Elevated Levels Of IFN-α Research Articles

Plasma Immune Biomarkers Predictive of Progression to Active Tuberculosis in Household Contacts of TB Patients.

The progression from Mycobacterium tuberculosis infection to active tuberculosis (TB) disease varies among individuals, and identifying biomarkers to predict progression is crucial for guiding interventions. In this study, we aimed to determine plasma immune biomarker profiles in healthy household contacts of index pulmonary TB (PTB) patients who either progressed to TB or remained as non-progressors. A cohort of household contacts of adults with PTB was enrolled, consisting of 15 contacts who progressed to TB disease and 15 non-progressors. Plasma samples were collected at baseline, 4 months, and 12 months to identify predictive TB progression markers. Our findings revealed that individuals in the progressor group exhibited significantly decreased levels of IFNγ, IL-2, TNFα, IL1α, IL1β, IL-17A, and IL-1Ra at baseline, months 4 and 12. In contrast, the progressor group displayed significantly elevated levels of IFNα, IFNβ, IL-6, IL-12, GM-CSF, IL-10, IL-33, CCL2, CCL11, CXCL8, CXCL10, CX3CL1, VEGF, Granzyme-B and PDL-1 compared to the non-progressor group at baseline, months 4 and 12. ROC analysis identified IFNγ, GM-CSF, IL-1Ra, CCL2 and CXCL10 as the most promising predictive markers, with an AUC of ≥90. Furthermore, combinatorial analysis demonstrated that GM-CSF, CXCL10 and IL-1Ra, when used in combination, exhibited high accuracy in predicting progression to active TB disease. Our study suggests that a specific set of plasma biomarkers GM-CSF, CXCL10 and IL-1Ra, can effectively identify household contacts at significant risk of developing TB disease. These findings have important implications for early intervention and preventive strategies in TB-endemic regions.

MtDNA regulates cGAS-STING signaling pathway in adenomyosis

In various hyperproliferative disorders, damaged mitochondria can release mitochondrial DNA (mtDNA) into the cytoplasm, activating the cGAS-STING signaling pathway and subsequent immune imbalances. Our previous research has demonstrated that hypoxia plays a role in the development of adenomyosis (AM) by inducing mitochondrial dysfunction. However, the precise involvement of the cGAS-STING signaling pathway and mtDNA in AM remains unclear. Therefore, this study aims to investigate the relationship between mtDNA secretion, changes in the cGAS-STING signaling pathway, and the abnormal cellular proliferation observed in AM. We found the cGAS, STING, TBK1, p-TBK1, IRF3, and p-IRF3 proteins levels were significantly elevated in the tissues of patients with AM compared to the control group. Additionally, there was an increase in the expression of the pro-inflammatory cytokines IL-6 and IFN-α in the AM tissues. Hypoxia-induced an increase in the proliferation and migration abilities of endometrial stromal cells (ESCs), accompanied by the activation of the cGAS-STING signaling pathway and elevated levels of IFN-α. Furthermore, hypoxia promoted the leakage of mtDNA into the cytoplasm in AM ESCs, and the deletion of mtDNA reduced the activation of the cGAS-STING pathway. Moreover, knockdown of the STING gene inhibited the expression of TBK1, p-TBK1, IRF3, and p-IRF3 and suppressed the secretion of the inflammatory cytokines IL-6 and IFN-α. Furthermore, the migration and invasion abilities of AM ESCs were significantly diminished after STING knockdown. These findings provide valuable insights into the role of mtDNA release and the cGAS-STING signaling pathway in the pathogenesis of AM.

Elevated Levels of Interferon-α Act Directly on B Cells to Breach Multiple Tolerance Mechanisms Promoting Autoantibody Production.

