Interferon Γ-induced Protein Research Articles

The Prostacyclin Analogue Iloprost Modulates CXCL10 in Systemic Sclerosis.

The prostacyclin analogue iloprost is used to treat vascular alterations and digital ulcers, the early derangements manifesting in systemic sclerosis (SSc), an autoimmune disease leading to skin and organ fibrosis. Bioindicator(s) of SSc onset and progress are still lacking and the therapeutic approach remains a challenge. The T helper 1 (Th1) chemokine interferon (IFN)γ-induced protein 10 (IP-10/CXCL10) associates with disease progression and worse prognosis. Endothelial cells and fibroblasts, under Th1-dominance, release CXCL10, further enhancing SSc’s detrimental status. We analyzed the effect of iloprost on CXCL10 in endothelial cells, dermal fibroblasts, and in the serum of SSc patients. Human endothelial cells and dermal fibroblasts activated with IFNγ/Tumor Necrosis Factor (TNF)α, with/without iloprost, were investigated for CXCL10 secretion/expression and for intracellular signaling cascade underlying chemokine release (Signal Transducer and Activator of Transcription 1, STAT1; Nuclear Factor kappa-light-chain-enhancer of activated B cells, NF-kB; c-Jun NH2-terminal kinase, JNK: Phosphatidyl-Inositol 3-kinase (PI3K)/protein kinase B, AKT; Extracellular signal-Regulated Kinase 1/2, ERK1/2). CXCL10 was quantified in sera from 25 patients taking iloprost, satisfying the American College of Rheumatology (ACR)/European Alliance of Associations for Rheumatology (EULAR) 2013 classification criteria for SSc, and in sera from 20 SSc sex/age-matched subjects without therapy, previously collected. In human endothelial cells and fibroblasts, iloprost targeted CXCL10, almost preventing IFNγ/TNFα-dependent cascade activation in endothelial cells. In SSc subjects taking iloprost, serum CXCL10 was lower. These in vitro and in vivo data suggest a potential role of iloprost to limit CXCL10 at local vascular/dermal and systemic levels in SSc and warrant further translational research aimed to ameliorate SSc understanding/management.

Performance analysis of Luminex and ELISA to profile serum IP-10 as a biomarker in systemic lupus erythematosus.

Interferon-γ inducible protein-10 (IP-10) is a promising biomarker in systemic lupus erythematosus (SLE). The optimal quantification platform has not yet been identified. We compared the performance of bead-based multiplex assay (Luminex) and high-sensitivity enzyme-linked immunosorbent assay (hs-ELISA) for profiling serum IP-10 as a biomarker of lupus activity. A cross-sectional study was conducted on outpatients with SLE. Serum IP-10 was measured simultaneously on Luminex and hs-ELISA, and correlation between platforms was assessed. Additionally, IP-10 levels were tested against disease activity and organ involvement. One-hundred and forty-one patients (88% women; 38 years old) were studied. Median IP-10 levels were 100.9 (125.2) pg/mL by Luminex and 156.5 (191.7) pg/mL by hs-ELISA. Correlation analysis showed Spearman's ρ = 0.621 (p < 0.0001) between Luminex and hs-ELISA. Quantification of IP-10 by Luminex showed a significant correlation (ρ = 0.198; p = 0.021) with disease activity, while this was not observed (ρ = 0.036; p = 0.683) when measured using hs-ELISA. Serum IP-10 levels were lower in quiescent patients than in those with active disease (70.8 [68.4] versus 114.3 [123.9] pg/mL; p = 0.024), with an AUC-ROC = 0.62 (p = 0.029), sensitivity = 47.9%, specificity = 77.5%, and positive likelihood ratio = 2.1. Patients with active arthritis had higher IP-10 levels than non-arthritis patients (158.1 [505.4] versus 94.1 [114.0] pg/mL; p = 0.008), with an AUC-ROC = 0.73 (p = 0.0009), sensitivity = 72.7%, specificity = 66.4%, and positive likelihood ratio = 2.1. No other type of organ involvement was identified by serum IP-10. Luminex performs better than hs-ELISA as a quantification platform for IP-10 as it correlates with disease activity and identifies active arthritis in SLE.

