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Mendelian susceptibility to mycobacterial disease (MSMD) is caused by approximately 21 genetic defects, including a mutation in Interferon-Gamma Receptor 1 (IFNGR1). IFNGR1 deficiency leads to a loss of cellular responsiveness to type II Interferon (IFN-γ), which plays a significant role in controlling intracellular bacteria. This study explored the response of IFN-β therapy in a patient with partial IFNGR1 deficiency to treat invasive mycobacterial infection. The biological therapy was used successfully as an adjuvant to anti-mycobacterial medications to treat a 17-year-old girl with partial IFNGR1 deficiency who presented with a recurrent mycobacterial infection that extended to her central nervous system, which resulted in clinical and radiological improvement. This report suggests that activation of type I IFN through Signal Transducers and Activators of Transcription1 (STAT1) could bypass the early IFN-γ signaling defects and activate IFN-γ production. For that reason, IFN-β might be used as a beneficial adjuvant therapy for managing extensive central nervous system mycobacterial infection, especially in patients with IFNGR1 deficiency., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Signaling by toll-like receptors (TLRs) initiates important immune responses against viral infection. The role of TLRs in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is not well elucidated. Thus, we investigated the interaction of TLRs agonists and SARS-COV-2 antigens with immune cells in vitro., Material & Methods: 30 coronavirus disease 2019 (COVID-19) patients (15 severe and 15 moderate) and 10 age and sex-matched healthy control (HC) were enrolled. Peripheral blood mononuclear cells (PBMCs) were isolated and activated with TLR3, 7, 8, and 9 agonists, the spike protein (SP) of SARS-CoV-2, and the receptor binding domain (RBD) of SP. Frequencies of CD3 + IFN-β + T cells, and CD3 + IFN-γ + T cells were evaluated by flow cytometry. Interferon (IFN)-β gene expression was assessed by qRT-PCR., Results: The frequency of CD3 + IFN-β + T cells was higher in PBMCs from moderate (p < 0.0001) and severe (p = 0.009) patients at baseline in comparison with HCs. The highest increase in the frequency of CD3 + IFN-β + T cells in cell from moderate patients was induced by TLR8 agonist and SP (p < 0.0001 for both) when compared to HC, while, the highest increase of the frequency of CD3 + IFN-β + T cells in sample of severe patients was seen with TLR8 and TLR7 agonists (both p = 0.002). The frequency of CD3 + IFN-γ + T cells was significantly increased upon stimulation with TLR agonists in cell from patients with moderate and severe COVID-19, compared with HC (all p < 0.01), except with TLR7 and TLR8 agonists. The TLR8 agonist did not significantly increase the frequency of CD3 + IFN-γ + T cells in PBMCs of severe patients, but did so in cells from patients with moderate disease (p = 0.01). Moreover, IFN-β gene expression was significantly upregulated in CD3 + T cells from moderate (p < 0.0001) and severe (p = 0.002) COVID-19 patients, compared to HC after stimulation with the TLR8 agonist, while, stimulation of T cells with SP, significantly up-regulated IFN-β mRNA expression in cells from patients with moderate (p = 0.0003), but not severe disease., Conclusion: Stimulation of PBMCs from COVID-19 patients, especially patients with moderate disease, with TLR8 agonist and SP increased the frequency of IFN-β-producing T cells and IFN-β gene expression., Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Shahid Beheshti medical University. Published by Elsevier Inc. All rights reserved.)

Increased susceptibility to bacterial infections like tuberculosis (TB) is one of the complications of type 2 diabetes, however the underlying mechanisms remains poorly characterized. To explore how chronic hyperglycemia in diabetes affects progression of active TB, we examined mRNA expression of M1 (proinflammatory) and M2 (anti-inflammatory) cytokines/markers, in monocyte-derived macrophages obtained from patients with PTB + DM (pulmonary TB + diabetes mellitus type 2), patients with DM alone, patients with PTB alone, and healthy individuals (controls). Our findings indicate a dysregulated cytokine response in patients with both PTB and DM, characterized by decreased expression levels of interferon-gamma (IFN-γ) and inducible nitric oxide synthase (iNOS), along with increased expression levels of interleukin-1 beta (IL-1β) and CD206. Furthermore, we observed a positive correlation of IL-1β and CD206 expression with levels of glycosylated hemoglobin (HbA1c) in both PTB + DM and DM groups, while IFN-γ showed a positive correlation with HbA1c levels, specifically in the PTB + DM group. Additionally, M1 cytokines/markers, IL-1β and iNOS were found to be significantly associated with the extent of sputum positivity in both PTB and PTB + DM groups, suggesting it to be a function of increased bacterial load and hence severity of infection. Our data demonstrates that tuberculosis in individuals with PTB + DM is characterized by altered M1/M2 cytokine responses, indicating that chronic inflammation associated with type 2 diabetes may contribute to increased immune pathology and inadequate control of tuberculosis infection., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Exploring the interaction of small molecules with therapeutic proteins can provide useful information about development of ligand-protein complexes as synergistically therapeutic platforms. In this study, the interaction of sinensetin with human interferon gamma (IFNγ) was evaluated experimentally and theoretically. Also, the synergistic effects of IFNγ- sinensetin complex on the inhibition of hepatocellular carcinoma HepG2 cell proliferation were assessed by cell viability and quantitative real time PCR assays. It was realized that sinensetin interacts with IFNγ through a static quenching mechanism and hydrophobic forces mediated by presence of Lys55 and Lys58 amino acid residues in the binding site were the main contributing forces in the spontaneous formation of IFNγ-sinensetin complex. Also, the interaction of sinensetin with IFNγ did not induce a significant change in the secondary and tertiary structure of the protein. Cellular assays revealed a synergistic effect of sinensetin on IFNγ -triggered anticancer action in HepG2 cells through overexpression of caspase-3 mRNA and protein. In conclusion, this study may hold great promise for the development of potential ligand- protein complexes for therapeutic purposes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Hemophagocytic lymphohistiocytosis (HLH) is characterized by hyperinflammation and multiorgan dysfunction. Infections, including the reactivation of viruses, contribute to significant disease mortality in HLH. Although T-cell and natural killer cell-driven immune activation and dysregulation are well described, limited data exist on the status of B-cell compartment and humoral immune function in HLH. We noted marked suppression of early B-cell development in patients with active HLH. In vitro B-cell differentiation studies after exposure to HLH-defining cytokines, such as interferon gamma (IFN-γ) and tumor necrosis factor, recapitulated B-cell development arrest. Messenger RNA sequencing of human CD34+ cells exposed to IFN-γ demonstrated changes in genes and pathways affecting B-cell development and maturation. In addition, patients with active HLH exhibited a marked decrease in class-switched memory B (CSMB) cells and a decrease in bone marrow plasmablast/plasma cell compartments. The decrease in CSMB cells was associated with a decrease in circulating T follicular helper (cTfh) cells. Finally, lymph node and spleen evaluation in a patient with HLH revealed absent germinal center formation and hemophagocytosis with associated lymphopenia. Reassuringly, the frequency of CSMB and cTfh improved with the control of T-cell activation. Taken together, in patients with active HLH, these changes in B cells may affect the humoral immune response; however, further immune studies are needed to determine its clinical significance., (© 2023 by The American Society of Hematology.)