Elevated levels of serum interferon-α (IFNα) and the disruption of B cell tolerance are central to systemic lupus erythematosus (SLE) immunopathogenesis; however, the relationship between these 2 processes remains unclear. The purpose of this study was to investigate the impact of elevated IFNα levels on B cell tolerance mechanisms in vivo and determine whether any changes observed were due to the direct effect of IFNα on B cells. Two classical mouse models of B cell tolerance were used in conjunction with an adenoviral vector encoding IFNα to mimic the sustained elevations of IFNα seen in SLE. The role of B cell IFNα signaling, T cells, and Myd88 signaling was determined using B cell-specific IFNα receptor-knockout, CD4+ T cell-depleted, or Myd88-knockout mice, respectively. Flow cytometry, enzyme-linked immunosorbent assay, real-time quantitative polymerase chain reaction, and cell cultures were used to study the effects of elevated IFNα on the immunologic phenotype. Elevation of serum IFNα disrupts multiple B cell tolerance mechanisms and leads to autoantibody production. This disruption was dependent upon B cell expression of IFNα receptor. Many of the IFNα-mediated alterations also required the presence of CD4+ T cells as well as Myd88, suggesting that IFNα acts directly on B cells to modify their response to Myd88 signaling and their ability to interact with T cells. The results provide evidence that elevated IFNα levels act directly on B cells to facilitate autoantibody production and further highlight the importance of IFN signaling as a potential therapeutic target in SLE.

NCF1-dependent production of ROS protects against lupus by regulating plasmacytoid dendritic cell development and functions.

Low capacity to produce reactive oxygen species (ROS) due to mutations in neutrophil cytosolic factor 1 (NCF1/p47phox), a component of NADPH oxidase 2 (NOX2) complex, is strongly associated with systemic lupus erythematosus in both humans and mouse models. Here, we aim to identify the key immune cell type(s) and cellular mechanisms driving lupus pathogenesis under the condition of NCF1-dependent ROS deficiency. Using a set of cell-specific Cre-deleter, the human NCF1-339 variant knock-in, and transgenic mouse strains, we show that low ROS production in plasmacytoid dendritic cells (pDCs) exacerbates both pristane-induced lupus and a newly established Yaa-related spontaneous model by promoting pDC accumulation in multiple organs during lupus development, accompanied by elevated IFNα levels and expression of IFN-stimulated genes. Mechanistic studies reveal that ROS deficiency enhances pDC generation through the AKT/mTOR pathway and CCR2-mediated migration to tissues, which together with hyperactivation of the redox-sensitive STING/IFNα/JAK1/STAT1 cascade further augments type I IFN responses. More importantly, by suppressing these pathways, restoration of NOX2-derived ROS specifically in pDCs protects against lupus. These discoveries explain the causative effect of dysfunctional NCF1 in lupus and demonstrate the protective role of pDC-derived ROS in disease development driven by NCF1-dependent ROS deficiency.

Interactions between the NLRP3-Dependent IL-1β and the Type I Interferon Pathways in Human Plasmacytoid Dendritic Cells.

Generally, a reciprocal antagonistic interaction exists between the antiviral type I interferon (IFN) and the antibacterial nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain containing 3 (NLRP3)-dependent IL-1β pathways that can significantly shape immune responses. Plasmacytoid dendritic cells (pDCs), as professional type I IFN-producing cells, are the major coordinators of antiviral immunity; however, their NLRP3-dependent IL-1β secretory pathway is poorly studied. Our aim was to determine the functional activity of the IL-1β pathway and its possible interaction with the type I IFN pathway in pDCs. We found that potent nuclear factor-kappa B (NF-κB) inducers promote higher levels of pro-IL-1β during priming compared to those activation signals, which mainly trigger interferon regulatory factor (IRF)-mediated type I IFN production. The generation of cleaved IL-1β requires certain secondary signals in pDCs and IFN-α or type I IFN-inducing viruses inhibit IL-1β production of pDCs, presumably by promoting the expression of various NLRP3 pathway inhibitors. In line with that, we detected significantly lower IL-1β production in pDCs of psoriasis patients with elevated IFN-α levels. Collectively, our results show that the NLRP3-dependent IL-1β secretory pathway is inducible in pDCs; however, it may only prevail under inflammatory conditions, in which the type I IFN pathway is not dominant.

High levels of circulating interferons type I, type II and type III associate with distinct clinical features of active systemic lupus erythematosus

