I Interferon Gene Research Articles

Efficacy and Safety of Janus Kinase Inhibitors in Type I Interferon-Mediated Monogenic Autoinflammatory Disorders: A Scoping Review

ImportanceType I interferon (IFN)-mediated monogenic autoinflammatory disorders (interferonopathies) are childhood-onset rare multisystemic diseases with limited treatment options. The Janus kinase (JAK) inhibitors are promising potential therapeutic candidates for immune-mediated chronic inflammatory skin diseases.ObjectiveTo review the use of JAK inhibitors to improve decision-making when treating interferonopathies with cutaneous manifestations.Evidence ReviewThe MEDLINE, EMBASE, CINAHL, Scopus, and Web of Science databases were searched for studies that used JAK protein inhibitors to treat IFN-related monogenic diseases with cutaneous manifestations in humans. The search results are reported using the scoping review approach.FindingsSeventeen open-label studies assessing the efficacy of ruxolitinib, baricitinib, or tofacitinib reported variable responses in patients with chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) and related syndromes, stimulator of IFN genes [STING]-associated vasculopathy with onset in infancy (SAVI), familial chilblain lupus (FCh-L), gain-of-function mutations of STAT1 (GOF-STAT1), or Aicardi-Goutiéres syndrome. JAK inhibitors improved clinical and analytical parameters and decreased flare numbers, plasma inflammatory markers, and expression of IFN-stimulated genes. BK viremia and upper respiratory infections were the most frequent and severe adverse events. Significant heterogeneity in efficacy assessment methods and poor reporting of safety events were detected.Conclusions and RelevanceEvidence of the use of JAK inhibitors in patients with interpheronopathies is scarce and of low methodological quality. Future clinical trials should use validated scales and report drug safety in a more accurate way.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13555-021-00517-9.

Lactobacillus rhamnosus GG induces cGAS/STING- dependent type I interferon and improves response to immune checkpoint blockade

ObjectiveOur goals were to evaluate the antitumour efficacy of Lactobacillus rhamnosus GG (LGG) in combination with immune checkpoint blockade (ICB) immunotherapies on tumour growth and to investigate the underlying mechanisms.DesignWe...

Staphylococcus aureus Induces IFN-β Production via a CARMA3-Independent Mechanism.

Type I interferon (IFN) induction is a critical component of innate immune response to viral and bacterial infection, including S. aureus, but whether it activates the signaling in macrophages and the regulation mechanisms is less well understood. Here we show that S. aureus infection promoted the IFN-β mRNA expression and stimulator of IFN genes (STING)/TANK-binding kinase 1 (TBK1)/interferon regulatory factor 3 (IRF3)-dependent production of IFN-β. Infection with S. aureus induced caspase recruitment domain and membrane-associated guanylate kinase-like domain protein 3 (CARMA3) expression at both the mRNA and protein levels. The heat-killed bacteria failed to trigger IRF3 phosphorylation and upregulation of CARMA3 expression. However, overexpression of CARMA3 did not affect phosphorylation of TBK1 or IRF3 in RAW264.7 cells, J774A.1 macrophages, and mouse embryonic fibroblast (MEF) cells. In conclusion, S. aureus infection induces STING/TBK1/IRF3-mediated IFN-β production in a CARMA3-independent manner.

Divergent effects of acute versus chronic glucocorticoids in COVID-19.

Divergent effects of acute versus chronic glucocorticoids in COVID-19.

COVID-19 vasculitis and novel vasculitis mimics.