Maternal Allergic Asthma Induces Prenatal Neuroinflammation.

Autism spectrum disorder (ASD) is a class of neurodevelopmental disorders characterized by impaired social interactions and communication skills and repetitive or stereotyped behaviors. Rates of ASD diagnosis continue to rise, with current estimates at 1 in 44 children in the US (Maenner 2021). Epidemiological studies have suggested a link between maternal allergic asthma and an increased likelihood of having a child diagnosed with ASD. However, a lack of robust laboratory models prevents mechanistic research from being carried out. We developed a novel mouse model of maternal asthma-allergy (MAA) and previously reported that offspring from these mothers exhibit behavioral deficits compared to controls. In addition, it was shown that epigenetic regulation of gene expression in microglia was altered in these offspring, including several autism candidate genes. To further elucidate if there is neuroinflammation in the fetus following MAA, we investigated how allergic asthma impacts the maternal environment and inflammatory markers in the placenta and fetal brain during gestation. Female C57Bl/6 mice were primed with ovalbumin (OVA) prior to allergic asthma induction during pregnancy by administering aerosolized ovalbumin or PBS control to pregnant dams at gestational days (GD)9.5, 12.5, and 17.5. Four hours after the final induction, placenta and fetal brains were collected and measured for changes in cytokines using a Luminex bead-based multiplex assay. Placental MAA tissue showed a decrease in interleukin (IL)-17 in male and female offspring. There was a sex-dependent decrease in female monocyte chemoattractant protein 1 (MCP-1). In male placentas, IL-4, C–X–C motif chemokine 10 (CXCL10)—also known as interferon γ-induced protein 10 kDa (IP-10)—and chemokine (C-C motif) ligand 5 (RANTES) were decreased. In fetal brains, elevated inflammatory cytokines were found in MAA offspring when compared to controls. Specifically, interferon-gamma (IFN-γ), granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin 1α (IL-1α), IL-6, and tumor necrosis factor α (TNFα) were elevated in both males and females. In contrast, a decrease in the cytokine IL-9 was also observed. There were slight sex differences after OVA exposures. Male fetal brains showed elevated levels of macrophage inflammatory protein-2 (MIP-2), whereas female brains showed increased keratinocytes-derived chemokine (KC). In addition, IL-1𝛽 and IP-10 in male fetal brains were decreased. Together, these data indicate that repeated exposure to allergic asthma during pregnancy alters cytokine expression in the fetal environment in a sex-dependent way, resulting in homeostatic and neuroinflammatory alterations in the fetal brain.

Fatigue and Pain Severity in Gulf War Illness Is Associated With Changes in Inflammatory Cytokines and Positive Acute Phase Proteins.

The aim of the study is to investigate relationships between inflammatory analytes and symptoms of pain and fatigue in Gulf War illness (GWI). In this preliminary study, 12 male veterans meeting GWI criteria provided daily blood samples and symptom ratings over 25 days. Linear mixed models were used to analyze associations between symptoms and sera concentrations of cytokines, acute phase proteins, insulin, and brain-derived neurotropic factor. Analyses included 277 days with both blood draws and self-reports. Days with worse fatigue severity were associated with higher C-reactive protein and serum amyloid A, and lower eotaxin 1. Muscle pain and joint pain were associated with leptin, monocyte chemoattractant protein 1, and interferon γ-induced protein. Joint pain was further associated with serum amyloid A and eotaxin 3. Gulf War illness involves fatigue and pain associated with inflammation. Conventional and novel anti-inflammatories should be further explored for the treatment of GWI.