Background and aimInterferons (IFNs) are considered to be key molecules in the pathogenesis of systemic lupus erythematosus (SLE). We measured levels of type I, II and III IFNs in a large cohort of patients with systemic lupus erythematosus (SLE) and controls and explored associations among high levels of different IFN types and distinct SLE features.MethodsFour hundred ninety-seven well-characterized SLE patients and 322 population controls were included. Disease activity was assessed by SLE Disease Activity Index (SLEDAI) and Systemic Lupus Activity Measure (SLAM). Functional type I IFN activity was estimated by a WISH reporter cell assay. Levels of IFN-γ were estimated by MSD 30-plex assay. IFN-α and IFN-λ1 were measured by ELISA. Values above the third quartile of patients’ measurements were defined as high. Associations among high IFN results and SLE features were investigated by nominal regression analysis.ResultsAll IFN measurements were higher in SLE patients than in controls. High type I IFN activity correlated with levels of IFN-γ and IFN-α and associated with active SLE in most domains: weight loss, fatigue, fever, rash, lymphadenopathy, arthritis, nephritis and haematological manifestations. Specific SLE subsets were linked to the upregulation of different subtypes of circulating IFNs: high IFN-γ to arthritis, nephritis and anti-Ro60 antibodies and high IFN-α to mucocutaneous engagement and anti-Ro52 and anti-La antibodies. Isolated high IFN-λ1 was coupled to anti-nucleosome antibodies and less severe SLE.ConclusionsHigh functional type I IFN activity captures active SLE in most domains, but more distinct patterns of organ involvement are associated with profiles of circulating IFNs. High IFN-γ as well as high functional type I IFN activity is a characteristic of severe SLE with nephritis and arthritis, while elevated levels of IFN-α associate with active mucocutaneous inflammation and a more benign cardiovascular profile. IFN-λ1 in isolation is associated with milder disease. Our findings suggest that IFNs contribute to the heterogeneity of clinical manifestations in SLE, and measuring circulating IFNs could assist in designing clinical trials with therapies targeting IFN pathways.

Overproduction of IL-6 and Type I IFN in a lethal case of Chikungunya virus infection in an elderly man during the 2017 Italian outbreak

Purpose: Chikungunya fever is a mosquito-borne viral disease caused by Chikungunya virus (CHIKV) and is generally considered self-limiting non-fatal disease. However, severe clinical presentations with high mortality rate (48%) are reported associated with the presence of several underlying medical conditions. Recently, a CHIKV epidemic occurred in Italy, involving 270 confirmed cases in Lazio and Calabria regions. Here, we report the virus characterization and an abnormal pattern of circulating cytokines in a lethal case of CHIKV during the 2017 Lazio region outbreak. Methods & Materials: In September 2017, a 77-year-old male with underlying cardiac diseases was admitted for acute neurological syndrome to the Santa Maria Goretti Hospital in Latina, Rome, and he died after 9 hour admission in sub-intensive unit care for acute cardiac arrest. Due to the ongoing CHIKV outbreak, RT-PCR and indirect immunofluorescence assays were performed to assess a possible infection. The virus was isolated on BHK-21 cells, and the near-complete genome sequencing was performed. Circulating IFNs and inflammatory cytokines were evaluated and quantified using ELISA, and the levels compared to those detected during the very early stages of the infection in four non-fatal cases belonging to the same outbreak. Results: Laboratory tests showed CHIKV infection, based on positive RT-PCR test (Ct: 12), in the absence of CHIKV-specific antibodies. The sequence of the isolate (CHIKV/ITA/Lazio-INMI2-2017) showed only one nucleotide difference (synonymous substitution) as compared to the outbreak prototype strain (CHIKV/ITA/Lazio-INMI1-2017), and clustered with recent isolates of the Indian Ocean sublineage of ECSA in the maximum-likelihood phylogenetic tree. The evaluation of the inflammatory response showed that IFN-α, IFN-β and IL-6 levels were extremely high as compared to non-fatal cases, while IFN-γ and TNF-α levels were in the same range. The elevated levels of IFN-α, IFN-β and IL-6 seemed not directly correlated to elevated levels of CHIKV-RNA. Conclusion: The analysis of inflammatory cytokines revealed a remarkable and strong increase of circulating type I IFN, as well as of the IL-6 pro-inflammatory cytokine, suggesting a possible role of type I IFN in cytokine storm, which may be correlated with unfavourable prognosis of CHIKV infection.

Receptor tyrosine kinase MerTK suppresses an allogenic type I IFN response to promote transplant tolerance.

