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Previous reports have shown that IL‐6 and IFN‐⍺ induce distinct transcriptomic and morphological changes in microglia. Here, we demonstrate that IL‐6 increases tissue surveillance, migration and phagocytosis in primary murine microglia, whereas IFN‐⍺ inhibits these functions. Our results provide a crucial link between transcriptome and function. It holds the potential to serve as the foundation for future studies aimed at identifying therapeutic targets for cytokine‐mediated neuroinflammatory diseases. [ABSTRACT FROM AUTHOR]

Objective　To investigate the change and potential role of Mindin protein in the treatment of chronic hepatitis B （CHB） with PEG-IFNα-2b. Methods　A total of 29 CHB patients who received the treatment with PEG-IFNα-2b in The Second Affiliated Hospital of Xi’an Jiaotong University from January 2018 to December 2019 were enrolled， and according to their clinical outcome， they were divided into cured group with 17 patients and uncured group with 12 patients. Peripheral blood samples were collected from both groups at baseline， 12 weeks， and 24 weeks to measure blood routine indices， liver function parameters， hepatitis B markers， and Mindin protein. HBsAg， alanine aminotransferase （ALT）， aspartate aminotransferase （AST）， and Mindin protein at different time points were compared between the two groups. The independent-samples t test was used for comparison of normally distributed continuous data between two groups， and the Mann-Whitney U test was used for comparison of non-normally distributed continuous data between two groups； a Spearman correlation analysis was used to investigate correlation； a multiple linear regression analysis was used to investigate the influence of HBsAg and ALT on the content of Mindin protein. Results　The analysis of baseline data showed that there were significant differences in the levels of HBsAg， HBeAb， albumin， and albumin/ globulin ratio between the cured group and the uncured group （all P<0.05）. The cured group tended to have a gradual increase in the level of Mindin， and the level of Mindin at 24 weeks was significantly higher than that at baseline （P<0.05）. The cured group had a significantly higher level of Mindin protein than the uncured group at 24 weeks （P=0.019）. The cured group had a significantly lower level of HBsAg than the uncured group （P<0.05）， with a significant change from baseline to each time point within the cured group （P<0.05）. In addition， the levels of ALT and AST in the cured group tended to first increase and then decrease， and the expression levels at 12 weeks were significantly higher than those at baseline （P<0.05）. At 12 weeks， there was a strong linear correlation between Mindin protein levels and ALT in the untreated group （r=0.760 8， P<0.05）， and further multiple linear regression analysis also demonstrated a linear relationship between the two （b=1.571， P=0.019）. Conclusion　There is a significant difference in the level of Mindin protein between the cured group and the non-cured group after 24 weeks of PEG-IFNα-2b antiviral treatment， and therefore， detecting the dynamic changes of Mindin protein can better predict the treatment outcome of CHB， which provides a reference for clinical practice. [ABSTRACT FROM AUTHOR]

Myeloproliferative neoplasms (MPN) are rare hematologic disorders characterized by clonal hematopoiesis. Familial clustering is observed in a subset of cases, with a notable proportion exhibiting heterozygous germline mutations in DNA double-strand break repair genes (e.g., BRCA1). We investigated the therapeutic potential of targeting BRCA1 haploinsufficiency alongside the JAK2V617F driver mutation. We assessed the efficacy of combining the PARP inhibitor olaparib with interferon-alpha (IFNα) in CRISPR/Cas9-engineered Brca1+/− Jak2V617F-positive 32D cells. Olaparib treatment induced a higher number of DNA double-strand breaks, as demonstrated by γH2AX analysis through Western blot (p = 0.024), flow cytometry (p = 0.013), and confocal microscopy (p = 0.071). RAD51 foci formation was impaired in Brca1+/− cells compared to Brca1+/+ cells, indicating impaired homologous recombination repair due to Brca1 haploinsufficiency. Importantly, olaparib enhanced apoptosis while diminishing cell proliferation and viability in Brca1+/− cells compared to Brca1+/+ cells. These effects were further potentiated by IFNα. Olaparib induced interferon-stimulated genes and increased endogenous production of IFNα in Brca1+/− cells. These responses were abrogated by STING inhibition. In conclusion, our findings suggest that the combination of olaparib and IFNα presents a promising therapeutic strategy for MPN patients by exploiting the synthetic lethality between germline BRCA1 mutations and the JAK2V617F MPN driver mutation. [ABSTRACT FROM AUTHOR]

Objective To investigate the value of PreS1 level in predicting HBsAg clearance in children with HBeAg-positive chronic hepatitis B (CHB) after 48 weeks of IFN-α treatment. Methods A total of 88 children with HBeAg-positive CHB, aged 1-16 years, who received 48 weeks of IFN-α treatment from June 2016 to January 2020 were enrolled. HBsAg quantification (qHBsAg), HBV DNA quantification, and alanine aminotransferase were measured every three months, and magnetic particle chemiluminescence immunoassay (double-antibody sandwich) was used to measure the level of PreS1. According to whether HBsAg clearance was achieved at the end of IFN-α treatment for 48 weeks, the 88 children were divided into HBsAg clearance group with 17 children and non-HBsAg clearance group with 71 children. The Mann-Whitney U test was used for comparison of quantitative data between the two groups, and the chi-square test or the Fisher’s exact test was used for comparison of qualitative data between the two groups. The Spearman rank correlation test was used to evaluate the correlation of PreS1 level with other biomarkers, and the area under the ROC curve (AUC) was used to investigate the value of different markers in predicting HBsAg clearance at the end of 48-week IFN-α treatment. Results PreS1 level was positively correlated with the serum levels of qHBsAg and HBV DNA (r=0.912 and 0.535, both P＜0.05), and baseline PreS1/qHBsAg ratio (AUC=0.694) had a better value than PreS1 level (AUC=0.530) and qHBsAg level (AUC=0.514) in predicting HBsAg clearance at week 48. PreS1 level (AUC=0.867, P＜0.001) and the reduction in PreS1/qHBsAg ratio (AUC=0.800, P=0.002) at week 12 of treatment had a good value in predicting HBsAg clearance at week 48. PreS1 level, qHBsAg level, and HBV DNA at week 24 of treatment could effectively predict HBsAg clearance at week 48, with AUCs of 0.917, 0.949, and 0.762, respectively (all P＜0.001). Conclusion Serum PreS1 level and the reduction in PreS1/qHBsAg ratio at week 12 of treatment can be used as candidate markers for predicting HBsAg clearance in children with CHB during IFN-α treatment. [ABSTRACT FROM AUTHOR]

Background: Neurodegenerative diseases (NDs) impose significant financial and healthcare burden on populations all over the world. The prevalence and incidence of NDs have been observed to increase dramatically with age. Hence, the number of reported cases is projected to increase in the future, as life spans continues to rise. Despite this, there is limited effective treatment against most NDs. Interferons (IFNs), a family of cytokines, have been suggested as a promising therapeutic target for NDs, particularly IFN-α, which governs various pathological pathways in different NDs. Objective: This systematic review aimed to critically appraise the currently available literature on the pathological role of IFN-α in neurodegeneration/NDs. Methods: Three databases, Scopus, PubMed, and Ovid Medline, were utilized for the literature search. Results: A total of 77 journal articles were selected for critical evaluation, based on the inclusion and exclusion criteria. The studies selected and elucidated in this current systematic review have showed that IFN-α may play a deleterious role in neurodegenerative diseases through its strong association with the inflammatory processes resulting in mainly neurocognitive impairments. IFN-α may be displaying its neurotoxic function via various mechanisms such as abnormal calcium mineralization, activation of STAT1-dependent mechanisms, and increased quinolinic acid production. Conclusion: The exact role IFN-α in these neurodegenerative diseases have yet to be determine due to a lack in more recent evidence, thereby creating a variability in the role of IFN-α. Future investigations should thus be conducted, so that the role played by IFN-α in neurodegenerative diseases could be delineated. [ABSTRACT FROM AUTHOR]

Erdheim-Chester disease (ECD), also known as non-Langerhans cell histiocytosis, is a multi-systemic disease with unclear pathogenesis. Based on a small number of case studies, pegylated interferon-a (PEG-IFN-α) has been used as the front-line treatment option. However, there are limited data regarding administration of ropegylated-interferon α-2b (ROPEG-IFN-α 2b) for ECD patients. Herein, we report two cases of severe ECD treated with two types of PEG-IFN-α. One patient with heart and skeleton involvement and BRAF V600E mutation was treated with weekly PEG-IFN-a 2a. Another patient with bone involvement and no BRAF V600E mutation was administered monthly ROPEG-IFN-α 2b. The two types of PEG-IFN-α showed excellent disease control, excellent survival outcomes, and manageable toxicities in ECD patients. These results suggest that ROPEG-IFN-a 2b could be used equivalently to PEG-IFN-α 2a for management of advanced ECD. [ABSTRACT FROM AUTHOR]

