生信网-文献期刊

Front Immunol

2021 Apr 9

Qiu W, Chen F, Chen R

C-type lectin (CTL), a well-known immune-related molecule, has received more and more attention due to its diverse functions, especially its important role in development and host defense of vertebrate and invertebrate. Since the research on crab CTLs is still lack, we screened a new CTL homolog, named SpCTL6 from mud crab Scylla paramamosain. The full-length cDNA sequence of SpCTL6 was 738 bp with a 486 bp of ORF, and the deduced amino acids were 161 aa. SpCTL6 was predicted to have a 17 aa signal peptide and its mature peptide was 144 aa (MW 16.7 kDa) with pI value of 5.22. It had typical CTL structural characteristics, such as a single C-type lectin-like domain, 4 conserved cysteines, similar tertiary structure to that of vertebrate CTLs and a mutated Ca2+ binding motif Gln-Pro-Thr (QPT), clustering into the same branch as the crustacean CTLs. SpCTL6 was highly expressed in the entire zoeal larval stages and widely distributed in adult crab tissues with the highest transcription level in testis. During the molting process of juvenile crabs, the expression level of SpCTL6 was remarkably increased after molting. SpCTL6 could be significantly upregulated in two larval stages (Z1 and megalopa) and adult crab testis under immune challenges. Recombinant SpCTL6 (rSpCTL6) was successfully obtained from eukaryotic expression system. rSpCTL6 exhibited binding activity with PAMPs (LPS, lipoteichoic acid, peptidoglycan, and glucan) and had a broad spectrum bacterial agglutination activity in a Ca2+-dependent manner. In addition, rSpCTL6 could enhance the encapsulation activity of hemocytes and has no cytotoxic effect on hemocytes. Although rSpCTL6 had no bactericidal activity on Vibrio alginolyticus, rSpCTL6 treatment could significantly reduce the bacterial endotoxin level in vitro and greatly improved the survival of S. paramamosain under V. alginolyticus infection in vivo. The immunoprotective effect of rSpCTL6 might be due to the regulatory role of rSpCTL6 in immune-related genes and immunological parameters. Our study provides new information for understanding the immune defense of mud crabs and would facilitate the development of effective strategies for mud crab aquaculture disease control.

2. Biofilm-Innate Immune Interface: Contribution to Chronic Wound Formation.

Front Immunol

2021 Apr 9

Versey Z, da Cruz Nizer WS, Russell E

3. TOX Acts as a Tumor Suppressor by Inhibiting mTOR Signaling in Colorectal Cancer.

Front Immunol

2021 Apr 9

Yang M, Huang Q, Li C

4. Liquid PRF Reduces the Inflammatory Response and Osteoclastogenesis in Murine Macrophages.

Front Immunol

2021 Apr 9

Kargarpour Z, Nasirzade J, Panahipour L

Macrophage activation and osteoclastogenesis are hallmarks of inflammatory osteolysis and may be targeted by the local application of liquid platelet-rich fibrin (PRF). Liquid PRF is produced by a hard spin of blood in the absence of clot activators and anticoagulants, thereby generating an upper platelet-poor plasma (PPP) layer, a cell-rich buffy coat layer (BC; termed concentrated-PRF or C-PRF), and the remaining red clot (RC) layer. Heating PPP has been shown to generate an albumin gel (Alb-gel) that when mixed back with C-PRF generates Alb-PRF having extended working properties when implanted in vivo. Evidence has demonstrated that traditional solid PRF holds a potent anti-inflammatory capacity and reduces osteoclastogenesis. Whether liquid PRF is capable of also suppressing an inflammatory response and the formation of osteoclasts remains open. In the present study, RAW 264.7 and primary macrophages were exposed to lipopolysaccharides (LPS), lactoferrin, and agonists of Toll-like receptors (TLR3 and TLR7) in the presence or absence of lysates prepared by freeze-thawing of liquid PPP, BC, Alb-gel, and RC. For osteoclastogenesis, primary macrophages were exposed to receptor activator of nuclear factor kappa B ligand (RANKL), macrophage colony-stimulating factor (M-CSF), and human transforming growth factor-β1 (TGF-β1) in the presence or absence of PPP, BC, Alb-gel, RC lysates and hemoglobin. We show here that it is mainly the lysates prepared from PPP and BC that consistently reduced the agonist-induced expression of interleukin 6 (IL6) and cyclooxygenase-2 (COX2) in macrophages, as determined by RT-PCR and immunoassay. With respect to osteoclastogenesis, lysates from PPP and BC but also from RC, similar to hemoglobin, reduced the expression of osteoclast marker genes tartrate-resistant acid phosphatase (TRAP) and cathepsin K, as well as TRAP histochemical staining. These findings suggest that liquid PRF holds a potent in vitro heat-sensitive anti-inflammatory activity in macrophages that goes along with an inhibition of osteoclastogenesis.

