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Concept: Interferon


ABSTRACT The recent emergence of a novel human coronavirus (HCoV-EMC) in the Middle East raised considerable concerns, as it is associated with severe acute pneumonia, renal failure, and fatal outcome and thus resembles the clinical presentation of severe acute respiratory syndrome (SARS) observed in 2002 and 2003. Like SARS-CoV, HCoV-EMC is of zoonotic origin and closely related to bat coronaviruses. The human airway epithelium (HAE) represents the entry point and primary target tissue for respiratory viruses and is highly relevant for assessing the zoonotic potential of emerging respiratory viruses, such as HCoV-EMC. Here, we show that pseudostratified HAE cultures derived from different donors are highly permissive to HCoV-EMC infection, and by using reverse transcription (RT)-PCR and RNAseq data, we experimentally determined the identity of seven HCoV-EMC subgenomic mRNAs. Although the HAE cells were readily responsive to type I and type III interferon (IFN), we observed neither a pronounced inflammatory cytokine nor any detectable IFN responses following HCoV-EMC, SARS-CoV, or HCoV-229E infection, suggesting that innate immune evasion mechanisms and putative IFN antagonists of HCoV-EMC are operational in the new host. Importantly, however, we demonstrate that both type I and type III IFN can efficiently reduce HCoV-EMC replication in HAE cultures, providing a possible treatment option in cases of suspected HCoV-EMC infection. IMPORTANCE A novel human coronavirus, HCoV-EMC, has recently been described to be associated with severe respiratory tract infection and fatalities, similar to severe acute respiratory syndrome (SARS) observed during the 2002-2003 epidemic. Closely related coronaviruses replicate in bats, suggesting that, like SARS-CoV, HCoV-EMC is of zoonotic origin. Since the animal reservoir and circumstances of zoonotic transmission are yet elusive, it is critically important to assess potential species barriers of HCoV-EMC infection. An important first barrier against invading respiratory pathogens is the epithelium, representing the entry point and primary target tissue of respiratory viruses. We show that human bronchial epithelia are highly susceptible to HCoV-EMC infection. Furthermore, HCoV-EMC, like other coronaviruses, evades innate immune recognition, reflected by the lack of interferon and minimal inflammatory cytokine expression following infection. Importantly, type I and type III interferon treatment can efficiently reduce HCoV-EMC replication in the human airway epithelium, providing a possible avenue for treatment of emerging virus infections.

Concepts: Immune system, Cytokine, Virus, Interferon, Influenza, Severe acute respiratory syndrome, Respiratory epithelium, Coronavirus


APS1/APECED patients are defined by defects in the autoimmune regulator (AIRE) that mediates central T cell tolerance to many self-antigens. AIRE deficiency also affects B cell tolerance, but this is incompletely understood. Here we show that most APS1/APECED patients displayed B cell autoreactivity toward unique sets of approximately 100 self-proteins. Thereby, autoantibodies from 81 patients collectively detected many thousands of human proteins. The loss of B cell tolerance seemingly occurred during antibody affinity maturation, an obligatorily T cell-dependent step. Consistent with this, many APS1/APECED patients harbored extremely high-affinity, neutralizing autoantibodies, particularly against specific cytokines. Such antibodies were biologically active in vitro and in vivo, and those neutralizing type I interferons (IFNs) showed a striking inverse correlation with type I diabetes, not shown by other anti-cytokine antibodies. Thus, naturally occurring human autoantibodies may actively limit disease and be of therapeutic utility.

Concepts: Immune system, Antibody, Protein, Cytokine, Diabetes mellitus type 1, Immunology, Interferon, Somatic hypermutation


Interferon-beta (IFNB) therapy for multiple sclerosis can lead to the induction of neutralizing antibodies (NAbs) against IFNB. Various methods are used for detection and quantification of NAbs.