Recipient infusion of donor apoptotic cells is an emerging strategy for inducing robust transplantation tolerance. Daily clearance of billions of self-apoptotic cells relies on homeostatic engagement of phagocytic receptors, in particular, receptors of the tyrosine kinase family TAM (Tyro3, Axl, and MerTK), to maintain self-tolerance. However, an outstanding question is if allogeneic apoptotic cells trigger the same receptor system for inducing allogeneic tolerance. Here, we employed allogeneic apoptotic splenocytes and discovered that the efferocytic receptor MerTK on recipient phagocytes is a critical mediator for transplantation tolerance induced by this strategy. Our findings indicate that the tolerogenic properties of allogeneic apoptotic splenocytes require MerTK transmission of intracellular signaling to suppress the production of inflammatory cytokine interferon α (IFN-α). We further demonstrate that MerTK is crucial for subsequent expansion of myeloid-derived suppressor cells and for promoting their immunomodulatory function, including maintaining graft-infiltrating CD4+ CD25+ Foxp3+ regulatory T cells. Consequently, recipient MerTK deficiency resulted in failure of tolerance by donor apoptotic cells, and this failure could be effectively rescued by IFN-α receptor blockade. These findings underscore the importance of the efferocytic receptor MerTK in mediating transplantation tolerance by donor apoptotic cells and implicate MerTK agonism as a promising target for promoting transplantation tolerance.

Abstract 2918: Interaction between MUC1 and STAT1 drives IFITM1 overexpression in aromatase inhibitor-resistant breast cancer cells

Abstract Aromatase inhibitors (AIs) successfully treat many estrogen receptor expressing breast cancers by depleting circulating estrogen levels. Unfortunately, many patients eventually develop resistance to this treatment. In order to elucidate the mechanism(s) of AI-resistance, our lab has developed an AI-resistant breast cancer cell line MCF-7:5C which was clonally derived from parental MCF-7 cells following long-term estrogen deprivation. Unlike MCF-7 cells, the AI-resistant MCF-7:5C cell line grows robustly in the absence of estrogen and is highly aggressive. We have previously reported that interferon induced transmembrane protein 1 (IFITM1) is overexpressed in MCF-7:5C cells and in AI-resistant breast tumors. Additionally, we have shown that loss of IFITM1 leads to cell death. What remains to be addressed is how IFITM1 expression is regulated in AI-resistant breast cancer cells. IFITM1 is a type 1 interferon (IFN) stimulated gene which is not expressed in normal tissue and is only induced by the type1 IFNs (IFNα/β). In previous studies we have found that MCF-7:5C cells produce elevated levels of IFNα, which binds to the type 1 IFN receptor, IFNAR, and induces JAK/STAT signaling, resulting in the overexpression of IFITM1. In this study, we further characterized the mechanisms of IFITM1 overexpression in AI-resistant MCF-7:5C cells. We have found that mucin 1 (MUC1) associates with STAT1 and stabilizes its phosphorylated form, thereby enhancing IFITM1 expression. This interaction is disrupted by treatment with the JAK inhibitor, Ruxolitinib. MUC1 is a transmembrane O-glycosylated protein that is overexpressed in 90% of breast cancers and known to promote the survival of the epithelium through formation of mucous, interaction with transcription factors and inhibition of apoptosis. A luciferase reporter determined that MUC1 contributes directly to IFITIM1 transcription. MUC1 expression is hormonally controlled and is normally enhanced by estrogen stimulation. In this study we found that MUC1 expression is dysregulated in AI-resistant MCF-7:5C cells and is instead reduced by estrogen stimulation. In contrast with the AI-sensitive MCF-7 cells, western blot and immunofluorescent staining showed that MUC1 expression was enhanced by treatment with the pure anti-estrogen, fulvestrant. Additionally, Annexin V/PI staining and PARP cleavage indicated that loss of MUC1 expression induced cell death in MCF-7:5C cells. We found that treatment with fulvestrant protects MCF-7:5C cells from this phenomenon, indicating that loss of MUC1 induces apoptosis in an ERα dependent manner. MCF-7:5C cells are sensitive to apoptosis following exposure to estrogen, which can be enhanced by loss of IFITM1 expression. We report that loss of MUC1 expression similarly enhances estrogen-induced apoptosis, suggesting that the communication between MUC1 and STAT1 also influences estrogen signaling in AI-resistant breast cancer. Citation Format: Asona Lui, Joan Lewis-Wambi. Interaction between MUC1 and STAT1 drives IFITM1 overexpression in aromatase inhibitor-resistant breast cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2918.