5. Kynurenic Acid Analog Attenuates the Production of Tumor Necrosis Factor-α, Calgranulins (S100A 8/9 and S100A 12), and the Secretion of HNP1-3 and Stimulates the Production of Tumor Necrosis Factor-Stimulated Gene-6 in Whole Blood Cultures of Patients With Rheumatoid Arthritis.

Front Immunol

2021 Apr 9

Balog A, Varga B, Fülöp F

Objectives: Rheumatoid arthritis (RA) is a chronic, inflammatory joint disease with complex pathogenesis involving a variety of immunological events. Recently, it has been suggested that kynurenic acid (KYNA) might be a potential regulator of inflammatory processes in arthritis. KYNA has a definitive anti-inflammatory and immunosuppressive function. The aim of the present study is to investigate the complex effects of a newly synthesized KYNA analog-SZR72 on the in vitro production of tumor necrosis factor-α (TNF-α), tumor necrosis factor-stimulated gene-6 (TSG-6), calprotectin (SA1008/9), SA100 12 (EN-RAGE), and HNP1-3 (defensin-α) in the peripheral blood of patients with RA and the various effects of the disease. Methods: Patients with RA (n = 93) were selected based on the DAS28 score, medication, and their rheumatoid factor (RF) status, respectively. Peripheral blood samples from 93 patients with RA and 50 controls were obtained, and activated by heat-inactivated S. aureus. Parallel samples were pretreated before the activation with the KYNA analog N-(2-N, N-dimethylaminoethyl)-4-oxo-1H-quinoline-2-carboxamide hydrochloride. Following the incubation period (18 h), the supernatants were tested for TNF-α, TSG-6, calprotectin, S100A12, and HNP1-3 content by ELISA. Results: SZR72 inhibited the production of the following inflammatory mediators: TNF-α, calprotectin, S100A12, and HNP1-3 in whole blood cultures. This effect was observed in each group of patients in various phases of the disease. The basic (control) levels of these mediators were higher in the blood of patients than in healthy donors. In contrast, lower TSG-6 levels were detected in patients with RA compared to healthy controls. In addition, the KYNA analog exerted a stimulatory effect on the TSG-6 production ex vivo in human whole blood cultures of patients with RA in various phases of the disease. Conclusion: These data further support the immunomodulatory role of KYNA in RA resulting in anti-inflammatory effects and draw the attention to the importance of the synthesis of the KYNA analog, which might have a future therapeutic potential.

6. Novel ELISA Protocol Links Pre-Existing SARS-CoV-2 Reactive Antibodies With Endemic Coronavirus Immunity and Age and Reveals Improved Serologic Identification of Acute COVID-19 via Multi-Parameter Detection.

Front Immunol

2021 Apr 9

Yuen RR, Steiner D, Pihl RMF

The COVID-19 pandemic has drastically impacted work, economy, and way of life. Sensitive measurement of SARS-CoV-2 specific antibodies would provide new insight into pre-existing immunity, virus transmission dynamics, and the nuances of SARS-CoV-2 pathogenesis. To date, existing SARS-CoV-2 serology tests have limited utility due to insufficient reliable detection of antibody levels lower than what is typically present after several days of symptoms. To measure lower quantities of SARS-CoV-2 IgM, IgG, and IgA with higher resolution than existing assays, we developed a new ELISA protocol with a distinct plate washing procedure and timed plate development via use of a standard curve. Very low optical densities from samples added to buffer coated wells at as low as a 1:5 dilution are reported using this 'BU ELISA' method. Use of this method revealed circulating SARS-CoV-2 receptor binding domain (RBD) and nucleocapsid protein (N) reactive antibodies (IgG, IgM, and/or IgA) in 44 and 100 percent of pre-pandemic subjects, respectively, and the magnitude of these antibodies tracked with antibody levels of analogous viral proteins from endemic coronavirus (eCoV) strains. The disease status (HIV, SLE) of unexposed subjects was not linked with SARS-CoV-2 reactive antibody levels; however, quantities were significantly lower in subjects over 70 years of age compared with younger counterparts. Also, we measured SARS-CoV-2 RBD- and N- specific IgM, IgG, and IgA antibodies from 29 SARS-CoV-2 infected individuals at varying disease states, including 10 acute COVID-19 hospitalized subjects with negative serology results by the EUA approved Abbott IgG chemiluminescent microparticle immunoassay. Measurements of SARS-CoV-2 RBD- and N- specific IgM, IgG, IgA levels measured by the BU ELISA revealed higher signal from 9 of the 10 Abbott test negative COVID-19 subjects than all pre-pandemic samples for at least one antibody specificity/isotype, implicating improved serologic identification of SARS-CoV-2 infection via multi-parameter, high sensitive antibody detection. We propose that this improved ELISA protocol, which is straightforward to perform, low cost, and uses readily available commercial reagents, is a useful tool to elucidate new information about SARS-CoV-2 infection and immunity and has promising implications for improved detection of all analytes measurable by this platform.

