The important roles of type I interferon and interferon-inducible genes in systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a severe autoimmune disease that causes multiple-organ dysfunction mainly affecting women in their childbearing years. Type I IFN synthesis is usually triggered by viruses, and its production is tightly regulated and limited in time in health individuals. However, many patients with systemic autoimmune diseases including SLE have signs of aberrant production of type I interferon (IFN) and display an increased expression of IFN-inducible genes. Continuous type I IFNs derived from activated plasmacytoid dendritic cells (pDCs) by interferogenic immune complexes (ICs) and migration of these cells to tissues both break immune tolerance and promote an on-going autoimmune reaction in human body. By the means of detecting type I IFNs and IFN-inducible genes, it can help with diagnosis and evaluation of SLE in early stage and more efficiently. Anti-IFN-α monoclonal antibodies in SLE patients were recently reported and is now being investigated in phase II clinical trails. In this review, we focus on recent research progress in type I IFN and IFN-inducible genes. Possible mechanisms behind the dysregulated type I IFN system in SLE and how they contribute to the development of an autoimmune process, and act as a biomarker and therapeutic target will be reviewed.     

Pharmacological methods to overcome IFN-β antibody formation in the treatment of multiple sclerosis

Diminished efficacy in terms of clinical relapses and lesion load on magnetic resonance images for patients developing neutralising antibodies (NAbs) to recombinant IFN-β may be found in multiple sclerosis. NAbs become detectable over the first few years of therapy, disappearing during the treatment course in some patients and persisting longer in some others. Therefore, the administration of concomitant therapies to recombinant IFNβ to prevent the formation of NAbs could be indicated mainly in the latter group of patients at the early stage of the treatment. Among those therapies, steroids meet the best criteria in terms of either safety or impact on the development of NAbs, at the present time.     

Antiviral activity of type I interferons and interleukins 29 and 28a (type III interferons) against Apeu virus

Interferons (IFNs) are cytokines with important immunomodulatory activity in vertebrates. Although type I IFNs and interleukins (IL) 29 and 28a (type III IFNs) bind to different cellular receptors and have distinct structures, most of their biological activities are redundant. Apeu virus (APEUV) is a member of the Bunyaviridae family isolated from the Brazilian rain forest. In this paper we evaluated the antiviral activity of type I and type III IFNs against APEUV. All tested IFNs were able to induce an antiviral state against the virus in a dose-dependent way. The activity of type III IFNs did not need the presence of type I IFNs. Mixing both types of IFNs did not improve the biological activity of each type alone. The tested IFNs were also able to protect human peripheral blood mononuclear cells from infection. IFN alpha2, IFN beta, IL-29 and IL-28a induced the expression of 2′,5′-oligoadenylate synthetase (2′5′OAS) and 6–16 genes. Although MxA gene was related to antiviral activity against Bunyaviruses, there was no induction of MxA in our model. We were able to show activity of type I and type III IFNs against a RNA virus, and that this activity is not dependent on MxA gene.     

Antiviral activity of type I interferons and interleukins 29 and 28a (type III interferons) against Apeu virus

Interferons (IFNs) are cytokines with important immunomodulatory activity in vertebrates. Although type I IFNs and interleukins (IL) 29 and 28a (type III IFNs) bind to different cellular receptors and have distinct structures, most of their biological activities are redundant. Apeu virus (APEUV) is a member of the Bunyaviridae family isolated from the Brazilian rain forest. In this paper we evaluated the antiviral activity of type I and type III IFNs against APEUV. All tested IFNs were able to induce an antiviral state against the virus in a dose-dependent way. The activity of type III IFNs did not need the presence of type I IFNs. Mixing both types of IFNs did not improve the biological activity of each type alone. The tested IFNs were also able to protect human peripheral blood mononuclear cells from infection. IFN alpha2, IFN beta, IL-29 and IL-28a induced the expression of 2′,5′-oligoadenylate synthetase (2′5′OAS) and 6–16 genes. Although MxA gene was related to antiviral activity against Bunyaviruses, there was no induction of MxA in our model. We were able to show activity of type I and type III IFNs against a RNA virus, and that this activity is not dependent on MxA gene.     