Abstract 717: Overexpression of interferon-stimulated genes is critical for the survival of aromatase inhibitor-resistant breast cancer cells

Abstract Aromatase inhibitors (AIs) successfully treat many estrogen receptor expressing breast cancers by depleting circulating estrogen levels. Unfortunately, the majority of patients treated with AIs eventually develop resistance to this treatment. In order to elucidate the mechanism(s) of AI-resistance our lab has developed an AI-resistant breast cancer cell line MCF-7:5C which was clonally derived from parental MCF-7 cells following long-term estrogen deprivation. The AI-resistant MCF-7:5C cells grow robustly in the absence of estrogen, are highly aggressive, and constitutively overexpress a panel of type 1 interferon (IFN) stimulated genes (ISGs) including IFITM1, IFIT1, IFI27, PLSCR1, STAT1/2, OAS1 and MX1 as compared to the AI-sensitive MCF-7 cells. Human tissue microarray analysis also indicates that IFITM1 and PLSCR1 are overexpressed in AI-resistant/recurrence breast tumors as compared to primary tumors. ISGs are not expressed basally in normal tissue and are only induced by type1 IFNs (IFNα and β) to protect the host from viral infections. IFNα signals through a specific receptor, IFNAR1/2, which uses JAK/STAT signaling to produce the ISGs. The significance of constitutive overexpression of ISGs in AI-resistant breast cancer is not known. In this study, we investigated the functional importance of ISGs in the AI-resistant breast cancer cell line, MCF-7:5C, and the mechanism(s) that drive their overexpression in these cells. Using ELISA, we detected a 3-fold higher level of IFNα in AI-resistant MCF-7:5C cells than in the parental MCF-7 cells and FACS analysis revealed that the IFNα was produced by all cells in culture, not a distinct subset of the population. Blockade of IFNα signaling using a neutralizing antibody to IFNAR, as well as transient knockdown of IFNα and its transcription factor IRF7 dramatically reduced ISG expression. Most notably, loss of IFNα and suppression of type 1 IFN signaling resulted in the death of the AI-resistant MCF-7:5C cells, while having no effect on the parental MCF-7 cells, thus confirming its pro-survival function. Apart from IFNα signaling, we also found evidence of post-transcriptional regulation of ISGs in the AI-resistant cells. Specifically, several of the ISGs had a significantly longer mRNA half-life in the MCF-7:5C cells than in the parental MCF-7 cells. Additionally, knockdown of the RNA binding protein Human Antigen R (HuR) significantly reduced the mRNA stability and expression of the ISGs. Electron microscopy confirmed that AI-resistant MCF-7:5C cells exhibit classic morphological signs of anti-viral response and ISG expression, including dilated ER, and enhanced cell-cell adhesion as compared with the AI-sensitive MCF-7 cell line. Overall, we have found that AI-resistant breast cancer cells maintain elevated levels of IFNα in order to drive constitutive overexpression of ISGs which sustains their survival in estrogen deprived conditions. Citation Format: Asona Lui, Hye-Joung Choi, Joan Lewis-Wambi. Overexpression of interferon-stimulated genes is critical for the survival of aromatase inhibitor-resistant breast cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 717. doi:10.1158/1538-7445.AM2015-717

Interferon-α and angiogenic dysregulation in pregnant lupus patients who develop preeclampsia.

To investigate whether an elevated interferon-α (IFNα) level early in pregnancy is associated with poor pregnancy outcomes and to examine the relationship of an elevated IFNα level to angiogenic imbalance. Women were enrolled in a longitudinal case-control study of pregnant patients with lupus. Serum samples obtained monthly throughout pregnancy were assayed for IFNα and for the antiangiogenic factor soluble Flt-1 and the proangiogenic factor placenta growth factor (PlGF). Each of 28 patients with systemic lupus erythematosus (SLE) with a poor pregnancy outcome was matched to an SLE patient with an uncomplicated pregnancy and to a pregnant healthy control. The effects of IFNα and/or soluble Flt-1 on human endothelial cells and endothelial cell-trophoblast interactions were assessed. Compared to SLE patients with uncomplicated pregnancies, patients with preeclampsia had increased IFNα levels before clinical symptoms. Patients without autoimmune disease who developed preeclampsia did not have increased IFNα levels. In SLE patients with low IFNα levels, marked angiogenic imbalance (higher soluble Flt-1, lower PlGF, and higher soluble Flt-1:PlGF ratios) preceded maternal manifestations of preeclampsia, whereas in SLE patients with high IFNα levels, preeclampsia occurred without evidence of systemic angiogenic imbalance. Treatment of human endothelial cells with soluble Flt-1 induced expression of sFLT1 messenger RNA, and IFNα dramatically amplified responses to soluble Flt-1. In a model of spiral artery transformation, only the combination of IFNα and soluble Flt-1 disrupted the ability of trophoblast cells to remodel endothelial tube structures. Our findings identify a new mechanism by which IFNα induces an antiangiogenic milieu and increases the sensitivity of endothelial cells to soluble Flt-1, and suggest that elevated IFNα levels may contribute to the pathogenesis of preeclampsia in some pregnant patients with SLE.