7. MicroRNA Expression Differences in Blood-Derived CD19+ B Cells of Methotrexate Treated Rheumatoid Arthritis Patients.

Front Immunol

2021 Apr 9

Heinicke F, Zhong X, Flåm ST

Rheumatoid arthritis (RA) is a complex disease with a wide range of underlying susceptibility factors. Recently, dysregulation of microRNAs (miRNAs) in RA have been reported in several immune cell types from blood. However, B cells have not been studied in detail yet. Given the autoimmune nature of RA with the presence of autoantibodies, CD19+ B cells are a key cell type in RA pathogenesis and alterations in CD19+ B cell subpopulations have been observed in patient blood. Therefore, we aimed to reveal the global miRNA repertoire and to analyze miRNA expression profile differences in homogenous RA patient phenotypes in blood-derived CD19+ B cells. Small RNA sequencing was performed on CD19+ B cells of newly diagnosed untreated RA patients (n=10), successfully methotrexate (MTX) treated RA patients in remission (MTX treated RA patients, n=18) and healthy controls (n=9). The majority of miRNAs was detected across all phenotypes. However, significant expression differences between MTX treated RA patients and controls were observed for 27 miRNAs, while no significant differences were seen between the newly diagnosed patients and controls. Several of the differentially expressed miRNAs were previously found to be dysregulated in RA including miR-223-3p, miR-486-3p and miR-23a-3p. MiRNA target enrichment analysis, using the differentially expressed miRNAs and miRNA-target interactions from miRTarBase as input, revealed enriched target genes known to play important roles in B cell activation, differentiation and B cell receptor signaling, such as STAT3, PRDM1 and PTEN. Interestingly, many of those genes showed a high degree of correlated expression in CD19+ B cells in contrast to other immune cell types. Our results suggest important regulatory functions of miRNAs in blood-derived CD19+ B cells of MTX treated RA patients and motivate for future studies investigating the interactive mechanisms between miRNA and gene targets, as well as the possible predictive power of miRNAs for RA treatment response.

8. High Dose IFN-β Activates GAF to Enhance Expression of ISGF3 Target Genes in MLE12 Epithelial Cells.

Front Immunol

2021 Apr 9

Kishimoto K, Wilder CL, Buchanan J

9. MR1-Restricted MAIT Cells From The Human Lung Mucosal Surface Have Distinct Phenotypic, Functional, and Transcriptomic Features That Are Preserved in HIV Infection.