COVID-19 has been occasionally linked to histologically confirmed cutaneous vasculitis and a Kawasaki-like vasculitis, with these entities generally having minimal or no lung involvement and a good prognosis. Unlike these vasculitis types, patients with severe COVID-19 pneumonia can develop cutaneous vasculitis-like lesions and systemic arterial and venous thromboemboli, including cryptogenic strokes and other vasculopathy features. Proposed underlying mechanisms for these severe manifestations have encompassed immune dysregulation, including an anti-phospholipid syndrome-like state, complement activation, viral dissemination with direct systemic endothelial infection, viral RNAaemia with immunothrombosis, clotting pathway activation mediated by hypoxaemia, and immobility. In this Viewpoint, we highlight how imaging and post-mortem findings from patients with COVID-19 indicate a novel thrombosis in the pulmonary venous territory distal to the alveolar capillary bed, a territory that normally acts as a clot filtration system, which might represent an unappreciated nidus for systemic microembolism. Additionally, we suggest that this mechanism represents a novel vasculitis mimic related to COVID-19 that might lead to cryptogenic strokes across multivessel territories, acute kidney injury with haematuria, a skin vasculitis mimic, intestinal ischaemia, and other organ ischaemic manifestations. This finding is supported by pathological reports of extensive pulmonary venular thrombosis and peripheral organ thrombosis with pauci-immune cellular infiltrates. Therefore, severe COVID-19 pneumonia with extensive pulmonary intravascular coagulopathy might help to explain the numerous systemic complications of COVID-19, in which the demonstration of direct organ infection has not adequately explained the pathology.

Nuclear Soluble cGAS Senses DNA Virus Infection

The cytosolic DNA sensor cGAS detects foreign DNA from pathogens or self-DNA from cellular damage and instigates type I interferon (IFN) expression. Recent studies find that cGAS also localizes in the nucleus and binds the chromatin. Despite how cGAS is inhibited in the nucleus is well elucidated, whether nuclear cGAS participates in DNA sensing is not clear. Here, we report that herpes simplex virus 1 (HSV-1) infection caused the release of cGAS from the chromatin into the nuclear soluble fraction. Like its cytosolic counterpart, the leaked nuclear soluble cGAS could sense viral DNA, produce cGAMP, and induce mRNA expression of type I IFN and interferon-stimulated genes. Furthermore, the nuclear cGAS limited HSV-1 infection. Taken together, our study demonstrates that HSV-1 infection releases cGAS from the chromatin tethering and, in turn, the nuclear soluble cGAS activates type I IFN production.

TAK-573, an Anti-CD38/Attenuated Ifnα Fusion Protein, Has Clinical Activity and Modulates the Ifnα Receptor (IFNAR) Pathway in Patients with Relapsed/Refractory Multiple Myeloma

TAK-573, an Anti-CD38/Attenuated Ifnα Fusion Protein, Has Clinical Activity and Modulates the Ifnα Receptor (IFNAR) Pathway in Patients with Relapsed/Refractory Multiple Myeloma

Oxidative DNA Damage Accelerates Skin Inflammation in Pristane-Induced Lupus Model

Systemic Lupus Erythematosus (SLE) is a chronic inflammatory autoimmune disease in which type I interferons (IFN) play a key role. The IFN response can be triggered when oxidized DNA engages the cytosolic DNA sensing platform cGAS-STING, but the repair mechanisms that modulate this process and govern disease progression are unclear. To gain insight into this biology, we interrogated the role of oxyguanine glycosylase 1 (OGG1), which repairs oxidized guanine 8-Oxo-2′-deoxyguanosine (8-OH-dG), in the pristane-induced mouse model of SLE. Ogg1−/− mice showed increased influx of Ly6Chi monocytes into the peritoneal cavity and enhanced IFN-driven gene expression in response to short-term exposure to pristane. Loss of Ogg1 was associated with increased auto-antibodies (anti-dsDNA and anti-RNP), higher total IgG, and expression of interferon stimulated genes (ISG) to longer exposure to pristane, accompanied by aggravated skin pathology such as hair loss, thicker epidermis, and increased deposition of IgG in skin lesions. Supporting a role for type I IFNs in this model, skin lesions of Ogg1−/− mice had significantly higher expression of type I IFN genes (Isg15, Irf9, and Ifnb). In keeping with loss of Ogg1 resulting in dysregulated IFN responses, enhanced basal and cGAMP-dependent Ifnb expression was observed in BMDMs from Ogg1−/− mice. Use of the STING inhibitor, H151, reduced both basal and cGAMP-driven increases, indicating that OGG1 regulates Ifnb expression through the cGAS-STING pathway. Finally, in support for a role for OGG1 in the pathology of cutaneous disease, reduced OGG1 expression in monocytes associated with skin involvement in SLE patients and the expression of OGG1 was significantly lower in lesional skin compared with non-lesional skin in patients with Discoid Lupus. Taken together, these data support an important role for OGG1 in protecting against IFN production and SLE skin disease.