Toll-like receptor 7-mediated enhancement of contextual fear memory in mice

Toll-like receptor (TLR) 7 recognizes viral single-stranded RNA and triggers production of the type I interferons (IFNs) IFN-α and IFN-β. Imiquimod, a synthetic TLR7 ligand, induces production of type I IFNs and is used clinically as an antiviral and antitumor drug. In the present study, we examined the effect of imiquimod on conditioned and innate fear behaviors in mice. Imiquimod was administered 2, 4, or 15 h before contextual fear conditioning. Imiquimod treatment 4 or 15 h before fear conditioning significantly enhanced context-dependent freezing behavior. This imiquimod-induced enhancement of fear-related behaviors was observed 120 h after fear conditioning. In contrast, imiquimod failed to enhance context-dependent freezing behavior in TLR7 knockout mice. Imiquimod had no significant effect on pain threshold or on innate fear-related behavior, as measured by the elevated plus-maze. The levels of type I IFN mRNA in the brain were significantly increased at 2 h after imiquimod treatment. Imiquimod also increased interleukin (IL)-1β mRNA expression in the brain at 4 h following administration, while mRNA expression of F4/80, a macrophage marker, was unaffected by imiquimod treatment. Our findings suggest that TLR7-mediated signaling enhances contextual fear memory in mice, possibly by inducing the expression of type I IFNs and IL-1β in the brain.     

The role of myeloid receptors on murine plasmacytoid dendritic cells in induction of type I interferon

This study tested the hypothesis that a set of predominantly myeloid restricted receptors (F4/80, CD36, Dectin-1, CD200 receptor and mannan binding lectins) and the broadly expressed CD200 played a role in a key function of plasmacytoid DC (pDC), virally induced type I interferon (IFN) production. The Dectin-1 ligands zymosan, glucan phosphate and the anti-Dectin-1 monoclonal antibody (mAb) 2A11 had no effect on influenza virus induced IFNα/β production by murine splenic pDC. However, mannan, a broad blocking reagent against mannose specific receptors, inhibited IFNα/β production by pDC in response to inactivated influenza virus. Moreover, viral glycoproteins (influenza virus haemagglutinin and HIV-1 gp120) stimulated IFNα/β production by splenocytes in a mannan-inhibitable manner, implicating the function of a lectin in glycoprotein induced IFN production. Lastly, the effect of CD200 on IFN induction was investigated. CD200 knock-out macrophages produced more IFNα than wild-type macrophages in response to polyI:C, a MyD88-independent stimulus, consistent with CD200's known inhibitory effect on myeloid cells. In contrast, blocking CD200 with an anti-CD200 mAb resulted in reduced IFNα production by pDC-containing splenocytes in response to CpG and influenza virus (MyD88-dependent stimuli). This suggests there could be a differential effect of CD200 on MyD88 dependent and independent IFN induction pathways in pDC and macrophages. This study supports the hypothesis that a mannan-inhibitable lectin and CD200 are involved in virally induced type I IFN induction.     

The clinical importance of neutralizing antibodies in relapsing-remitting multiple sclerosis

ABSTRACT

Background: Neutralizing antibodies (NAbs) develop in patients receiving interferon beta (IFN-β) for multiple sclerosis (MS). Debate continues concerning the relevance of NAb development on treatment efficacy.

Objective: To determine the incidence and clinical importance of NAbs in patients with relapsing-remitting MS (RRMS).

Methods: A comprehensive literature review was conducted using PubMed (accessed from 1983 to June 2005), Cochrane MS Group trials register (accessed June 2005), MEDLINE (accessed 1983 to June 2005), and Toxnet (accessed June 2005) databases. NAb-induced changes in clinical efficacy and disease progression were evaluated according to the clinical guidelines established by the American Academy of Neurology.

Results: Currently, there is no standardized assay to comparatively assess NAbs among different treatments. NAbs develop independent of age, sex, disease duration and progression index at the onset of treatment. The occurrence of NAbs varies from 2–45% depending on the treatment initiated. NAb+ patients demonstrate accelerated disease progression as confirmed by an approximate 1‐point increase in the Expanded Disability Status Scale score. The odds of relapse during a NAb+ period are between 1.51 and 1.58 (?p < 0.03) with the time to first relapse being shortened by an average of 244 days after 12 months of IFN‐β therapy. NAb+ patients experience an approximately four-fold increase (?p = 0.009) in the median number of active T2 magnetic resonance imaging (MRI) lesions compared to NAb-negative patients (1.4 vs. 0.3 respectively, p < 0.01).