Introduction: Juvenile systemic lupus erythematosus (j-SLE) is a rare chronic autoimmune disease affecting multiple organs. Ranging from minor features, such as headache or mild cognitive impairment, to serious and life-threatening presentations, j-neuropsychiatric SLE (j-NPSLE) is a therapeutic challenge. Thus, the diagnosis of NPSLE remains difficult, especially in pediatrics, with no specific biomarker of the disease yet validated. Objectives: To identify central nervous system (CNS) disease biomarkers of j-NPSLE. Methods: A 5-year retrospective tertiary reference monocentric j-SLE study. A combination of standardized diagnostic criteria and multidisciplinary pediatric clinical expertise was combined to attribute NP involvement in the context of j-SLE. Neopterin and interferon-alpha (IFN-α) protein levels in cerebrospinal fluid (CSF) were assessed, together with routine biological and radiological investigations. Results: Among 51 patients with j-SLE included, 39% presented with j-NPSLE. J-NPSLE was diagnosed at onset of j-SLE in 65% of patients. No specific routine biological or radiological marker of j-NPSLE was identified. However, CSF neopterin levels were significantly higher in active j-NPSLE with CNS involvement than in j-SLE alone (p = 0.0008). Neopterin and IFN-α protein levels in CSF were significantly higher at diagnosis of j-NPSLE with CNS involvement than after resolution of NP features (respectively p = 0.0015 and p = 0.0010) upon immunosuppressive treatment in all patients tested (n = 10). Both biomarkers correlated strongly with each other (Rs = 0.832, p < 0.0001, n = 23 paired samples). Conclusion: CSF IFN-α and neopterin constitute promising biomarkers useful in the diagnosis and monitoring of activity in j-NPSLE. [ABSTRACT FROM AUTHOR]

Systemic Lupus Erythematosus (SLE) is a multifactorial chronic systemic autoimmune disease. It is characterized by a lack of immune tolerance to autoantigens such as nuclear antigens. The aim of the study is to assess the interferon-alpha (IFN-α) serum level in Iraqi patients with SLE and determine its potential relation to different clinical and laboratory parameters and disease activity. 100 SLE patients were all females and with a mean of age 31.3 ± 10 years (16- 63years) and disease duration of 5.8 ± 3.7years (1 month to 15 years). The average of SLEDAI score ranged from 2 to 22 with a mean of (8.53 ±3.42). Proteinuria, ESR, creatinine and AST were significantly higher (65% vs. 10% and 0.62±0.11 vs. 0.70±0.14 mg/dl respectively) while the PLT was significantly lower (231.9±88.8 vs. 282.3±67.3 10³ /mL) (p< 0.001) among SLE patients as compared to control. Serum levels of IFN-α were increased in the SLE patients compared to control, and no significant difference has been observed (208.7±530.0 vs. 63.7±34.8 pg/ml) respectively (P=0.245). Interferon-alpha showed a significant negative correlation with the SLE Disease Activity Index (SLEDAI) in the active and inactive groups. There were no significant variations in all study parameters across IFN-α serum levels (p greater than 0.05). In conclusion, the results suggest a risk effect for female gender and age in etiology of SLE. IFN-α could not be considered as biomarker or to have a risk effect in SLE patients or perpetuate the disease activity. No evidence for any correlation between the IFN-α serum level and any clinical manifestations or laboratory investigation of the disease in current study except for age and disease duration, which suggests them as a risk factor for increasing the IFN-α serum level. [ABSTRACT FROM AUTHOR]

A deep and stable molecular response (DMR) is a prerequisite for a successful treatment-free remission (TFR) in chronic myeloid leukemia (CML). In order to better identify and analyze potential candidates of successful TFR, we examined the phenotypic and functional host immune compartment in DMR patients who had received TKI treatment only (TKI-only) or had been previously treated with interferon-alpha (IFNα + TKI) or had received IFNα treatment only (IFNα-only). The T/NK-cell subset distribution, NK- and T-cell cytokine production, activation and maturation markers were measured in 44 patients in DMR treated with IFNα only (9), with IFNα + TKI (11) and with TKI-only (24). IFNα + TKI and TKI-only groups were eligible to TKI discontinuation according to the NCCN and ESMO guidelines (stable MR4 for more than two years). In IFNα-treated patients, we documented an increased number of lymphocytes capable of producing IFNγ and TNFα compared to the TKI-only group. In INFα + TKI patients, the percentage of NKG2C expression and its mean fluorescence intensity were significantly higher compared to the TKI-only group and to the INFα-only group in the CD56dim/CD16+ NK cell subsets (INFα + TKI vs. TKI-only p = 0.041, p = 0.037; INFα + TKI vs. INFα-only p = 0.03, p = 0.033, respectively). Furthermore, in INFα-only treated patients, we observed an increase of NKp46 MFI in the CD56bright/CD16- NK cell subset that becomes significant compared to the INFα + TKI group (p = 0.008). Our data indicate that a previous exposure to IFNα substantially and persistently modified the immune system of CML patients in memory T lymphocytes, differentiated NKG2C+ "long-lived" NK cells responses, even years after the last IFNα contact. [ABSTRACT FROM AUTHOR]

Systemic Lupus Erythematosus (SLE) is a multifactorial chronic systemic autoimmune disease. It is characterized by a lack of immune tolerance to autoantigens such as nuclear antigens. The aim of the study is to assess the interferon-alpha (IFN-α) serum level in Iraqi patients with SLE and determine its potential relation to different clinical and laboratory parameters and disease activity. 100 SLE patients were all females and with a mean of age 31.3 ± 10 years (16- 63years) and disease duration of 5.8 ± 3.7years (1 month to 15 years). The average of SLEDAI score ranged from 2 to 22 with a mean of (8.53 ±3.42). Proteinuria, ESR, creatinine and AST were significantly higher (65% vs. 10% and 0.62±0.11 vs. 0.70±0.14 mg/dl respectively) while the PLT was significantly lower (231.9±88.8 vs. 282.3±67.3 103/mL) (p< 0.001) among SLE patients as compared to control. Serum levels of IFN-α were increased in the SLE patients compared to control, and no significant difference has been observed (208.7±530.0 vs. 63.7±34.8 pg/ml) respectively (P=0.245). Interferon-alpha showed a significant negative correlation with the SLE Disease Activity Index (SLEDAI) in the active and inactive groups. There were no significant variations in all study parameters across IFN-α serum levels (p greater than 0.05). In conclusion, the results suggest a risk effect for female gender and age in etiology of SLE. IFN-α could not be considered as biomarker or to have a risk effect in SLE patients or perpetuate the disease activity. No evidence for any correlation between the IFN-α serum level and any clinical manifestations or laboratory investigation of the disease in current study except for age and disease duration, which suggests them as a risk factor for increasing the IFN-α serum level. [ABSTRACT FROM AUTHOR]

Summary: Patients with essential thrombocythaemia (ET) have an increased risk of thromboembolic events, which may differ according to different cytoreductive drugs. We investigated the effect of cytoreductive treatment on platelet function and turnover in ET patients. Blood samples were obtained at 1 and 24 h after aspirin intake. Platelet function was evaluated by platelet aggregation and flow cytometry. Platelet turnover was assessed by immature platelet count, immature platelet fraction (IPF) and mean platelet volume (MPV). A total of 47 ET patients were included and grouped into 21 patients not receiving cytoreductive treatment, 15 patients receiving hydroxycarbamide and 11 patients receiving pegylated interferon alpha (peg‐IFN). Patients receiving peg‐IFN had significantly higher IPF and MPV than the other ET groups. Patients not receiving cytoreductive treatment had significantly higher platelet aggregation 24 h after aspirin intake than the other ET groups (p‐values from 0.03 to 0.0002). Patients receiving hydroxycarbamide had significantly higher expression of platelet granule makers, P‐selectin and CD63, than patients receiving peg‐IFN (p‐values ≤0.003). Cytoreduction provides more consistent platelet inhibition compared with no cytoreductive treatment. Moreover, peg‐IFN provides superior inhibition of platelet activation markers than hydroxycarbamide, which in part may explain differences in risk of thromboembolic events in ET patients. [ABSTRACT FROM AUTHOR]