IFI16-dependent STING signaling is a crucial regulator of anti-HER2 immune response in HER2+ breast cancer

Relapse to anti-HER2 monoclonal antibody (mAb) therapies, such as trastuzumab in HER2+ breast cancer (BC), is associated with residual disease progression due to resistance to therapy. Here, we identify interferon-γ inducible protein 16 (IFI16)-dependent STING signaling as a significant determinant of trastuzumab responses in HER2+ BC. We show that down-regulation of immune-regulated genes (IRG) is specifically associated with poor survival of HER2+, but not other BC subtypes. Among IRG, IFI16 is identified as a direct target of EZH2, the underexpression of which leads to deficient STING activation and downstream CXCL10/11 expression in response to trastuzumab treatment. Dual inhibition of EZH2 and histone deacetylase (HDAC) significantly activates IFI16-dependent immune responses to trastuzumab. Notably, a combination of a novel histone methylation inhibitor with an HDAC inhibitor induces complete tumor eradication and long-term T cell memory in a HER2+ BC mouse model. Our findings demonstrate an epigenetic regulatory mechanism suppressing the expression of the IFI16-CXCL10/11 signaling pathway that provides a survival advantage to HER2+ BC to confer resistance to trastuzumab treatment.

GPR39 Deficiency Impairs Memory and Alters Oxylipins and Inflammatory Cytokines Without Affecting Cerebral Blood Flow in a High-Fat Diet Mouse Model of Cognitive Impairment.

Vascular cognitive impairment (VCI) is the second most common cause of dementia. There is no treatment for VCI, in part due to a lack of understanding of the underlying mechanisms. The G-protein coupled receptor 39 (GPR39) is regulated by arachidonic acid (AA)-derived oxylipins that have been implicated in VCI. Furthermore, GPR39 is increased in microglia of post mortem human brains with VCI. Carriers of homozygous GPR39 SNPs have a higher burden of white matter hyperintensity, an MRI marker of VCI. We tested the hypothesis that GPR39 plays a protective role against high-fat diet (HFD)-induced cognitive impairment, in part mediated via oxylipins actions on cerebral blood flow (CBF) and neuroinflammation. Homozygous (KO) and heterozygous (Het) GPR39 knockout mice and wild-type (WT) littermates with and without HFD for 8 months were tested for cognitive performance using the novel object recognition (NOR) and the Morris water maze (MWM) tests, followed by CBF measurements using MRI. Brain tissue and plasma oxylipins were quantified with high-performance liquid chromatography coupled to mass spectrometry. Cytokines and chemokines were measured using a multiplex assay. KO mice, regardless of diet, swam further away from platform location in the MWM compared to WT and Het mice. In the NOR test, there were no effects of genotype or diet. Brain and plasma AA-derived oxylipins formed by 11- and 15-lipoxygenase (LOX), cyclooxygenase (COX) and non-enzymatically were increased by HFD and GPR39 deletion. Interleukin-10 (IL-10) was lower in KO mice on HFD than standard diet (STD), whereas IL-4, interferon γ-induced protein-10 (IP-10) and monocyte chemotactic protein-3 (MCP-3) were altered by diet in both WT and KO, but were not affected by genotype. Resting CBF was reduced in WT and KO mice on HFD, with no change in vasoreactivity. The deletion of GPR39 did not change CBF compared to WT mice on either STD or HFD. We conclude that GPR39 plays a role in spatial memory retention and protects against HFD-induced cognitive impairment in part by modulating inflammation and AA-derived oxylipins. The results indicate that GPR39 and oxylipin pathways play a role and may serve as therapeutic targets in VCI.

Circulating IL-1β, IL-17, and IP-10 as Potential Predictors of Hepatitis B Virus Infection Prognosis.

Circulating cytokines and chemokines play critical roles in hepatitis B virus (HBV) infection. Here, we explored the effects of proinflammatory and anti-inflammatory effector molecules on HBV progression, e antigen seroconversion, and liver function. Our results showed that circulating interleukin (IL)-17 may be helpful in HBV spontaneous clearance [odds ratio (OR) = 1.468, 95%confidence interval (CI) = 1.080–1.995, P = 0.014] and protective against HBV-related hepatoma development (OR = 0.933, 95%CI = 0.910–0.957, P < 0.001). IL-1β negatively affected HBV clearance (OR = 0.052, 95%CI = 0.005–0.534, P = 0.013). In patients with chronic hepatitis B, interferon-γ-inducible protein-10 (IP-10) levels significantly increased in the group of abnormal liver function (P = 0.006). Furthermore, positive correlations of IP-10 with alanine aminotransferase and aspartate aminotransferase levels were observed (rs = 0.546 and 0.644, respectively; P < 0.001). In conclusion, inflammatory cytokines and chemokines may be a “double-edged sword” for HBV clearance and progression. Further exploration of the roles of IL-17, IL-1β, and IP-10 in chronic HBV infection is needed.