Concepts: Immune system, Antibody, Cytokine, Natural killer cell, Interferon, Multiple sclerosis, Interferon beta-1a, Interferon beta-1b


BACKGROUND: Oral lichen planus (OLP) is seen frequently in patients with hepatitis C virus (HCV) infection. The aim of this study was to evaluate the occurrence of oral candidiasis, other mucosal lesions, and xerostomia during interferon (IFN) therapy for HCV infection. METHODS: Of 124 patients with HCV-infected liver diseases treated with IFN therapy in our hospital, 14 (mean age 56.00 +/- 12.94 years) who attended to receive administration of IFN once a week were identified and examined for Candida infection and other oral lesions and for the measurement of salivary flow. Serological assays also were carried out. RESULTS: Cultures of Candida from the tongue surfaces were positive in 7 (50.0%) of the 14 patients with HCV infection at least once during IFN therapy. C. albicans was the most common species isolated. The incidence of Candida during treatment with IFN did not increase above that before treatment. Additional oral mucosal lesions were observed in 50.0% (7/14) of patients: OLP in three (21.4%), angular cheilitis in three (21.4%) and recurrent aphthous stomatitis in one (7.1%). OLP occurred in one patient before treatment with IFN, in one during treatment and in one at the end of treatment. 85.7% of the oral lesions were treated with topical steroids. We compared the characteristics of the 7 patients in whom Candida was detected at least once during IFN therapy (group 1) and the 7 patients in whom Candida was not detected during IFN therapy (group 2). The prevalence of oral mucosal lesions (P=0.0075) and incidence of external use of steroids (P=0.0308) in group 1 were significantly higher than in group 2. The average body weight of group 1 decreased significantly compared to group 2 (P=0.0088). Salivary flow decreased in all subjects throughout the course of IFN treatment and returned at 6th months after the end of treatment. In group 1, the level of albumin at the beginning of the 6th month of IFN administration was lower than in group 2 (P=0.0550). According to multivariate analysis, one factor, the presence of oral mucosal lesions, was associated with the detection of Candida. The adjusted odds ratio for the factor was 36.00 (95% confidence interval 2.68-1485.94). CONCLUSION: We should pay more attention to oral candidiasis as well as other oral mucosal lesions, in patients with weight loss during IFN treatment.

Concepts: Interferon, Hepatitis C, Candida albicans, Candidiasis, Aphthous ulcer, Oral pathology, Lichen planus, Stomatitis


Two populations of human natural killer (NK) cells can be identified in peripheral blood. The majority are CD3(-)CD56(dim) cells while the minority exhibits a CD3(-)CD56(bright) phenotype. In vitro evidence indicates that CD56(bright) cells are precursors of CD56(dim) cells, but in vivo evidence is lacking. Here, we studied NK cells from a patient that suffered from a melanoma and opportunistic fungal infection during childhood. The patient exhibited a stable phenotype characterized by a reduction in the frequency of peripheral blood CD3(-)CD56(dim) NK cells, accompanied by an overt increase in the frequency and absolute number of CD3(-)CD56(bright) cells. These NK cells exhibited similar expression of perforin, CD57 and CD158, the major activating receptors CD16, NKp46, NKG2D, DNAM-1, and 2B4, as well as the inhibitory receptor CD94/NKG2A, on both CD56(bright) and CD56(dim) NK cells as healthy controls. Also, both NK cell subpopulations produced IFN-γ upon stimulation with cytokines, and CD3(-)CD56(dim) NK cells degranulated in response to cytokines or K562 cells. However, upon stimulation with cytokines, a substantial fraction of CD56(dim) cells failed to up-regulate CD57 and CD158, showed a reduction in the percentage of CD16(+) cells, and CD56(bright) cells did not down-regulate CD62L, suggesting that CD56(dim) cells could not acquire a terminally differentiated phenotype and that CD56(bright) cells exhibit a maturation defect that might result in a potential altered migration pattern. These observations, support the notion that NK cells of this patient display a maturation/activation defect that precludes the generation of mature NK cells at a normal rate accompanied by CD56(dim) NK cells that cannot completely acquire a terminally differentiated phenotype. Thus, our results provide evidence that support the concept that in vivo CD56(bright) NK cells differentiate into CD56(dim) NK cells, and contribute to further understand human NK cell ontogeny.