Aim To determine the value of IFN (intzerferon)-α in the patients with systemic lupus erythematosus (SLE) and to correlate IFN-α with values of non-specific biochemical parameters of inflammation (C-reactive protein, leukocytes values, erythrocyte sedimentation rate, albumins and globulins). Methods Research included 55 patients with SLE diagnosis and a control group consisted of 25 healthy subjects (during period 2019-2020). IFN (Interferon)-α and non-specific biochemical parameters of inflammation were obtained using standard protocols. Results IFN-α values were independent of gender (p=0.95). The difference in serum IFN-α values in relation with the age in the SLE group was statistically significant (p=0.036). Only serum globulin was significantly higher (p=0.0023) in IFN-α positive compared to IFN-α negative SLE patients. A statistically significant correlation between the values of IFN-α and globulin was proved (r=0.315; p=0.019). No significant correlation was found between other non-specific biochemical parameters and IFN-α values. Conclusion Increased IFN-α values were observed in younger patients, and the correlation between IFN and globulin was proved. [ABSTRACT FROM AUTHOR]

Background: Systemic lupus erythematosus (SLE) is an autoimmune disorder affecting various organ systems with unknown etiology. Interleukin-6 (IL-6) and interferon-alpha (IFN-α) have been shown to have a major role in disease pathogenesis, and they correlate with SLE disease activity, but reports in the literature are conflicting. The present study aims to investigate the significance of IL-6 and IFN-α levels in SLE pathogenesis in an eastern Indian cohort. Material and Methods: 70 SLE patients fulfilled SLICC 2012 criteria, and 40 age- and gender-matched healthy controls (HC) were enrolled. Baseline characteristics along with disease activity were recorded for all patients. Levels of IL-6 and IFN-α were measured by using ELISA. For the meta-analysis, published articles were searched through different databases. Two independent researchers extracted data, and the meta-analysis was performed with CMA v3.1. Results: The plasma levels of IL-6 and IFN-α in SLE patients were significantly elevated compared to HC (IL-6: p <.0001, IFN-α: p = 0.01). SLEDAI score correlated positively with plasma IL-6 (p <.0001, r = 0.46) and IFN-α levels (p <.0001; r = 0.47). Meta-analysis of previous reports, including our case–control data, revealed higher IL-6 (p <.0001) and IFN-α (p =.005) in SLE patients compared to HC. Furthermore, IL-6 (p <.0001, r = 0.526) and IFN-α (p <.0001; r = 0.371) levels positively correlated with the disease activity. Conclusion: IL-6 and IFN-α levels are elevated in SLE and they correlate with disease activity. Further studies with a larger sample size in different populations are required to validate our findings. [ABSTRACT FROM AUTHOR]

Immunotherapy, which stimulates the body's immune system, has received a considerable amount of press in recent years because of its powerful benefits. Cancer immunotherapy has shown long-term results in patients with advanced disease that are not seen with traditional chemotherapy. Immune checkpoint inhibitors, cytokines like interleukin 2 (IL-2) and interferon-alpha (IFN), and the cancer vaccine sipuleucel-T have all been licensed and approved by the FDA for the treatment of various cancers. These immunotherapy treatments boost anticancer responses by stimulating the immune system. As a result, they have the potential to cause serious, even fatal, inflammatory and immune-related side effects in one or more organs. Immune checkpoint inhibitors (ICPIs) and chimeric antigen receptor (CAR) T-cell therapy are two immunotherapy treatments that are increasingly being used to treat cancer. Following their widespread usage in the clinic, a wave of immune-related adverse events (irAEs) impacting virtually every system has raised concerns about their unpredictability and randomness. Despite the fact that the majority of adverse effects are minimal and should be addressed with prudence, the risk of life-threatening complications exists. Although most adverse events are small and should be treated with caution, the risk of life-threatening toxicities should not be underestimated, especially given the subtle and unusual indications that make early detection even more difficult. Treatment for these issues is difficult and necessitates a multidisciplinary approach involving not only oncologists but also other internal medicine doctors to guarantee quick diagnosis and treatment. This study's purpose is to give a fundamental overview of immunotherapy and cancer-related side effect management strategies. [ABSTRACT FROM AUTHOR]

Aicardi-Goutières syndrome (AGS) is an autoinflammatory disease characterized by aberrant interferon (IFN)-α production. The major cause of morbidity in AGS is brain disease, yet the primary source and target of neurotoxic IFN-α remain unclear. Here, we demonstrated that the brain was the primary source of neurotoxic IFN-α in AGS and confirmed the neurotoxicity of intracerebral IFN-α using astrocyte-driven Ifna1 misexpression in mice. Using single-cell RNA sequencing, we demonstrated that intracerebral IFN-α-activated receptor (IFNAR) signaling within cerebral endothelial cells caused a distinctive cerebral small vessel disease similar to that observed in individuals with AGS. Magnetic resonance imaging (MRI) and single-molecule ELISA revealed that central and not peripheral IFN-α was the primary determinant of microvascular disease in humans. Ablation of endothelial Ifnar1 in mice rescued microvascular disease, stopped the development of diffuse brain disease, and prolonged lifespan. These results identify the cerebral microvasculature as a primary mediator of IFN-α neurotoxicity in AGS, representing an accessible target for therapeutic intervention. [Display omitted] • Neurotoxic IFN-α in Aicardi-Goutières syndrome (AGS) is primarily of cerebral origin • Endothelial cells are critical cellular targets of neurotoxic IFN-α • Chronically elevated intracerebral IFN-α causes a distinct cerebral microangiopathy • Neurodegeneration arises as a secondary consequence of IFN-α-driven microangiopathy Aicardi-Goutières syndrome is an autoinflammatory brain disease associated with increased interferon-α production, but the primary source and mediators of neurotoxicity are poorly described. Viengkhou et al. show that neurotoxic interferon-α originates in the central nervous system and mediates disease primarily through its effects on the cerebral microvasculature. This represents an accessible target for therapeutic intervention. [ABSTRACT FROM AUTHOR]

Background: Elevated production of the cytokines interleukin (IL)-6 or interferon (IFN)-α in the central nervous system (CNS) is implicated in the pathogenesis of neurological diseases such as neuromyelitis optica spectrum disorders or cerebral interferonopathies, respectively. Transgenic mice with CNS-targeted chronic production of IL-6 (GFAP-IL6) or IFN-α (GFAP-IFN) recapitulate important clinical and pathological features of these human diseases. The activation of microglia is a prominent manifestation found both in the human diseases and in the transgenic mice, yet little is known about how this contributes to disease pathology.Methods: Here, we used a combination of ex vivo and in situ techniques to characterize the molecular, cellular and transcriptomic phenotypes of microglia in GFAP-IL6 versus GFAP-IFN mice. In addition, a transcriptomic meta-analysis was performed to compare the microglia response from GFAP-IL6 and GFAP-IFN mice to the response of microglia in a range of neurodegenerative and neuroinflammatory disorders.Results: We demonstrated that microglia show stimulus-specific responses to IL-6 versus IFN-α in the brain resulting in unique and extensive molecular and cellular adaptations. In GFAP-IL6 mice, microglia proliferated, had shortened, less branched processes and elicited transcriptomic and molecular changes associated with phagocytosis and lipid processing. In comparison, microglia in the brain of GFAP-IFN mice exhibited increased proliferation and apoptosis, had larger, hyper-ramified processes and showed transcriptomic and surface marker changes associated with antigen presentation and antiviral response. Further, a transcriptomic meta-analysis revealed that IL-6 and IFN-α both contribute to the formation of a core microglia response in animal models of neurodegenerative and neuroinflammatory disorders, such as Alzheimer's disease, tauopathy, multiple sclerosis and lipopolysaccharide-induced endotoxemia.Conclusions: Our findings demonstrate that microglia responses to IL-6 and IFN-α are highly stimulus-specific, wide-ranging and give rise to divergent phenotypes that modulate microglia responses in neuroinflammatory and neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Coronaviruses (CoVs) have caused several global outbreaks with relatively high mortality rates, including Middle East Respiratory Syndrome coronavirus (MERS)-CoV, which emerged in 2012, and Severe Acute Respiratory Syndrome (SARS)-CoV-1, which appeared in 2002. The recent emergence of SARS-CoV-2 highlights the need for immediate and greater understanding of the immune evasion mechanisms used by CoVs. Interferon (IFN)-α is the body's natural antiviral agent, but its Janus kinase/signal transducer and activators of transcription (JAK/STAT) signalling pathway is often antagonized by viruses, thereby preventing the upregulation of essential IFN stimulated genes (ISGs). Therapeutic IFN-α has disappointingly weak clinical responses in MERS-CoV and SARS-CoV-1 infected patients, indicating that these CoVs inhibit the IFN-α JAK/STAT pathway. Here we show that in lung alveolar A549 epithelial cells expression of MERS-CoV-nsp2 and SARS-CoV-1-nsp14, but not MERS-CoV-nsp5, increased basal levels of total and phosphorylated STAT1 & STAT2 protein, but reduced IFN-α-mediated phosphorylation of STAT1-3 and induction of MxA. While MERS-CoV-nsp2 and SARS-CoV-1-nsp14 similarly increased basal levels of STAT1 and STAT2 in bronchial BEAS-2B epithelial cells, unlike in A549 cells, they did not enhance basal pSTAT1 nor pSTAT2. However, both viral proteins reduced IFN-α-mediated induction of pSTAT1-3 and ISGs (MxA, ISG15 and PKR) in BEAS-2B cells. Furthermore, even though IFN-α-mediated induction of pSTAT1-3 was not affected by MERS-CoV-nsp5 expression in BEAS-2B cells, downstream ISG induction was reduced, revealing that MERS-CoV-nsp5 may use an alternative mechanism to reduce antiviral ISG induction in this cell line. Indeed, we subsequently discovered that all three viral proteins inhibited STAT1 nuclear translocation in BEAS-2B cells, unveiling another layer of inhibition by which these viral proteins suppress responses to Type 1 IFNs. While these observations highlight cell line-specific differences in the immune evasion effects of MERS-CoV and SARS-CoV-1 proteins, they also demonstrate the broad spectrum of immune evasion strategies these deadly coronaviruses use to stunt antiviral responses to Type IFN. [ABSTRACT FROM AUTHOR]