Conclusion: The induction of NAbs in IFN‐β treated patients reduce clinical effect and accelerate disease progression.     

Subcutaneous interferon-beta-1a : new formulation

The new formulation of subcutaneous interferon-beta-1a was developed without serum-derived components with the aim of improving immunogenicity and injection tolerability in patients with relapsing forms of multiple sclerosis (MS). In a prospectively defined interim analysis at 48 weeks of an ongoing, single-arm, phase IIIb trial, 13.9% of MS patients receiving the new formulation of subcutaneous interferon-beta-1a 44 microg three times weekly had developed neutralising antibodies (NAbs). In the EVIDENCE trial, which served as an historical control, 24.4% of patients receiving the same dosage of the current formulation had developed NAbs at 48 weeks. The new formulation demonstrated similar pharmacokinetic activity to that of the current formulation in a phase I, double-blind, placebo-controlled study in healthy volunteers. About two-thirds of patients with MS who received the new formulation of subcutaneous interferon-beta-1a were relapse free in the interim, 48-week analysis of the single-arm trial; this is similar to results for the current formulation from historical data. A comparison of results from the interim, 48-week analysis with historical-control data from the EVIDENCE trial indicates that the new formulation of interferon-beta-1a may be associated with a lower incidence of injection-site reactions and a higher incidence of influenza-like symptoms than the current formulation. Adverse events associated with the new formulation were mostly mild to moderate in severity     

Antiviral activity of type I and type III interferons against porcine reproductive and respiratory syndrome virus (PRRSV)

The newly identified type III interferons (IFNs), also known as IFN-λ1/IL-29, IFN-λ2/IL-28A and IFN-λ3/IL-28B, like type I IFNs, have antiviral activity against a broad spectrum of viruses. We therefore examined whether type III IFNs, as well as type I IFNs, has the ability to inhibit porcine reproductive and respiratory syndrome virus (PRRSV) replication in MARC-145 cells. We found that replication of PRRSV in MARC-145 cells was significantly reduced following treatment with IFN-λ1, IFN-λ2 and IFN-λ3, respectively, and such inhibition was dose-dependent. However, type III IFNs (IFN-λ1, IFN-λ2 and IFN-λ3) was less effective than type I IFNs (IFN-α and IFN-β) in antiviral activity against PRRSV. Mixture of two types of IFNs could not improve the antiviral activity of each type alone. In addition, all types of IFNs in our study were able to induce the expression of ISG56, 2′,5′-OAS and MxA in MARC-145 cells. These data demonstrate that type III IFNs had antiviral activity against PRRSV and may serve as useful antiviral agents against infectious swine diseases.     

CpG and poly(I:C) stimulation of dendritic cells and fibroblasts limits herpes simplex virus type 1 infection in an IFNβ-dependent and -independent way

Viral activation of toll-like receptors (TLRs) on dendritic cells (DCs) leads to production of various cytokines, including antiviral type I interferons (IFNs). Synthetic ligands specific for TLRs are also able to induce the production of type I IFNs (IFNα/β) by DCs, suggesting that these ligands have potential as antiviral drugs. In this in vitro study we extensively investigated the antiviral activity of various TLR ligands. Mouse bone marrow (BM) cells were differentiated into plasmacytoid and conventional DCs (pDCs and cDCs), stimulated with various TLR ligands and tested the antiviral abilities of collected supernatants in an in vitro herpes simplex virus type 1 (HSV-1) infection model. We observed a significant IFNβ-, (but not IFNα-) dependent reduction in HSV-1 infection when a mixed pDC/cDC population was stimulated with the TLR9 ligand CpG. In the absence of pDCs, TLR stimulation resulted in less pronounced antiviral effects. The most pronounced antiviral effect was observed when both DC subsets were stimulated with poly(I:C). A similar noticeable antiviral effect was observed when fibroblasts (L929 cells) were stimulated directly with poly(I:C). These poly(I:C)-mediated antiviral effects were only partially IFNβ-mediated and probably TLR independent. These data demonstrate that TLR ligands are not only able to produce type I IFN but can indeed act as antiviral drugs. In particular poly(I:C), which exerts its antiviral effects even in the absence of DCs, may become a promising drug e.g. to prevent respiratory infections by topical intranasal application.     