Concepts: Immune system, Antibody, Natural killer cell, Interferon, Interleukin, Cytotoxicity, Perforin, Granzyme


Despite impressive clinical success, cancer immunotherapy based on immune checkpoint blockade remains ineffective in many patients due to tumoral resistance. Here we use the autochthonous TiRP melanoma model, which recapitulates the tumoral resistance signature observed in human melanomas. TiRP tumors resist immunotherapy based on checkpoint blockade, cancer vaccines or adoptive T-cell therapy. TiRP tumors recruit and activate tumor-specific CD8(+) T cells, but these cells then undergo apoptosis. This does not occur with isogenic transplanted tumors, which are rejected after adoptive T-cell therapy. Apoptosis of tumor-infiltrating lymphocytes can be prevented by interrupting the Fas/Fas-ligand axis, and is triggered by polymorphonuclear-myeloid-derived suppressor cells, which express high levels of Fas-ligand and are enriched in TiRP tumors. Blocking Fas-ligand increases the anti-tumor efficacy of adoptive T-cell therapy in TiRP tumors, and increases the efficacy of checkpoint blockade in transplanted tumors. Therefore, tumor-infiltrating lymphocytes apoptosis is a relevant mechanism of immunotherapy resistance, which could be blocked by interfering with the Fas/Fas-ligand pathway.

Concepts: Immune system, Cancer, Oncology, Tumor, Interferon, Melanoma, Cancer immunotherapy


It is known that natural killer (NK) cell function is downregulated in chronic hepatitis B (CHB)-infected patients and in hepatic carcinoma (HCC) patients, but the mechanisms underlying this functional downregulation are largely unclear. In this study, microRNA (miR)-146a expression increased in NK cells from CHB and HCC patients compared with NK cells from healthy donors, and miR-146a levels were negatively correlated to NK cell functions. Overexpression of miR-146a reduced NK cell-mediated cytotoxicity and the production of interferon (IFN)-γ and tumor necrosis factor-α, which were reversed upon inhibition of miR-146a. In NK cells, miR-146a expression was induced by interleukin (IL)-10 and transforming growth factor-β, but reduced after treatment with interleukin-12, IFN-α and IFN-β. We further revealed that miR-146a regulated NK cell functions by targeting STAT1. Taken together, upregulated miR-146a expression, at least partially, attributes to NK cell dysfunction in CHB and HCC patients. Therefore, miR-146a may become a therapeutic target with great potential to ameliorate NK cell functions in liver disease.Cellular & Molecular Immunology advance online publication, 21 March 2016; doi:10.1038/cmi.2015.113.

Concepts: Immune system, Cirrhosis, Hepatitis, Natural killer cell, Interferon, Cytotoxicity, Hepatitis C, Hepatitis B


Immunotherapy has produced durable clinical benefit in patients with metastatic renal cell cancer (RCC). In the past, patients treated with interferon-alpha (IFN) and interleukin-2 (IL-2) have achieved complete responses, many of which have lasted for multiple decades. More recently, a large number of new agents have been approved for RCC, several of which attack tumor angiogenesis by inhibiting vascular endothelial growth factors (VEGF) and VEGF receptors (VEGFR), as well as tumor metabolism, inhibiting the mammalian target of rapamycin (mTOR). Additionally, a new class of immunotherapy agents, immune checkpoint inhibitors, is emerging and will play a significant role in the treatment of patients with RCC. Therefore, the Society for Immunotherapy of Cancer (SITC) convened a Task Force, which met to consider the current role of approved immunotherapy agents in RCC, to provide guidance to practicing clinicians by developing consensus recommendations and to set the stage for future immunotherapeutic developments in RCC.

Concepts: Immune system, Cancer, Angiogenesis, Vascular endothelial growth factor, Interferon, VEGF receptors, Renal cell carcinoma, Immunotherapy


HIV-HCV co-infection is associated with accelerated progression to hepatic fibrosis, cirrhosis and hepatocellular carcinoma than HCV mono-infection. The contribution of innate immunity during HIV-HCV co-infection has been a relatively under-investigated area. Natural killer (NK) cells are pivotal sentinels of innate immunity against viruses and tumour cells. In this study we evaluated the effect of HIV-HCV co-infection on peripheral blood NK cell subsets with emphasis on the phenotype of CD56(bright) NK cells.

Concepts: Immune system, Antibody, Gene, Cancer, Virus, Cirrhosis, Natural killer cell, Interferon


Hepatitis C virus infection and interferon treatment are often associated with anxiety, depressive symptoms and poor health-related quality of life. To evaluate the Silybin-vitamin E-phospholipids complex effect on work ability and whether health related factors (anxiety and depression) were associated with work ability in subjects with chronic hepatitis C treated with Pegylated-Interferon-α2b (Peg-IFN) and Ribavirin (RBV).

Concepts: Virus, Hepatitis, Hepatocellular carcinoma, Interferon, Hepatitis C, Ribavirin, Hepatitis B, Hepatitis C virus