IFN-Type-I Response and Systemic Immunity in Rectal Adenocarcinoma Patients Treated with Conventional or Hypofractionated Neoadjuvant Radiotherapy.

The IFN-type-I pathway is involved in radiotherapy (RT)-mediated immune responses. Large RT fractions have been suggested to potently induce this pathway. Neoadjuvant hypofractionated short-course (scRT) and conventional long-course (lcRT) RT applied for the treatment of locally advanced rectal adenocarcinoma patients provides a unique model to address the immuno-stimulatory properties of RT on a systemic level. We prospectively analyzed the IFNß plasma levels and lymphocyte counts (LCs) of rectal adenocarcinoma patients before and after treatment with scRT (n = 22) and lcRT (n = 40). Flow cytometry was conducted to assess the effects on lymphocytic subpopulations in a subset of 20 patients. A statistically significant increase in the post-RT IFNß plasma levels was noted in patients undergoing scRT (p = 0.004). Improved pathological tumor regression was associated with elevated post-RT IFNß levels (p = 0.003). Although all patients experienced substantial lymphopenia after treatment, the post-RT LC of patients treated with scRT were significantly higher compared to lcRT (p = 0.001). Patients undergoing scRT displayed significantly lower percentages of regulatory CD4+/CD25+ T-cells after therapy (p = 0.02). scRT enables effective stimulation of the IFN-type-I pathway on a systemic level and confers decreased lymphocytic cytotoxicity and limited regulatory T-cell activation compared to lcRT, supporting its increasing role in immuno-RT trials.

Early plasma interferon-ß levels as a predictive marker of COVID-19 severe clinical events in adult patients.

We assessed relationships between early peripheral blood type I interferons (IFN) levels, clinical new early warning scores (NEWS), and clinical outcomes in hospitalized coronavirus disease-19 (COVID-19) adult patients. Early IFN-ß levels were lower among patients who further required intensive care unit (ICU) admission than those measured in patients who did not require an ICU admission during severe acute respiratory syndrome coronavirus type 2 infection. IFN-ß levels were inversely correlated with NEWS only in the subgroup of patients who further required ICU admission. To assess whether peripheral blood IFN-ß levels could be a potential relevant biomarker to predict further need for ICU admission, we performed receiver operating characteristic (ROC) curve analyses that showed for all study patients an area under ROC curve of 0.77 growing to 0.86 (p = 0.003) when the analysis was restricted to a subset of patients with NEWS ≥5 at the time of hospital admission. Overall, our findings indicated that early peripheral blood IFN-ß levels might be a relevant predictive marker of further need for an ICU admission in hospitalized COVID-19 adult patients, specifically when clinical score (NEWS) was graded as upper than 5 at the time of hospital admission.

Participation of interferon type I during canine parvovirus infection.

Canine parvovirus (CPV) is a single-stranded DNA virus that causes severe and fatal gastrointestinal diseases in dogs. CPV has developed several strategies to evade innate immune response mediated by type I interferons (IFN-I) to achieve a successful infection. The aim of this work was to evaluate the capability of CVP-2c to evade the IFN-I mediated response in infected cells. To establish the role of this response, the gene expression of interferon ß (IFNß), IFIT1, IFIT3, MAVS, and STING were estimated in MDCK cells infected with CPV-2c. Viral replication and gene expression was evaluated by quantitative PCR, also, a treatment with IFN-I (interferon omega) was included to confirm the role of IFN-I during CPV infection. The results revealed that CPV-2c infection stimulates the expression of IFNß moderately, in these cells. Due to low IFNß induction, the IFIT1 and IFIT3 expression were also low, and therefore CPV-2c was able to replicate in these cells. However, when the cells were treated with exogenous IFN-I, the IFNß expression was higher, leading to an increased gene expression of IFIT1 and IFIT3, responsible for antiviral control. The overexpression of these proteins reduced the expression of NS1 and VP2 viral genes and hence viral replication. MAVS and STING expression on infected cells showed a mild increase compared to IFNß, suggesting that the viral infection could partially modify its expression. All results obtained in this study showed that during CPV-2c infection in MDCK cells, the IFNß expression was altered since this cytokine is one of the most critical factors for the control and inhibition of viral replication.