Front Immunol

2021 Apr 9

Khuzwayo S, Mthembu M, Meermeier EW

Mucosal associated invariant T (MAIT) cells are a class of innate-like T cells that utilize a semi-invariant αβ T cell receptor to recognize small molecule ligands produced by bacteria and fungi. Despite growing evidence that immune cells at mucosal surfaces are often phenotypically and functionally distinct from those in the peripheral circulation, knowledge about the characteristics of MAIT cells at the lung mucosal surface, the site of exposure to respiratory pathogens, is limited. HIV infection has been shown to have a profound effect on the number and function of MAIT cells in the peripheral blood, but its effect on lung mucosal MAIT cells is unknown. We examined the phenotypic, functional, and transcriptomic features of major histocompatibility complex (MHC) class I-related (MR1)-restricted MAIT cells from the peripheral blood and bronchoalveolar compartments of otherwise healthy individuals with latent Mycobacterium tuberculosis (Mtb) infection who were either HIV uninfected or HIV infected. Peripheral blood MAIT cells consistently co-expressed typical MAIT cell surface markers CD161 and CD26 in HIV-negative individuals, while paired bronchoalveolar MAIT cells displayed heterogenous expression of these markers. Bronchoalveolar MAIT cells produced lower levels of pro-inflammatory cytokine IFN-γ and expressed higher levels of co-inhibitory markers PD-1 and TIM-3 than peripheral MAIT cells. HIV infection resulted in decreased frequencies and pro-inflammatory function of peripheral blood MAIT cells, while in the bronchoalveolar compartment MAIT cell frequency was decreased but phenotype and function were not significantly altered. Single-cell transcriptomic analysis demonstrated greater heterogeneity among bronchoalveolar compared to peripheral blood MAIT cells and suggested a distinct subset in the bronchoalveolar compartment. The transcriptional features of this bronchoalveolar subset were associated with MAIT cell tissue repair functions. In summary, we found previously undescribed phenotypic and transcriptional heterogeneity of bronchoalveolar MAIT cells in HIV-negative people. In HIV infection, we found numeric depletion of MAIT cells in both anatomical compartments but preservation of the novel phenotypic and transcriptional features of bronchoalveolar MAIT cells.

10. Inhibition of IL-6 in the LCWE Mouse Model of Kawasaki Disease Inhibits Acute Phase Reactant Serum Amyloid A but Fails to Attenuate Vasculitis.

Front Immunol

2021 Apr 9

Porritt RA, Chase Huizar C, Dick EJ

11. Modulatory Effects of Probiotics During Pathogenic Infections With Emphasis on Immune Regulation.

Front Immunol

2021 Apr 8

Raheem A, Liang L, Zhang G

12. The Evolving Landscape of Biomarkers in Celiac Disease: Leading the Way to Clinical Development.

Front Immunol

2021 Apr 7

Smithson G, Siegelman J, Oki T

13. Breastfeeding and COVID-19: From Nutrition to Immunity.

Front Immunol

2021 Apr 7

Vassilopoulou E, Feketea G, Koumbi L

14. Identification of Prognostic Genes in the Tumor Microenvironment of Hepatocellular Carcinoma.

Front Immunol

2021 Apr 7

Xiang S, Li J, Shen J

Background: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in the world. The efficacy of immunotherapy usually depends on the interaction of immunomodulation in the tumor microenvironment (TME). This study aimed to explore the potential stromal-immune score-based prognostic genes related to immunotherapy in HCC through bioinformatics analysis. Methods: ESTIMATE algorithm was applied to calculate the immune/stromal/Estimate scores and tumor purity of HCC using the Cancer Genome Atlas (TCGA) transcriptome data. Functional enrichment analysis of differentially expressed genes (DEGs) was analyzed by the Database for Annotation, Visualization, and Integrated Discovery database (DAVID). Univariate and multivariate Cox regression analysis and least absolute shrinkage and selection operator (LASSO) regression analysis were performed for prognostic gene screening. The expression and prognostic value of these genes were further verified by KM-plotter database and the Human Protein Atlas (HPA) database. The correlation of the selected genes and the immune cell infiltration were analyzed by single sample gene set enrichment analysis (ssGSEA) algorithm and Tumor Immune Estimation Resource (TIMER). Results: Data analysis revealed that higher immune/stromal/Estimate scores were significantly associated with better survival benefits in HCC within 7 years, while the tumor purity showed a reverse trend. DEGs based on both immune and stromal scores primarily affected the cytokine-cytokine receptor interaction signaling pathway. Among the DEGs, three genes (CASKIN1, EMR3, and GBP5) were found most significantly associated with survival. Moreover, the expression levels of CASKIN1, EMR3, and GBP5 genes were significantly correlated with immune/stromal/Estimate scores or tumor purity and multiple immune cell infiltration. Among them, GBP5 genes were highly related to immune infiltration. Conclusion: This study identified three key genes which were related to the TME and had prognostic significance in HCC, which may be promising markers for predicting immunotherapy outcomes.

15. Omega-3 Polyunsaturated Fatty Acid Intervention Against Established Autoimmunity in a Murine Model of Toxicant-Triggered Lupus.