Initial case series of small number of patients at the beginning of the pandemic reported a rather guarded prognosis for Behçet's syndrome (BS) patients infected with SARS-CoV-2. In this prospective study, we describe the incidence, clinical characteristics, disease course, management, and outcome in a large cohort of BS patients with laboratory-confirmed infection of SARS-CoV-2. We defined a cohort of 1047 registered BS patients who were aged between 16 and 60 years and seen routinely before the pandemic at the multidisciplinary outpatient clinic. We followed prospectively this cohort from beginning of April 2020 until the end of April 2021. During 13 months of follow-up, of the 1047 (599 M/448 F) patients, 592 (56.5%) were tested for SARS-CoV-2 PCR at least once and 215 (20.5%; 95% CI 0.18–0.23) were tested positive. We observed 2 peaks which took place in December 2020 and April 2021. Of the 215 PCR positive patients, complete information was available in 214. Of these 214, 14 (6.5%) were asymptomatic for COVID-19. In the remaining, the most common symptoms were anosmia, fatigue, fever, arthralgia, and headache. A total of 40 (18.7%) had lung involvement, 25 (11.7%) were hospitalized, 1 was admitted to the intensive care unit while none died. Favipiravir was the most prescribed drug (74.3%), followed by colchicine (40.2%), and hydroxychloroquine (20.1%) in the treatment of COVID-19. After COVID-19, 5 patients (2.3%) were given supplemental O2 and 31 (14.5%) antiaggregant or anticoagulants. During COVID-19, of the 214 PCR positive patients, 116 (54.2%) decreased the dose of their immunosuppressives or stopped taking completely; 36 (16.8%) experienced a BS flare which was mostly oral ulcers (10.3%). None of the patients reported a thrombotic event. A total of 93 (43.5%) patients reported BS flares after a median 45 days of COVID-19 infection and this was found to be significantly associated with immunosuppressive drug discontinuation. Multiple regression analysis adjusted for age and gender indicated that smoking and using interferon-alpha decreased the likelihood of getting COVID-19. The incidence and severity of COVID-19 did not differ between those who were using colchicine or not. The cumulative incidence of COVID-19 in this prospectively followed cohort of BS patients was almost two folds of that estimated for the general population living in Istanbul, Turkey, however, the clinical outcome of COVID-19 was not severe and there was no mortality. The protective effect of smoking and interferon deserves further investigation. On the other hand, colchicine did not have any positive or negative effect against COVID-19. Significant number of patients flared after COVID-19, however, this was significantly associated with immunosuppressive discontinuation during the infection. Contrary to our previous observations, COVID-19 did not seem to exacerbate thrombotic events during or after the infection. [ABSTRACT FROM AUTHOR]

Summary: Lymphocyte‐variant hypereosinophilic syndrome (L‐HES) is a rare disease driven by immunophenotypically aberrant T cells producing eosinophilopoetic cytokines such as interleukin‐5 (IL‐5). Treatment is challenging because L‐HES is relatively steroid resistant and not amenable to tyrosine kinase inhibitors. We searched the literature for clinical trials and observational studies, including case reports, of patients treated for L‐HES. In all, 25 studies were selected; two were randomised controlled trials of IL‐5 blockade, which included some patients with L‐HES, and the rest were observational studies. Corticosteroids are often used as first‐line therapy, but patients with L‐HES have lower response rates than other types of HES. Treatments that reduce symptoms and steroid dependence in some patients include interferon‐alpha (IFN‐α), anti‐IL‐5 monoclonal antibodies, cyclosporine and mycophenolate. These drugs target T‐cell activation and proliferation, or IL‐5 directly. Although effective, IFN‐α and cyclosporine were commonly reported to cause side‐effects resulting in discontinuation. Alemtuzumab can induce remissions, but these are generally short lived. The anti‐IL‐5 monoclonal antibodies mepolizumab and benralizumab are effective and well tolerated, but with a high rate of relapse once withdrawn. Hydroxyurea, methotrexate, imatinib were unsuccessful in most patients studied. More prospective clinical trials are needed for patients with L‐HES. [ABSTRACT FROM AUTHOR]

Objectives: Treatment‐free remission (TFR) has emerged as a treatment goal in chronic myeloid leukemia in the chronic phase (CML‐CP). Attempts to increase proportion of patients achieving TFR include combination of tyrosine kinase inhibitors (TKI) and other drugs. Interferon‐α in addition to TKI has shown promising efficacy but with dose‐dependent toxicity and discontinuations. NordCML007 was initiated to study the efficacy and safety of low dose pegylated IFN‐α (PegIFN‐α) in combination with dasatinib (DAS) in CML‐CP. Methods: Forty patients with newly diagnosed CML‐CP were given DAS upfront. After month 3 (M3) 15 μg/wk of PegIFN‐α was added and increased to 25 μg/wk from M7 until M15. DAS treatment was continued and adverse events and BCR‐ABL1 qRT‐PCR values were reported yearly after M24. Results from M1 to M18 have previously been published, and here we present long‐term data. Results: After 5 years of follow‐up, there were no suspected unexpected serious adverse reactions, no increase in serosal effusions, no disease progressions and no CML‐related deaths. Rates of MR3.0 (MMR), MR4.0 and MR4.5 were 84.6%, 64.1% and 51.3% respectively at M60, and 95% of patients reached MMR at some point during the study. Conclusion: Initial addition of PegIFN‐α to DAS shows good long‐term efficacy without increased toxicity. [ABSTRACT FROM AUTHOR]

• IFN-α is a key pathogenic player in multiple autoimmune rheumatic diseases. • Anti IFN-α drugs may benefit to lupus, Sjögren, systemic sclerosis and dermatomyositis patients. • Several anti IFN-α treatments are currently evaluated in clinical and preclinical studies. • Patients will most likely benefit from anti IFN-α therapies within a precision medicine approach. Interferon (IFN)-α has emerged as a major therapeutic target for several autoimmune rheumatic diseases. In this review, we focus on clinical and preclinical advances in anti-IFN-α treatments in systemic lupus erythematosus (SLE), primary Sjögren syndrome (pSS), systemic sclerosis (SSc), and dermatomyositis (DM), for which a high medical need persists. Promising achievements were obtained following direct IFN-α neutralization, targeting its production through the cytosolic nucleic acid sensor pathways or by blocking its downstream effects through the type I IFN receptor. We further focus on molecular profiling and data integration approaches as crucial steps to select patients most likely to benefit from anti-IFN-α therapies within a precision medicine approach. [ABSTRACT FROM AUTHOR]

