Journal of Interferon and Cytokine Research最新文献

Autoantibodies (AABs) neutralizing type I interferons (IFN) underlie about 15% of cases of critical coronavirus disease 2019 (COVID-19) pneumonia. The impact of autoimmunity toward type III IFNs remains unexplored. We included samples from 1,002 patients with COVID-19 (50% with severe disease) and 1,489 SARS-CoV-2-naive individuals. We studied the prevalence and neutralizing capacity of AABs toward IFNλ and IFNα. Luciferase-based immunoprecipitation method was applied using pooled IFNα (subtypes 1, 2, 8, and 21) or pooled IFNλ1-IFNλ3 as antigens, followed by reporter cell-based neutralization assay. In the SARS-CoV-2-naive cohort, IFNλ AABs were more common (8.5%) than those targeting IFNα2 (2.9%) and were related with older age. In the COVID-19 cohort the presence of autoreactivity to IFNλ did not associate with severe disease [odds ratio (OR) 0.84; 95% confidence interval (CI) 0.40-1.73], unlike to IFNα (OR 4.88; 95% CI 2.40-11.06; P < 0.001). Most IFNλ AAB-positive COVID-19 samples (67%) did not neutralize any of the 3 IFNλ subtypes. Pan-IFNλ neutralization occurred in 5 patients (0.50%), who all suffered from severe COVID-19 pneumonia, and 4 of them neutralized IFNα2 in addition to IFNλ. Overall, AABs to type III IFNs are rarely neutralizing, and do not seem to predispose to severe COVID-19 pneumonia on their own.

Globally, ∼56.8 million people are chronically infected with hepatitis C virus (HCV), with about half residing in Asia. The cost and efficiency of delivering regimens based on direct-acting antiviral agents for HCV are important considerations in implementing these curative treatments. For sofosbuvir-based regimens, most patients are treated for 12 weeks; however, treatment for 8 weeks has been shown to cure HCV infection in 95% of patients without cirrhosis. Furthermore, virological failure after 8-week treatment occurs in only 1%-2% of individuals without cirrhosis, who have a favorable IFNL4 genotype, which is present in >50% of South Asians and >80% of East Asians. We propose that sofosbuvir-based treatment for 8 weeks, or perhaps shorter, would yield high response rate regimens in Asian countries and markedly increase the number of patients who could be cured for a given cost of the medication. We propose that a noninferiority trial in an East Asian population be conducted to test this hypothesis.

Type III interferons (IFN-lambdas, IFN-λs) are important antiviral cytokines that can also modulate immune responses by acting through a heterodimeric receptor composed of the specific and limited expressed IFN-λR1 chain and the ubiquitous IL-10R2 chain, which is shared with IL-10 family cytokines. Conflicting data have been reported regarding which cells express the IFN-λR1 subunit and directly respond to IFN-λs. This is, in part, owing to transcript levels of the IFN-λR1 gene, IFNLR1, not always correlating with cell surface protein levels. In this study, we tested a panel of novel monoclonal antibodies (mAbs) that specifically recognize human IFN-λR1. Initially, antigen specificity was confirmed by enzyme-linked immunosorbent assay (ELISA), from which a subset of antibodies was selected for additional flow cytometry and neutralization assays. We further characterized two antibodies based on their strong ELISA binding activity (HLR1 and HLR14) and found only HLR14 could reliably detect cell surface IFN-λR1 protein on a variety of cell lines by flow cytometry. HLR14 could also detect IFN-λR1 protein on certain primary human blood cells, including plasmacytoid dendritic cells and B cells from peripheral blood. Availability of the HLR14 mAb will enable the quantification of IFN-λR1 protein levels on cells and better characterization of the cell specificity of the IFN-λ response.

Interferon lambda 4 (IFN-λ4) is a novel type-III interferon that can be expressed only by carriers of the genetic variant rs368234815-dG within the first exon of the IFNL4 gene. Genetic inability to produce IFN-λ4 (in carriers of the rs368234815-TT/TT genotype) has been associated with improved clearance of hepatitis C virus (HCV) infection. The IFN-λ4-expressing rs368234815-dG allele (IFNL4-dG) is most common (up to 78%) in West sub-Saharan Africa (SSA), compared to 35% of Europeans and 5% of individuals from East Asia. The negative selection of IFNL4-dG outside Africa suggests that its retention in African populations could provide survival benefits, most likely in children. To explore this hypothesis, we conducted a comprehensive association analysis between IFNL4 genotypes and the risk of childhood Burkitt lymphoma (BL), a lethal infection-associated cancer most common in SSA. We used genetic, epidemiologic, and clinical data for 4,038 children from the Epidemiology of Burkitt Lymphoma in East African Children and Minors (EMBLEM) and the Malawi Infections and Childhood Cancer case-control studies. Generalized linear mixed models fit with the logit link controlling for age, sex, country, P. falciparum infection status, population stratification, and relatedness found no significant association between BL risk and 3 coding genetic variants within IFNL4 (rs368234815, rs117648444, and rs142981501) and their combinations. Because BL occurs in children 6-9 years of age who survived early childhood infections, our results suggest that additional studies should explore the associations of IFNL4-dG allele in younger children. This comprehensive study represents an important baseline in defining the health effects of IFN-λ4 in African populations.