Early cytokine dysregulation and viral replication are associated with mortality during lethal influenza infection.

Infection with influenza A virus (IAV) leads to acute lung injury and possibly fatal complications, especially in immunocompromised, elderly, or chronically infected individuals. Therefore, it is important to study the factors that lead to pathology and mortality in infected hosts. In this report, we analyze immune responses to infection at a sublethal (0.1 LD(50)) and lethal (1 LD(50)) dose of the highly pathogenic IAV A/Puerto Rico/8/34 (PR8). Our experiments revealed that infection with a 1 LD(50) dose induced peak viral titers at day 2 compared to day 4 in the 0.1 LD(50) dose. Moreover, early cytokine dysregulation was observed in the lethal dose with significantly elevated levels of IFN-α, TNF-α, CXCL9, IL-6, and MCP-1 produced at day 2. Early inflammatory responses following infection with 1 LD(50) correlated with a greater influx of neutrophils into the lung. However, depletion of neutrophils enhanced morbidity following IAV infection. Though no differences in CD8+ cell function were observed, CD4+ effector responses were impaired in the lungs 8 days after infection with 1 LD(50). Histological analysis revealed significant pathology in lethally infected mice at day 2 and day 6 postinfection, when viral titers remained high. Treating lethally infected mice with oseltamivir inhibited viral titers to sublethal levels, and abrogated the pathology associated with the lethal dose. Together, these results suggest that early cytokine dysregulation and viral replication play a role in pulmonary damage and high mortality in lethally infected mice.

Association of Serum C‐Reactive Protein Levels With Lupus Disease Activity in the Absence of Measurable Interferon‐α and a C‐Reactive Protein Gene Variant

ObjectiveThe type I interferon (IFN) system is important in the pathogenesis of systemic lupus erythematosus (SLE). We previously demonstrated an inhibitory effect of IFNα on interleukin‐6 (IL‐6)–induced C‐reactive protein (CRP) in vitro, hypothetically explaining the poor correlation between disease activity and CRP levels in SLE. This study was undertaken to investigate disease activity, IL‐6 levels, and CRP levels in relation to a CRP gene polymorphism and IFNα.MethodsSera from 155 SLE patients and 100 controls were analyzed for CRP. Patients were genotyped for a CRP single‐nucleotide polymorphism (rs1205) associated with low CRP levels. Serum IFNα and IL‐6 levels were quantified by immunoassays. Clinical disease activity was assessed using the SLE Disease Activity Index 2000 (SLEDAI‐2K).ResultsCRP levels were increased in SLE patients compared to controls, but were not associated with SLEDAI‐2K or IL‐6 levels. However, exclusion of patients carrying at least one rs1205 minor allele revealed an association between disease activity and CRP levels (P = 0.005). We found a strong association between disease activity and CRP levels (P < 0.0005) when patients with measurable IFNα levels as well as the minor allele of rs1205 were excluded from the analysis. Similarly, when patients with elevated IFNα levels and/or the rs1205 polymorphism were excluded, IL‐6 levels were associated with CRP levels.ConclusionThe present study demonstrates that the serum IFNα level as well as the CRP genotype affect the CRP response in SLE patients. Lack of correlation between serum levels of CRP and disease activity could therefore be explained by activation of the type I IFN system and polymorphisms in the CRP gene.