Background: Interferon-alpha (IFN-α) is a general therapeutic regimen to be utilized in hepatocellular carcinoma (HCC). However, regulatory mechanisms of IFN-α on competing endogenous RNAs (ceRNAs) level in anti-HCC relapse are rarely understood. Methods: HCC patients with and without IFN-α treatment were calculated to analyze the expression profile of mRNA, long non-coding RNA (lncRNA), microRNA (miRNA), and circular RNA (circRNA) by RNA sequence, and significant differential expression (DE) of these types of RNAs were selected for further analysis. A ceRNA regulatory network was constructed to explore the potential mechanisms of IFN-α intervention on anti-HCC relapse. Finally, the potential prognostic associated genes among these DE RNAs were identified. Results: Totally, 556 mRNAs, 120 circRNAs, 87 lncRNAs, and 96 miRNAs were differentially expressed in patients who received IFN-α treatment. A ceRNA regulatory network including a circRNA-miRNA-mRNA network which composed of 4 up- and 10 down-regulated circRNAs, 8 up- and 5 down-regulated miRNAs, 28 up- and 9 down-regulated mRNAs, and a lncRNA-miRNA-mRNA network which composed of 10 up- and 3 down-regulated lncRNAs, 11 up- and 5 down-regulated miRNAs, 28 up- and 10 down-regulated mRNAs was constructed. Gene enrichment and pathway analysis revealed that the ceRNA network was associated with immune-related pathway and corresponding molecular function in patients who accepted IFN-α treatment. Next, we identified 3 most relevant to IFN-α treatment to HCC among these DE RNAs, namely FAM20A, IGFBP4 and MARCH3, as the prognostic associated genes for HCC. Furthermore, MARCH3 expression correlated with infiltrating levels of tumor infiltrating immune cells (TICCs) in HCC. MARCH3 expression also showed strong correlations with the gene markers of diverse immune cells in HCC. Conclusion: Our data discovered a novel ceRNA network in HCC patients receiving IFN-α therapy, which might lay the foundation for better understand the regulatory mechanism of IFN-α treatment. [ABSTRACT FROM AUTHOR]

Background: Cytokine treatment with Interferon-alpha (IFN-α) represents a clinical model of immune associated depression, but it remains unclear if it is of the same entity as major depressive disorder (MDD). The study focuses on possible gender differences in IFN-α induced depression and effects of a pre-emptive antidepressant treatment.Methods: Data from 181 patients with chronic hepatitis C infection (cHC) without history of mental illnesses undergoing treatment with IFN-α 2a and ribavirin were re-analyzed for gender effects. Patients with a pre-emptive antidepressant therapy with Escitalopram (n = 90, verum group) to prevent IFN-induced depression were compared to patients who received placebo (n = 91). Depressive symptoms before and during HCV-treatment were assessed using the Montgomery-Asberg Depression Rating Scale (MADRS), Beck's Depression Inventory (BDI) and the Hamilton Anxiety Rating Scale.Results: We found significant differences regarding the incidence and severity of depressive symptoms between men and women for patients without antidepressant pre-treatment (placebo group). Significantly more women without pre-emptive antidepressant therapy suffered from clinically relevant depression (MADRS values ≥ 13, p = 0.041) and self-rated depressive symptoms (BDI ≥ 17, p = 0.024). Antidepressant pre-treatment showed comparable effects regarding the reduction of incidence and severity of depression in both women and men.Conclusions: Compared to MDD, IFN-alpha-induced depression in patients with cHC is also characterized by gender differences with an increased risk for women but no gender difference regarding the effects of an antidepressant pre-treatment is found. Our data strengthens the hypothesis that Interferon-induced depression serves as a clinical model for immune related depressive disorders. [ABSTRACT FROM AUTHOR]

Interferon α (IFNα) is a type I interferon, an essential cytokine employed by the immune system to fight viruses. Although a number of the structures of type I interferons have been reported, most of the known structures of IFNα are in complex with its receptors. There are only two examples of structures of free IFNα: one is a dimeric X-ray structure without side-chain information; and another is an NMR structure of human IFNα. Although we have shown that Sortilin is involved in the secretion of IFNα, the details of the molecular interaction and the secretion mechanism remain unclear. Recently, we solved the X-ray structure of mouse Sortilin, but the structure of mouse IFNα remained unknown. In this study, we determined the crystal structure of mouse IFNα2 at 2.1 Å resolution and investigated its interaction with Sortilin. Docking simulations suggested that Arg22 of mouse IFNα2 is important for the interaction with mouse Sortilin. Mutation of Arg22 to alanine facilitated IFNα2 secretion, as determined by flow cytometry, highlighting the contribution of this residue to the interaction with Sortilin. These results suggest an important role for Arg22 in mouse IFNα for Sortilin-mediated IFNα trafficking. [ABSTRACT FROM AUTHOR]

The coronavirus disease (COVID-19) caused by a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread rapidly worldwide. Given that this contagious viral outbreak is still unfolding, it is urgent to understand the pathogenesis of SARS-CoV-2 infection and explore effective treatments to protect patients from developing a severe illness related to COVID-19. Recently, IFN-α has been considered a potential therapeutic strategy to treat COVID-19 disease, mainly because the innate immune system rapidly produces IFN-α as the first line of defense to combat viral infections. However, IFN-α can also play a role in immunoregulatory effects, causing pathogenic damage and uncontrolled inflammatory responses. There are 13 human IFN-α subtypes that bind to the same receptor and induce different interferon-stimulated gene (ISG) expression, regulating various antiviral and immunoregulatory effects. The varying degrees of inflammatory regulations may raise concerns about the possible side effects to enlarge the inflammatory responses, exacerbating the severity of infection. Thus, the analysis of various IFN-α subtype induction during SARS-CoV-2 infection is necessary in exploring the mechanism of COVID-19 pathogenesis. This review summarizes the current understanding of IFN-α in the pathogenesis of respiratory virus diseases and IFN-α based clinical intervention used in SARS-CoV-2 infection and other respiratory virus diseases. Besides, new ideas in selecting suitable IFN-α subtypes or combinations as drug candidates for viral infection treatment will also be discussed. Key Points • IFN-α plays an important role in anti-viral and immunoregulatory effects in COVID-19 patients caused by SARS-CoV-2. • The uncontrolled inflammation and disease severity correlated to the diversity of IFN-α subtype induction. • Selecting suitable IFN-α subtypes or combinations as drug candidates will be beneficial for the treatment of patients with COVID-19. [ABSTRACT FROM AUTHOR]

Monophosphoryl lipid A (MPLA) is a toll-like receptor 4 ligand that promotes immune activation in mice and humans, without undesired inflammation. Immunotherapy by the combining immune checkpoint blockade and MPLA has shown promising anti-cancer effects in both mice and humans. In this study, we explored how MPLA enhanced the anti-cancer effects of anti-PD-L1 antibodies (Abs). Anti-cancer immunity induced by the combination of anti-PD-L1 Abs and MPLA failed in CD4 and CD8 cell-depleted mice. Moreover, the combination treatment of anti-PD-L1 Abs and MPLA synergistically enhanced the activation of plasmacytoid dendritic cells (pDCs) in the mouse in vivo, while conventional DCs were not. In addition, mice treated with anti-PD-L1 Abs and MPLA were not protected from B16 melanoma by blockade of interferon-alpha receptor (IFNAR). The combination of anti-PD-L1 Abs and MPLA also promoted human peripheral blood pDC activation and induced IFN-α-dependent T cell activation. Therefore, these results demonstrate that MPLA enhances anti-PD-L1 Ab-mediated anti-cancer immunity through the activation and IFN-α production of pDCs. [ABSTRACT FROM AUTHOR]

Despite increasing immunisation rates, developing countries continue to report subacute sclerosing pan encephalitis (SSPE). The defective measles virus causng SSPE persists in brain cells because of hypermutated M protein and deranged host's immune responses. Patients usually present with cognitive decline and myoclonus. However, atypical presentations such as seizures and visual loss are also quite common, causing wrong or delayed diagnosis in a significant number of cases. Diagnosis is based on suggestive clinical features, electroencephalographic findings and elevated cerebrospinal fluid (CSF) antimeasles antibody titre. Newer methods of reporting antibody levels such as CSF/serum quotient (CSQrel) result in increased specificity, but individual values of serum and CSF antimeasles antibody titres should also be checked if CSQrel is negative or equivocal. In highly suspicious cases with negative CSF antimeasles antibody profile, repeat testing should be done. Combination therapy with interferon-alpha and isoprinosine is the most common starting regimen. Intraventricular administration of interferon-alpha is theoretically the most effective route but requires meticulous hygiene and complications are frequent. Hence, the proper route and frequency of interferon-alpha treatment should be chosen depending on efficacy, affordability, disease stage and parent's expectations. Though treatment has largely remained unsatisfactory, reported rates of improvement or stabilisation (34%-35%) are much better than that for spontaneous remission (5%-10%). Fusion inhibitors and adenovirus-delivered small interfering RNA are being studied as new therapies. However, increasing immunisation rates can be the only long-term answer to tackle the menace of measles and its complications. [ABSTRACT FROM AUTHOR]