It has been reported that infection of chicken coccidian could inhibit the production of Th1 cytokine IFN-γ, thereby evading clearance by the host immune system. The present study aimed to have a further investigation into the effects of Eimeria maxima IFN-γ inhibitory molecules (EmHPSP-2 and EmHPSP-3) on the immune function of chicken peripheral blood mononuclear cells (PBMC) and various T cell subsets. First, separated PBMC or sorted T cell subsets were used for incubation with recombinant proteins of EmHPSP-2 (rEmHPSP-2) and EmHPSP-3 (rEmHPSP-3). Subsequently, the effects of rEmHPSP-2 and rEmHPSP-3 on proliferative capacity, nitric oxide (NO) release and mRNA levels of cytokines of the above cells were detected. The sorting purity of CD8 + , CD4 + CD25 - , CD4 + , and CD4 + CD25 + T cells was 93.01, 88.88, 87.04, and 81.26%, respectively. The NO release of PBMC was significantly inhibited by rEmHPSP-2 and rEmHPSP-3. The proliferation of PBMC and CD4 + T cells was significantly inhibited by rEmHPSP-2 and rEmHPSP-3, whereas CD8 + , CD4 + CD25 - , and CD4 + CD25 + T cells was significantly promoted by the 2 proteins. The 2 proteins significantly downregulated interferon-gamma (IFN-γ) mRNA level, upregulated the transcriptional levels of interleukin-10 (IL-10) and transforming growth factor-beta1 (TGF-β1) in PBMC. IFN-γ and IL-2 transcriptional levels were markedly inhibited in CD8 + T cells. IFN-γ transcriptional level was significantly inhibited, but IL-4 was promoted by rEmHPSP-2 and rEmHPSP-3 in CD4 + CD25 - T cells. Meanwhile, the inhibitory effects of rEmHPSP-2 and rEmHPSP-3 on the transcriptional levels of IFN-γ and IL-2 were more obvious in CD4 + T cells containing CD25 + cells compared with the CD25 + cells depletion group. It was found that IL-10, TGF-β1, and cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) mRNA levels were significantly upregulated upon stimulation of chicken CD4 + CD25 + T cells by proteins. This study is not only of great significance to clarify the immune evasion mechanism of chicken coccidia, but also provides candidate antigen molecules for development of a novel vaccine against chicken coccidiosis., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The IL-12/23/ISG15-IFN-γ pathway is the main immunological pathway for controlling intra-macrophagic microorganisms such as Mycobacteria, Salmonella, and Leishmania spp. Consequently, upon mutations in genes of the IL-12/23/ISG15-IFN-γ pathway cause increased susceptibility to intra-macrophagic pathogens, particularly to Mycobacteria. Therefore, the purpose of this study was to characterize the mutations in genes of the IL-12/23/ISG15-IFN-γ pathway in severe tuberculosis (TB) patients., Methods: Clinically suspected TB was initially confirmed in four patients (P) (P1, P2, P3, and P4) using the GeneXpert MTB/RIF and culturing techniques. The patients' Peripheral blood mononuclear cells (PBMCs) were then subjected to ELISA to measure Interleukin 12 (IL-12) and interferon gamma (IFN-γ). Flow cytometry was used to detect the surface expressions of IFN-γR1 and IFN-γR2 as well as IL-12Rβ1and IL-12Rβ2 on monocytes and T lymphocytes, respectively.The phosphorylation of signal transducer and activator of transcription 1(STAT1) on monocytes and STAT4 on T lymphocytes were also detected by flow cytometry. Sanger sequencing was used to identify mutations in the IL-12Rβ1, STAT1, NEMO, and CYBB genes., Results: P1's PBMCs exhibited reduced IFN-γ production, while P2's and P3's PBMCs exhibited impaired IL-12 induction. Low IL-12Rβ1 surface expression and reduced STAT4 phosphorylation were demonstrated by P1's T lymphocytes, while impaired STAT1 phosphorylation was detected in P2's monocytes. The impaired IκB-α degradation and abolished H2O2 production in monocytes and neutrophils of P3 and P4 were observed, respectively. Sanger sequencing revealed novel nonsense homozygous mutation: c.191 G>A/p.W64 * in exon 3 of the IL-12Rβ1 gene in P1, novel missense homozygous mutation: c.107 A>T/p.Q36L in exon 3 of the STAT1 gene in P2, missense hemizygous mutation:: c.950 A>C/p.Q317P in exon 8 of the NEMO gene in P3, and nonsense hemizygous mutation: c.868 C>T/p.R290X in exon 8 of CYBB gene in P4., Conclusion: Our findings broaden the clinical and genetic spectra associated with IL-12/23/ISG15-IFN-γ axis anomalies. Additionally, our data suggest that TB patients in Pakistan should be investigated for potential genetic defects due to high prevalence of parental consanguinity and increased incidence of TB in the country., Competing Interests: Declaration of Competing Interest All authors certify that there are no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The immunosuppressive receptor TIGIT plays a vital role in the regulation of the immune system's response to pathogens. However, the expression pattern of this receptor in mouse brains during infection with Toxoplasma gondii cysts is not known. Here, we provide evidence of immunological changes and TIGIT expression in infected mouse brains through flow cytometry and QPCR. The obtained results show that TIGIT expression on brain T cells rose considerably after infection. T. gondii infection triggered the conversion of TIGIT + T CM cells to TIGIT + T EM cells and reduced their cytotoxicity. During the whole period of T. gondii infection, high intensity and persistent expression of IFN-γ and TNF-α in brain and serum of mice. This study shows that chronic T. gondii infection increases TIGIT expression on brain T cells and affects their immune function., Competing Interests: Declaration of Competing Interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Mendelian susceptibility to mycobacterial disease (MSMD) is characterized by a selective predisposition to infections caused by intracellular pathogens, such as mycobacteria, due to impaired IFN-γ immunity. To date, 18 different genes associated with MSMD have been reported., Objectives: This review describes recent discoveries, a 2020-2021 update, in MSMD through the introduction of three novel genetic disorders, namely, AR IFN-γ, T-bet, and ZNFX1 complete deficiency, as well as molecular mechanisms underlying multifocal osteomyelitis in patients with this condition., Sources: PubMed databases were searched for reports of MSMD since January 2020. Relevant articles and their references were screened., Content: The review covers a general overview, known genes, classifications, symptoms, and treatments for MSMD. MSMD is classified into two groups: isolated MSMD and syndromic MSMD. Among the 18 genes responsible, 13 cause isolated MSMD, which is characterized by selective predisposition to one or more mycobacterial and related infections, and 8 cause syndromic MSMD, which involves the combination of the mycobacterial disease infectious phenotype with additional clinical phenotypes. Among the three genetic etiologies described herein, AR IFN-γ deficiency is classified as isolated MSMD, whereas AR T-bet and ZNFX1 deficiency are classified as syndromic MSMD. Multifocal osteomyelitis is a representative symptom of MSMD, and a high frequency of multifocal osteomyelitis is reported in MSMD patients due to impaired IFN-γ responses, such as with AD IFN-γR1, AD IFN-γR2, or AD STAT1 deficiency. Impaired inhibition of osteoclast differentiation and bone resorption owing to a poor response to IFN-γ has been shown to be in association with multifocal osteomyelitis in MSMD., Implications: Over the past decade, genetic dissection by next-generation sequencing techniques has contributed to the understanding of the molecular bases of human immunity to mycobacteria. However, genetic etiologies are lacking for half of MSMD cases. Further studies will be needed to elucidate the pathogenesis of MSMD., (Copyright © 2022 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Peripheral T-cell lymphomas (PTCLs) are heterogenous T-cell neoplasms often associated with epigenetic dysregulation. We investigated de novo DNA methyltransferase 3A (DNMT3A) mutations in common PTCL entities, including angioimmunoblastic T-cell lymphoma and novel molecular subtypes identified within PTCL-not otherwise specified (PTCL-NOS) designated as PTCL-GATA3 and PTCL-TBX21. DNMT3A-mutated PTCL-TBX21 cases showed inferior overall survival (OS), with DNMT3A-mutated residues skewed toward the methyltransferase domain and dimerization motif (S881-R887). Transcriptional profiling demonstrated significant enrichment of activated CD8+ T-cell cytotoxic gene signatures in the DNMT3A-mutant PTCL-TBX21 cases, which was further validated using immunohistochemistry. Genomewide methylation analysis of DNMT3A-mutant vs wild-type (WT) PTCL-TBX21 cases demonstrated hypomethylation in target genes regulating interferon-γ (IFN-γ), T-cell receptor signaling, and EOMES (eomesodermin), a master transcriptional regulator of cytotoxic effector cells. Similar findings were observed in a murine model of PTCL with Dnmt3a loss (in vivo) and further validated in vitro by ectopic expression of DNMT3A mutants (DNMT3A-R882, -Q886, and -V716, vs WT) in CD8+ T-cell line, resulting in T-cell activation and EOMES upregulation. Furthermore, stable, ectopic expression of the DNMT3A mutants in primary CD3+ T-cell cultures resulted in the preferential outgrowth of CD8+ T cells with DNMT3AR882H mutation. Single-cell RNA sequencing(RNA-seq) analysis of CD3+ T cells revealed differential CD8+ T-cell subset polarization, mirroring findings in DNMT3A-mutated PTCL-TBX21 and validating the cytotoxic and T-cell memory transcriptional programs associated with the DNMT3AR882H mutation. Our findings indicate that DNMT3A mutations define a cytotoxic subset in PTCL-TBX21 with prognostic significance and thus may further refine pathological heterogeneity in PTCL-NOS and suggest alternative treatment strategies for this subset.