Biologics targeting type I interferons in SLE: A meta-analysis and systematic review of randomised controlled trials.

The feed-forward loop of type I interferons (IFNs) production and subsequent immunopathology of systemic lupus erythematosus (SLE) has been hypothesised to be disrupted with inhibition of IFNα or type I IFN receptor subunit 1 (IFNAR). This systematic review and meta-analysis present the treatment efficacy and safety profile of monoclonal antibodies inhibiting IFNα or IFNAR. A search was done using Medline, Embase and ClinicalTrials.gov for biologics targeting IFNα or IFNAR in SLE up to 3 Jan 2020. For the meta-analysis, analyses of binary variables were pooled using odds ratio (OR) with the Mantel Haenszel model. Anifrolumab 300 mg (n = 3 studies, 927 patients) was more effective than placebo in achieving SRI(4) (pooled OR = 1.91, CI 1.11-3.28, P = 0.02) and BICLA response (pooled OR = 2.25, CI 1.72-2.95, P < 0.00001). In SLE patients with high type I IFN gene signature, SRI(4) response was not achieved with anifrolumab in 2 studies, 450 patients. Treatment with IFNα and IFNAR inhibitors (n = 7 studies, 1590 patients) increased the risk of herpes zoster infection (pooled OR = 3.72, CI 1.88-7.39, P = 0.0002), upper respiratory tract infections, nasopharyngitis and bronchitis. This meta-analysis substantiates IFNAR as a therapeutic target in SLE. Inhibition of type I IFNs predisposes to herpes zoster and other viral infections.

VDAC oligomer pores: A mechanism in disease triggered by mtDNA release.

A recent study suggests that voltage-dependent anion channel (VDAC) oligomer pores promote mitochondrial outer membrane permeabilization and allow mitochondrial DNA (mtDNA) to be released into the cytosol in live cells. It challenges the notion that only occurs in apoptotic cells via BAX/BAK macropores. Cytosolic mtDNA activates cyclic GMP-AMP synthase (cGAS)-stimulator of IFN gene (STING) pathway and triggers type I interferon (IFN) response thereafter, which ultimately causes systemic lupus erythematosus. Mechanistically, mtDNA can interact with three positively charged residues (Lys12, Arg15, and Lys20) at the N-terminus of VDAC1, thereby strengthening VDAC1 oligomerization and facilitating mtDNA release. In addition, there are other pathways that can mediate mtDNA release, such as BAX/BAK macropores and virus-derived pores. The mtDNA released into the cytosol also triggers type I IFN response via the generally accepted cGAS-STING-TANK-binding kinase 1-IFN regulatory factor 3 axis. Collectively, VDAC oligomer pores provide us an attractive direction for us to understand mtDNA release-related diseases.

OP0049 EFFICACY OF ANIFROLUMAB IN ACTIVE SYSTEMIC LUPUS ERYTHEMATOSUS: PATIENT SUBGROUP ANALYSIS OF BICLA RESPONSE IN 2 PHASE 3 TRIALS