Screening for MG in patients with PV positive for JAK2V617F mutation can help in early diagnosis and treatment, resulting in a significant reduction in morbidity and mortality. [ABSTRACT FROM AUTHOR]

In many mammalian species, the production of new neurons in the hippocampal dentate gyrus continues throughout life. Previous studies using rodents suggest that adult-born neurons are involved in memory and cognition tasks and mood regulation. Interferon-alpha (IFNα), a proinflammatory cytokine used for the treatment of chronic viral hepatitis and malignancies, frequently causes depressive symptoms in patients and animals, including non-human primates. We have previously demonstrated that chronic IFNα treatment decreases hippocampal neurogenesis in mice. Here, we investigated the effects of four-week human pegylated IFNα treatment on hippocampal neurogenesis and behavior in common marmosets. Continuous monitoring of voluntary activity levels using an actigraphy device suggested that adaptive ability is impaired in IFNα-treated animals. Analyses of BrdU-labeled cells expressing a marker for immature or mature neurons revealed a significant reduction in the number of new neurons in the hippocampus of IFNα-treated animals. These data indicate that chronic human IFNα treatment causes behavioral changes and a decrease in hippocampal neurogenesis in common marmosets. [ABSTRACT FROM AUTHOR]

Purpose: To assess the efficacy and tolerability of interferon alpha (IFN-α) treatment in patients with refractory Behçet uveitis (BU).Methods: The patients with BU who were treated with subcutaneous IFN-α were divided into groups according to treatment response. Demographic features, best corrected visual acuity (BCVA), central macular thickness (CMT) value, and fluorescein angiography (FA) scores were compared between the groups.Results: Twenty-one (84%) of the 25 patients responded to IFN-α treatment. Active inflammation resolved at the first month's visit in all patients. The improvement in mean BCVA and CMT achieved at the first month's visit in all groups; however, the improvement in mean CMT in the non-responder group could not be maintained at the last visit. Main FA score significantly decreased in both the complete and partial remission group; however, it decreased minimally in the non-responder group.Conclusion: IFN-α seems an effective and safe treatment option in the management of refractory BU. [ABSTRACT FROM AUTHOR]

Objectives Lower extremity deep vein thrombosis (LEDVT) is a serious complication of Behçet's syndrome. Management constitutes mainly of administration of immunosuppressives, but the predictors of relapse and the optimal choice of immunosuppressives remain unclear. In this prospective study, we aimed to detect the risk and predictors of relapse and treatment response to different modalities. Methods All Behçet's syndrome patients who presented with a first episode of acute LEDVT between 2010 and 2014 were prospectively followed with a standard protocol. Acute LEDVT was confirmed by Doppler ultrasonography. Serial planned Doppler ultrasonography assessments were performed during follow-up and additionally repeated in case of clinical suspicion. Recanalization rate was assessed at each visit. Our first-line treatment strategy consisted of AZA and CSs. IFN-alpha was used in patients who were refractory to or could not tolerate AZA or had concomitant eye involvement requiring further treatment. Results Thirty-three patients with LEDVT (26 M/7 F) were prospectively followed for 40.7 ± 13.4 months. Among the 33 patients, 23 relapses were observed in 15 patients. Relapse rates were 29%, 37% and 45% at 6, 12 and 24 months, respectively. Among the possible predictors of relapse, poor recanalization was the only significant factor [hazard ratio 4.34 (95% CI 1.96, 10.0)]. Overall 29 patients were treated with AZA and 17 with IFN-alpha. The relapse rate was lower and recanalization rate was higher with IFN-alpha compared with AZA (12% vs 45% and 86% vs 45%). Conclusion The relapse rate for LEDVT in Behçet's syndrome is high despite AZA treatment. IFN-alpha seems to be a promising agent for preventing LEDVT relapses and achieving good recanalization. [ABSTRACT FROM AUTHOR]

Objective To investigate the effect of synergistic intervention of interferonα(IFNα) and thymopentin(TP5) on the mRNA expression of apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3 A(APOBEC3 A) and apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3 B(APOBEC3 B) in HepG2. 2. 15 cells. Methods HepG2. 2. 15 cells were divided into blank control group, IFNα treatment group, TP5 treatment group, and IFNα + TP5 treatment group, and at 12, 24, 48, and 72 hours of treatment, quantitative real-time PCR was used to measure the mRNA expression of APOBEC3 A and APOBEC3 B in HepG2. 2. 15 cells. An analysis of variance was used for comparison of continuous data between multiple groups, and the least significant difference t-test was used for further comparison between two groups. Results Compared with the blank control group, the IFNα treatment group and the IFNα + TP5 treatment group had a significant increase in the mRNA expression of APOBEC3 A at 12, 24, 48, and 72 hours of treatment(all P < 0. 001). Compared with the IFNα treatment group, the IFNα + TP5 treatment group had a significant increase in the mRNA expression of APOBEC3 A at these four time points(all P < 0. 001). TP5 treatment had no significant influence on the mRNA expression of APOBEC3 A at each time point(all P > 0. 05). There was no significant difference in the mRNA expression of APOBEC3 B between the blank control group and the treatment groups(all P > 0. 05). Conclusion IFNα combined with TP5 can significantly upregulate the mRNA expression of APOBEC3 A in HepG2. 2. 15 cells. [ABSTRACT FROM AUTHOR]

• The mechanisms underlying the effect of interferon (IFN)-alpha treatment for hepatitis C virus (HCV) are still not clear. • We investigated the in vitro effect of serum from depressed and non-depressed HCV patients on human hippocampal neurogenesis. • Lower neurogenesis upon treatment with serum were predictive of later development of depression. • The systemic milieu exerts a fundamental role in the regulation of the neurogenic process. Interferon (IFN)-α treatment for hepatitis C virus (HCV) is a well-recognized clinical model for inflammation-induced depression, but the brain cellular mechanisms underlying these effects are still not clear. Previous data reported an alteration in peripheral levels of inflammatory and neuroplasticity markers in the blood of depressed versus non-depressed patients. We investigated the in vitro effect of serum from depressed and non-depressed HCV patients (at baseline, before IFN-α; and after four weeks of IFN-α), on the apoptotic and neurogenic processes in a human hippocampal progenitor cells model. Results show that higher apoptosis during proliferation observed upon treatment of cells with baseline serum, and lower neuronal differentiation observed upon treatment with serum after 4 weeks of IFN-α, were predictive of later development of IFN-α–induced depression (odds ratio = 1.26, p = 0.06, and = 0.80, p = 0.01, respectively). While serum after IFN-α increased neurogenesis compared with baseline serum, a lower increase in neurogenesis was also predictive of later development of depression (odds ratio = 0.86; p = 0.006). Our results provide evidence for the fundamental role of the systemic milieu (captured by serum samples) in the regulation of hippocampal neurogenesis by inflammation, a putative mechanism involved in the development of neuropsychiatric conditions. [ABSTRACT FROM AUTHOR]

Gorham-stout disease (gsd), is a rare disorder of unknown etiology. although a non-malignant, non-infectious condition, gsd results in massive destruction of bones by osteolysis secondary to proliferation of blood vessels. we present a young man afflicted with this condition with coexisting tuberculous pleural effusion and the successful outcome with treatment. [ABSTRACT FROM AUTHOR]

Ubiquitin‐specific protease 18 (USP18) is an important inhibitor of interferon (IFN) antiviral activity, and the aim of this study was to investigate the association between the USP18 mRNA level change in peripheral blood mononuclear cells (PBMCs) when stimulated with IFN in vitro before initiating treatment and the treatment outcomes in HBeAg‐positive chronic hepatitis B (CHB) patients treated with IFN. A total of 44 patients who received standard IFN‐based anti‐HBV therapy and follow‐up were enrolled in the study. The in vitro IFN‐induced USP18 mRNA change (USP18IFN‐N) was measured via comparison of quantitative PCR‐determined USP18 transcription levels of BPMCs cultured with and without IFN stimulation. Either for virological (VR) or serological response (SR), the baseline USP18IFN‐N was significantly higher (P = 0.018 for VR, P = 0.008 for SR) among nonresponders (n = 23 for VR, n = 33 for SR) than that of responders (n = 21 for VR, n = 11 for SR). Multivariate analyses revealed baseline USP18IFN‐N was a novel independent predictor for either VR (OR = 0.292, 95% CI = 0.102‐0.835, P = 0.022) or SR (OR = 0.173, 95% CI = 0.035‐0.849, P = 0.031) in our cohort. In addition, baseline USP18IFN‐N in combination with HBV DNA loads or HBeAg levels showed improved accuracy of pretreatment prediction for VR or SR responders, respectively. Baseline USP18IFN‐N levels are associated with both virological and serological response, and have the potential to become a clinical predictor for treatment outcomes in HBeAg‐positive CHB patients before initiating IFN‐α therapy. [ABSTRACT FROM AUTHOR]