Background: Toxoplasmosis is a deleterious parasitic disease with harmful impact on both humans and animals. The present study was carried out to evaluate the antiparasitic effect of chloroquine (CQ), spiramycin (SP), and combination of both against the highly virulent RH HXGPRT (-) strain of Toxoplasma gondii (T. gondii) and to explore the mechanisms underlying such effect., Methods: We counted the tachyzoites in the peritoneal fluid and liver smears of mice and performed scanning and transmission electron microscopy and immunofluorescence staining of tachyzoites. Moreover, relative caspase 3 gene expression was measured by real time polymerase chain reaction of liver tissues and immunoassay of anti-apoptotic markers [B cell lymphoma-2 (Bcl-2) and X-chromosome linked inhibitor of apoptosis (XIAP)] and interferon gamma (IFN-γ) was done in liver tissues by ELISA. In addition, we estimated serum levels of aspartate transaminase (AST) and alanine transaminase (ALT) and performed histopathological examination of liver sections for scoring of inflammation., Results: We found that both CQ and CQ/SP combination significantly reduced parasitic load in the peritoneal fluid and liver smears, induced apical disruption of tachyzoites, triggered host cell apoptosis through elevation of relative caspase 3 gene expression and suppression of both Bcl-2 and XIAP. Also, they upregulated IFN-γ level, reduced serum AST and ALT, and ameliorated liver inflammation., Conclusions: Either of CQ and CQ/SP combination was more effective than SP alone against T. gondii with the CQ/SP combination being more efficient. Therefore, adding CQ to other anti-Toxoplasma therapeutic regimens may be considered in future research., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Introduction: Programmed death-ligand 1 (PD-L1) copy number gains may be predictive of clinical response to immunotherapy in NSCLC. This study investigated PD-L1 copy number variations in tumor resection and bronchoscopy biopsies and its relationship with PD-L1 tumor cell staining and inflammatory gene expression., Methods: PD-L1 gene copy number and mRNA expression were evaluated by real-time polymerase chain reaction in surgically resected NSCLC tumor biopsies (n = 87) and control biopsies (n = 20). A second cohort (n = 15) of bronchoscopy-derived tumor biopsies was analyzed, including multiple biopsies from the same patient across different anatomical sites., Results: PD-L1 mRNA levels strongly correlated with PD-L1 tumor staining (r = 0.55, p < 0.0001). Interferon-γ mRNA expression associated with PD-L1 immune cell staining, but not PD-L1 tumor cell staining. In contrast, PD-L1 copy number positively associated PD-L1 tumor staining, but not PD-L1 immune cell staining. PD-L1 copy number analysis detected loss (15 of 87 = 17%) and gain (5 of 87 = 7%) of copy number. Tumors with low PD-L1 copy number expressed significantly reduced levels of inflammatory (interferon-γ, interleukin [IL]-6, IL-1β, MMP-9) and immunosuppressive (IL-10, transforming growth factor β) mediators. Analysis of bronchoscopy-derived biopsies revealed low heterogeneity in copy number values across different anatomical sites, in contrast to more variable PD-L1 mRNA expression., Conclusions: Low PD-L1 copy number tumors display reduced PD-L1 expression, reduced PD-L1 tumor cell staining, and an immunologic cold tumor microenvironment. Because PD-L1 copy number values are highly stable across different tumor regions, its evaluation may represent a robust and complimentary biomarker for predicting response to immunotherapy, where low copy number may predict lack of response., (Copyright © 2022 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Interferon gamma (IFN-γ) is a widely expressed cytokine that has potent antiviral and immunomodulatory effects. The expression and bioactivity of IFN-γ have been reported in several fish species. However, the molecular mechanism mediated by IFN-γ in fish macrophages has not been completely elucidated. This study used the macrophage cell line to investigate the functional activities and regulation mechanism of large yellow croaker IFN-γ (LcIFN-γ). Herein, the mRNA expression of Lcifn-γ was significantly upregulated in macrophages after LPS and poly(I:C) treatment. Recombinant LcIFN-γ protein (rLcIFN-γ) significantly enhanced the phagocytic ability and respiratory burst activity of macrophages. Meanwhile, rLcIFN-γ induced M1 phenotype polarization of macrophages with the upregulated expressions of pro-inflammatory gene. Moreover, rLcIFN-γ upregulated the IFN-stimulated genes (ISGs) expression and activated JAK (Janus tyrosine kinases)-STAT (signal transducer and activator of transcription) signaling pathway by causing the phosphorylation of JAK1 and STAT1 Tyr701 . Furthermore, the promoter activity of IFN-regulatory factor 1 (IRF1) was significantly upregulated by the phosphorylated transcription factor STAT1 through binding to its promoter region. In addition to the classical JAK-STAT pathway, rLcIFN-γ also activated multiple distinct signaling cascades such as mitogen-activated protein kinase (MAPK) and protein kinase B (AKT) pathways. Overall, this study indicated the powerful effects of LcIFN-γ on macrophage activation of large yellow croaker and its molecular mechanism., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The immunoproteasomes are specific proteasomes that clear oxidant-damaged proteins under inflammatory conditions in various diseases. Toxoplasma gondii (T. gondii) infects the central nervous system and causeencephalitis. However, the relationship between the immunoproteasomes and brain inflammation during T. gondii infection is not well characterized. In this study, we established an in vivo mouse model of T. gondii PLK strain infection via intraperitoneal injection and evaluated the expression of immunoproteasome subunits in the brains of infected mice. The results demonstrated that first, pathological changes in the brains of infected mice increase in severity over time. Second, following T. gondii infection, activated microglia and astrocytes undergo a series of functional alterations and morphological transformations, including proliferation and migration. Third, T. gondii infection induces expression of inflammatory cytokines, including IFN-γ, IL-1β, TNF-α, and IL-6. Fourth, the immunoproteasome subunits low-molecular-weight polypeptide 2 (LMP2), LMP7, and LMP10 mRNA and protein levels are significantly upregulated in T. gondii-infected mouse brains, as shown by RT-qPCR and western blot analysis, compared with that in vehicle-treated brains, and their expression is localized in the microglia, astrocytes, and neurons of T. gondii-infected brains, as determined via immunofluorescence staining. Furthermore, the western blot mean gray value for the immunoproteasome subunits and the positive microglia and astrocyte immunohistochemical signals in the brains of T. gondii-infected mice were positively correlated, indicating that the observed relationships were highly significant. Therefore, it was concluded that the induction of the immunoproteasomes is a pathogenic mechanism underlying T. gondii infection-induced inflammation., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Both human and mouse allergic contact dermatitis (ACD) frequently demonstrates a combined type 1 and type 2 immune response. However, the relative importance of type 2 immunity in this setting has been incompletely understood yet., Objective: To explore an effector function of type 2 immunity in ACD with mixed type 1/type 2 immune response., Methods: Gene expression characteristics of contact hypersensitivity (CHS) model was examined by quantitative polymerase chain reaction. Cytokine profile of T cells was analyzed by flow cytometry. The involvement of type 2 immunity was assessed by antibody-mediated cytokine neutralization and cell depletion. The role of specific subset of cutaneous dendritic cells was evaluated using diphtheria toxin-induced cell-depleting mouse strains., Results: Oxazolone-induced CHS revealed a combination of type 1/type 2 gene expression. The severity of oxazolone-induced CHS was ameliorated by neutralization of IL-4 but not of IFN-γ, indicating that type 2 immunity plays a dominant effector function in this mixed type 1/type 2 model. Mechanistically, type 2 effector immunity was mounted by CD301b+Langeirn- dermal dendritic cells in part through thymic stromal lymphopoietin-interleukin 7 receptor alpha signaling-dependent manner., Conclusion: Our findings suggest the clinical rationale for targeting type 2 immunity as a relevant therapeutic strategy for the mixed immune phenotype of ACD., (Copyright © 2021 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.)