Type III interferon, or interferon lambda (IFNλ), was discovered 20 years ago and has been studied primarily for its role in combatting viral infections. However, it is also induced in response to certain bacterial infections but its roles and effects in this context are relatively poorly understood. In this mini review, we discuss the roles of IFNλ signaling in bacterial infections, highlighting its deleterious or protective effects for different infections. We also discuss a couple of recent studies showing that some bacteria possess defense mechanisms against the effects of IFNλ. We hope that this review will spur further investigation into the roles of IFNλ in the context of bacterial infections and will promote considerations of its therapeutic potential for these infections.

Type III interferons (IFN-λ) are central to host defense against viral infection of epithelial barrier surfaces. IFN-λ binding to its receptor induces a JAK-STAT cascade through kinases Janus-associated kinase 1 (JAK1) and tyrosine kinase 2 (TYK2), which are associated on either subunit of the heterodimeric type III IFN receptor. Recent studies have shown that TYK2 is not necessary for IFN-λ to signal, in contrast to IFN-α, which uses the same JAK-STAT pathway activated by the type I IFN receptor. The mechanism for this differential TYK2 requirement is unknown. Our study uses synthetic IFN receptors in TYK2-deficient U2OS epithelial cells to define the processes in type I and III IFN signaling that require TYK2. We find that TYK2 deficiency reduces signaling equally from heterodimers of either type I or III IFN receptor intracellular domains. In contrast, JAK1-associated homodimers of IFNAR2 or IFNLR1 are both fully signaling competent even in the absence of TYK2. These results suggest that heterodimerization of the type III IFN receptor is insufficient to confer TYK2-independent signaling. Thus, we propose that noncanonical receptor complexes may participate in endogenous type III IFN signaling to confer TYK2-independent signaling downstream of IFN-λ stimulation.

It has now been 20 years since the original discovery of the interferon λ (IFN-λ) family (Kotenko et al., 2003; Sheppard et al., 2003) and 10 years since the subsequent discovery of IFN-λ4 (Prokunina-Olsson et al., 2013). The IFN-λ family (type III IFNs) includes 4 members: IFN-λ1, 2, 3, and 4, and all 4 of these proteins signal through the same heterodimeric receptor complex: IFN-λR1 plus IL-10R2. Throughout the past 20 years, much has been learned about the IFN-λ family and the important role of these cytokines in antiviral responses against viruses such as hepatitis C virus, influenza A virus, and SARS-CoV-2. This special issue of the Journal of Interferon & Cytokine Research (JICR) features a group of new reports that highlight recent developments regarding various aspects of IFN-λ-mediated responses. Many of these reports were first presented during the Interferon Lambda 2022 Satellite Meeting after the "Cytokines 2022" meeting in Hawaii. These articles underscore the fact that our understanding of the IFN-λ family continues to evolve and remains a critical subject area for additional future research.

Interleukin-7 (IL-7) is essential for maintaining the immune system's defense functions by regulating the development and homeostasis of lymphocytes. Findings have shown the high efficacy of IL-7/IL-7 receptor (IL-7R)-based immunotherapy on various malignancies, with confirmation in both animal models and humans. In recent years, the progression-free survival and overall survival of patients suffering from gliomas significantly increased by introducing C7R-expressing chimeric antigen receptor (CAR)-T cells and long-acting IL-7 agonists such as NT-I7 (rhIL-7-hyFc, Efineptakin alfa). However, the effect of IL-7-based immunotherapies on the resistance of tumor cells to chemotherapy (when used simultaneously with chemotherapy agents) is still ambiguous and requires further studies. This article first reviews the pathophysiological roles of IL-7/IL-7R in tumors, focusing on gliomas. Subsequently, it discusses the therapeutic values of IL-7/IL-7R and the recombinant derivatives in gliomas.

Rheumatoid arthritis (RA) is an inflammatory autoimmune illness affecting around 1% of the population globally. Cytokines have a crucial role in the pathogenesis of RA. The objectives of the present study were to compare the serum cytokine profiles between methotrexate (MTX)-treated and MTX-naive RA patient groups, MTX-treated RA patient group and healthy controls, and MTX-naive RA patient group and healthy controls. Enzyme linked immunosorbent assay (ELISA) kits were used to quantify the serum concentrations of tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β, IL-17, IL-6, interferon-gamma (IFN-γ), and IL-10 in 80 RA patients (48 MTX treated and 32 MTX naive) and 80 healthy controls. For all cytokine assays, absorbance was measured at 450 nm using a microplate reader (Bio-Rad). Independent sample t-test was used to compare the serum cytokine concentrations between the study groups using SPSS version 25. MTX-treated RA patient group had significantly reduced serum levels of TNF-α (36.13 ± 17.64 versus 45.82 ± 23.07, *P = 0.037), IL-17 (307.85 ± 151.74 versus 435.42 ± 241.19, **P = 0.006), and IFN-γ (414.93 ± 212.13 versus 527.15 ± 269.61, *P = 0.041) compared to MTX-naive RA patients. Both MTX-treated and MTX-naive RA patient groups had significantly high serum levels of TNF-α, IL-1β, IL-17, IL-6, IFN-γ, and IL-10 when compared to healthy controls (***P < 0.001). Downregulation of the serum concentrations of certain key cytokines, viz. TNF-α, IL-17, and IFN-γ, demonstrates the anti-inflammatory effect of MTX in RA patients.