Abatacept enhances blood regulatory B cells of rheumatoid arthritis patients to a level that associates with disease remittance.

Abatacept, an inhibitor of CD28 mediated T-cell activation, has been shown to be effective in controlling inflammation during rheumatoid arthritis (RA). However, its effects on immune regulatory B and T cells (Bregs and Tregs) has not been fully explored. Thirty-one RA patients treated with abatacept for ≥ 6 months along with 31 RA patients treated with other modalities as well as 30 healthy controls were recruited. Of these 62 RA patient, 49 (79%) were females with a mean age of 54 ± 12 years and disease duration of 10 ± 6 years. The blood levels of Tregs and Bregs and their production of immunosuppressive cytokines, were determined using FACS analysis and Luminex Multiplex assay. Treatment with abatacept significantly enhanced the blood level of IL-35+ IL-10+ Bregs (P = 0.0007). Their levels were higher in the blood of remitted patients (DAS28-CRP < 2.6) compared to the unremitted ones (P = 0.0173), 6 months following abatacept treatment initiation. Moreover, abatacept treatment significantly enhanced the blood levels of LAG3+ conventional and unconventional Tregs of RA patients. This increase in the blood levels of Bregs and Tregs was accompanied with an elevated serum level of IL-35 and IFN-ß in abatacept-treated patients. Therefore, Abatacept efficiency to achieve remittance in RA could be attributed, in part, to its ability to enhance immune regulatory cells, especially IL-135+ IL-10+ Bregs.

Genomic monitoring of SARS-CoV-2 uncovers an Nsp1 deletion variant that modulates type I interferon response.

The SARS-CoV-2 virus, the causative agent of COVID-19, is undergoing constant mutation. Here, we utilized an integrative approach combining epidemiology, virus genome sequencing, clinical phenotyping, and experimental validation to locate mutations of clinical importance. We identified 35 recurrent variants, some of which are associated with clinical phenotypes related to severity. One variant, containing a deletion in the Nsp1-coding region (Δ500-532), was found in more than 20% of our sequenced samples and associates with higher RT-PCR cycle thresholds and lower serum IFN-ß levels of infected patients. Deletion variants in this locus were found in 37 countries worldwide, and viruses isolated from clinical samples or engineered by reverse genetics with related deletions in Nsp1 also induce lower IFN-ß responses in infected Calu-3 cells. Taken together, our virologic surveillance characterizes recurrent genetic diversity and identified mutations in Nsp1 of biological and clinical importance, which collectively may aid molecular diagnostics and drug design.

Variety of endosomal TLRs and Interferons (IFN-α, IFN-ß, IFN-γ) expression profiles in patients with SLE, SSc and MCTD.

We investigated Toll-like receptor (TLR)-3/-7/-8/-9 and interferon (IFN)-α/ß/γ mRNA expression in whole blood and serum IFN-α/ß/γ levels in patients with mixed connective tissue disease (MCTD), systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) and in healthy subjects to assess the association between the TLR-IFN expression and severity of and susceptibility to diseases, and identify potential biomarkers. Expression of the IFN-γ, TLR-3 and TLR-8 was detected only in SLE patients. TLR-7, IFN-α and IFN-ß expression was highest in SLE, while TLR-9 expression was highest in SSc patients. In SLE and MCTD patients a strong correlation was observed between TLR-7 and IFN-α expression and IFN-ß and IFN-α expression. In MCTD patients, negative correlation between IFN-α and TLR-9 and TLR-7 and TLR-9 was revealed. TLR-9 expression in anti-U1-70k-negative, anti-C negative and anti-SmB-negative MCTD patients was higher than in MCTD-positive patients. We observed negative correlations between serum IFN-α levels and TLR-7 expression and C3 and C4 levels in SLE patients. In SLE patients we observed that with increased IFN-γ, TLR-3 and TLR-8 expression increased the value of C3 and C4. Our results confirmed that the endosomal TLR-IFN pathway seems to be more important in SLE than in MCTD or SSc, and that IFN-α and IFN-ß may be possible biomarkers for SLE.