Background:Treatment of patients with systemic lupus erythematosus (SLE) with the type I interferon (IFN) receptor inhibitor anifrolumab resulted in higher British Isles Lupus Assessment Group (BILAG)–based Composite Lupus Assessment (BICLA) response rates vs placebo at Week 52 in the phase 3 randomized trials, TULIP-2 (primary endpoint; 16.3% difference)1and TULIP-1 (secondary endpoint; 16.4% difference).2BICLA is a validated composite global disease measure that registers both partial and complete improvement within organ systems.Objectives:TULIP-2 and TULIP-1 data were analyzed to evaluate BICLA responses to anifrolumab vs placebo at Week 52 in protocol-defined subgroups of patients with active SLE.Methods:TULIP-2 and TULIP-1 were randomized, double-blind, placebo-controlled trials that evaluated efficacy and safety of intravenous anifrolumab vs placebo administered every 4 weeks, with the primary endpoints assessed at Week 52, in patients with moderate to severe SLE despite standard-of-care treatment.1,2BICLA responses are defined by all of the following: reduction of baseline BILAG-2004 A and B domain scores to B/C/D and C/D, respectively, and no worsening in any organ system; no worsening of the SLE Disease Activity Index 2000 (SLEDAI-2K) score; no worsening of ≥0.3 points in the Physician’s Global Assessment (range 0–3); no trial treatment discontinuation; and no use of medications restricted by the protocol.3BICLA responses were compared between anifrolumab 300 mg and placebo groups, and robustness of BICLA responses was assessed across protocol-defined subgroups. TULIP-1 data were analyzed incorporating the amended restricted medication rules, as described.2Results:In TULIP-2 and TULIP-1, 180 patients in each trial received anifrolumab 300 mg (182 and 184 patients received placebo, respectively). Baseline demographics, disease characteristics, and standard-of-care medications were balanced between anifrolumab and placebo groups within both TULIP trials. Patients in TULIP-2 and TULIP-1 had comparable BICLA responses (Figure). Across multiple subgroups, higher percentages of patients achieved BICLA responses at Week 52 in the anifrolumab vs placebo arms (Figure). There was concordance of BICLA responses favoring anifrolumab across the protocol-defined subgroups of baseline disease severity (SLEDAI-2K &lt;10 points [difference 15.3%, TULIP-2; 16.9%, TULIP-1] vs ≥10 points [difference 16.7%, TULIP-2; 17.1%, TULIP-1]) and baseline oral corticosteroid use (prednisone or equivalent &lt;10 mg/d [difference 20.1%, TULIP-2; 16.2%, TULIP-1] vs ≥10 mg/d [difference 12.0%, TULIP-2; 17.7%, TULIP-1]). Numerically different BICLA effect sizes between the anifrolumab vs placebo arms were observed in both studies in relation to baseline IFN gene signature status (high [difference 17.3%, TULIP-2; 19.1%, TULIP-1] vs low [difference 11.2%, TULIP-2; 7.5%, TULIP-1]). Other subgroups including age, sex, age at onset, race, and anti-drug antibody status showed similar uniformity of response.Conclusion:The uniformity of robust BICLA response rates across prespecified subgroups in both phase 3 trials shows consistent clinical benefit of anifrolumab irrespective of patient baseline characteristics. However, given the small patient numbers in some subgroups, these results should be interpreted with caution.

Modulation of Type I Interferon System by African Swine Fever Virus.

African Swine Fever Virus (ASFV) has tropism for macrophages, which seems to play a crucial role in disease pathogenesis and viral dissemination. Previous studies showed that ASFV developed mechanisms to evade type I interferon (IFN) responses. Hence, we analyzed the ability of ASFV strains of diverse virulence to modulate IFN-β and IFN-α responses. Porcine monocyte-derived macrophages un-activated (moMΦ) or activated with IFN-α (moMΦ + FN-α) were infected with virulent (22653/14) or attenuated (NH/P68) ASFV strains, and expressions of IFN-β and of 17 IFN-α subtypes genes were monitored over time. ASFV strains of diverse virulence induced different panels of IFN genes: infection of moMΦ with either strains caused statistically significant up-regulation of IFN-α3, -α7/11, whereas only attenuated NH/P68 determined statistically significant up-regulation of IFN-α10, -α12, -α13, -α15, -α17, and IFN-β. Infection of activated moMΦ with either strains resulted in up-regulation of IFN-β and many IFN-α subtypes, but statistical significance was found only for IFN-α1, -α10, -α15, -α16, -α17 in response to NH/P68-infection only. These data revealed differences in type I IFNs expression patterns, with differences between strains of diverse virulence. In addition, virulent 22653/14 ASFV seems to have developed mechanisms to suppress the induction of several type I IFN genes.