Background: The IL-12/IFN-γ axis plays a vital role in the control of intramacrophagic pathogens including Leishmania infections., Objective: The aim of this study was to investigate genetic defects in the IL-12/IFN-γ axis in cutaneous leishmaniasis patients, using immunological and genetic evaluation., Methods: Enzyme-linked immunosorbent assay was used to quantify IFN-γ , while flow cytometry was performed to analyze surface IL-12Rβ1/IL-12Rβ2 expression and phosphorylation of signal transducers as well as the activator of transcription 4 (pSTAT4). Sequencing was carried out for genetic analysis., Results: The peripheral blood mononuclear cells from the two patients (P1 and P2) demonstrated impaired production of IFN-γ. Furthermore, abolishment of the surface expression of Il-12Rβ1 was observed in lymphocytes, with consequent impairment of STAT4 phosphorylation in the lymphocytes of P1 and P2. IL-12Rβ1 deficiency was identified, which was caused by a novel homozygous missense mutation (c.485>T/p.P162L) and a novel homozygous nonsense mutation (c.805G>T/P.E269*) in the IL-12Rβ2 gene of P1 and P2, respectively. In silico analyses predicted these novel mutations as being pathogenic, causing truncated proteins, with consequent inactivation., Conclusion: Our data have expanded the phenotype and mutation spectra associated with IL-12Rβ1 deficiency, and suggest that patients with CL should be screened for mutations in genes of the IL-12/IFN-γ axis., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background Previous gene expression studies have identified genes IFNγ, TNFα, RNase 3, CXCL9, and CD55 as potential biomarkers for sarcoidosis and/or chronic beryllium disease (CBD). We hypothesized that differential expression of these genes could function as diagnostic biomarkers for sarcoidosis and CBD, and prognostic biomarkers for sarcoidosis. Study Design/Methods We performed RT-qPCR on whole blood samples from CBD (n = 132), beryllium sensitized (BeS) (n = 109), and sarcoidosis (n = 99) cases and non-diseased controls (n = 97) to determine differential expression of target genes. We then performed logistic regression modeling and generated ROC curves to determine which genes could most accurately differentiate: 1) CBD versus sarcoidosis 2) CBD versus BeS 3) sarcoidosis versus controls 4) non-progressive versus progressive sarcoidosis. Results CD55 and TNFα were significantly upregulated, while CXCL9 was significantly downregulated in CBD compared to sarcoidosis (p < 0.05). The ROC curve from the logistic regression model demonstrated high discriminatory ability of the combination of CD55, TNFα, and CXCL9 to distinguish between CBD and sarcoidosis with an AUC of 0.98. CD55 and TNFα were significantly downregulated in sarcoidosis compared to controls (p < 0.05). The ROC curve from the model showed a reasonable discriminatory ability of CD55 and TNFα to distinguish between sarcoidosis and controls with an AUC of 0.86. There was no combination of genes that could accurately differentiate between CBD and BeS or sarcoidosis phenotypes. Interpretation CD55, TNFα and CXCL9 expression levels can accurately differentiate between CBD and sarcoidosis, while CD55 and TNFα expression levels can accurately differentiate sarcoidosis and controls., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Lung cancer is one of the deadliest cancers in various populations. Apart from the effects that anticancer drugs such as paclitaxel (PTX) have on cancer cells, they also have many side effects on healthy cells. Interferon gamma (IFN-γ) is also one of the cytokines used in the treatment of cancer. Current research is focused on providing new drug carriers to find new therapeutic goals. After synthesis of nanogels and loading of PTX and IFN-γ, the cytotoxicity of these nanogels on A549 and HEK293 healthy cell line was measured by MTT assay and flow cytometry analysis. Finally, the expression of STAT1 gene was investigated using Real time-PCR. The results of MTT assay showed that the survival rate of healthy cells treated with PTX and IFN-γ-loaded nanogels was 2.15 and 2.39 times higher than cancer cells, respectively. The results also showed that the gene expression STAT1 in A549 cells exposed to these nanogels was higher than healthy cells (p < 0.05). Based on flow cytometry results, the death rate of healthy cells treated with the mentioned nanogels was lower than cancer cells (p < 0.05). Therefore, Studies showed that synthesized nanogels have positive effects on cancer cells and also have fewer side effects on healthy cells., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objectives: Current diagnostic tests for tuberculosis (TB) in children living in low-endemic countries are limited by low specificity and the inability of the current tests to differentiate between active TB and latent TB infection (LTBI). This study aimed to evaluate the blood IP-10 mRNA expression level to detect LTBI in Egyptian pediatric household contacts (PHC)., Methods: TB-specific IP-10 and IFN-γ mRNA levels were assessed by real-time quantitative PCR (RT-qPCR) in 72 Egyptian PHC of active pulmonary TB cases. All study participants were also assessed by Tuberculin Skin Test (TST) and Quantiferon gold in tube (QFN-GIT) assay., Results: IP-10 and IFN-γ mRNA expression levels were significantly higher in PHC with active TB or LTBI than TB negative (p < 0.0001). The level of IP-10 mRNA expression was significantly higher in PHC with active TB than LTBI (p = 0.0008). In contrast, there was no significant differences in the IFN-γ mRNA expression between PHC with active TB compared to LTBI (p = 0.49). The sensitivity and specificity of the IP-10 RT-qPCR were 94.2% and 95.2%, respectively, in PHC with active TB compared to 85.7% and 81.8% in PHC with LTBI. The negative and positive predictive values and accuracy of IP-10 RT-qPCR for distinguishing active TB from LTBI were 85.2%, 58.3%, and 72.6% respectively., Conclusion: Blood IP-10 mRNA expression level may be a potential diagnostic marker to help distinguish active TB from LTBI in PHC., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Patients with graft-versus-host disease (GVHD) develop characteristic mucocutaneous phenomena consisting of erosive erythema with histopathological findings including interface dermatitis and keratinocyte (KC) death, resulting in widespread sclerodermatous changes. We found that KCs exhibit marked production of TGFβ1 in skin lesions of chronic GVHD but not in those of acute GVHD. To further investigate the roles of KCs, the main targets of donor T cells, in sclerodermatous changes followed by interface dermatitis, we established a murine model of chronic GVHD-like sclerodermatous changes followed by acute GVHD-like mucocutaneous injury in genetically modified mice transferred with KC-specific CD8 T cells. Although transfer of granzyme B-deficient CD8 T cells did not result in either mucocutaneous injury or sclerodermatous changes in recipients, IFN-γ-deficient CD8 T-cell recipients developed severe acute mucocutaneous injury but milder sclerodermatous changes than wild-type CD8 T-cell recipients. Moreover, IFN-γ-deficient CD8 T-cell recipients had a lower expression of TGFβ1 in the epidermis than the control. Murine primary KCs undergoing FasL-induced apoptosis and incubated with IFN-γ produced TGFβ1, the production of which was inhibited by a pan-caspase inhibitor. Our results indicate that IFN-γ promotes TGFβ1 production by apoptotic KCs, which mediates the development of widespread sclerodermatous changes in KC-targeting GVHD., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Patients with isolated pulmonary embolism (PE) have a distinct clinical profile from those with deep vein thrombosis (DVT)-associated PE, with more pulmonary conditions and atherosclerosis. These findings suggest a distinct molecular pathophysiology and the potential involvement of alternative pathways in isolated PE. To test this hypothesis, data from 532 individuals from the Genotyping and Molecular Phenotyping of Venous ThromboEmbolism Project, a multicenter prospective cohort study with extensive biobanking, were analyzed. Targeted, high-throughput proteomics, machine learning, and bioinformatic methods were applied to contrast the acute-phase plasma proteomes of isolated PE patients (n = 96) against those of patients with DVT-associated PE (n = 276) or isolated DVT (n = 160). This resulted in the identification of shared molecular processes between PE phenotypes, as well as an isolated PE-specific protein signature. Shared processes included upregulation of inflammation, response to oxidative stress, and the loss of pulmonary surfactant. The isolated PE-specific signature consisted of 5 proteins: interferon-γ, glial cell line-derived neurotrophic growth factor, polypeptide N-acetylgalactosaminyltransferase 3, peptidyl arginine deiminase type-2, and interleukin-15 receptor subunit α. These proteins were orthogonally validated using cis protein quantitative trait loci. External replication in an independent population-based cohort (n = 5778) further validated the proteomic results and showed that they were prognostic for incident primary isolated PE in individuals without history of VTE (median time to event: 2.9 years; interquartile range: 1.6-4.2 years), supporting their possible involvement in the early pathogenesis. This study has identified molecular overlaps and differences between VTE phenotypes. In particular, the results implicate noncanonical pathways more commonly associated with respiratory and atherosclerotic disease in the acute pathophysiology of isolated PE., (© 2021 by The American Society of Hematology.)

Background and Aims: Polymorphisms within genes encoding the cytokines involved in anti-tuberculosis immunity have been widely studied and sometimes associated with an increased risk of developing the active form of tuberculosis (TB). This study analyzes for the first time the impact of two polymorphisms, namely IFNG+874 T/A and IL10-1082 G/A, in the Algerian population where tuberculosis is moderately endemic., Methods: This case-control study included 104 healthy controls and 141 active TB patients: 75 extrapulmonary (EPTB) and 66 pulmonary (PTB). They were all genotyped by refractory mutational system-PCR amplification. In order to measure the functional impact of IFNG+874 T/A on the production rate of IFN-γ, 43 patients performed a QuantiFERON®Gold In-tube test., Results: The IFNG+874 AA genotype was associated with a higher risk of developing EPTB (OR = 2.52; 95%CI = 1.23-5.18; p = 0.012) while the IFNG+874 TA genotype was associated with a greater protection (OR = 0.34, 95%CI = 0.16-0.74; p = 0.006) which was further characterized by a high production of IFN-γ (p = 0.001). Similarly, the allele A of SNP IL10-1082 G/A, especially in its homozygous form (AA), were overrepresented in PTB patients (p = 0.010 and 0.019, respectively). The combination of both susceptibility genotypes (AA/AA) was strongly associated with risk of development of active TB (OR = 8.58; 95% C.I = 1.95-37.70, p = 0.004). This susceptibility combination was only significant in men regarding PTB (OR = 11.05; 95% C.I = 1.32-92.72, p = 0.027). Additionally, IFNG+874 TA and IL10-1082G∗ genotypes combination was mostly encountered in men controls and conferred the highest protection rate against EPTB (OR = 0.25; 95% C.I = 0.08-0.76, p = 0.015)., Conclusion: These two cytokines genes polymorphisms are associated with active TB susceptibility in the Algerian population. They act synergistically in terms of protection and susceptibility regarding the two forms of the disease. Moreover, these associations were more marked among males suggesting a potential role of gender., Competing Interests: Conflicts of interest The authors have none to declare., (Copyright © 2020 Tuberculosis Association of India. Published by Elsevier B.V. All rights reserved.)

Natural killer (NK) cells play critical roles in protection against hematological malignancies but can acquire a dysfunctional state, which limits antitumor immunity. However, the underlying reasons for this impaired NK cell function remain to be uncovered. We found that NK cells in aggressive B-cell lymphoma underwent substantial transcriptional reprogramming associated with increased lipid metabolism, including elevated expression of the transcriptional regulator peroxisome activator receptor-γ (PPAR-γ). Exposure to fatty acids in the lymphoma environment potently suppressed NK cell effector response and cellular metabolism. NK cells from both diffuse large B-cell lymphoma patients and Eµ-myc B-cell lymphoma-bearing mice displayed reduced interferon-γ (IFN-γ) production. Activation of PPAR-γ partially restored mitochondrial membrane potential and IFN-γ production. Overall, our data indicate that increased lipid metabolism, while impairing their function, is a functional adaptation of NK cells to the fatty-acid rich lymphoma environment., (© 2020 by The American Society of Hematology.)