Front Immunol

2021 Apr 7

Pestka JJ, Akbari P, Wierenga KA

Workplace exposure to respirable crystalline silica dust (cSiO2) has been etiologically linked to the development of lupus and other human autoimmune diseases. Lupus triggering can be recapitulated in female NZBWF1 mice by four weekly intranasal instillations with 1 mg cSiO2. This elicits inflammatory/autoimmune gene expression and ectopic lymphoid structure (ELS) development in the lung within 1 week, ultimately driving early onset of systemic autoimmunity and glomerulonephritis. Intriguingly, dietary supplementation with docosahexaenoic acid (DHA), an ω-3 polyunsaturated fatty acid (PUFA) found in fish oil, beginning 2 week prior to cSiO2 challenge, prevented inflammation and autoimmune flaring in this novel model. However, it is not yet known how ω-3 PUFA intervention influences established autoimmunity in this murine model of toxicant-triggered lupus. Here we tested the hypothesis that DHA intervention after cSiO2-initiated intrapulmonary autoimmunity will suppress lupus progression in the NZBWF1 mouse. Six-week old NZWBF1 female mice were fed purified isocaloric diet for 2 weeks and then intranasally instilled with 1 mg cSiO2 or saline vehicle weekly for 4 consecutive weeks. One week after the final instillation, which marks onset of ELS formation, mice were fed diets supplemented with 0, 4, or 10 g/kg DHA. One cohort of mice (n = 8/group) was terminated 13 weeks after the last cSiO2 instillation and assessed for autoimmune hallmarks. A second cohort of mice (n = 8/group) remained on experimental diets and was monitored for proteinuria and moribund criteria to ascertain progression of glomerulonephritis and survival, respectively. DHA consumption dose-dependently increased ω-3 PUFA content in the plasma, lung, and kidney at the expense of the ω-6 PUFA arachidonic acid. Dietary intervention with high but not low DHA after cSiO2 treatment suppressed or delayed: (i) recruitment of T cells and B cells to the lung, (ii) development of pulmonary ELS, (iii) elevation of a wide spectrum of plasma autoantibodies associated with lupus and other autoimmune diseases, (iv) initiation and progression of glomerulonephritis, and (v) onset of the moribund state. Taken together, these preclinical findings suggest that DHA supplementation at a human caloric equivalent of 5 g/d was an effective therapeutic regimen for slowing progression of established autoimmunity triggered by the environmental toxicant cSiO2.

16. Membrane Particles Derived From Adipose Tissue Mesenchymal Stromal Cells Improve Endothelial Cell Barrier Integrity.

Front Immunol

2021 Apr 7

Merino A, Sablik M, Korevaar SS

Proinflammatory stimuli lead to endothelial injury, which results in pathologies such as cardiovascular diseases, autoimmune diseases, and contributes to alloimmune responses after organ transplantation. Both mesenchymal stromal cells (MSC) and the extracellular vesicles (EV) released by them are widely studied as regenerative therapy for the endothelium. However, for therapeutic application, the manipulation of living MSC and large-scale production of EV are major challenges. Membrane particles (MP) generated from MSC may be an alternative to the use of whole MSC or EV. MP are nanovesicles artificially generated from the membranes of MSC and possess some of the therapeutic properties of MSC. In the present study we investigated whether MP conserve the beneficial MSC effects on endothelial cell repair processes under inflammatory conditions. MP were generated by hypotonic shock and extrusion of MSC membranes. The average size of MP was 120 nm, and they showed a spherical shape. The effects of two ratios of MP (50,000; 100,000 MP per target cell) on human umbilical vein endothelial cells (HUVEC) were tested in a model of inflammation induced by TNFα. Confocal microscopy and flow cytometry showed that within 24 hours >90% of HUVEC had taken up MP. Moreover, MP ended up in the lysosomes of the HUVEC. In a co-culture system of monocytes and TNFα activated HUVEC, MP did not affect monocyte adherence to HUVEC, but reduced the transmigration of monocytes across the endothelial layer from 138 ± 61 monocytes per microscopic field in TNFα activated HUVEC to 61 ± 45 monocytes. TNFα stimulation induced a 2-fold increase in the permeability of the HUVEC monolayer measured by the translocation of FITC-dextran to the lower compartment of a transwell system. At a dose of 1:100,000 MP significantly decreased endothelial permeability (1.5-fold) respect to TNFα Stimulated HUVEC. Finally, MP enhanced the angiogenic potential of HUVEC in an in vitro Matrigel assay by stimulating the formation of angiogenic structures, such as percentage of covered area, total tube length, total branching points, total loops. In conclusion, MP show regenerative effects on endothelial cells, opening a new avenue for treatment of vascular diseases where inflammatory processes damage the endothelium.