Evolution of IFN subgroups in bony fish - 2. analysis of subgroup appearance and expansion in teleost fish with a focus on salmonids

A relatively large repertoire of type I interferon (IFN) genes is apparent in rainbow trout/Atlantic salmon, that includes six different IFN subgroups (IFNa-IFNf) belonging to the three known type I IFN groups (1–3) in bony fish. Whether this is true for other salmonids, and how the various type I subgroups evolved in teleost fish was studied using the extensive genomic resources available for fish. This confirmed that salmonids, at least the Salmoninae, indeed have a complex (in terms of IFN subgroups present) and large (number of genes) IFN repertoire relative to other teleost fish. This is in part a consequence of the salmonid 4 R WGD that duplicated the growth hormone (GH) locus in which type I IFNs are generally located. Divergence of the IFN genes at the two GH loci was apparent but was not seen in common carp, a species that also underwent an independent 4 R WGD. However, expansion of IFN gene number can be found at the CD79b locus of some perciform fish (both freshwater and marine), with expansion of the IFNd gene repertoire. Curiously the primordial gene order of GH-IFNc-IFNb-IFNa-IFNe is largely retained in many teleost lineages and likely reflects the tandem duplications that are taking place to increase IFN gene number. With respect to the evolution of the IFN subgroups, a complex acquisition and/or loss has occurred in different teleost lineages, with complete loss of IFN genes at the GH or CD79b locus in some species, and reduction to a single IFN subgroup in others. It becomes clear that there are many variations to be discovered regarding the mechanisms by which fish elicit protective (antiviral) immune responses.

Role of Interferon-γ-Producing Th1 Cells in a Murine Model of Type I Interferon-Independent Autoinflammation Resulting From DNase II Deficiency.

Patients with hypomorphic mutations in DNase II develop a severe and debilitating autoinflammatory disease. This study was undertaken to compare the disease parameters in these patients to those in a murine model of DNase II deficiency, and to evaluate the role of specific nucleic acid sensors and identify the cell types responsible for driving the autoinflammatory response. To avoid embryonic death, Dnase2-/- mice were intercrossed with mice that lacked the type I interferon (IFN) receptor (Ifnar-/- ). The hematologic changes and immune status of these mice were evaluated using complete blood cell counts, flow cytometry, serum cytokine enzyme-linked immunosorbent assays, and liver histology. Effector cell activity was determined by transferring T cells from Dnase2-/- × Ifnar-/- double-knockout (DKO) mice into Rag1-/- mice, and 4 weeks after cell transfer, induced changes were assessed in the recipient mice. In Dnase2-/- × Ifnar-/- DKO mice, many of the disease features found in DNase II-deficient patients were recapitulated, including cytopenia, extramedullary hematopoiesis, and liver fibrosis. Dnase2+/+ × Rag1-/- mice (n > 22) developed a hematologic disorder that was attributed to the transfer of an unusual IFNγ-producing T cell subset from the spleens of donor Dnase2-/- × Ifnar-/- DKO mice. Autoinflammation in this murine model did not depend on the stimulator of IFN genes (STING) pathway but was highly dependent on the chaperone protein Unc93B1. Dnase2-/- × Ifnar-/- DKO mice may be a valid model for exploring the innate and adaptive immune mechanisms responsible for the autoinflammation similar to that seen in DNASE2-hypomorphic patients. In this murine model, IFNγ is required for T cell activation and the development of clinical manifestations. The role of IFNγ in DNASE2-deficient patient populations remains to be determined, but the ability of Dnase2-/- mouse T cells to transfer disease to Rag1-/- mice suggests that T cells may be a relevant therapeutic target in patients with IFN-related systemic autoinflammatory diseases.

Ultraviolet light induces increased T cell activation in lupus-prone mice via type I IFN-dependent inhibition of T regulatory cells

Ultraviolet (UV) light is a known trigger of skin and possibly systemic inflammation in systemic lupus erythematosus (SLE) patients. Although type I interferons (IFN) are upregulated in SLE skin after UV exposure, the mechanisms to explain increased UVB-induced inflammation remain unclear. This paper compares the role of type I IFNs in regulating immune cell activation between wild-type and lupus-prone mice following UVB exposure. 10-week old female lupus-prone (NZM2328), wild-type (BALB/c) and iNZM mice (lack a functional type I IFN receptor on NZM2328 background) were treated on their dorsal skin with 100 mJ/cm2 of UVB for 5 consecutive days. Following UVB treatment, draining lymph node cell populations were characterized via flow cytometry and suppression assays; treated skin was examined for changes in expression of type I IFN genes. Only NZM2328 mice showed an increase in T cell numbers and activation 2 weeks post UVB exposure. This was preceded by a significant increase in UVB-induced type I IFN expression in NZM2328 mice compared to BALB/c mice. Following UVB exposure, both BALB/c and iNZM mice demonstrated an increase in functional T regulatory (TReg) cells; however, this was not seen in NZM2328 mice. These data suggest a skewed UVB-mediated T cell response in lupus-prone mice where activation of T cells is enhanced secondary to a type I IFN-dependent suppression of TReg cells. Thus, we propose type I IFNs are important for UVB-induced inflammation in lupus-prone mice and may be an effective target for prevention of UVB-mediated flares.