Cognitive impairment, acute or long-term, is a common complication in patients with severe bacterial infection. However, the underlying mechanisms are not fully verified and effective medicine is not available in clinics. Interferon gamma (IFNγ) is a pivotal cytokine against infection and is believed to be a tune in homeostasis of cognitive function. Here, we collected blood and cerebrospinal fluid (CF) from human subjects and mice, and found that plasma and CF levels of IFNγ were significantly increased in septic patients and endotoxin-challenged mice when compared with healthy controls. IFNγ signaling was boosted in the hippocampus of mice after a challenge of lipopolysaccharide (LPS), which was accompanied with cognitive impairment and decline of neurogenesis. Deficiency of IFNγ or its receptor (IFNγR) dramatically attenuated microglia-induced A1 astrocytes and consequently restored neurogenesis and cognitive function in endotoxemia mice model. Using primary microglia, astrocytes and neurons, we found that IFNγ remarkably increased LPS-mediated release of TNFα and IL-1α in microglia and consequently induced the transformation of astrocyte to A1 subtype, which ultimately resulted in neuron damage. Thus, IFNγ promotes cognitive impairment in endotoxemia by enhancing microglia-induced A1 astrocytes. Targeting IFNγ would be a novel strategy for preventing or treating cognitive dysfunction in patients with Gram-negative infection., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Nanodiamonds (NDs), which are safe carbon nanomaterials, have been used for the transmission of DNA, proteins and drugs. The feasibility of utilizing NDs to deliver NH 2 -PLGA nanoparticle-encapsulated fig polysaccharides for strongly enhanced immune responses has not been clearly studied. In this study, we aimed to use NDs as carriers to deliver NH 2 -PLGA nanoparticle-encapsulated fig polysaccharides for strongly enhanced immune responses. ND particles with a diameter of 5 nm were functionalized by surface carboxylation and covalently conjugated with NH 2 -PLGA nanoparticle-encapsulated fig polysaccharides. NDs-PLGA-FP/OVA could promote antigen uptake and lymphocyte proliferation, increase the expression levels of MHC II, CD80 and CD86, and upregulate the ratio of Th1/Th2 cells in immunized mice. NDs-PLGA-FP/OVA could also upregulate the IL-17 signalling pathway for further immunological enhancement. NDs-PLGA-FP/OVA induced increased TNF-α, IFN-γ, IL-4, and IL-6 cytokine secretion and the levels of OVA-specific antibodies (IgG). These findings demonstrate that NDs-PLGA-FP/OVA have the potential to serve as an effective vaccine delivery and adjuvant system to induce vigorous and long-term immune responses., (Copyright © 2020. Published by Elsevier B.V.)

Particulate matter 2.5 (PM 2.5 ) exposure can increase the prevalence of allergic rhinitis (AR), the mechanism underlying which may include oxidative stress and inflammatory response. As a ROS quenching agent, N-acetylcysteine (NAC) can attenuate the accumulation of inflammatory cells and hyper-responsiveness in animal asthma models. To explore the effect of NAC on the oxidative stress and inflammatory reactions in AR rats exposed to PM 2.5 , we analyzed the components of PM 2.5 and examined the nasal symptoms, redox level in nasal mucosa, Th1/Th2-related serum cytokines, nasal mucosal histopathology and ultrastructure in AR rat models with NAC intervention after PM 2.5 exposure. The results showed that the high concentrations of metal cations and PAHs in PM 2.5 could aggravate Th2-dominant allergic inflammation in AR model and cause redox imbalance, accompanied by nasal epithelial cell stripping and eosinophil infiltration, while NAC intervention could alleviate the clinical symptoms of AR model after PM 2.5 exposure, correct the redox imbalance, reduce the Th2 cytokines, reduce eosinophil infiltration, and promote the moderate regeneration of epithelial cells. The mechanism of NAC reversing PM 2.5 -mediated action may be related to its anti-oxidant and anti-inflammatory effects, which may provide some new insights for the prevention of AR exacerbated by exposure to PM 2.5 ., Competing Interests: Declaration of competing interest The authors have no competing interests to declare., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Pseudomonas aeruginosa is the main conditional pathogen of immunodeficiency individuals. The mechanisms governing immune response to P. aeruginosa infection by macrophages remain incompletely defined. Herein, we demonstrate that protein tyrosine phosphatase-1B (PTP1B) is a critical negative regulator of P. aeruginosa infection response by macrophages. PTP1B-deficient macrophages display greatly enhanced bacterial phagocytosis and killing, accompanied by increased lysosome formation during P. aeruginosa infection. We also found that PTP1B repressed nitric oxide (NO) production and nitric oxide synthase (iNOS) induction following P. aeruginosa infection. PTP1B deficiency tended to upregulate the production of TRIF-interferon (IFN) pathway cytokines and chemokines, including IFN-β and interferon γ-inducible protein 10 (CXCL10, IP-10). Unexpectedly, the phosphorylation level of STAT1 was not regulated by PTP1B. In vivo experiments also confirmed that the regulatory function of PTP1B was not dependent on STAT1. These findings demonstrate that STAT1 is dispensable for negative regulation of P. aeruginosa clearance by macrophages., Competing Interests: Declaration of competing interest The authors have declared that no competing interests exist., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

The histone methylase EZH2 is frequently dysregulated in melanoma and is associated with DNA methylation and silencing of genes involved in tumor suppression. In this study, we used chromatin immunoprecipitation and sequencing to identify key suppressor genes that are silenced by histone methylation in constitutively active EZH2 (Y641) mutant melanoma and assessed whether these regions were also sites of DNA methylation. The genes identified were validated by their re-expression after treatment with EZH2 and DNA methyltransferase inhibitors. The expression of putative EZH2 target genes was shown to be highly relevant to the survival of patients with melanoma in clinical datasets. To determine correlates of response to EZH2 inhibitors, we screened a panel of 53 melanoma cell lines for drug sensitivity. We compared RNA sequencing profiles of sensitive to resistant melanoma cells and performed pathway analysis. Sensitivity was associated with strong downregulation of IFN-γ and IFN-α gene signatures that were reversed by treatment with EZH2 inhibitors. This is consistent with EZH2-driven dedifferentiated invasive states associated with treatment resistance and defects in antigen presentation. These results suggest that EZH2 inhibitors may be most effectively targeted to immunologically cold melanoma to both induce direct cytotoxicity and increase immune responses in the context of checkpoint inhibitor immunotherapy., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