Safety, Tolerability, and Pharmacokinetics of PF-06823859, an Anti-Interferon ß Monoclonal Antibody: A Randomized, Phase I, Single- and Multiple-Ascending-Dose Study.

This double-blind, randomized, placebo-controlled, dose-ascending, first-in-human study (NCT02766621) assessed the safety, tolerability, and pharmacokinetics (PK) of PF-06823859, an anti-interferon ß monoclonal antibody. Healthy subjects were randomized to single ascending doses (SADs) of intravenous PF-06823859 30, 100, 300, 900, or 2000 mg or placebo; to multiple ascending doses (MADs) of subcutaneous PF-06823859 100 or 300 mg or placebo (once every 2 weeks for a total of 3 doses); or to MAD of intravenous PF-06823859 600 mg or placebo (once every 3 weeks or once every 4 weeks for a total of 2 doses). The incidence, severity, and causal relationship of adverse events (AEs) were assessed, along with immunogenicity and PK. In total, 62 subjects were randomized to treatment (SAD, n = 35; MAD, n = 27). There were 76 treatment-emergent all-causality AEs in the SAD (PF-06823859: n = 25; placebo: n = 4) and MAD (PF-06823859: n = 40; placebo: n = 7) cohorts. In the SAD cohorts, all treatment-emergent all-causality AEs were mild in severity; 4 AEs of moderate severity were identified in the MAD cohorts. No dose-limiting AEs, serious AEs, treatment-related discontinuations, dose reductions, or deaths occurred. PF-06823859 exposure increased dose-proportionally, with half-life values ranging between 23 and 35 days. The estimated subcutaneous bioavailability was 43% to 44%. Immunogenicity incidence rates were low (antidrug antibodies, 12.5%; neutralizing antibodies, 2.1%). No immunogenically related clinical responses of concern were observed. In conclusion, PF-06823859 demonstrated an acceptable safety, tolerability, and PK profile that supports clinical development for treating disorders associated with increased interferon ß levels, such as dermatomyositis or systemic lupus erythematosus.

Evaluation of the Relationships between Intestinal Regional Lymph Nodes and Immune Responses in Viral Infections in Children.

Viral infections increase the risk of developing allergies in childhood, and disruption of mucosal homeostasis is presumed to be involved. However, no study has reported a role for viral infections in such disruption. In this study, we clarified the mechanism of immunoglobulin A (IgA) overproduction in viral infections. Autopsies were performed on 33 pediatric cases, IgA and interferon (IFN)ß levels were measured, and histopathological and immunohistochemical examinations were conducted. Furthermore, we cultured human cells and measured IFNß and IgA levels to examine the effect of viral infections on IgA production. Blood IgA levels in viral infections were higher than in bacterial infections. Moreover, IFNß levels in most viral cases were below the detection limit. Cell culture revealed increased IgA in gastrointestinal lymph nodes, especially in Peyer's patches, due to enhanced IFNß after viral stimulation. Conversely, respiratory regional lymph nodes showed enhanced IgA with no marked change in IFNß. Overproduction of IgA, identified as an aberration of the immune system and resulting from excessive viral infection-induced IFNß was observed in the intestinal regional lymph nodes, particularly in Peyer's patches. Further, increased IgA without elevated IFNß in the respiratory system suggested the possibility of a different mechanism from the gastrointestinal system.

Commensal Microbiota Modulation of Natural Resistance to Virus Infection.