Interferons and their role In inflammation.

Cytokines are pleiotropic molecules showing a wide variety of biologic functions on various cells and tissues, and several different cytokines exert similar and overlapping functions on certain cells. Interferons (IFNs), among the first cytokines identified, play a crucial role in human disease. The IFN cytokine family consists of type I IFNs (IFN-a and IFN-b) and type II IFN (IFN-g). In the first decades of IFN research, type I IFNs were considered primarily as viral inhibitors, whereas type II IFN, also termed "immune IFN", was generally considered to be uniquely involved in immune reactions. This view has changed considerably in the last years. The importance of type I IFNs in inflammation, immunoregulation and T-cell responses has been identified and has changed dramatically our interpretation of the biological relevance of type I and II IFNs. Recent data suggest that IFN-a is a multifunctional immunomodulatory cytokine with profound effects on the cytokine cascade including several anti-inflammatory properties, whereas IFN-g remains a classical proinflammatory cytokine. These different effects on critical mediators of inflammation may also explain why type I and II IFNs are clinically successful in different diseases. These newly identified immunoregulatory and anti-inflammatory functions of type I IFNs may be of importance in the treatment of diseases such as chronic viral hepatitis or multiple sclerosis and help to explain some of the mechanisms of IFNs.     

Pharmacological methods to overcome IFN-beta antibody formation in the treatment of multiple sclerosis

Diminished efficacy in terms of clinical relapses and lesion load on magnetic resonance images for patients developing neutralising antibodies (NAbs) to recombinant IFN-beta may be found in multiple sclerosis. NAbs become detectable over the first few years of therapy, disappearing during the treatment course in some patients and persisting longer in some others. Therefore, the administration of concomitant therapies to recombinant IFNbeta to prevent the formation of NAbs could be indicated mainly in the latter group of patients at the early stage of the treatment. Among those therapies, steroids meet the best criteria in terms of either safety or impact on the development of NAbs, at the present time.     

Novel plant-derived recombinant human interferons with broad spectrum antiviral activity

Type I interferons (IFNs) are potent mediators of the innate immune response to viral infection. IFNs released from infected cells bind to a receptor (IFNAR) on neighboring cells, triggering signaling cascades that limit further infection. Subtle variations in amino acids can alter IFNAR binding and signaling outcomes. We used a new gene crossbreeding method to generate hybrid, type I human IFNs with enhanced antiviral activity against four dissimilar, highly pathogenic viruses. Approximately 1400 novel IFN genes were expressed in plants, and the resultant IFN proteins were screened for antiviral activity. Comparing the gene sequences of a final set of 12 potent IFNs to those of parent genes revealed strong selection pressures at numerous amino acids. Using three-dimensional models based on a recently solved experimental structure of IFN bound to IFNAR, we show that many but not all of the amino acids that were highly selected for are predicted to improve receptor binding.     

Novel plant-derived recombinant human interferons with broad spectrum antiviral activity

Type I interferons (IFNs) are potent mediators of the innate immune response to viral infection. IFNs released from infected cells bind to a receptor (IFNAR) on neighboring cells, triggering signaling cascades that limit further infection. Subtle variations in amino acids can alter IFNAR binding and signaling outcomes. We used a new gene crossbreeding method to generate hybrid, type I human IFNs with enhanced antiviral activity against four dissimilar, highly pathogenic viruses. Approximately 1400 novel IFN genes were expressed in plants, and the resultant IFN proteins were screened for antiviral activity. Comparing the gene sequences of a final set of 12 potent IFNs to those of parent genes revealed strong selection pressures at numerous amino acids. Using three-dimensional models based on a recently solved experimental structure of IFN bound to IFNAR, we show that many but not all of the amino acids that were highly selected for are predicted to improve receptor binding.     