17. Programmed Death-1/Programmed Death-Ligand 1-Axis Blockade in Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma Stratified by Human Papillomavirus Status: A Systematic Review and Meta-Analysis.

Front Immunol

2021 Apr 7

Xu Y, Zhu G, Maroun CA

18. PU.1 and IRF8 Modulate Activation of NLRP3 Inflammasome via Regulating Its Expression in Human Macrophages.

Front Immunol

2021 Apr 7

Yashiro T, Yamamoto M, Araumi S

19. Expansion of an Unusual Virtual Memory CD8(+) Subpopulation Bearing Vα3.2 TCR in Themis-Deficient Mice.

Front Immunol

2021 Apr 7

Prasad M, Wojciech L, Brzostek J

20. Immune Subtyping in Latent Tuberculosis.

Front Immunol

2021 Apr 7

Banerjee U, Baloni P, Singh A

21. Clonally Focused Public and Private T Cells in Resected Brain Tissue From Surgeries to Treat Children With Intractable Seizures.

Front Immunol

2021 Apr 6

Chang JW, Reyes SD, Faure-Kumar E

Using a targeted transcriptomics approach, we have analyzed resected brain tissue from a cohort of 53 pediatric epilepsy surgery cases, and have found that there is a spectrum of involvement of both the innate and adaptive immune systems as evidenced by the differential expression of immune-specific genes in the affected brain tissue. The specimens with the highest expression of immune-specific genes were from two Rasmussen encephalitis cases, which is known to be a neuro-immunological disease, but also from tuberous sclerosis complex (TSC), focal cortical dysplasia, and hemimegalencephaly surgery cases. We obtained T cell receptor (TCR) Vβ chain sequence data from brain tissue and blood from patients with the highest levels of T cell transcripts. The clonality indices and the frequency of the top 50 Vβ clonotypes indicated that T cells in the brain were clonally restricted. The top 50 Vβ clonotypes comprised both public and private (patient specific) clonotypes, and the TCR Vβ chain third complementarity region (CDR3) of the most abundant public Vβ clonotype in each brain sample was strikingly similar to a CDR3 that recognizes an immunodominant epitope in either human cytomegalovirus or Epstein Barr virus, or influenza virus A. We found that the frequency of 14 of the top 50 brain Vβ clonotypes from a TSC surgery case had significantly increased in brain tissue removed to control recurrent seizures 11 months after the first surgery. Conversely, we found that the frequency in the blood of 18 of the top 50 brain clonotypes from a second TSC patient, who was seizure free, had significantly decreased 5 months after surgery indicating that T cell clones found in the brain had contracted in the periphery after removal of the brain area associated with seizure activity and inflammation. However, the frequency of a public and a private clonotype significantly increased in the brain after seizures recurred and the patient underwent a second surgery. Combined single cell gene expression and TCR sequencing of brain-infiltrating leukocytes from the second surgery showed that the two clones were CD8 effector T cells, indicating that they are likely to be pathologically relevant.

22. GILZ Regulates the Expression of Pro-Inflammatory Cytokines and Protects Against End-Organ Damage in a Model of Lupus.

Front Immunol

2021 Apr 6

Nataraja C, Dankers W, Flynn J

23. Novel Flow Cytometric Immunoassay for Detection of Proinsulin Autoantibodies in Diabetes Mellitus Employing a Recombinant Autoantigen Expressed in E. coli.

Front Immunol

2021 Apr 6

Sabljic AV, Bombicino SS, Marfía JI

INTRODUCTION: Insulin and proinsulin autoantibodies (IAA/PAA) are usually the first markers to appear in patients with type 1 Diabetes Mellitus (T1DM) and their prevalence ranges from 10 to 60% in the child-adolescent population. The reference method for IAA/PAA detection is the Radioligand Binding Assay (RBA), a highly specific and sensitive technique, but expensive and polluting. The aim of this work was to develop a novel flow cytometric microsphere-based immunoassay (FloCMIA) for PAA detection, employing recombinant human proinsulin (PI), as an alternative method to RBA, less expensive and harmful to the environment. MATERIALS AND METHODS: Human PI was expressed as Thioredoxin fusion protein (TrxPI) in E. coli and a fraction was biotinylated. A double paratope model was used in which samples were incubated with TrxPI-biotin and microspheres adsorbed with TrxPI. The immune complexes were revealed using Streptavidin-Phycoerythrin. The geometric mean of the signals was analyzed, and the results were expressed as Standard Deviation scores (SDs). Sera from 100 normal human control and from 111 type 1 diabetic patients were evaluated by FloCMIA. To correlate the novel assay with RBA, 51 diabetic patients were selected, spanning a wide range of PAA reactivity by RBA. RESULTS: The study of ROC curves allowed choosing a cut-off value of 3.0 SDs and the AUC was 0.705, indicating that FloCMIA has fair ability to distinguish between samples from each group. A prevalence of 50% for PAA was obtained in the population of diabetic patients studied. The specificity was 96% and the analytical sensitivity (percentage of patients RBA positive, also positive by FloCMIA) was 69%. There was a substantial agreement between methods (kappa statistic=0.700). CONCLUSIONS: A novel immunoassay based on flow cytometry that uses easy-to produce recombinant PI was developed. This assay constitutes an innovative and cost-effective alternative to RBA for the determination of PAA in patients' sera. The method developed here, presents good performance and a wide dynamic range together with a small required sample volume. Furthermore, these results make it possible to develop multiplex immunoassays that allow the combined detection of autoantibodies present in T1DM and other related autoimmune diseases.