Evaluation of a single amino acid substitution at position 79 of human IFN-α2b in interferon-receptor assembly and activity

Type I interferons (IFNs) are homologous cytokines that bind to a cell surface receptor and establish signaling pathways that motivate immune responses. The purpose of the current study is to assess the activity of a novel-engineered IFN-α2b. The crystallographic structure of IFN-α2b and its receptors was acquired from Protein Data Bank. Various amino acid substitutions were designed based on structural properties and other biological characteristics of residues to find the most effective amino acid on IFN affinity to advanced activities. The IFN-α2b mutants and receptors have been modeled and the interactions between two proteins have been studied as in silico by protein–protein docking for both mutants and native forms. The proper nucleic acid sequence IFN-α2 (T79Q) has been prepared based on the selected mutant. The modified IFN gene was cloned in pcDNA 3.1(−) and introduced to Chinese Hamster Ovary (CHO) cell line. Antiviral and antiproliferative assays of native and IFN-α2 (T79Q) proteins were performed in vitro. The results showed two-fold increasing in IFN-α2 (T79Q) activity (antiviral and antiproliferative activity) in comparison to native IFN-α2b. This engineered IFN-α2b may have significant novel therapeutic applications and in silico studies can be an influential method for practical research function and structure of these molecules.

Coordination between innate immune cells, type I IFNs and IRF5 drives SLE pathogenesis

Systemic lupus erythematosus (SLE) is a complex autoimmune disease which affects multiple organs. The type I interferon (IFN) gene signature and circulating autoantibodies are hallmarks of SLE. Plasmacytoid dendritic cells (pDCs) are considered the main producers of type I IFN and production is modulated by multiple other immune cell types. In SLE, essentially every immune cell type is dysregulated and aberrant deregulation is thought to be due, in part, to direct or indirect exposure to IFN. Genetic variants within or around the transcription factor interferon regulatory factor 5 (IRF5) associate with SLE risk. Elevated IFNα activity was detected in the sera of SLE patients carrying IRF5 risk polymorphisms who were positive for either anti-RNA binding protein (anti-RBP) or anti-double-stranded DNA (anti-dsDNA) autoantibodies. Neutrophils are also an important source of type I IFNs and are found in abundance in human blood. Neutrophil extracellular traps (NETs) are considered a potential source of antigenic trigger in SLE that can lead to type I IFN gene induction, as well as increased autoantibody production. In this review, we will focus on immune cell types that produce type I IFNs and/or are affected by type I IFN in SLE. In addition, we will discuss potential inducers of endogenous type I IFN production in SLE. Last, we will postulate how the different immune cell populations may be affected by an IRF5-SLE risk haplotype.

Safety and Tolerability of Omalizumab: A Randomized Clinical Trial of Humanized Anti-IgE Monoclonal Antibody in Systemic Lupus Erythematosus.