Type I IFNs and their role in the development of autoimmune diseases

Background: Since their initial use in the 1980s, IFNs have become an essential component of the therapy for many diseases such as hepatitis and multiple sclerosis. Although they have been extremely useful in conditions that pose therapeutic challenges, complications associated with their use have been widely reported including emerging reports of several autoimmune diseases. Many of these reports have shed light on the pathogenesis of autoimmune disorders and helped to highlight not only the critical role of type I IFNs in defense against viral infections but also the pivotal role they occupy in the interface between innate and adaptive immunity. Many patients with autoimmune disease have increased responsiveness to type I IFNs (α/β), and therapy with these cytokines has induced or unmasked autoimmune disease in many additional patients. Objective: The objective of this paper is to discuss the role of type I IFNs in autoimmunity. Methods: The literature regarding type I IFNs and autoimmunity was reviewed using the Medline database from 1950 to 2009. Search terms included ‘interferon alpha’ and ‘autoimmune disease’ and ‘interferon beta’ and ‘autoimmune disease’. Case reports, case series, reviews and prospective studies were included in the analysis. Results/conclusions: In the literature a variety of autoimmune disorders have reportedly been induced by the use of type I IFNs, being used, although these are primarily in the form of case reports and case series. Nevertheless, there is a growing body of molecular evidence to support the clinical association. The role of IFNs in the induction of autoimmunity is complex with interplay of many genetic and environmental factors that influence the balance between normal and aberrant immune responsiveness, ultimately leading to the observed clinical manifestations.     

The clinical importance of neutralizing antibodies in relapsing-remitting multiple sclerosis

BACKGROUND: Neutralizing antibodies (NAbs) develop in patients receiving interferon beta (IFN-beta) for multiple sclerosis (MS). Debate continues concerning the relevance of NAb development on treatment efficacy. OBJECTIVE: To determine the incidence and clinical importance of NAbs in patients with relapsing-remitting MS (RRMS). METHODS: A comprehensive literature review was conducted using PubMed (accessed from 1983 to June 2005), Cochrane MS Group trials register (accessed June 2005), MEDLINE (accessed 1983 to June 2005), and Toxnet (accessed June 2005) databases. NAb-induced changes in clinical efficacy and disease progression were evaluated according to the clinical guidelines established by the American Academy of Neurology. RESULTS: Currently, there is no standardized assay to comparatively assess NAbs among different treatments. NAbs develop independent of age, sex, disease duration and progression index at the onset of treatment. The occurrence of NAbs varies from 2-45% depending on the treatment initiated. NAb+ patients demonstrate accelerated disease progression as confirmed by an approximate 1-point increase in the Expanded Disability Status Scale score. The odds of relapse during a NAb+ period are between 1.51 and 1.58 (p < 0.03) with the time to first relapse being shortened by an average of 244 days after 12 months of IFN-beta therapy. NAb+ patients experience an approximately four-fold increase (p = 0.009) in the median number of active T2 magnetic resonance imaging (MRI) lesions compared to NAb-negative patients (1.4 vs. 0.3 respectively, p < 0.01). CONCLUSION: The induction of NAbs in IFN-beta treated patients reduce clinical effect and accelerate disease progression.     

Type I Interferons as Regulators of Human Antigen Presenting Cell Functions

Type I interferons (IFNs) are pleiotropic cytokines, initially described for their antiviral activity. These cytokines exhibit a long record of clinical use in patients with some types of cancer, viral infections and chronic inflammatory diseases. It is now well established that IFN action mostly relies on their ability to modulate host innate and adaptive immune responses. Work in recent years has begun to elucidate the mechanisms by which type I IFNs modify the immune response, and this is now recognized to be due to effects on multiple cell types, including monocytes, dendritic cells (DCs), NK cells, T and B lymphocytes. An ensemble of results from both animal models and in vitro studies emphasized the key role of type I IFNs in the development and function of DCs, suggesting the existence of a natural alliance between these cytokines and DCs in linking innate to adaptive immunity. The identification of IFN signatures in DCs and their dysregulation under pathological conditions will therefore be pivotal to decipher the complexity of this DC-IFN interaction and to better exploit the therapeutic potential of these cells.