The implantation process requires precisely controlled interactions between the maternal uterine endometrium and the implanting conceptus. Conceptus-derived secretions affect endometrial cells to facilitate the adhesion and attachment of trophoblasts, and endometrial secretions support the growth and development of the conceptus. In pigs, the conceptus secretes a large amount of type II interferon, interferon-γ (IFNG), during the implantation period. However, the role of IFNG in the implantation process has not been fully understood in pigs. Thus, to determine the role of IFNG in the endometrium during early pregnancy in pigs, we treated endometrial explant tissues with increasing doses of IFNG and analyzed the transcriptome regulated by IFNG using an RNA-sequencing analysis. Data analyses identified 276 differentially regulated genes, their Gene Ontology terms, and 94 signature genes in a Gene Set Enrichment Analysis. Furthermore, we analyzed the expression of IFNG-regulated genes, including CIITA, KYNU, IDO1, WARS, and MHC class II molecules, in the endometrium throughout pregnancy and found that levels of those genes in the endometrium were highest on Day 15 of pregnancy, corresponding to the time of peak IFNG secretion by porcine conceptuses. In addition, immunohistochemical analyses revealed that CIITA, KYNU, and IDO proteins were expressed in a cell type- and pregnancy status-specific manner in the endometrium. These results show that genes overrepresented in endometrial tissues in response to IFNG were mainly related to immune responses, suggesting that conceptus-derived IFNG could play critical roles in regulating the maternal immune response for the establishment of pregnancy in pigs., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The IFN-γ and TGF-β1 cytokines perform antagonistic activities in the immune response, and polymorphisms in these genes may induce changes in their plasma levels and influence the course of chronic Hepacivirus C (HCV) infection. The present study evaluated the IFNG +874A/T and TGFB1 -509 C/T polymorphisms in 99 samples from patients with chronic hepatitis C and in 300 samples from healthy donors, and the present study also investigated the association of cytokine plasma level with disease stage. Polymorphisms were identified by real-time PCR, and cytokine levels were measured by enzyme-linked immunosorbent assay. The frequency of the IFNG +874A/T polymorphic allele was not associated with susceptibility to HCV infection, but it was associated with lower inflammatory activity (p = 0.0432). The frequency of the TGFB1 -509C/T polymorphic (TT) genotype was associated with HCV infection (p = 0.0062) and a higher risk of infection (OR = 2.0465; p = 0.0091). Plasma levels of IFN-γ were higher in TT genotype carriers among the control (p = 0.0012) and HCV groups (p = 0.0064) as well as in patients with fibrosis (p = 0.0346) and patients with a high degree of inflammatory activity (p = 0.0381). The highest TGF-β1 levels were found in HCV-infected (p = 0.0329) individuals and in TT genotype carriers. Patients with cirrhosis had higher TGF-β1 (p = 0.0400). IFN-γ and TGF-β1 levels showed a negative correlation (p = 0.0001). In conclusion, the TGFB1 -509C > T polymorphism is associated with a risk of developing chronic hepatitis C, leading to increased TGF-β1, which inhibits IFN-γ production, contributing to the progression to cirrhosis., (Copyright © 2020 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Natural killer (NK) cells are pivotal effectors of the innate immunity protecting an individual from microbes. They are the first line of defense against invading viruses, given their substantial ability to directly target infected cells without the need for specific antigen presentation. By establishing cellular networks with a variety of cell types such as dendritic cells, NK cells can also amplify and modulate antiviral adaptive immune responses. In this review, we will examine the role of NK cells in SARS-COV2 infections causing the ongoing COVID19 pandemic, keeping in mind the controversial role of NK cells specifically in viral respiratory infections and in inflammatory-driven lung damage. We discuss lessons learnt from previous coronavirus outbreaks in humans (caused by SARS-CoV-1 and MERS-COV)., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Aims: In this study, we will investigate the therapeutic effects of berberine (BBR) in Helicobacter pylori (H. pylori) induced chronic atrophic gastritis (CAG). Furthermore, potential mechanisms of BBR in regulating IRF8-IFN-γ signaling axis will also be investigated., Materials and Methods: H. pylori were utilized to establish CAG model of rats. Therapeutic effects of BBR on serum supernatant indices, and histopathology of stomach were analyzed in vivo. Moreover, GES-1 cells were infected by H. pylori, and intervened with BBR in vitro. Cell viability, morphology, proliferation, and quantitative analysis were detected by high-content screening (HCS) imaging assay. To further investigate the potential mechanisms of BBR, relative mRNA, immunohistochemistry and protein expression in IRF8-IFN-γ signaling axis were measured., Key Findings: Results showed serum supernatant indices including IL-17, CXCL1, and CXCL9 were downregulated by BBR intervention, while, G-17 increased significantly. Histological injuries of gastric mucosa induced by H. pylori also were alleviated. Moreover, cell viability and morphology changes of GES-1 cells were improved by BBR intervention. In addition, proinflammatory genes and IRF8-IFN-γ signaling axis related genes, including Ifit3, Upp1, USP18, Nlrc5, were suppressed by BBR administration in vitro and in vivo. The proteins expression related to IRF8-IFN-γ signaling axis, including Ifit3, IRF1 and Ifit1 were downregulated by BBR intervention., Competing Interests: Declaration of competing interest All authors of this manuscript state that they do not have any conflict of interests, and there is nothing to disclose., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Hemodynamic aberrations after severe burns are treated with aggressive intravenous (IV) fluid resuscitation however, oral resuscitation has been proposed in resource poor scenarios. Previously we have shown that animals receiving oral fluid following burns were able to recover kidney function. However, immune function such as circulating and splenic immune cell populations after oral or intravenous fluid administration was not examined. Herein, we perform a follow up analysis of splenic tissue and plasma from the previous animal study to examine the splenic response following these resuscitation strategies after burn injury., Methods: Eighteen anesthetized Yorkshire swine receiving 40%TBSA contact burns were randomized to receive either: (1) no fluids (Fluid Restricted; negative control), (2) 70 mL/kg/d Oral Rehydration Salt solution (Oral), or (3) 2 mL/kg/%TBSA/d of lactated Ringer's solution IV. Blood was drawn for blood cell analysis, and CT scans were performed before and 48 h post-burn, at which point spleens were harvested for histological, Western blot, and RT-PCR analyses., Results: Splenic artery diameter decreased by -0.97 ± 0.14 mm in fluid-restricted animals, while IV led to an increase of 0.68 ± 0.30 mm. No significant differences were detected in white and red pulp. IV fluids reduced the population of splenic monocytes (CD163; P = 0.001) and neutrophils (MPO protein; P = 0.13), as well as cytokines IL-8 (P = 0.003), IFN-γ (P = 0.11) and TNFα (P = 0.05). Additionally, withholding IV fluids consistently decreased the expression of FoxP3, CCR6, and IL17β in spleen, suggesting a shift in T-cell phenotype with IV resuscitation., Conclusions: The route of fluid administration has a minor influence on the changes in circulating and splenic leukocytes post-burn in the acute phase. Further research is needed to help guide resuscitation approaches using immunologic markers of splenic function following burns., (Published by Elsevier Ltd.)

Objective: To evaluate the effects of a hypoenergetic diet (HD)associated with açaí pulp consumption on oxidative stress, antioxidant status and inflammatory biomarkers in overweight, dyslipidemic individuals., Research Methods & Procedures: A randomized, double-blind, placebo-controlled clinical trial was conducted for 90 days. The study began with a 30-day run-in period, during which the intervention was exclusively a HD. Following this period, volunteers were randomized into 2 groups, and 200 g of either açaí pulp or placebo were added to the HD for 60 days. Anthropometric measurements, arterial pressure, oxidative stress and antioxidant status biomarkers, inflammatory and biochemical biomarkers were evaluated., Results: Sixty-nine volunteers completed the clinical trial, 30 of which were in the HD + açaí group and 39 in HD + placebo group. Plasma 8-isoprostane concentrations significantly reduced 60 days after the intervention in the açaí group (p = 0.000), and there was a significant difference between the groups (açaí versus placebo; p = 0.037). Regarding inflammatory status parameters, a significant reduction in IL-6 was observed in the HD + açaí group (p = 0.042), and IFN-γ decreased significantly in both groups, HD + açaí (p = 0.001) and HD + placebo (p = 0.008); there were, however, no differences between the groups. Lipid profile parameters and blood glucose levels did not show change, regardless of nutritional intervention., Conclusion: The addition of açaí to a HD, for 60 days, reduced oxidative stress and improved inflammation in overweight, dyslipidemic individuals., (Copyright © 2019 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Interferon-γ (IFN-γ) is important for host defense against various intracellular organisms including a protozoan pathogen Toxoplasma gondii. Various immune cells are recently shown to produce IFN-γ in T. gondii infection, however, it remains elusive which cell types are important for anti-T. gondii host defense so far. Here we generate a new IFN-γ reporter "GREVEN" mouse line in which a fusion protein of Venus and NanoLuc to analyze IFN-γ producing cells during T. gondii infection and find that CD4 + , CD8 + , γδ T cells and natural killer cells express Venus in a time dependent manner. Furthermore, Lck-Cre/Ifng fl/fl mice are highly susceptible to T. gondii infection. Taken together, our results demonstrate that T cell-derived IFN-γ plays an important role in anti-T. gondii host defense., Competing Interests: Declaration of Competing Interest The authors have no conflicting financial interests to declare., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Seasonal influenza is related to lifestyle-associated risk factors and it has been suggested that the epigenetic state of the individual plays an important role in the severity of infection. It is well known that epigenetics stringently regulate gene expression in each tissue and that aberrant epigenetic states can influence disease development. Despite some studies, limited information is available on changes in epigenetic states before and after influenza virus infection; in particular, it is unknown whether the epigenetic state at specific sites affects subsequent infection. Here, we analyzed CpG methylation states in clones derived from human primary small airway epithelial cells with the same genetic background but different viral replication rates. Our study revealed that demethylating CpGs downstream of the IFN-β transcription start site using a CRISPR/dCas9 system suppressed viral replication during subsequent influenza virus infection. Thus, our observations suggest that epigenome editing might provide adequate protection against the influenza virus., (Copyright © 2019 Elsevier Inc. All rights reserved.)