Serum and Urine Interferon Gamma-Induced Protein 10 (IP-10) Levels in Lupus Nephritis.

Background: Lupus nephritis (LN) is a prevalent and severe complication of systemic lupus erythematosus (SLE). Non-invasive diagnostics are limited, and current therapies have inadequate response rates. Expression of the chemokine Interferon-γ-induced protein 10 (IP-10) is regulated by Interferon-γ signaling and NF-κB, and its molecular activity and enhanced urine concentrations are implicated in LN, but its utility as a diagnostic marker and association with demographic, clinical, or pathologic features is not defined. Methods: 38 LN patients and 11 patients with non-LN glomerular diseases (GD) with active disease were included. Eighteen of the LN patients had achieved remission at one follow-up during the study time. Serum and urine were obtained from these samples, and the IP-10 levels were measured. Results: Serum and urine IP-10 levels are significantly enhanced in LN patients with active disease as compared with normal individuals (serum average 179.7 pg/mL vs. 7.2 pg/mL, p < 0.0001; urine average 28.7 pg/mg vs. 1.6 pg/mg, p = 0.0019) and patients with other forms of glomerular disease (serum average 179.7 pg/mL vs. 84.9 pg/mL, p = 0.0176; urine average 28.7 pg/mg vs. 0.18 pg/mg, p = 0.0011). Urine IP-10 levels are significantly higher in patients with proliferative LN (PLN) than those with membranous LN (MLN) (average 32.8 pg/mg vs. 7.6 pg/mg, p = 0.0155). Urine IP-10 levels are also higher in MLN versus primary membranous nephropathy (MN) (average 7.6 pg/mg vs. 0.2 pg/mg, p = 0.0193). Importantly, serum IP-10 levels remain elevated during active LN and LN remission, but urine IP-10 levels are decreased from active LN to remission in 72% of our patients. Lastly, serum, but not urine IP-10 levels are significantly higher in African American than White American LN patients in active LN (average 227.8 pg/mL vs. 103.4 pg/mL, p = 0.0309) and during LN remission (average 254.6 pg/mL vs. 89.2 pg/mL, p = 0.0399). Conclusions: Our findings suggest that serum and urine IP-10 measurements provide promising tests for monitoring LN activity, differentiation between classifications of LN, and differentiation between LN and other forms of glomerular disease. We also conclude that further assessment of elevated IP-10 levels in the serum and urine of high-risk populations (i.e., African American) could be beneficial in determining why many of these patients have worse outcomes and are non-responsive to standard therapeutics.

Serum Levels of Chemokine Ligand-7 and Interferon-γ-induced Protein-10: Possible Severity and Prognostic Markers in Patients with COVID-19

Patients with coronavirus disease-19 (COVID-19) present as mildly, moderately, or severely and critically ill. Cytokine storm is responsible for fatal pneumonia and acute respiratory distress syndrome. Interferon-γ-induced protein-10 (IP-10) and chemokine ligand-7 (CCL-7) are chemokines that play a role in the chemotaxis of inflammatory cells and the release of pro-inflammatory cytokines. In this study, we assessed the serum levels of IP-10 and CCL-7 chemokines in COVID-19 patients and their correlation with disease severity and prognosis. The serum levels of CCL-7 and IP-10 were assessed in 67 COVID-19 patients and 10 healthy controls. Serum samples were collected and examined for these two markers using direct enzyme-linked immunosorbent assay. Patients were divided into two groups according to their disease severity. Serum levels of the test markers were compared between patients and controls, and between patients with different disease severities and correlated with other clinical and laboratory parameters. CCL-7 and IP-10 levels were significantly higher in patients than in controls and in severe than in mild/moderate cases. The receiver operating characteristic curve analysis of the two markers showed better performance of the combined markers as predictors of disease severity (area under the curve = 0.792). The results of our study suggest a potential role of IP-10 and CCL-7 as predictors of COVID-19 severity.