Autoreactive IgE antibodies have been implicated in the pathogenesis of systemic lupus erythematosus (SLE). We hypothesize that omalizumab, a monoclonal antibody binding IgE, may improve SLE activity by reducing type I interferon (IFN) production by hampering plasmacytoid dendritic cells and basophil activation. This study was undertaken to assess the safety, tolerability, and clinical efficacy of omalizumab in mild to moderate SLE. Sixteen subjects with SLE and a Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score of ≥4 and elevated autoreactive IgE antibody levels were randomized to receive omalizumab or placebo (2:1) for 16 weeks, followed by 16 weeks of open-label treatment and a 4-week washout period. The SLEDAI-2K score, British Isles Lupus Assessment Group index (BILAG 2004) score, and physician's global assessment of disease activity were recorded at each visit. The type I IFN-induced gene signature was determined using quantitative polymerase chain reaction. Omalizumab was well tolerated with no allergic reactions, and mostly mild adverse events comparable to those experienced with placebo treatment. SLEDAI-2K scores improved in the omalizumab group compared to the placebo group at week 16 (P = 0.038), as well as during the open-label phase in subjects initially receiving placebo (P = 0.02). No worsening in BILAG scores or the physician's global assessment was detected. There was a trend toward a reduction in IFN gene signature in subjects treated with omalizumab (P = 0.11), especially in subjects with a high baseline IFN signature (P = 0.052). Our findings indicate that omalizumab is well tolerated in SLE and is associated with improvement in disease activity. Larger randomized clinical trials will be needed to assess the efficacy of omalizumab in patients with SLE.

Sphingosine 1-phosphate lyase promotes the type I interferon-mediated innate immune response to influenza but is subjected to degradation by influenza A virus NS1

Abstract Influenza viruses cause seasonal and pandemic influenza, remaining a threat to human health. The type I interferon (IFN)-mediated innate immune response is one of the central obstacles influenza A virus (IAV) must overcome to successfully replicate within the host. Here, we demonstrate that sphingosine 1-phosphate (S1P) lyase (SPL) enhances the type I IFN response, but this antiviral innate immunity is counteracted by IAV infection. Although SPL is an enzyme that metabolizes S1P, SPL was found to interact with IKKɛ and promote IKKɛ-mediated type I IFN responses. Thus, when SPL was knocked out of host cells, IAV replication increased and the elements of IKKɛ-induced type I IFN response decreased. However, IAV infection destabilized the SPL-mediated type I IFN response by inducing the degradation of SPL. Importantly, nonstructural protein 1 (NS1) of IAV triggered the depletion of SPL. SPL was ubiquitinated upon IAV infection or NS1 expression, whereas NS1-deficient IAV failed to elicit ubiquitination or downregulation of SPL. Transiently overexpressed SPL increased the levels of auto-phosphorylation of IKKɛ, resulting in enhanced expression of type I IFN and IFN-stimulated genes. However, this induction was markedly inhibited by IAV NS1. Collectively, this study reveals a pro-IFN function of SPL as well as a novel strategy employed by IAV to subvert the type I IFN response, providing new insights into the interplay between IAV and host innate immunity.

768 Type I interferons modulate ultraviolet radiation induced suppression of immune responses via Stimulator of Interferon Genes (STING)

UV (ultraviolet) B induced immune suppression contributes in a major way to the growth and development of UVB-induced skin cancers. Type I interferons (IFNs) are cytokines that play a role in regulation of proliferation, differentiation, and immune function. All characterized type I IFNs transmit their signals through the type I IFN receptor (IFNAR) composed of IFNAR1 and IFNAR2 components. Loss of either subunit results in complete abrogation of receptor function. There is limited information on the role for type I IFNs (IFN-α/β) signaling in UVB induced immune responses. Stimulator of IFN genes (STING) is an adaptor that responds to intracytoplasmic DNA by stimulating the production of type I IFN. The purpose of this study was to determine whether type I IFNs contributed to UV-induced DNA damage and immunosuppression via Stimulator of Interferon genes (STING) pathway. IFNAR1 deficient (IFNAR1-/-) and STING deficient (STING-/-) on C57BL/6 background and wild type (WT) mice were subjected to a local UVB regimen consisting of 100 mJ/cm2 UVB radiation for 4 days followed by sensitization with the hapten 2, 4-dinitrofluorobenzene (DNFB). UVB radiation in wild type mice induced significant (p<0.001) suppression of contact hypersensitivity response which was greatly enhanced (p<0.001) in IFNAR1-/- and STING-/- mice. The enhanced immune suppression was associated with significant decrease (p<0.001) in CD8+ T-cells and increase (p<0.001) in CD4+CD25+Foxp3+ populations in IFNAR1-/- and STING-/- mice when compared with WT mice. These findings can be used to develop type I IFN agonists for prevention against UVB induced immune suppression.