Sialic acid binding preference of influenza A viruses regulates pathological leukocyte recruitment (VIR2P.1012)

Abstract Influenza A virus (IAV), a seasonal respiratory pathogen, has a high capacity to cause pandemic infections resulting in severe lung pathology. Multiple studies using pathological IAV strains have demonstrated the importance of macrophages and neutrophils, but whether the pathological inflammation induced by different IAV isolates is identical has not been directly compared. Here we demonstrate that while both A/WSN/33 (WSN) and A/PR/8/34 (PR8) influenza viruses cause significant immunopathology in mice the inflammatory milieu differs between the two isolates. Specifically, PR8 infection was associated with greater neutrophil recruitment and CCL4 and CXCL2 expression; in contrast, WSN infection was associated mast cell activation, recruitment of a unique Ly6ghigh Ly6chigh monocyte population, and elevated levels of IFNα, G-CSF, and CCL2. One difference between WSN and PR8 is their hemaggultinin molecules preferentially bind to α2,6- and α2,3-linked sialic acids, respectively. Using a recombinant WSN strain whose sialic acid binding preference is switched to α2,3-linkages, we observed minimal mast cell activation and a switch to a more neutrophilic inflammation. Thus, sialic acid binding preference of IAV isolates has clinically important alterations to the inflammatory cascade(s) activated. These findings have important implications for our ability to therapeutically target the host inflammatory response to limit morbidity following influenza virus infection

Interferon-α is not elevated in idiopathic thrombotic thrombocytopenic purpura patients.

Idiopathic thrombotic thrombocytopenic purpura (TTP) patients have ADAMTS13 deficiency, which is usually caused by ADAMTS13 autoantibodies. However, the triggering factors for the autoantibody production remain unclear. Interferon-α (IFN-α) is a cytokine involved with many autoimmune processes such as inducing the activation of peripheral dendritic cells and stimulating T cells and B cells. It also plays an important role in some autoimmune diseases. Elevated IFN-α levels have been observed in some TTP patients and previous case reports have shown the occurrence of TTP after IFN-α treatment. Thus, we hypothesized that high levels of IFN-α would correlate with presence of ADAMTS13 autoantibodies. However, we did not observe elevated IFN-α levels in 36 TTP patients (mean 5.29 pg/ml, standard deviation (SD) 26.56 pg/ml) compared to healthy controls (mean 0 pg/ml, SD 0 pg/ml), P = 0.59. IFN-α levels of most patients (94%) were undetectable. Only two patients had increased IFN-α levels and ADAMTS13 autoantibodies were detected in these two patients. Interestingly, both the patients had an underlying autoimmune disease. Although there have been cases of secondary TTP following IFN-α treatment, no evidence supports a role of IFN-α in the development of idiopathic TTP in our patient population.

Dendritic Cells in Cardiovascular Diseases

Cardiovascular diseases (CVDs) are one of the leading causes of mortality worldwide.1 It has been so for decades, notwithstanding a wide array of – mostly preventive – treatment modalities targeting known risk factors, such as hyperlipidemia, type 2 diabetes mellitus, hypertension, or obesity. Recent technical and conceptual advances have unveiled important contributions of the immune system in the pathophysiology of a variety of CVDs such as atherosclerosis, ischemic stroke, chronic heart failure, and other myocardial conditions like myocardial ischemia and reperfusion, viral myocarditis, and cardiac transplantation.2–4 In many of these disorders, so-called danger-associated molecular patterns (DAMPs), released from necrotic tissue and dying cells, can lead to the activation of certain immune cell populations such as monocytes/ macrophages, granulocytes, and T cells, thus aggravating ongoing inflammatory processes at the lesion site. Dendritic cells (DCs) are key modulators of immunity, pivotal in directing innate and adaptive immune responses against microbial, viral, but also modified self-antigens present at the sites of injury. Given the tissue trauma underlying various CVDs, it is not surprising that recent observations have allocated a regulatory role for DCs in CVD-associated immune responses. Interestingly, nondiseased arteries of young individuals were seen to host a network of resident vascular DCs (CD1a+ S100+ lag+ CD31− CD83− CD86−),5 representing a phenotype related to Langerhans cells in the skin. In agreement, monocyte-derived CD11c+ CD68+ dendritic cells could be detected in the atherosclerosis-prone lesser curvature and aortic sinus in inbred atherosclerosis-susceptible (C57Bl/6), but not resistant mouse strains (balb/c).6 Murine vascular resident DCs express an immature phenotype with low expression of costimulatory molecules, and are present in the subendothelial space with occasional probing into the vascular lumen. DCs have …

Increased level of type I Interferon (IFN) during type I diabetes (T1D) induces apoptosis in spleen-homing T cells