Cell-Target-Specific Anti-Inflammatory Effect of Empagliflozin: In Vitro Evidence in Human Cardiomyocytes.

The antidiabetic sodium–glucose cotransporter type 2 inhibitor (SGLT2i) empagliflozin efficiently reduces heart failure (HF) hospitalization and cardiovascular death in type 2 diabetes (T2D). Empagliflozin-cardioprotection likely includes anti-inflammatory effects, regardless glucose lowering, but the underlying mechanisms remain unclear. Inflammation is a primary event in diabetic cardiomyopathy (DCM) and HF development. The interferon (IFN)γ-induced 10-kDa protein (IP-10/CXCL10), a T helper 1 (Th1)-type chemokine, promotes cardiac inflammation, fibrosis, and diseases, including DCM, ideally representing a therapeutic target. This preliminary study aims to explore whether empagliflozin directly affects Th1-challenged human cardiomyocytes, in terms of CXCL10 targeting. To this purpose, empagliflozin dose–response curves were performed in cultured human cardiomyocytes maintained within a Th1-dominant inflammatory microenvironment (IFNγ/TNFα), and CXCL10 release with the intracellular IFNγ-dependent signaling pathway (Stat-1) was investigated. To verify possible drug–cell-target specificity, the same assays were run in human skeletal muscle cells. Empagliflozin dose dependently inhibited CXCL10 secretion (IC50 = 76,14 × 10-9 M) in association with Stat-1 pathway impairment only in Th1-induced human cardiomyocytes, suggesting drug-selective cell-type-targeting. As CXCL10 plays multifaceted functions in cardiac remodeling toward HF and currently there is no effective method to prevent it, these preliminary data might be hypothesis generating to open new scenarios in the translational approach to SGLT2i-dependent cardioprotection.

Higher Cerebrospinal Fluid Soluble Urokinase-type Plasminogen Activator Receptor, But Not Interferon γ-inducible Protein 10, Correlate With Higher Working Memory Deficits.

We hypothesized that the induction of monocyte activation biomarkers, especially soluble urokinase-type plasminogen activator receptor (suPAR) and interferon γ-inducible protein 10 (IP-10), is lower in HIV-1C than HIV-1B, owing to a defective Tat cysteine dimotif (C30S). A total of 68 paired cerebrospinal fluid (CSF) and blood samples from people with HIV (PWH), free of CNS opportunistic infections, from a Southern Brazil outpatient HIV clinic were evaluated such as HIV-1B subtype (n = 27), HIV-1C (n = 26), other (n = 15), and 19 HIV-negative controls. The levels of suPAR, IP-10, neopterin, and β2 microglobulin (β2m) in the CSF and serum were quantified using different immunoassays. Overall, in PWH, increases in CSF suPAR, CSF/serum suPAR, and CSF/serum β2m correlated with worse working memory deficits (r = 0.303, 0.353, and 0.289, respectively, all P < 0.05). The medians of IP-10, suPAR, neopterin, and β2m in CSF and serum and the CSF/serum ratio and suPAR index were comparable between the HIV-1B and HIV-1C subtypes. CSF IP-10 and neopterin and serum IP-10 and suPAR levels were higher in PWH than the HIV-negative controls (P = 0.015, P = 0.001, P < 0.0001, and P < 0.001, respectively). The serum β2m level was higher in HIV-associated dementia than neuropsychologically normal or asymptomatic (P = 0.024). We observed that higher levels of CSF suPAR and the suPAR quotient correlated with worse working memory deficit. Elevated levels of monocyte activation were similar in both HIV-1 B and C subtypes, providing no evidence of reduced neuropathogenicity of HIV-1 subtype C Tat compared with subtype B.

Does Hyperuricemia in Falciparum Malaria Infected Children Explains the Etiology of Burkitt’s Lymphoma?

