial Comparing Itraconazole and Amphotericin B

2000 ◽  
Vol 44 (7) ◽  
pp. 1887-1893 ◽  
Author(s):  
J. L. Harousseau ◽  
A. W. Dekker ◽  
A. Stamatoullas-Bastard ◽  
A. Fassas ◽  
W. Linkesch ◽  
...  
Keyword(s):  
Fungal Infection ◽  
Invasive Aspergillosis ◽  
Amphotericin B ◽  
Hematological Malignancy ◽  
Fungal Infections ◽  
Treated Group ◽  
Multicenter Trial ◽  
Oral Solution ◽  
Double Blind ◽  
Systemic Fungal Infection

ABSTRACT Systemic and superficial fungal infections are a major problem among immunocompromised patients with hematological malignancy. A double-blind, double-placebo, randomized, multicenter trial was performed to compare the efficacy and safety of itraconazole oral solution (2.5 mg/kg of body weight twice a day) with amphotericin B capsules (500 mg orally four times a day) for prophylaxis of systemic and superficial fungal infection. Prophylactic treatment was initiated on the first day of chemotherapy and was continued until the end of the neutropenic period (>0.5 × 109 neutrophils/liter) or up to a maximum of 3 days following the end of neutropenia, unless a systemic fungal infection was documented or suspected. The maximum treatment duration was 56 days. In the intent-to-treat population, invasive aspergillosis was noted in 5 (1.8%) of the 281 patients assigned to itraconazole oral solution and in 9 (3.3%) of the 276 patients assigned to oral amphotericin B; of these, 1 and 4 patients died, respectively. Proven systemic fungal infection (including invasive aspergillosis) occurred in 8 patients (2.8%) who received itraconazole, compared with 13 (4.7%) who received oral amphotericin B. Itraconazole significantly reduced the incidence of superficial fungal infections as compared to oral amphotericin B (2 [1%] versus 13 [5%]; P = 0.004). Although the incidences of suspected fungal infection (including fever of unknown origin) were not different between the groups, fewer patients were administered intravenous systemic antifungals (mainly intravenous amphotericin B) in the group receiving itraconazole than in the group receiving oral amphotericin B (114 [41%] versus 132 [48%];P = 0.066). Adequate plasma itraconazole levels were achieved in about 80% of the patients from 1 week after the start of treatment. In both groups, the trial medication was safe and well tolerated. Prophylactic administration of itraconazole oral solution significantly reduces superficial fungal infection in patients with hematological malignancies and neutropenia. The incidence of proven systemic fungal infections, the number of deaths due to deep fungal infections, and the use of systemic antifungals tended to be lower in the itraconazole-treated group than in the amphotericin B-treated group, without statistical significance. Itraconazole oral solution is a broad-spectrum systemic antifungal agent with prophylactic activity in neutropenic patients, especially for those at high risk of prolonged neutropenia.

scholarly journals T helper type 1–specific Brg1 recruitment and remodeling of nucleosomes positioned at the IFN-γ promoter are Stat4 dependent

2006 ◽  
Vol 203 (6) ◽  
pp. 1493-1505 ◽  
Author(s):  
Fuping Zhang ◽  
Mark Boothby
Keyword(s):  
Interferon Γ ◽  
T Cell Differentiation ◽  
T Helper ◽  
Nucleosome Remodeling ◽  
Specific Manner ◽  
Ifn Γ ◽  
Calcineurin Phosphatase ◽  
Th2 Differentiation ◽  
Early Recruitment

Transcriptional competence of the interferon-γ (IFN-γ) locus is enhanced as Th1 effectors develop from naive CD4 T lymphocytes; conversely, this gene is repressed during Th2 differentiation. We now show that the Switch (Swi)–sucrose nonfermenter (SNF) component Brahma-related gene 1 (Brg1) is recruited, and positioned nucleosomes are remodeled, in a Th1-specific manner that is dependent on the transcription factor Stat4 and calcineurin phosphatase activity. Interference with specific components of mammalian Swi–SNF complexes decreased CD4 T cell differentiation into IFN-γ–positive Th1 cells. These findings reveal a collaborative mechanism of IFN-γ gene regulation during Th1 differentiation and suggest that a Th1-specific chromatin structure is created by early recruitment of Swi–SNF complexes and nucleosome remodeling dependent on Stat4 and calcineurin activation.

scholarly journals Natural killer T-cell autoreactivity leads to a specialized activation state