24. Stroma Involvement in Pancreatic Ductal Adenocarcinoma: An Overview Focusing on Extracellular Matrix Proteins.

Front Immunol

2021 Apr 6

Liot S, Balas J, Aubert A

25. The Unique Immunomodulatory Properties of MSC-Derived Exosomes in Organ Transplantation.

Front Immunol

2021 Apr 6

Zheng Q, Zhang S, Guo WZ

26. EVA1B to Evaluate the Tumor Immune Microenvironment and Clinical Prognosis in Glioma.

Front Immunol

2021 Apr 6

Qu S, Liu J, Wang H.

BACKGROUND: Previous research indicated that the tumor cells and microenvironment interactions are critical for the immunotherapeutic response. However, predicting the clinical response to immunotherapy remains a dilemma for clinicians. Hence, this study aimed to investigate the associations between EVA1B expression and prognosis and tumor-infiltrating immune cells in glioma. METHODS: Firstly, we detected the EVA1B expression in glioma tissues through biological databases. The chi-squared test, Kaplan-Meier, and univariate and multivariate Cox regression analyses were used to analyze the clinical significance of EVA1B expression. The correlation between EVA1B expression and levels of tumor-infiltrating immune cells in glioma tissues was investigated. Receiver operating characteristic (ROC) analysis was performed to compare the predictive power between EVA1B and other commonly immune-related markers. RESULTS: In the CGGA cohort of 325 glioma patients, we found that EVA1B was upregulated in glioma, and increased with tumor grade. High EVA1B expression was prominently associated with unfavorable clinicopathological features, and poorer survival of patients, which were further confirmed by TCGA (n=609) and GEO (n=74) cohorts. Furthermore, multivariate analysis indicated that EVA1B is an independent prognostic biomarker for glioma. Importantly, EVA1B overexpression was associated with a higher infiltration level of CD4+ T cells, CD8+ T cells, B cells, macrophages, and neutrophils in glioma. ROC curves showed that, compared with PD-L1, CTLA-4, and Siglec15, EVA1B presented a higher area under the curve (AUC) value (AUC=0.824) for predicting high immune infiltration levels in glioma. CONCLUSIONS: We found that EVA1B was upregulated and could act as a poor prognostic biomarker in glioma. Importantly, EVA1B overexpression was associated with the immune infiltration levels of immune cells including B cells, CD4+ T cells, CD8+ T cells, macrophages, and neutrophils, and strongly with the overall immune infiltration levels of glioma. These findings suggested that EVA1B might be a potential biomarker for evaluating prognosis and immune infiltration in glioma.

27. Tumor-Associated Antigens (TAAs) for the Serological Diagnosis of Osteosarcoma.

Front Immunol

2021 Apr 30

Li J, Qin B, Huang M

28. High-Resolution Analysis Identifies High Frequency of KIR-A Haplotypes and Inhibitory Interactions of KIR With HLA Class I in Zhejiang Han.

Front Immunol

2021 Apr 30

Tao S, He Y, Kichula KM

29. Bridging Therapy for Acute Stroke as the Initial Manifestation of Takayasu Arteritis: A Case Report and Review of Literature.

Front Immunol

2021 Apr 30

Dai Y, Zhong Y, Jian B

30. MSCs and Inflammatory Cells Crosstalk in Regenerative Medicine: Concerted Actions for Optimized Resolution Driven by Energy Metabolism.