Falciparum malaria still represents the big obstacle to communities in Sub-Sahara African countries and more concentrated efforts against COVID-19 pandemic, may influence the lives of millions of children in that malaria-endemic area. Hyperuricemia associated with plasmodium falciparum infection reflects the density of parasitemia and it may lead to kidney injury, resulting in low vitamin D production. Furthermore, hyperuricemia leads to high levels of proinflammatory cytokines counting interferon γ-induced protein, which is invested vitamin D deficiency in the development of Burkitt’s lymphoma. Experimental research is required.

The Effects of 21-Day General Rehabilitation after Hip or Knee Surgical Implantation on Plasma Levels of Selected Interleukins, VEGF, TNF-α, PDGF-BB, and Eotaxin-1.

Rehabilitation in osteoarthritis (OA) patients aims to reduce joint pain and stiffness, preserve or improve joint mobility, and improve patients’ quality of life. This study evaluated the effects of the 21-day individually adjusted general rehabilitation program in 36 OA patients 90 days after hip or knee replacement on selected interleukins (IL) and cytokines using the Bio-Plex® Luminex® system. Serum concentrations of almost all selected anti/pro-inflammatory markers: IL-1 receptor antagonist (IL-1RA), IL-2, IL-4, IL-5, IL-6, IL-10, IL-13, IL-15, and of some chemokines: macrophage inflammatory protein-1 alpha (MIP-1α/CCL3), and RANTES/CCL5, and of eotaxin-1/CCL11, the vascular endothelial growth factor (VEGF) significantly increased, whereas basic fibroblast growth factor (FGF basic) significantly decreased after the 21-day general rehabilitation. The levels of interferon-γ induced protein 10 (IP-10), MIP-1β/CCL4, macrophage/monocyte chemoattractant protein-1 (MCP-1/CCL2 (MCAF)), granulocyte macrophage-colony stimulating factor (GM-CSF), platelet-derived growth factor-BB (PDGF-BB), and granulocyte colony-stimulating factor (G-CSF) remained unchanged. There were no changes in pro-inflammatory cytokines levels: tumor necrosis factor-alpha (TNF-α), interferon-γ (IFN-γ), and IL-12 (p70)) after the 21-day general rehabilitation, indicating the stable and controlled inflammatory status of osteoarthritis patients. Significantly higher levels of anti-inflammatory factors after 21 days of moderate physical activity confirm the beneficial outcome of the applied therapy. The increased level of IL-6 after the rehabilitation may reflect its anti-inflammatory effect in osteoarthritis patients.

Inflammatory markers in saliva and urine reflect disease activity in patients with systemic lupus erythematosus

BackgroundLaboratory tests of blood and sometimes urine are used to diagnose and to monitor disease activity (DA) in SLE. Clinical practice would be simplified if non-invasive urine and salivary tests...

IGF-1 regulates astrocytic phagocytosis and inflammation through the p110α isoform of PI3K in a sex-specific manner.

Insulin‐like growth factor‐I (IGF‐I) signaling plays a key role in neuroinflammation. Here we show that IGF‐1 also regulates phagocytosis of reactive astrocytes through p110α isoform of phosphatidylinositol 3‐kinase (PI3K), differentially in both sexes. Systemic bacterial lipopolysaccharide (LPS)‐treatment increased the expression of GFAP, a reactive astrocyte marker, in the cortex of mice in both sexes and was blocked by IGF‐1 only in males. In primary astrocytes, LPS enhanced the mRNA expression of Toll‐like receptors (TLR2,4) and proinflammatory factors: inducible nitric oxide synthase (iNOS), chemokine interferon‐γ‐inducible protein‐10 (IP‐10) and cytokines (IL‐1β, IL‐6, and IL‐10) in male and female. Treatment with IGF‐1 counteracted TLR4 but not TLR2, iNOS, and IP10 expression in both sexes and cytokines expression in males. Furthermore, reactive astrocyte phagocytosis was modulated by IGF‐1 only in male astrocytes. IGF‐1 was also able to increase AKT‐phosphorylation only in male astrocytes. PI3K inhibitors, AG66, TGX‐221, and CAL‐101, with selectivity toward catalytic p110α, p110β, and p110δ isoforms respectively, reduced AKT‐phosphorylation in males. All isoforms interact physically with IGF‐1‐receptor in both sexes. However, the expression of p110α is higher in males while the expression of IGF‐1‐receptor is similar in male and female. AG66 suppressed the IGF‐1 effect on cytokine expression and counteracted the IGF‐1‐produced phagocytosis decrease in male reactive astrocytes. Results suggest that sex‐differences in the effect of IGF‐1 on the AKT‐phosphorylation could be due to a lower expression of the p110α in female and that IGF‐1‐effects on the inflammatory response and phagocytosis of male reactive astrocytes are mediated by p110α/PI3K subunit.