Interferon (IFN)-Is are crucial mediators of antiviral immunity and homeostatic immune system regulation. However, the source of IFN-I signaling under homeostatic conditions is unclear. We discovered that commensal microbes regulate the IFN-I response through induction of IFN-ß by colonic DCs. Moreover, the mechanism by which a specific commensal microbe induces IFN-ß was identified. Outer membrane (OM)-associated glycolipids of gut commensal microbes belonging to the Bacteroidetes phylum induce expression of IFN-ß. Using Bacteroides fragilis and its OM-associated polysaccharide A, we determined that IFN-ß expression was induced via TLR4-TRIF signaling. Antiviral activity of this purified microbial molecule against infection with either vesicular stomatitis virus (VSV) or influenza was demonstrated to be dependent on the induction of IFN-ß. In a murine VSV infection model, commensal-induced IFN-ß regulated natural resistance to virus infection. Due to the physiological importance of IFN-Is, discovery of an IFN-ß-inducing microbial molecule represents a potential approach for the treatment of some human diseases.

Prognostic factors for survival of herpes simplex virus-associated hemophagocytic lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) occurs in neonates with disseminated infection of herpes simplex virus (HSV). Little has been reported on the control of rapid HLH progression. We studied the cytokine profile and genetic basis of two index cases with divergent outcomes after early treatment of type 2 HSV infection. One survivor had fever and elevated serum levels of tumor necrosis factor (TNF)-α, interleukin-6 (IL-6), interferon (IFN)-ß, and IFN-γ at diagnosis. The other neonate had no fever or TNF-α production, but significant IL-6 or IFN responses during the treatment course, and died 19 days after birth. Among 16 reported cases of neonatal HSV-HLH including index cases, eight deceased neonates experienced significantly less fever at presentation (p = 0.028), lower platelet counts (p = 0.019), and lower ratios of soluble IL-2 receptor (sIL-2R) to ferritin levels (p = 0.044) than eight survivors. The 100-day overall survival rates were significantly higher in patients with fever (p = 0.004), > 100 × 109/L of platelet counts (p = 0.035) or > 20 of sIL-2R/ferritin ratio at diagnosis (p = 0.004). The first febrile and cytokine responses to HSV infection predict the early outcome of neonatal HSV-HLH.

IFN-λ3 as a host immune response in acute hepatitis E virus infection.

BACKGROUND AND AIM: Hepatitis E virus (HEV) is mainly transmitted orally, either waterborne or zoonotic foodborne. Intestinal viruses such as rotavirus are known to induce type III interferon (IFN) in the gastrointestinal (GI) tract where type III IFN dominantly functions in comparison with type I IFN. Therefore, the aim of this study is to investigate the significance of type III IFN (IFN-λ3) in acute hepatitis E. METHODS: IFN-λ3 and HEV RNA levels in the sera of patients with acute HEV infection and in the supernatant of HEV-inoculated cells were measured, using an in-house high-sensitivity method and reverse transcription-polymerase chain reaction, respectively. RESULTS: High serum IFN-λ3 levels were found in the early phase of acute HEV infection, which normalized after resolution. Interestingly, serum IFN-λ3 levels correlated well with serum HEV RNA titers in the same sera, both of which showed the peak before the robust increase of transaminases. In vitro experiments demonstrated that HEV replicated well in the cells with little IFN-λ3 induction (Caco-2, A549) and recombinant IFN-λ3 inhibited HEV replication in a dose-dependent manner. In contrast, in HT-29 cells, a colon cancer cell line, HEV poorly replicated and induced IFN-λ3 in a titer-dependent manner. CONCLUSIONS: These clinical and experimental observations suggest that HEV induced IFN-λ3 as a host innate immune response, which may play a protective role against HEV.

Bone marrow mesenchymal stem cells from patients with SLE maintain an interferon signature during in vitro culture.