Blood ◽  
2008 ◽  
Vol 112 (10) ◽  
pp. 4128-4138 ◽  
Author(s):  
Xiaohua Wang ◽  
Xiuxu Chen ◽  
Lance Rodenkirch ◽  
William Simonson ◽  
Sarah Wernimont ◽  
...  
Keyword(s):  
Natural Killer ◽  
Mapk Pathway ◽  
Nkt Cells ◽  
Interferon Γ ◽  
Janus Kinase ◽  
Mitogen Activated Protein Kinase ◽  
Calcium Flux ◽  
Nkt Cell ◽  
Ifn Γ ◽  
Natural Killer T

Abstract Natural killer T (NKT) cells are innate-like T cells that recognize specific microbial antigens and also display autoreactivity to self-antigens. The nature of NKT-cell autoreactive activation remains poorly understood. We show here that the mitogen-activated protein kinase (MAPK) pathway is operative during human NKT-cell autoreactive activation, but calcium signaling is severely impaired. This results in a response that is biased toward granulocyte macrophage colony-stimulating factor (GM-CSF) secretion because this cytokine requires extracellular signal-regulated kinase (ERK) signaling but is not highly calcium dependent, whereas interferon-γ (IFN-γ), interleukin (IL)–4, and IL-2 production are minimal. Autoreactive activation was associated with reduced migration velocity but did not induce arrest; thus, NKT cells retained the ability to survey antigen presenting cells (APCs). IL-12 and IL-18 stimulated autoreactively activated NKT cells to secrete IFN-γ, and this was mediated by Janus kinase-signal transducers and activators of transcription (JAK-STAT)–dependent signaling without induction of calcium flux. This pathway did not require concurrent contact with CD1d+ APCs but was strictly dependent on preceding autoreactive stimulation that induced ERK activation. In contrast, NKT-cell responses to the glycolipid antigen α-galactosyl ceramide (α-GalCer) were dampened by prior autoreactive activation. These results show that NKT-cell autoreactivity induces restricted cytokine secretion and leads to altered basal activation that potentiates innate responsiveness to costimulatory cytokines while modulating sensitivity to foreign antigens.

Jak1 deficiency leads to enhanced Abelson-induced B-cell tumor formation

Blood ◽  
2003 ◽  
Vol 101 (12) ◽  
pp. 4937-4943 ◽  
Author(s):  
Veronika Sexl ◽  
Boris Kovacic ◽  
Roland Piekorz ◽  
Richard Moriggl ◽  
Dagmar Stoiber ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lines ◽  
Interferon Γ ◽  
Tumor Formation ◽  
Scid Mice ◽  
Janus Kinase ◽  
Interferon Α ◽  
Ifn Γ ◽  
Transformed Cell Lines

AbstractThe Janus kinase Jak1 has been implicated in tumor formation by the Abelson oncogene. In this study we show that loss of Jak1 does not affect in vitro transformation by v-abl as defined by the ability to induce cytokine-independent B-cell colony formation or establishment of B-cell lines. However, Jak1-deficient, v-abl–transformed cell lines were more tumorgenic than wild-type cells when transplanted subcutaneously into severe combined immunodeficient (SCID) mice or injected intravenously into nude mice. Jak1 deficiency was associated with a loss in the ability of interferon-γ (IFN-γ)to induce growth arrest and/or apoptosis of v-abl–transformed pre-B cells or tumor growth in SCID mice. Moreover, IFN-γ mRNA could be detected in growing tumors, and tumor cells explanted from SCID mice had lost the ability to respond to IFN-γ in 9 of 20 cases, whereas the response to interferon-α (IFN-α) remained intact. Importantly, a similar increase in tumorgenicity was observed when IFN-γ–deficient cells were injected into SCID mice, identifying the tumor cell itself as the main source of IFN-γ. These findings demonstrate that Jak1, rather than promoting tumorgenesis as previously proposed, is critical in mediating an intrinsic IFN-γ–dependent tumor surveillance.

scholarly journals Interferon γ Stabilizes the T Helper Cell Type 1 Phenotype

2001 ◽  
Vol 194 (2) ◽  
pp. 165-172 ◽  
Author(s):  
Yongkang Zhang ◽  
Ron Apilado ◽  
John Coleman ◽  
Shlomo Ben-Sasson ◽  
Sharon Tsang ◽  
...  
Keyword(s):  
Critical Role ◽  
Interferon Γ ◽  
T Helper Cell ◽  
Helper Cell ◽  
Wild Type ◽  
T Helper ◽  
Helper Cell Type ◽  
Ifn Γ ◽  
Th 1

T helper cell (Th)1-primed CD4 T cells from wild-type donors make little interleukin (IL)-4 when restimulated under Th2 conditions. However, such restimulation of Th1-primed cells from interferon (IFN)-γ2/− or IFN-γ receptor (IFN-γR)−/− mice resulted in substantial production of IL-4 and other Th2 cytokines. Adding IFN-γ to the priming culture markedly diminished the capacity of Th1-primed IFN-γ2/− cells to express IL-4. Even IFN-γ–producing cells from IFN-γR−/− mice could acquire IL-4–producing capacity. Thus, IFN-γ is not required for the development of IFN-γ–producing capacity, but it plays a critical role in suppressing the IL-4–producing potential of Th1 cells.