Endometrial cytokines in patients with and without endometriosis evaluated for infertility

To evaluate whether endometrial molecular profiles distinguish subsets of patients according to clinical characteristics, and to infer dysregulated immune networks, by measuring cytokines, chemokines, and growth factors in endometrial biopsy specimens from a cohort of infertile women with a high incidence of endometriosis. Prospective cohort study. Department of Gynecology at a university hospital. Patients undergoing laparoscopy for infertility assessment (n = 103). Endometrial biopsies were performed during surgery. Fertility outcome and clinical parameters were registered preoperatively and after 6 months. The concentrations of 48 factors in endometrial biopsy specimens were analyzed with respect to clinical status in univariate and multivariate frameworks. The concentrations of 44 factors from endometrial tissues of 74 patients were suitable for analysis. Although the tissue concentrations of interleukin (IL)15, IL-7, and interferon γ-induced protein (IP)-10 were individually lower in patients with endometriosis than in those without endometriosis, the differences were not significant after multiple comparison. However, multivariate modeling incorporating covariation showed separation between subsets of endometriotic and nonendometriotic patients, based predominantly on IP-10, monocyte chemoattractant protein-1, IL-16, and IL-18; this result was independent of cycle and fertility status. Analysis restricted to endometrial tissues from the secretory phase separated endometriotic and nonendometriotic patients by a combination of IL-15, IP-10, monocyte chemoattractant protein-1, IL-16, and IL-18. This combination suggests a uterine natural killer cell defect. We found no significant correlations between endometrial cytokines and fertility outcome. A molecular signature in endometrial tissue was able to distinguish endometriotic from nonendometriotic patients, implicating uterine natural killer cells in endometriosis.

Persistent Autoimmune Activation and Proinflammatory State in Post-Coronavirus Disease 2019 Syndrome.

BackgroundThe immunopathological pathways enabling post-coronavirus disease 2019 (COVID-19) syndrome (PCS) development are not entirely known. We underwent a longitudinal analysis of patients with COVID-19 who developed PCS aiming to evaluate the autoimmune and immunological status associated with this condition.MethodsThirty-three patients were included for longitudinal clinical and autoantibody analyses, 12 of whom were assessed for cytokines and lymphocyte populations. Patients were followed for 7–11 months after acute COVID-19. Autoimmune profile and immunological statuses were evaluated mainly by enzyme-linked-immunosorbent assays and flow cytometry.ResultsLatent autoimmunity and overt autoimmunity persisted over time. A proinflammatory state was observed in patients with PCS characterized by up-regulated interferon-α, tumor necrosis factor-α, granulocyte colony-stimulating factor (G-CSF), interleukin (IL)-17A, IL-6, IL-1β, and IL-13, whereas interferon-γ-induced protein 10 (IP-10) was decreased. In addition, PCS was characterized by increased levels of Th9, CD8+ effector T cells, naive B cells, and CD4+ effector memory T cells. Total levels of immunoglobulin G S1-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies remained elevated over time.ConclusionsThe clinical manifestations of PCS are associated with the persistence of a proinflammatory and effector phenotype induced by SARS-CoV-2 infection. This long-term persistent immune activation may contribute to the development of latent and overt autoimmunity. Results suggest the need to evaluate the role of immunomodulation in the treatment of PCS.