BACKGROUND: We have previously shown that SLE BMSC have decreased proliferation, increased ROS, increased DNA damage and repair (DDR), a senescence associated secretory phenotype, and increased senescence-associated ß-galactosidase. We have also shown SLE BMSC produce increased amounts of interferon beta (IFNß), have increased mRNA for several genes induced by IFNß, and have a pro-inflammatory feedback loop mediated by a MAVS. To better understand the phenotype of SLE BMSC we conducted mRNA sequencing. METHODS: Patients fulfilling SLE classification criteria and age and sex matched healthy controls were recruited under an Institutional Review Board approved protocol. Bone marrow aspirates and peripheral blood samples were obtained. BMSC were isolated and grown in tissue culture. Early passage BMSC were harvested and mRNA samples were sent for RNAseq. Serum samples were assayed for IFNß by ELISA. RESULTS: On the basis of top differentially expressed genes between SLE and healthy controls, SLE patients with high levels of serum IFNß clustered together while SLE patients with low levels of IFNß clustered with healthy controls. Those genes differentially expressed in SLE patients generally belonged to known IFN pathways, and showed a strong overlap with the set of genes differentially expressed in IFNß high subjects, per se. Moreover, gene expression changes induced by treating healthy BMSC with exogenous IFNß were remarkably similar to gene expression differences in SLE IFNß high vs low BMSC. CONCLUSIONS: BMSCs from SLE patients are heterogeneous. A subgroup of SLE BMSC is distinguished from other SLE BMSC and from controls by increased levels of mRNAs induced by type I interferons. This subgroup of SLE patients had increased levels of IFNß in vivo.

Mesenchymal stem cell transplantation alleviates experimental Sjögren's syndrome through IFN-ß/IL-27 signaling axis.

Rationale: Although mesenchymal stem cell (MSC) transplantation has been proved to be an effective therapeutic approach to treat experimental Sjögren's syndrome (SS), the detailed underlying mechanisms remains unknown. IL-27 has diverse influences on the regulation of T cell differentiation and was involved in SS through modulating immune response. Here we aimed to explore whether IL-27-mediated regulation of immune cells was responsible for the beneficial effects of MSC transplantation on SS. Methods: The SS-like symptoms were evaluated in IL-27 deficient and recombinant IL-27-treated NOD mice. The MSCs were infused into NOD mice via the tail vein. The histological features of submandibular glands, saliva flow rate and serum IL-27 were examined. The effects of MSCs on the IL-27 production and Th17/Treg cell in SS patients and mice in vitro and in vivo were determined for the mechanistic study. Results: This study showed that SS patients had decreased IL-27 level and increased ratio of Th17/Treg cells. Consistently, exacerbated SS-like symptoms were observed in IL-27 deficient NOD mice, along with increased ratio of Th17/Treg cells. Importantly, MSC transplantation alleviated SS-like symptoms by elevating the level of IL-27 to restore Th17/Treg balance in NOD mice. Mechanistically, MSC-secreted interferon-ß (IFN-ß) promote dendritic cells to produce IL-27. Conclusions: Thus, we have revealed a previously unrecognized function of MSC-mediated IL-27 production by DCs in suppressing SS-like syndrome, which provided evidences for clinical application of MSC in patients with SS.

Plasma Type I IFN Protein Concentrations in Human Tuberculosis.

Tuberculosis (TB) remains one of the leading causes of mortality worldwide, and a lack of understanding of basic disease pathogenesis is hampering development of new vaccines and treatments. Multiple studies have previously established a role for type I interferon (IFN) in TB disease. Type I IFNs are critical immune mediators for host responses to viral infection, yet their specific influence in bacterial infection remains unclear. As IFN-stimulated genes (ISGs) can have both stimulatory and inhibitory effects on immune function, clarifying the role of type I interferon in TB remains an important question. The quantification of interferon proteins in the circulation of patients has been restricted until the recent development of digital ELISA. To test the hypothesis that patients with active TB disease have elevated circulating type I IFN we quantified plasma IFNα and ß proteins with Simoa digital ELISA in patients with active disease and asymptomatic M. tuberculosis infection. Strikingly no differences were observed between these two groups, while plasma from acute influenza infection revealed significantly higher plasma levels of both IFNα and IFNß proteins. These results suggest a discordance between ISG mRNA expression by blood leukocytes and circulating type I IFN in TB.

The association of nucleotide-binding oligomerization domain 2 gene polymorphisms with the risk of asthma in the Chinese Han population.