scholarly journals Expression of Cd28 and Cd86 by Human Eosinophils and Role in the Secretion of Type 1 Cytokines (Interleukin 2 and Interferon γ)

1999 ◽  
Vol 190 (4) ◽  
pp. 487-496 ◽  
Author(s):  
Gaëtane Woerly ◽  
Nadine Roger ◽  
Sylvie Loiseau ◽  
David Dombrowicz ◽  
André Capron ◽  
...  
Keyword(s):  
Costimulatory Molecule ◽  
Interleukin 2 ◽  
Interferon Γ ◽  
Biologically Active ◽  
Immunoregulatory Cytokines ◽  
Type 2 Cytokines ◽  
Ifn Γ ◽  
Blood Eosinophils

Eosinophils are the source of various immunoregulatory cytokines, but the membrane molecules involved in their secretion have not been clearly identified. Here we show that peripheral blood eosinophils from hypereosinophilic patients could express membrane CD86 but not CD80. The T cell costimulatory molecule CD28 is also detected on the eosinophil surface. CD28 ligation but not CD86 ligation resulted in interleukin (IL)-2 and interferon (IFN)-γ secretion by eosinophils, whereas IL-4, IL-5, and IL-10 were not detected. In contrast to T cells requiring two signals for effective stimulation, CD28 ligation alone was sufficient for optimal eosinophil activation. Eosinophil-derived IL-2 and IFN-γ were biologically active, as supernatants from anti-CD28–treated cells were able to induce CTLL-2 proliferation and major histocompatibility complex class II expression on the colon carcinoma cell line Colo 205, respectively. Addition of secretory immunoglobulin (Ig)A–anti-IgA complexes, which could induce the release of IL-10, very significantly inhibited both CD28-mediated IL-2 and IFN-γ release. These results suggest that the release of type 1 (IFN-γ and IL-2) versus type 2 cytokines by eosinophils is not only differential but also dependent on cross-regulatory signals. They confirm that through activation of costimulatory molecules, eosinophils could function as an immunoregulatory cell involved in the release of both type 1 and type 2 cytokines.

scholarly journals Human Cytomegalovirus Inhibits Major Histocompatibility Complex Class II Expression By Disruption of the Jak/Stat Pathway

1998 ◽  
Vol 187 (5) ◽  
pp. 675-683 ◽  
Author(s):  
Daniel M. Miller ◽  
Brian M. Rahill ◽  
Jeremy M. Boss ◽  
Michael D. Lairmore ◽  
Joan E. Durbin ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Mhc Class Ii ◽  
Human Cytomegalovirus ◽  
Laboratory Strain ◽  
Class Ii ◽  
Interferon Γ ◽  
Janus Kinase ◽  
Mobility Shift ◽  
Ifn Γ ◽  
Stat Pathway

Human cytomegalovirus (HCMV) is a ubiquitous herpesvirus that is able to persist for decades in its host. HCMV has evolved protean countermeasures for anti-HCMV cellular immunity that facilitate establishment of persistence. Recently it has been shown that HCMV inhibits interferon γ (IFN-γ)–stimulated MHC class II expression, but the mechanism for this effect is unknown. IFN-γ signal transduction (Jak/Stat pathway) and class II transactivator (CIITA) are required components for IFN-γ–stimulated MHC class II expression. In this study, we demonstrate that both a clinical isolate and a laboratory strain of HCMV inhibit inducible MHC class II expression at the cell surface and at RNA level in human endothelial cells and fibroblasts. Moreover, reverse transcriptase polymerase chain reaction and Northern blot analyses demonstrate that neither CIITA nor interferon regulatory factor 1 are upregulated in infected cells. Electrophoretic mobility shift assays reveal a defect in IFN-γ signal transduction, which was shown by immunoprecipitation to be associated with a striking decrease in Janus kinase 1 (Jak1) levels. Proteasome inhibitor studies with carboxybenzyl-leucyl-leucyl-leucine vinyl sulfone suggest an HCMV-associated enhancement of Jak1 protein degradation. This is the first report of a mechanism for the HCMV-mediated disruption of inducible MHC class II expression and a direct virus-associated alteration in Janus kinase levels. These findings are yet another example of the diverse mechanisms by which HCMV avoids immunosurveillance and establishes persistence.