Type I diabetes (TID) is an autoimmune disease characterized by abnormalities in the defense mechanisms against a variety of infectious agents. Susceptibility to infections occurring in diabetic individuals is attributed to the decrease in the number of lymphocytes, which is probably a clinical consequence of the occurrence of apoptosis described in diabetes. TID is associated with increased cytokines that dampen lymphocytes proliferation, functions and subsequently increase risk to infection. Previous studies have reported an increase in IFN-α level which is associated with TID pathogenesis. In the present study, we further investigated the effect of blocking type I IFN receptor signaling pathway on the lymphocyte proliferation and functions within spleen as a secondary lymphoid organ in a streptozotocin (STZ)-induced type I diabetic mouse model. Three groups of mice were used (10 mice in each group): group 1, control non-diabetic mice; group 2, diabetic mice; and group 3, diabetic mice intraperitoneal injected with anti-IFNAR1 (10 mg/kg body weight once/day for up to 20 days). We found that diabetic mice exhibited increase in the apoptosis, DNA fragmentation, chromatin condensation and cell shrinkage; prolonged elevation in IFN-α and TNF-α levels and obvious reduction in spleen-homing T lymphocytes as compared to control mice. Interestingly, blocking type I IFN receptor of diabetic mice significantly decreased (P< 0.05) apoptotic changes of the diabetic lymphocyte, significantly restored the distribution and numbers of T lymphocytes in the spleen and also decreased the level of IFN-α and TNF-α as compared to diabetic non treated mice. Our data revealed the correlation between the elevated levels of IFN-α during TID and the perturbation in lymphocyte architecture and distribution within lymphoid organs. Key words: Diabetes mellitus, IFN-α, apoptosis, lymphocytes, spleen.

The Presence of Alpha Interferon at the Time of Infection Alters the Innate and Adaptive Immune Responses to Porcine Reproductive and Respiratory Syndrome Virus

Porcine reproductive and respiratory syndrome (PRRS) is one of the most devastating and costly diseases to the swine industry worldwide. Overall, the adaptive immune response to PRRS virus (PRRSV) is weak, which results in delayed elimination of virus from the host and inferior vaccine protection. PRRSV has been shown to induce a meager alpha interferon (IFN-α) response, and we hypothesized that elevated IFN-α levels early in infection would shorten the induction time and increase elements of the adaptive immune response. To test this, we measured both antibody and cell-mediated immunity in pigs after the administration of a nonreplicating human adenovirus type 5 vector expressing porcine IFN-α (Ad5-pIFN-α) at the time of PRRSV infection and compared the results to those for pigs infected with PRRSV alone. Viremia was delayed, and there was a decrease in viral load in the sera of pigs administered the Ad5-pIFN-α. Although seroconversion was slightly delayed in pigs receiving Ad5-pIFN-α, probably due to the early reduction in viral replication, little difference in the overall or neutralizing antibody response was seen. However, there was an increase in the number of virus-specific IFN-γ-secreting cells detected in the pigs receiving Ad5-pIFN-α, as well as an altered cytokine profile in the lung at 14 days postinfection, indicating that the presence of IFN-α at the time of infection can alter innate and adaptive immune responses to PRRSV.

Cognitive dysfunction in HIV encephalitic SCID mice correlates with levels of Interferon-α in the brain

Interferon alpha (IFNalpha) is an antiviral cytokine produced in response to viral infection. IFNalpha also acts as a neuromodulatory molecule in the central nervous system (CNS). Elevated IFNalpha in the CNS causes cognitive deficits. To determine if elevated levels of IFNalpha in an HIV encephalitis mouse model correlate with cognitive deficits. C57BL/6J SCID mice were inoculated intracerebrally (i.c.) with HIV infected or uninfected (control) macrophages and cognitively tested in a water escape radial arm maze. After behavioral testing was completed, immunohistochemistry and ELISA were used to examine brain pathology and IFNalpha expression. Mice injected i.c. with HIV infected macrophages exhibited significantly more working memory errors, particularly in trials with the highest memory load. Immunohistochemistry indicated increased mouse IFNalpha staining prevalent on neurons and glial cells in the brains of mice with HIV infected macrophages compared to mice with uninfected control macrophages. In addition, IFNalpha levels in the brain correlated directly with working memory errors for mice with HIV infected macrophages. These data suggest that the cognitive deficit noted for the C57BL/6J SCID mice with HIV infected macrophages is mediated by the infection induced increase in IFNalpha.

Interpreting interest in interferon-alpha.

Interpreting interest in interferon-alpha.