BACKGROUND: Genetic background is one of the important risk factors for development of asthma. The nucleotide-binding oligomerization domain 2 (NOD2) has been involved in the pathogenesis of asthma. The purpose of this study was to explore the relationship between NOD2 gene polymorphisms and asthma susceptibility in the Chinese Han population. METHODS: Children with asthma (n = 309) and Healthy children (n = 163) were recruited from Yancheng Third People's Hospital, Yancheng, China, between January 2016 and December 2017. The NOD2 gene polymorphisms were measured by the Snapshot SNP genotyping assays. Genotyping was performed for 4 tag SNPs of NOD2. Serum IFN-ß levels were measured by ELISA. RESULTS: The serum IFN-ß levels were significantly lower in Asthmatic children than those in the controls (p < 0.001). Low levels of IFN-ß may be related to the susceptibility to severe asthma. The rs3135499 C allele was associated with a significantly increased risk of asthma as compared with the rs3135499 A allele. CONCLUSION: The rs3135499 polymorphism of NOD2 gene and IFN-ß may play a role in the pathogenesis of asthma.

AIM2 levels and DNA-triggered inflammasome response are increased in peripheral leukocytes of patients with abdominal aortic aneurysm.

OBJECTIVE AND DESIGN: Abdominal aortic aneurysm (AAA) is heavily infiltrated with leukocytes, expressing the DNA sensor absent in melanoma 2 (AIM2) and other inflammasome components. METHODS: Using multicolour flow cytometry, we here compared the expression of the inflammasome components AIM2, NLRP3, and ASC in different peripheral immune cells derived from AAA patients with those from non-AAA patients in a case-control study. In parallel, peripheral blood mononuclear cells (PBMC) of AAA patients and controls were stimulated in vitro with poly-dA:dT or lipopolysaccharide (LPS) to analyze inflammasome activation. RESULTS: AIM2 expression was significantly increased in peripheral granulocytes (P = 0.026), monocytes (P = 0.007), B lymphocytes (P < 0.0001), and T lymphocytes (P = 0.004) of AAA patients. Expression of other inflammasome components did not differ between the groups. Following in vitro stimulation with foreign DNA, PBMC derived from AAA patients released significantly more IL-1ß (P = 0.022) into the supernatant than PBMC from control patients. In contrast, IL-1ß release upon LPS stimulation did not differ between the PBMC groups. CONCLUSION: The data indicate the increased activation of an AIM2 inflammasome in peripheral immune cells of AAA patients and point to a systemic AIM2-associated immune response to AAA.

[The mechanism of stimforte action on herpesvirus infection.]

Increased protease activity and a significant amount of granzyme B were observed in in organs of mice infected with acute herpes simplex virus HSV-1 with the introduction of Stimforte (100 or 250 µg/mouse). Thus, this drug activates killer cells, which play an extremely important role in the suppression of HSV-1 infection. Although the administration of Stimforte (100 µg/mouse) to intact mice results in the activation of IFN-ß production and does not activate the production of IFN-λ, Stimforte administration to animals infected with HSV-1 reduces production of IFN-ß in serum, brain and lungs, whereas the production of IFN-λ considerably increases as the result of administration of 100 µg/mouse of Stimforte.

Caspase-8 Collaborates with Caspase-11 to Drive Tissue Damage and Execution of Endotoxic Shock.

The execution of shock following high dose E. coli lipopolysaccharide (LPS) or bacterial sepsis in mice required pro-apoptotic caspase-8 in addition to pro-pyroptotic caspase-11 and gasdermin D. Hematopoietic cells produced MyD88- and TRIF-dependent inflammatory cytokines sufficient to initiate shock without any contribution from caspase-8 or caspase-11. Both proteases had to be present to support tumor necrosis factor- and interferon-ß-dependent tissue injury first observed in the small intestine and later in spleen and thymus. Caspase-11 enhanced the activation of caspase-8 and extrinsic cell death machinery within the lower small intestine. Neither caspase-8 nor caspase-11 was individually sufficient for shock. Both caspases collaborated to amplify inflammatory signals associated with tissue damage. Therefore, combined pyroptotic and apoptotic signaling mediated endotoxemia independently of RIPK1 kinase activity and RIPK3 function. These observations bring to light the relevance of tissue compartmentalization to disease processes in vivo where cytokines act in parallel to execute diverse cell death pathways.