Liraglutide Exerts Potential Anti-inflammatory Effect in Type 1 Diabetes by Inhibiting IFN-γ Production via Suppressing JAK-STAT Pathway

2019 ◽  
Vol 19 (5) ◽  
pp. 656-664
Author(s):  
Yunjuan Zhao ◽  
Yunliang Xie ◽  
Wangen Li
Keyword(s):  
Type 1 Diabetes ◽  
Signaling Pathway ◽  
Interferon Γ ◽  
Janus Kinase ◽  
Janus Kinase 2 ◽  
Signal Transducers ◽  
High Glucose Condition ◽  
Glucose Condition ◽  
Signal Transducers And Activators

Background: Type 1 diabetes is a T cell-mediated autoimmune disease. Interferon γ plays a critical role in the pathogenesis of type 1 diabetes. Signal transducer and activator of transcription transduces type I interferon cytokines in T cells, leading to Th1 cell differentiation and production of interferon γ. Recent studies suggest that liraglutide reduces the plasma concentration of C-reative protein in patients with type 1 diabetes and protects β cell function in the non-obese diabetic mouse. Objective: The study aimed to explore the effect of glucagon-like peptide-1 analogue on interferon γ production and the underlying signaling pathway in vitro. Methods: Jurkat E6-1 cells were intervened with different concentrations of glucose and liraglutide during different time periods. Protein was extracted from Jurkat E6-1 cells. The target proteins (total and activated Janus kinase 2, signal transducers and activators of transcription 4 and interferon γ) were detected by Western blot. Results: Glucose stimulates interferon γ expression and activates Janus kinase 2/signal transducers and activators of transcription 4 signaling pathway in Jurkat E6-1 cells in a concentration and timedependent manner. Under high glucose condition, liraglutide inhibits interferon γ expression and Janus kinase 2/signal transducers and activators of transcription 4 signaling pathway in Jurkat E6-1 cells in a concentration and time-dependent manner. The Janus kinase responsible for liraglutide-inhibited signal transducers and activators of transcription 4 phosphorylation is Janus kinase 2, which is also required for the interferon γ induction. Finally, we demonstrated that under high glucose condition, liraglutide inhibits interferon γ expression via Janus kinase 2/signal transducers and activators of transcription 4 signaling pathway in Jurkat E6-1 cells. Conclusion: Liraglutide inhibits Jurkat E6-1 cells to produce interferon γ via the Janus kinase/signal transducers and activators of transcription signaling pathway under high glucose condition, which implies its potential in the immunoregulatory effect of type 1 diabetes.

scholarly journals Interleukin 12 Protects from a T Helper Type 1–mediated Autoimmune Disease, Experimental Autoimmune Uveitis, through a Mechanism Involving Interferon γ, Nitric Oxide, and Apoptosis

1999 ◽  
Vol 189 (2) ◽  
pp. 219-230 ◽  
Author(s):  
Teresa K. Tarrant ◽  
Phyllis B. Silver ◽  
Jennifer L. Wahlsten ◽  
Luiz V. Rizzo ◽  
Chi-Chao Chan ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
T Cells ◽  
Interferon Γ ◽  
Effector T Cells ◽  
T Helper ◽  
Experimental Autoimmune Uveitis ◽  
Ifn Γ ◽  
Helper Type ◽  
Experimental Autoimmune

Pathogenic effector T cells in experimental autoimmune uveitis (EAU) are T helper type 1–like, and interleukin (IL)-12 is required for their generation and function. Therefore, we expected that IL-12 administration would have disease-enhancing effects. Mice were immunized with a uveitogenic regimen of the retinal antigen interphotoreceptor retinoid-binding protein, treated with IL-12 (100 ng/d for 5 d), and EAU was assessed by histopathology. Unexpectedly, IL-12 treatment failed to enhance EAU in resistant strains and downregulated disease in susceptible strains. Only treatment during the first, but not during the second, week after immunization was consistently protective. High levels of interferon γ (IFN-γ) were present in the serum during IL-12 treatment, but subsequent antigen-specific IFN-γ production in protected mice was diminished, as were IL-5 production, lymph node cell proliferation, and serum antibody levels. Treated mice had fewer cells and evidence of enhanced apoptosis in the draining lymph nodes. Unlike wild-type mice, IFN-γ–deficient, inducible nitric oxide synthase (iNOS)-deficient, and Bcl-2lck transgenic mice were poorly protected by IL-12, whereas IL-10–deficient mice were protected. We conclude that administration of IL-12 aborts disease by curtailing development of uveitogenic effector T cells. The data are compatible with the interpretation that IL-12 induces systemic hyperinduction of IFN-γ, causing activation of iNOS and production of NO, which mediates protection at least in part by triggering Bcl-2 regulated apoptotic deletion of the antigen-specific T cells as they are being primed.

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