In this study, the ELP sequence was fused to human interferon-γ (hIFN-γ) and hIFN-γ-ELP fusion protein accumulated with high levels of yield and purity, compared with the corresponding unfused hIFN-γ protein. The hIFN-γ was exclusively produced in the form of insoluble inclusion bodies while the hIFN-γ was relatively soluble when expressed as an ELP fusion protein. The insoluble inclusion bodies were then solubilized under denaturing conditions, refolded in the presence of arginine and purified by single-step ion-exchange chromatography. The fusion to ELP signidficantly increased the accumulation of hIFN-γ by 10-fold with a stable expression on average of 46.85% of total soluble protein (TSP). Furthermore, three rounds of Inverse Transition Cycling (ITC) purification increased overall purity of the hIFN-γ-ELP to 98 ± 5%. The recovery amount of the fusion protein found to be dependent on the NaCl concentration, with increase of NaCl concentration, a greater fraction of the hIFN-γ-ELP was aggregated. However, due to the presence of an aliphatic guest residue in ELP sequence, the high concentration of salt was necessary to trigger the inverse phase transition of hIFN-γ-ELP fusion protein. Moreover, recombinant hIFN-γ and hIFN-γ-ELP proteins purified from E. coli possessed a relatively similar bioactivity based on viral cytopathic assay., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objectives: This study examined the epidemiological, clinical, and immunological characteristics of the 2015 dengue outbreak in Taiwan., Methods: Clinical data were collected from dengue fever (DF) and dengue hemorrhagic fever (DHF) patients. A phylogenetic tree was used to analyze the source of the outbreak strain. Paired plasma samples from DF/DHF patients were used for antibody-dependent enhancement (ADE) assay and cytokine multiplex biometric immunoassay to validate the immunological mechanism., Results: This outbreak mainly occurred in two of the southern cities of Taiwan: Tainan (n=22 777; 52%) and Kaohsiung (n=19 784; 45%). A high DHF death rate was noted (34.6%). The case (DHF) and control (DF) study indicated that older age (>60 years), type II diabetes, and hypertension were risk factors correlated with the development of DHF (p< 0.0001). The phylogenetic tree results suggested that the outbreak-associated strain was dengue virus serotype 2 and cosmopolitan genotype, forming a stable cluster with the isolates from Thailand and Indonesia (bootstrap value of 99%). Cytokine analyses demonstrated that levels of interleukin (IL)-6, IL-4, IL-13, IL-1β, interferon gamma (IFN-γ), and granulocyte-macrophage colony-stimulating factor (GM-CSF) were significantly higher in DHF patients compared to DF patients (p< 0.001). The ADE assay showed that diluted plasma containing preexisting dengue antibodies from DHF patients significantly enhanced dengue infection (p< 0.05)., Conclusion: The results suggest that older age, type II diabetes, hypertension, immunological cytokine dysregulation, and preexisting dengue antibodies inducing ADE infection are correlated with dengue severity. This study also indicates that the largest dengue outbreak in Taiwan might have been a result of imported DF from dengue epidemic regions., (Copyright © 2019 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Not all HIV-infected patients receiving cART are able to recover optimal CD4-T cell levels despite achieving undetectable viremia. We evaluated the potential association between polymorphisms (SNPs) in cytokines involved in immune response (IL15, IFNγ and IL19) and the failure to achieve optimal CD4 T-cells restoration after cART. For this, we carried out a retrospective study in 412 HIV-infected patients starting cART with CD4<200 cells/μL. These patients were classified as immunological non-responders (INR) if having a CD4 increase (ΔCD4) below 200 cells/μL after two years on successful cART. IL15, IFNγ and IL19 polymorphisms were genotyped using Sequenom's MassARRAY platform. We found 134 INR patients with a median [IQR] ΔCD4 = 133[73-174] cells/μL. In the multivariate analysis adjusted for age, sex, infection route, ethnic origin, hepatitis co-infection and HIV infection length, the AA genotype of the SNP rs2430561 in IFNγ (OR:2.01[1.13-3.56], p = 0.017) and the TT genotype of polymorphism rs2243191 in IL19 (OR:2.58 [1.17-5.68], p = 0.019) showed significant association with the INR status. Our results show that polymorphisms in IFNγ and IL19 genes significantly impacts in the probability of not achieving an optimal immune recovery in HIV-patients starting cART with CD4 T-cells <200 cells/μL. Thus, these SNPs could represent potential predictive markers of the immunodiscordant response., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Preclinical assays play a key role in research in research on the neurobiology of pain and the development of novel analgesics. Drugs available for the treatment of inflammatory pain are not fully effective and show adverse effects. Thus, we investigated the antinociceptive, anti-inflammatory and anti-hyperalgesic effects of bis(3-amino-2-pyridine) diselenide (BAPD), a new analgesic drug prototype. BAPD effects were investigated using nociception models induced by chemical (glutamate), immunologic (Freund's Complete Adjuvant - CFA) and thermal stimuli in Swiss mice. Mice were orally (p.o.) treated with BAPD (0.1-50 mg/kg) 30 min prior to the glutamate and hot-plate tests and a time-course (0.5 up to 8 h) of the antinociceptive effect of BAPD (50 mg/kg, p. o.) was evaluated in a CFA model. In the CFA model, BAPD effects on cyclooxygenase-2 (COX-2), tumor necrosis factor (TNFα) and interferon-γ (INF-γ) expression, myeloperoxidase (MPO) activity, oxidative (2,2'-Azino-bis-3-ethylbenzothiazoline 6-sulfonic acid and 2,2-diphe- nyl-1-picrylhydrazyl levels) and histological parameters were evaluated. The safety of the compound (50 and 300 mg/kg, p. o.) was verified for 72 h. BAPD reduced the licking time induced by glutamate and caused an increase in latency response to thermal stimulus. Naloxone reversed the antinociceptive effect of BAPD. Paw edema formation induced by glutamate or CFA injection was reduced by BAPD. Mechanical hyperalgesia induced by CFA was attenuated by BAPD. BAPD did not protect against the increase in MPO activity and decrease of the 2,2'-Azino-bis-3-ethylbenzothiazoline 6-sulfonic acid and 2,2-diphe- nyl-1-picrylhydrazyl levels induced by CFA. BAPD protected against histological alterations and reduction on the levels of gene expression COX-2 and INF-γ in the paw of mice exposed to CFA. BAPD was safe at the doses and time evaluated. BAPD exerts acute antinociceptive, anti-inflammatory and anti-hyperalgesic actions, suggesting that it may represent an alternative in the future development of new therapeutic strategies., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The delivery of DNA vaccines is the principle impediment for implementation of DNA vaccination on a mass scale. In this study, we report a temperature induced conditionally expressed phage PhiX174 gene E mediated lysis of Salmonella under in vivo conditions that can increase the immunogenicity of a DNA vaccine delivered via Salmonella carrier system. We electroporated gene E encoding lysis plasmid pJHL187 along with the pcDNA-HA plasmid encoding H1N1 HA into attenuated Salmonella Typhimurium, strain JOL1893. Using C57BL/6 mice as the model, we showed that the mice intragastrically vaccinated with JOL1893 induced significant production of HA-specific humoral and cell mediated immune responses compared to the JOL1837, which carry pcDNA-HA plasmid alone. Furthermore, mice vaccinated with JOL1893 vaccine were fully protected against the lethal H1N1 challenge compared to the JOL1837 strain, which showed 90% protection only. However, none of the animals survived treated with either the PBS or the Salmonella carrying empty vector. Taken together, our results indicate that mucosal immunization with conditional lysis enabled live attenuated S. Typhimurium as a DNA vaccine carrier can induce efficient systemic and mucosal immune responses, and improves immune protection against a highly pathogenic H1N1 infection in mice model., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Equine herpesvirus 1 (EHV-1) is the causative agent of a number of equine disease manifestations, including severe disease of the central nervous system, respiratory infections, and abortion storms. Our results showed that intranasal treatment with CpG-B oligodeoxynucleotides (ODN 1826) protected CBA mice from pathogenic EHV-1 RacL11 challenge. The IFN-γ gene and seven interferon-stimulated genes (ISGs) were upregulated 39.4- to 260.3-fold at 8 h postchallenge in the lungs of RacL11-challenged mice that had been treated with CpG-B ODN. Interestingly, IFN-γ gene expression was upregulated by 26-fold upon RacL11 challenge in CpG-B ODN-treated mice lungs as compared to that of CpG-A ODN (ODN 1585)-treated mice lungs; however, the seven ISGs were upregulated by 2.4-5.0-fold, suggesting that IFN-γ is a major factor in the protection of CBA mice from the lethal challenge. Pre-treatment with IFN-γ significantly reduced EHV-1 yield in murine alveolar macrophage MH-S cells, but not in mouse lung epithelial MLE12 cells. These results suggest that CpG-B ODN may be used as a prophylactic agent in horses and provide a basis for more effective treatment of EHV-1 infection., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Aims: Coronary artery disease (CAD) ranks the leading cause of death globally. Interferon-γ (IFN-γ) gene, along with long noncoding RNA (lncRNA) BRAF-activated noncoding RNA (BANCR), could coordinately function in the occurrence of CAD. We hypothesized that level of IFN-γ, genetic variants of IFN-γ and BANCR gene should be associated with the occurrence of CAD., Materials and Methods: A case-control study was conducted in Chinese population., Key Findings: We found that serum level of IFN-γ in CAD cases was significantly higher than that in controls (P < 0.001). Compared with the first quartile, all of the second (OR: 1.87; 95% CIs: 1.33-2.62), the third (OR: 1.79; 95% CIs: 1.30-2.45), and the fourth (OR: 3.98; 95% CIs: 2.59-6.12) quartiles of serum level of IFN-γ were associated with increased risk of CAD (P < 0.05). We found IFN-γ gene (rs2069705 and rs2430561), and 2 variants in lncRNA BANCR (rs6559446 and rs79823312) could increase CAD susceptibility in allelic and dominant model, while IFN-γ rs2069705 and rs2430561, BANCR rs79823312 were also associated with CAD risk in additive model. IFN-γ rs2069705 and rs2430561 were associated with higher level of serum IFN-γ in CAD patients (P < 0.001)., Significance: This study confirmed the crucial role of IFN-γ and lncRNA BANCR in the occurrence of CAD, and might serve as the biomarkers of CAD screening and prevention., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Salmonella enterica serovar Typhimurium (S. Typhimurium) is a primary avian pathogen responsible for severe intestinal pathology in younger chickens and economic losses to poultry industry. Furthermore, S. Typhimurium is also able to cause infection in humans, characterized by acute gastrointestinal disease. A study was conducted to investigate antibody response and expression kinetics of interferon gamma (IFNγ), interleukin (IL-12, and IL-18) genes in broiler chicken at 0, 1, 3, 5, 7, 9, 11, 13, and 15 D post infection following experimental infection of S. Typhimurium. Immunological studies showed higher titres of IgG and IgM in the infected group as compared to the age-matched un-infected control group. The Real-Time PCR-based gene expression analysis revealed significant increase of IFNγ, IL-12, and IL-18 mRNA levels in the infected group as compared to their respective controls (P < 0.05). The present study shall help in understanding the immune responses in birds, thus allowing development of more effective vaccines and vaccination strategies., (© 2018 Poultry Science Association Inc.)