Despite multiple antitumor activities, interferon-alpha (IFNα) therapy alone is less effective in solid tumors. Autophagy has been reported to play a key role in tumor chemoresistance. Therefore, it is meaningful to explore whether autophagy can be activated by IFNα in head and neck squamous cell carcinoma (HNSCC) and serve as a potential target to improve efficacy of IFNα therapy. In this study, we report that IFNα not only exhibits anti-proliferation activity and induces apoptosis, but also activates autophagy in HNSCC cells. Moreover, silencing autophagy-related protein 5 (ATG5) and signal transducer and activator of transcription 1 (STAT1) suppresses autophagy flux. Furthermore, IFNα and autophagy inhibitors (hydroxychloroquine and wortmannin) show clear synergistic effects on inhibiting growth and promoting apoptosis in HNSCC cells and xenograft models. Our findings indicate that IFNα-induced autophagy plays a cytoprotective role and blocking autophagy flux promotes IFNα-mediated apoptosis in HNSCC. These results suggest that the combination of IFNα and autophagy inhibitors represents a novel strategy for HNSCC treatment. [ABSTRACT FROM AUTHOR]

In this prospective study conducted from October 2013 to June 2015 in Brighton, England, we examined differences between men and women in new-onset major depressive disorder (MDD) during interferon- alpha-based (IFN-α) therapy for hepatitis C virus (HCV). We included 155 HCV-infected patients (47 women), eligible to receive HCV therapy, including direct-acting antivirals. The Semi-Structured Clinical Interview was used to assess MDD. Severity of depressive symptoms was assessed using the Hamilton Depression Rating Scale. Patients were assessed at baseline, during treatment and 6 months after treatment completion. A significant increase in depressive symptoms was observed in the total sample from baseline to week 4, and a significant decrease was observed from end of treatment (week 24) to the sustained virological response (SVR) end point at 6 months posttreatment. Women were more likely to have a MDD at week 24. In both men and women, neurovegetative and mood-cognitive syndromes increased significantly at the early stage of treatment but remitted by the end of HCV therapy. Proportions with SVR were similar among females and males (91.5 percent vs. 87 percent). Under an inflammatory condition, boosted by interferonbased treatments, these results suggest that female gender is not associated with increased vulnerability for developing depression during IFN-α therapy. [ABSTRACT FROM AUTHOR]

Interferon-alpha (IFN-α)-based therapy is associated with several hematological adverse events in hepatitis C virus (HCV)-infected patients with advanced fibrosis. We performed this study to evaluate the association between Fibrosis-4 (Fib-4) index and hematological adverse events in patients with chronic HCV infection, undergoing IFN-α-based triple therapy. We included 120 HCV-infected patients, receiving triple therapy: weekly PegIFN-α, daily ribavirin (1,000–1,200 mg), and daily sofosbuvir (400 mg) for 12 weeks. We compared Fib-4 scores for patients who developed hematological adverse events at weeks 4 (w4) and w12 of treatment and w12 post-treatment versus those who did not. Treatment with the aforementioned triple regimen was associated with a sustained virological response (SVR)-12 rate of 93.9%. We found no significant associations (P > 0.05) between SVR12 rate and the degree of fibrosis or the risk of hematological adverse events. The Fib-4 score could predict patients who developed hematological adverse events (anemia, leukopenia, and neutropenia) in the first month of treatment, but not in later stages. A Fib-4 cutoff value of 3.59 had high specificity for anemia, leukopenia, and neutropenia (85.1%, 87.2%, and 88.2%, respectively), but had low sensitivity for detecting the 3 events. In conclusion, the Fib-4 score may predict early hematological adverse effects in HCV-infected patients on IFN-based triple therapy. [ABSTRACT FROM AUTHOR]

Supplemental Digital Content is Available in the Text. Background: HIV-exposed seronegative people who inject drugs (HESN-PWID) have been shown to have increased natural killer (NK) cell and myeloid activation when compared with control donors. Methods: We investigated potential mechanisms maintaining NK activation by conducting quantitative proteome comparisons of NK cells from HESN-PWID subjects and control donors. Proteins upregulated in NK cells were measured in the plasma of HESN-PWID subjects by ELISA and further investigated for their ability to induce innate immune activation in vitro. Results: The NK cell proteome comparison showed markedly higher levels of interferon-stimulated proteins and S100 proteins, including S100A14. Consistent with these results, we observed significantly higher levels of S100A14 in the plasma of HESN-PWID subjects compared with controls (P = 0.033, n = 25). In vitro, the addition of recombinant S100A14 protein significantly activated NK cells in a peripheral blood mononuclear cell mixture (P = 0.011, n = 9), but not purified NK cells alone. Treatment of purified monocytes with recombinant S100A14 protein induced secretion of TNF-alpha and led to significantly higher NK CD69 activation (P = 0.0156, n = 7) in a co-culture through a TLR4-dependent interaction. Conclusions: Our study identified S100A14 as a novel protein increased within NK cells and plasma of HESN-PWID subjects with the capacity to sustain NK activation through TLR4-dependent activation of myeloid cells. [ABSTRACT FROM AUTHOR]

Introduction: Treatment with interferon-alpha (IFNa) can induce depression that is likely the result of its effect on the tryptophan-kynurenine pathway. Kynurenine passes through the blood-brain barrier and breaks to neurotoxic metabolites, such as quinolinic acid, with agonistic effect on N-methyl-D-aspartate receptor (NMDAR). Thus, tryptophan available for serotonin synthesis declines. The aim was to evaluate the effect of NMDAR antagonists on IFNa-induced depression in mice model of despair. Materials and Methods: The total immobility time in the forced swimming test (FST) was assessed as an indicator of depression in mice. Depression was induced by IFNa injection (16 × 105 IU/kg) for 6 consecutive days. The optimum dose of dextromethorphan, memantine, and dizocilpine (MK-801) was administered on the 7th day following IFNa injection. Results: Immobility time in the FST was increased following IFNa injection (181 s ± 7 vs. control 122 s ± 10, P < 0.05) which indicated depression behavior. Dextromethorphan (15 mg/kg) and MK-801 (0.075 mg/kg) administration reduced the immobility time in IFNa-treated animals (57 s ± 14 and 46 s ± 6, respectively). Memantine (5 mg/kg) reduced the immobility time when it was administered alone but failed to decrease the immobility time induced by IFNa. The animals' locomotor activity was normal in the experimented groups. Conclusion: Dextromethorphan and MK-801 inhibited IFNa-induced depression. Thus, at least part of IFNa depressive behavior is caused by NMDAR that is stimulated by the production of metabolites in the tryptophan-kynurenine pathway. Administrating NMDAR antagonists should be further evaluated for patients suffering from the neurologic side effects of IFNa. [ABSTRACT FROM AUTHOR]

Liver metastases are associated with poor response to current pharmacological treatments, including immunotherapy. We describe a lentiviral vector (LV) platform to selectively engineer liver macrophages, including Kupffer cells and tumor-associated macrophages (TAMs), to deliver type I interferon (IFNα) to liver metastases. Gene-based IFNα delivery delays the growth of colorectal and pancreatic ductal adenocarcinoma liver metastases in mice. Response to IFNα is associated with TAM immune activation, enhanced MHC-II-restricted antigen presentation and reduced exhaustion of CD8+ T cells. Conversely, increased IL-10 signaling, expansion of Eomes CD4+ T cells, a cell type displaying features of type I regulatory T (Tr1) cells, and CTLA-4 expression are associated with resistance to therapy. Targeting regulatory T cell functions by combinatorial CTLA-4 immune checkpoint blockade and IFNα LV delivery expands tumor-reactive T cells, attaining complete response in most mice. These findings support a promising therapeutic strategy with feasible translation to patients with unmet medical need. [Display omitted] • IFNα from in vivo LV-engineered liver macrophages curbs liver metastasis growth • IFNα activates antigen presentation and CD8+ T cell effector function • Resistance to IFNα is associated with Eomes CD4+ T cells, IL-10 signaling, and CTLA-4 • IFNα combined with anti-CTLA-4 bypasses resistance attaining complete response In this study, Kerzel et al. describe a lentiviral vector platform to selectively engineer liver macrophages to deliver IFNα to liver metastases from within the tissue achieving therapeutic efficacy. Simultaneous combination with anti-CTLA-4 bypassed resistance mechanisms and expanded tumor-reactive T cells, attaining complete response in most mice. [ABSTRACT FROM AUTHOR]