Household contact investigation for the detection of active tuberculosis and latent tuberculosis: A comprehensive evaluation in two high-burden provinces in Iran

BackgroundSystematic evaluation of household contacts of persons with pulmonary tuberculosis (TB) in low- and middle-income countries is recommended by the World Health Organization (WHO). This study recruited adult household contacts of diagnosed TB patients in two high burden provinces of Iran to estimate the prevalence and incidence of active disease and latent TB infection (LTBI) among individuals exposed to TB cases. MethodsWe conducted a cohort study among adults in household contact with a pulmonary TB index case. All subjects were assessed for active disease through evaluation of symptoms. Tuberculin skin test (TST) and QuantiFERON®-TB Gold Plus (QFT-Plus) were used to define LTBI. These tests were performed at the time of the index TB case diagnosis and repeated if the previous result was negative, at three-, 12-, and 18-months post recruitment. In addition, interferon-γ-induced protein-10 (IP-10) concentrations were measured in QFT-Plus supernatants for all participants three months after diagnosing the index case. ResultsA total of 451 individuals who had close contact with 95 active TB patients were enrolled in this study. Five (1.1%) contacts were diagnosed with active TB and 285 (63.2%) were identified with LTBI during our study. The incidence rate of LTBI among adult household contacts of TB index cases was 0.44 per person per year. ConclusionThe overall rate of LTBI was high. Systematic screening of all household contacts of pulmonary TB should be expanded in Iran to make the timely achievement of the global end TB strategy feasible.

Association of chemokines IP-10/CXCL10 and I-TAC/CXCL11 with insulin resistance and enhance leukocyte endothelial arrest in obesity.

Obesity is a key contributing factor to incidental type 2 diabetes and cardiovascular disease. CXCR3 receptor and its ligands CXCL 10 and 11 are associated with atherosclerosis and cardiovascular disease. The aim of our study was to analyse the role of the CXCR3 ligands on insulin resistance (IR) and endothelial dysfunction in human obesity. We have studied 45 obese patients (mean age 44±6years, body mass index 45±9kg/m2) who were selected for Roux-Y-gastric bypass surgery and 21 non obese control subjects with similar age and gender distribution. We measured by ELISA the circulating levels of the CXCR3 ligands interferon-γ inducible protein 10 (IP-10/CXCL10) and interferon-γ-inducible T-cell alpha chemoattractant (I-TAC/CXCL11). Using an ex vivo procedure with the flow chamber assay, we have investigated the effect of such chemokines on endothelial leukocytes arrest under dynamic conditions. Peripheral blood levels of CXCL10 and CXCL11 were significantly higher in obese subjects than in controls (p<0.001) and significantly correlated with BMI, waist circunference and HOMA-IR. Obese patients with HOMA-IR index above 75th percentile showed highest increase of circulating CXCL10 and CXCL11 values. Under dynamic flow conditions, the enhanced adhesion of patient leukocytes to TNFα-induced human arterial endothelial cells was partly dependent on CXCR3. The study demonstrates that CXCL10 and CXCL11 are associated with IR and enhance leukocyte endothelial arrest in obese subjects. Blockade of CXCR3 signaling might be a new therapeutic approach for the prevention of obesity-associated cardiovascular co-morbidities.

Serum IFNγ–induced protein 10 (IP10/CXCL10): association with asthma exacerbations and severity in children

Objective Asthma is a chronic disorder of the airways, in which chemokines coordinate airway inflammation and determine its severity. We aimed to study the chemokine interferonγ–inducible protein 10 kDa (IP10/CXCL10), a member of the CXC receptor 3 (CXCR3) ligand family, at the protein level in the serum of children, to evaluate the association between CXCL10 and exacerbations of childhood asthma. Methods Patients experiencing an asthma exacerbation (42 patients) and stable patients (43 patients) were investigated for serum CXCL10 levels. Results Patients with an asthma exacerbation expressed significantly higher CXCL10 levels in the serum than stable patients (p < 0.001). Additionally, CXCL10 values were elevated in severe asthma compared with moderate and mild disease (p < 0.001). In patients experiencing asthma exacerbations, higher values of CXCL10 were observed in atopic patients compared with non-atopic patients (p = 0.027) and in uncontrolled and partly controlled patients compared with controlled patients (p = 0.046). Conclusions CXCL10 is proposed as an inflammatory serum marker for asthma exacerbations and worsening asthma symptoms. The levels of CXCL10 are representative of the clinical severity of asthma.