Prediction of autoimmune connective tissue disease in an at-risk cohort: prognostic value of a novel two-score system for interferon status.

OBJECTIVE: To evaluate clinical, interferon and imaging predictors of progression from 'At Risk' to autoimmune connective tissue diseases (AI-CTDs). METHODS: A prospective observational study was conducted in At-Risk of AI-CTD (defined as antinuclear antibody (ANA) positive; ≤1 clinical systemic lupus erythematosus (SLE) criterion; symptom duration <12 months and treatment-naïve). Bloods and skin biopsy (non-lesional) were analysed for two interferon-stimulated gene expression scores previously described (IFN-Score-A and IFN-Score-B). Forty-nine healthy controls (HCs) and 114 SLE were used as negative and positive controls. Musculoskeletal ultrasound was performed. Progression was defined by meeting classification criteria for AI-CTDs at 12 months. RESULTS: 118 individuals with 12-month follow-up were included. Of these, 19/118 (16%) progressed to AI-CTD (SLE=14, primary Sjogren's=5). At baseline, both IFN scores differed among At-Risk, HCs and SLE groups (p<0.001) and both were elevated in At-Risk who progressed to AI-CTD at 12 months versus non-progressors, to a greater extent for IFN-Score-B (fold difference (95% CI) 3.22 (1.74 to 5.95), p<0.001) than IFN-Score-A (2.94 (1.14 to 7.54); p=0.018). Progressors did not have significantly greater baseline clinical characteristics or ultrasound findings. Fold difference between At-Risk and HCs for IFN-Score-A was markedly greater in skin than blood. In multivariable logistic regression, only family history of autoimmune rheumatic disease, OR 8.2 (95% CI 1.58 to 42.53) and IFN-Score-B, 3.79 (1.50-9.58) increased the odds of progression. CONCLUSION: A two-factor interferon score and family history predict progression from ANA positivity to AI-CTD. These interferon scores may allow stratification of individuals At-Risk of AI-CTD permitting early intervention for disease prevention and avoid irreversible organ damage.

Toll-like receptor signaling and serum levels of interferon ß and lipopolysaccharide binding protein are related to abdominal obesity: a case-control study between metabolically healthy and metabolically unhealthy obese individuals.

It is still unclear whether toll-like receptor (TLR) signaling and serum levels of inflammatory markers in metabolically unhealthy abdominally obese (MUAO) are due to their obesity and/or their metabolic state. We hypothesized that abdominal obesity is an important mediator of the association of metabolic state with TLR signaling and serum inflammatory markers. Therefore, in this case-control study, we compared the expression levels of TLR4 and Toll/interleukin-1 receptor domain containing adaptor protein-inducing interferon ß (TRIF) and serum concentrations of interferon ß and lipoprotein-binding protein (LBP) in metabolically healthy abdominally obese (MHAO) and MUAO individuals. Basal blood samples from 65 abdominally obese subjects with waist circumference (WC) of at least 95 cm were collected to determine serum metabolic parameters, IFNß, and LBP. Those with 3 or more metabolic alterations were defined as MUAO (n = 34), and those having 2 or less were classified as MHAO (n = 31). Furthermore, messenger RNA (mRNA) was isolated from peripheral blood mononuclear cells. TLR4 and TRIF gene expression assay was performed using quantitative real-time polymerase chain reaction. There were significant differences in serum fasting blood sugar (P = .017), triglyceride (P < .001), cholesterol (P = .002), and low-density lipoprotein cholesterol (P = .034) between the MUAO and MHAO groups, whereas no significant difference was observed in the expression ratio of TLR4 and TRIF mRNA and serum levels of IFNß and LBP. However, a significant correlation was noticed between mRNA expression levels of TLR4 and TRIF (r = 0.50, P < .001) and serum IFNß and LBP (r = 0.70, P < .001). It is concluded that the expression levels of TLR4 and TRIF as well as serum IFNß and LBP are more related to abdominal obesity than to metabolic health.