Abstract: Interferon‐α2 reduces elevated blood cell counts and splenomegaly in patients with myeloproliferative neoplasms (MPN) and may restore polyclonal hematopoiesis. Its use is limited by inflammation‐mediated toxicity, leading to treatment discontinuation in 10‐30% of patients. Ruxolitinib, a potent anti‐inflammatory agent, has demonstrated benefit in myelofibrosis (MF) and polycythemia vera (PV) patients. Combination therapy (CT) with these two agents may be more efficacious than monotherapy with either, potentially improving tolerability of interferon‐α2 as well. We report the preliminary results from a phase II study of CT with pegylated interferon‐α2 and ruxolitinib in 50 MPN patients (PV, n = 32; low‐/intermediate‐1‐risk MF, n = 18), the majority (n = 47) being resistant and/or intolerant to interferon‐α2 monotherapy. Objectives included remission (2013 revised criteria encompassing histologic, hematologic, and clinical responses), complete hematologic response (CHR), molecular response, and toxicity. Follow‐up was 12 months. Partial remission (PR) and sustained CHR were achieved in 9% and 44% of PV patients, respectively. In MF patients, complete or partial remission was achieved in 39%, and sustained CHR in 58%. The median JAK2V617F allele burden declined significantly in both groups. Hematologic toxicity was the most common adverse event and was managed by dose reduction. Thirty‐seven serious adverse events were recorded in 23 patients; the discontinuation rate was 20%. We conclude that CT with interferon‐α2 and ruxolitinib is efficacious in patients with low‐/intermediate‐1‐risk MF and, to a lesser extent, in patients with PV. These preliminary results encourage phase III studies as well as a study with CT in newly diagnosed MPN patients. [ABSTRACT FROM AUTHOR]

Background & objectives: Genetic aberrations disrupting toll-like receptor and interferon homeostasis enhance the risk of systemic lupus erythematosus (SLE). Raised serum interferon-alpha (IFN-α) levels in SLE patients have been ascribed to polymorphism (rs2004640 G/T) in interferon regulatory factor 5 (IRF5) gene, resulting in enhanced transcript splicing. A positive association between IRF5 polymorphism and SLE risk has been reported in many populations. This study was aimed to find out frequency of IRF5 rs2004640 G/T polymorphism in patients with SLE and healthy controls and to assess its influence on susceptibility, clinical and serological characteristics of SLE. Methods: IRF5 rs2004640 (G/T) polymorphism was analyzed in 300 SLE patients and 460 age and sex matched controls by real-time PCR. Results: The IRF5 rs2004640 (G/T) polymorphism did not confer risk of SLE or influence clinical or serological phenotype. However, the mutant allele conferred a borderline risk to develop thrombocytopenia (odds ratio: 2.05, 95% confidence interval: 0.97-4.3, P=0.06) in patients with SLE. Interpretation & conclusions: Our study revealed that the IRF5 rs2004640 polymorphism was not a risk factor for SLE in population from south India. It may, however, be a useful genetic marker for thrombocytopenia in SLE patients. Although we could not demonstrate susceptibility toward lupus in the presence of IRF5 rs2004640 (G/T) polymorphism, further exploration of the genetic variability of IRF5 may help uncover its pathogenic role in Indian SLE patients. [ABSTRACT FROM AUTHOR]

Antiviral therapy is the basic treatment of chronic hepatitis B, and pegylated interferon-α is one of the first-line treatment drugs. At present, several consensuses have been reached on individualized treatment with pegylated interferon-α, which is playing an important role in clinical practice. New clinical demands appear along with the clinical application of pegylated interferon-α. With reference to relevant literature and personal clinical experience, this article elaborates on some knowledge of individualized treatment with pegylated interferon-α for chronic hepatitis B. [ABSTRACT FROM AUTHOR]

Background & Aims GS-9620, an oral agonist of toll-like receptor 7, is in clinical development for the treatment of chronic hepatitis B (CHB). GS-9620 was previously shown to induce prolonged suppression of serum viral DNA and antigens in the chimpanzee and woodchuck models of CHB. Herein, we investigated the immunomodulatory mechanisms underlying these antiviral effects. Methods Archived liver biopsies and paired peripheral blood mononuclear cell samples from a previous chimpanzee study were analyzed by RNA sequencing, quantitative reverse transcription PCR, immunohistochemistry (IHC) and in situ hybridization (ISH). Results GS-9620 treatment of CHB chimpanzees induced an intrahepatic transcriptional profile significantly enriched with genes associated with hepatitis B virus (HBV) clearance in acutely infected chimpanzees. Type I and II interferon, CD8 + T cell and B cell transcriptional signatures were associated with treatment response, together with evidence of hepatocyte death and liver regeneration. IHC and ISH confirmed an increase in intrahepatic CD8 + T cell and B cell numbers during treatment, and revealed that GS-9620 transiently induced aggregates predominantly comprised of CD8 + T cells and B cells in portal regions. There were no follicular dendritic cells or IgG-positive cells in these lymphoid aggregates and very few CD11b + myeloid cells. There was no change in intrahepatic natural killer cell number during GS-9620 treatment. Conclusion The antiviral response to GS-9620 treatment in CHB chimpanzees was associated with an intrahepatic interferon response and formation of lymphoid aggregates in the liver. Our data indicate these intrahepatic structures are not fully differentiated follicles containing germinal center reactions. However, the temporal correlation between development of these T and B cell aggregates and the antiviral response to treatment suggests they play a role in promoting an effective immune response against HBV. Lay summary New therapies to treat chronic hepatitis B (CHB) are urgently needed. In this study we performed a retrospective analysis of liver and blood samples from a chimpanzee model of CHB to help understand how GS-9620, a drug in clinical trials, suppressed hepatitis B virus (HBV). We found that the antiviral response to GS-9620 was associated with accumulation of immune cells in the liver that can either kill cells infected with HBV or can produce antibodies that may prevent HBV from infecting new liver cells. These findings have important implications for how GS-9620 may be used in patients and may also help guide the development of new therapies to treat chronic HBV infection. [ABSTRACT FROM AUTHOR]

Background & Aims GS-9620, an oral agonist of toll-like receptor 7 (TLR7), is in clinical development for the treatment of chronic hepatitis B (CHB). GS-9620 was previously shown to induce prolonged suppression of serum viral DNA and antigens in the woodchuck and chimpanzee models of CHB. Herein, we investigated the molecular mechanisms that contribute to the antiviral response to GS-9620 using in vitro models of hepatitis B virus (HBV) infection. Methods Cryopreserved primary human hepatocytes (PHH) and differentiated HepaRG (dHepaRG) cells were infected with HBV and treated with GS-9620, conditioned media from human peripheral blood mononuclear cells treated with GS-9620 (GS-9620 conditioned media [GS-9620-CM]), or other innate immune stimuli. The antiviral and transcriptional response to these agents was determined. Results GS-9620 had no antiviral activity in HBV-infected PHH, consistent with low level TLR7 mRNA expression in human hepatocytes. In contrast, GS-9620-CM induced prolonged reduction of HBV DNA, RNA, and antigen levels in PHH and dHepaRG cells via a type I interferon (IFN)-dependent mechanism. GS-9620-CM did not reduce covalently closed circular DNA (cccDNA) levels in either cell type. Transcriptional profiling demonstrated that GS-9620-CM strongly induced various HBV restriction factors – although not APOBEC3A or the Smc5/6 complex – and indicated that established HBV infection does not modulate innate immune sensing or signaling in cryopreserved PHH. GS-9620-CM also induced expression of immunoproteasome subunits and enhanced presentation of an immunodominant viral peptide in HBV-infected PHH. Conclusions Type I IFN induced by GS-9620 durably suppressed HBV in human hepatocytes without reducing cccDNA levels. Moreover, HBV antigen presentation was enhanced, suggesting additional components of the TLR7-induced immune response played a role in the antiviral response to GS-9620 in animal models of CHB. Lay summary GS-9620 is a drug currently being tested in clinical trials for the treatment of chronic hepatitis B virus (HBV) infection. GS-9620 has previously been shown to suppress HBV in various animal models, but the underlying antiviral mechanisms were not completely understood. In this study, we determined that GS-9620 does not directly activate antiviral pathways in human liver cells, but can induce prolonged suppression of HBV via induction of an antiviral cytokine called interferon. However, interferon did not destroy the HBV genome, suggesting that other parts of the immune response ( e.g. activation of immune cells that kill infected cells) also play an important role in the antiviral response to GS-9620. [ABSTRACT FROM AUTHOR]