Background: Mouse models of allergic asthma play a crucial role in exploring of asthma pathogenesis and testing of novel anti-inflammatory drugs. Widely used acute asthma models usually developed with adjuvant (aluminum hydroxide (alum)) do not reproduce one of the main asthma feature - airway remodeling while chronic asthma model mimic the pathophysiology of human disease. Moreover, the use of alum causes distress in experimental animals and impedes the test of adjuvant-containing drugs. In this study, we aimed to develop a chronic adjuvant-free asthma model with pronounced asthmatic phenotype., Methods: Female BALB/c mice were divided into 3 groups. The first group was sensitized with intraperitoneal injections of ovalbumin (OVA) emulsified in aluminum hydroxide on days 0, 14, 28 followed by two stages of intranasally challenge with OVA on days 41-43 and 62-64. The second group was subcutaneously sensitized with the same dose of OVA without adjuvant and challenged on the same days. The third group (negative control) included mice which did not received any kind of treatment (i.e. sensitization and challenge). Serum levels of OVA-specific IgE, IgG2a and IgG1 antibodies were detected by ELISA. Airway hyper-responsiveness was measured by non-invasive plethysmography on days 44 and 65. Bronchoalveolar lavage fluids (BALF) sampled in all groups on days 45 and 66 were analyzed by light microscopy. The left lung was removed for histological analysis. The IL-4 and IFNγ mRNA expression in BALF cells was evaluated by RT-PCR., Results: The OVA-specific IgE antibody response was two-fold increased in mice from adjuvant-free group compared to the adjuvant group that reflects reorientation of immune response towards Th2 phenotype. At the same time, the level of OVA-specific IgG1 and IgG2a antibodies was increased in the adjuvant group. Airway hyperresponsiveness to methacholine in mice of both experimental groups was two-fold higher than in control. Analysis of cell composition in BAL has shown a significant increase in eosinophil count in both experimental groups that indicate the development of allergic inflammation. Lung histology revealed airway remodeling in both experimental groups including goblet cell hyperplasia/metaplasia, thickening of airway walls, collagen deposition in the wall of distal airways. Additionally, the tendency to develop hypertrophy of bronchial smooth muscle layer was observed. Study of gene expression in BAL cells revealed the increase of IL-4 level in both adjuvant and adjuvant-free groups while IFNγ expression in both experimental groups was similar to control group., Conclusion: We have developed a chronic adjuvant-free mouse asthma model which possesses all necessary features of the disease including airway remodeling and is more suitable for pre-clinical evaluation of novel therapeutic approaches including adjuvant-containing drugs., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Malaria-associated acute respiratory distress syndrome (MA-ARDS) and acute lung injury (ALI) are complications that cause lung damage and often leads to death. The MA-ARDS/ALI is associated with a Type 1 inflammatory response mediated by T lymphocytes and IFN-γ. Here, we used the Plasmodium berghei NK65 (PbN)-induced MA-ALI/ARDS model that resembles human disease and confirmed that lung CD4 + and CD8 + T cells predominantly expressed Tbet and IFN-γ. Surprisingly, we found that development of MA-ALI/ARDS was dependent on functional CCR4, known to mediate the recruitment of Th2 lymphocytes and regulatory T cells. However, in this Type 1 inflammation-ARDS model, CCR4 was not involved in the recruitment of T lymphocytes, but was required for the emergence of TNF-α/iNOS producing dendritic cells (Tip-DCs) in the lungs. In contrast, recruitment of Tip-DCs and development of MA-ALI/ARDS were not altered in CCR2 -/ - mice. Importantly, we showed that NOS2 -/ - mice are resistant to PbN-induced lung damage, indicating that reactive nitrogen species produced by Tip-DCs play an essential role in inducing MA-ARDS/ALI. Lastly, our experiments suggest that production of IFN-γ primarily by CD8 + T cells is required for inducing Tip-DCs differentiation in the lungs and the development of MA-ALI/ARDS model.

Multiple lines of inquiry demonstrate alterations to immune function in psychosis. Clinically, this is reflected by elevated proinflammatory cytokines in serum, indicating activation of circulating immune cells. Data from isolated cells in clinical populations support the presence of altered activity of pertinent intracellular signaling pathways. Here, we focus on the well-characterized IFN-γ mediated JAK-STAT1 signaling pathway, which is involved in multiple aspects of immunity, including activation of circulating immune cells to a proinflammatory phenotype. By measuring a transcriptional signature characteristic of activation of this pathway, we demonstrate that JAK-STAT1 signature gene expression is suppressed in participants with psychosis who are early in illness and in participants who are hospitalized with an acute exacerbation of psychosis. Furthermore, we find that this expression signature normalizes in participants who have a longer illness duration and chronic, but not acute, psychopathology. This relationship of JAK-STAT1 signature gene expression with clinical characteristics highlights the temporal and contextual complexity of alterations to immune activity in psychosis and provides important insight into the functional state of circulating immune cells. These findings are of particular interest given recent research illustrating the importance of peripherally derived immune cells and the effectors they secrete in mediating neurophysiological processes of relevance for psychiatric illness., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Rice hull polysaccharides (RHPS) have been reported to activate innate immunity in mice. This study investigated the effects of RHPS on natural killer (NK) cell-mediated cytotoxicity in vitro and the possible underlying anticancer mechanisms in vivo. The results showed that sustained exposure to RHPS increased NK-92MI cell-mediated cytotoxicity in a time- and concentration-dependent manner. In addition, RHPS upregulated the expression of Fas ligand, TNF-related apoptosis-inducing ligand, perforin, and granzyme B of NK-92MI cells and induced the secretion of IFN-γ and TNF-α. In the in vivo experiment, colon cancer CT26-bearing mice were used to investigate the effects of RHPS in cytotoxicity and anticancer. The results revealed that RHPS inhibited cancer weight and volume in CT26-bearing mice and significantly upregulated splenic cytotoxicity and NK-cell population. Moreover, RHPS treatment increased NK-cell infiltration in tumors. Thus, RHPS can enhance NK-cell activation in vivo and in vitro, thereby exhibiting anticancer activity., (Copyright © 2018. Published by Elsevier B.V.)

Toxoplasma gondii is a common perorally transmitted parasite; however, its immunopathogenesis in gut-associated tissues remains unclear. Here, we compared disease manifestation in C57BL/6 immunocompetent wild type (WT) mice and immunocompromised interferon (IFN)-γ-deficient (GKO) mice after peroral infection (PI) with T. gondii cysts (Fukaya strain). Strong PI-induced Th1 cytokine expression was detected in WT mice. Moreover, bradyzoite-specific T.g.HSP30/bag1 mRNA was detected in the ileum parenchyma and Peyer's patches (PP), but not in the mesenteric lymph nodes, at 7 days post-infection in WT mice, and was significantly higher than that in GKO mice. Nested PCR showed that parasites existed in ileum parenchyma at days 1 and 1.5 post-PI in GKO and WT mice, respectively. In addition, quantitative competitive-PCR indicated that T. gondii first colonized the PP (day 3 post-PI), followed by the ileum parenchyma and mesenteric lymph nodes, spleen, and portal and aortic blood (day 7 post-PI). Although parasites were consistently more abundant in GKO mice, similar invasion and dissemination patterns were observed in the two hosts. Collectively, these data suggest that some zoites differentiate from tachyzoites to bradyzoites in the ileum and that T. gondii initially invades the ileum parenchyma, and then accumulates and proliferates in the PP before disseminating through the lymphatic systems of both GKO and WT hosts., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Allergic rhinitis (AR) is a common chronic inflammatory disease that has a significant impact on the quality of life of patients. Our previous study suggested that PM2.5 might affect pediatric AR through epigenetic regulation, but the underlying mechanisms remained unclear. In this study, an experimental murine AR model was created, and the nasal symptoms, pathological changes, the DNA methylation level of the IFN-γ gene promoter and activation of the ERK-DNMT pathway were evaluated after treatment with PM2.5. Our results showed that PM2.5 exposure led to more severe symptoms of AR in mice. In addition, PM2.5 exposure significantly decreased the percentage of Th1 T cells in the AR group, and this change was correlated with increased DNA methylation of the IFN-γ gene promoter in CD4 + T cells (r=-0.916, p = 0.029). In addition, PM2.5 exposure increased the activation of the ERK-DNMT pathway in CD4+ T cells, and inhibiting this effect rescued the polarization of the Th1/Th2 balance toward Th2, thereby decreasing the risk of AR. Our findings demonstrate that PM2.5 exposure could exacerbate AR by increasing the DNA methylation of the IFN-γ gene promoter in CD4 + T cells via the ERK-DNMT pathway, and these effects were rescued when the ERK-DNMT pathway was inhibited., (Copyright © 2018 Elsevier B.V. All rights reserved.)