Front Immunol

2021 Apr 30

Planat-Benard V, Varin A, Casteilla L.

31. Identifying New Hybrid Insulin Peptides (HIPs) in Type 1 Diabetes.

Front Immunol

2021 Apr 30

Mannering SI, Rubin AF, Wang R

32. Anti-HIV-1 ADCC and HIV-1 Env Can Be Partners in Reducing Latent HIV Reservoir.

Front Immunol

2021 Apr 30

Suryawanshi P, Bagul R, Shete A

33. Mucosal Immunoregulatory Properties of Tsukamurella inchonensis to Reverse Experimental Food Allergy.

Front Immunol

2021 Apr 30

Smaldini PL, Trejo FM, Rizzo GP

34. The Role of Lectin Receptors and Their Ligands in Controlling Allergic Inflammation.

Front Immunol

2021 Apr 30

Peters K, Peters M.

35. Commentary: Mesenchymal Stem Cells: A New Piece in the Puzzle of COVID-19 Treatment.

Front Immunol

2021 Apr 29

Carvalho JL, Silva-Carvalho AE, Garcez EM

36. Respiratory Impairment Predicts Response to IL-1 and IL-6 Blockade in COVID-19 Patients With Severe Pneumonia and Hyper-Inflammation.

Front Immunol

2021 Apr 29

Della-Torre E, Lanzillotta M, Campochiaro C

37. Single-Cell Transcriptional Heterogeneity of Neutrophils During Acute Pulmonary Cryptococcus neoformans Infection.

Front Immunol

2021 Apr 29

Deerhake ME, Reyes EY, Xu-Vanpala S

38. Induction of IL-9 in Peripheral Lymphocytes of Rheumatoid Arthritis Patients and Healthy Donors by Th17-Inducing Cytokine Conditions.

Front Immunol

2021 Apr 29

Heim J, Almanzar G, Schmalzing M

39. PRV-1 Infected Macrophages in Melanized Focal Changes in White Muscle of Atlantic Salmon (Salmo salar) Correlates With a Pro-Inflammatory Environment.

Front Immunol

2021 Apr 29

Malik MS, Bjørgen H, Nyman IB

40. The Promiscuous Profile of Complement Receptor 3 in Ligand Binding, Immune Modulation, and Pathophysiology.

Front Immunol

2021 Apr 29

Lamers C, Plüss CJ, Ricklin D.

41. Characterization of T-Cell Responses to SMX and SMX-NO in Co-Trimoxazole Hypersensitivity Patients Expressing HLA-B*13:01.

Front Immunol

2021 Apr 29

Pratoomwun J, Thomson P, Jaruthamsophon K

HLA-B*13:01-positive patients in Thailand can develop frequent co-trimoxazole hypersensitivity reactions. This study aimed to characterize drug-specific T cells from three co-trimoxazole hypersensitive patients presenting with either Stevens-Johnson syndrome or drug reaction with eosinophilia and systemic symptoms. Two of the patients carried the HLA allele of interest, namely HLA-B*13:01. Sulfamethoxazole and nitroso sulfamethoxazole specific T cell clones were generated from T cell lines of co-trimoxazole hypersensitive HLA-B*13:01-positive patients. Clones were characterized for antigen specificity and cross-reactivity with structurally related compounds by measuring proliferation and cytokine release. Surface marker expression was characterized via flow cytometry. Mechanistic studies were conducted to assess pathways of T cell activation in response to antigen stimulation. Peripheral blood mononuclear cells from all patients were stimulated to proliferate and secrete IFN-γ with nitroso sulfamethoxazole. All sulfamethoxazole and nitroso sulfamethoxazole specific T cell clones expressed the CD4+ phenotype and strongly secreted IL-13 as well as IFN-γ, granzyme B and IL-22. No secretion of IL-17 was observed. A number of nitroso sulfamethoxazole-specific clones cross-reacted with nitroso dapsone but not sulfamethoxazole whereas sulfamethoxazole specific clones cross-reacted with nitroso sulfamethoxazole only. The nitroso sulfamethoxazole specific clones were activated in both antigen processing-dependent and -independent manner, while sulfamethoxazole activated T cell responses via direct HLA binding. Furthermore, activation of nitroso sulfamethoxazole-specific, but not sulfamethoxazole-specific, clones was blocked with glutathione. Sulfamethoxazole and nitroso sulfamethoxazole specific T cell clones from hypersensitive patients were CD4+ which suggests that HLA-B*13:01 is not directly involved in the iatrogenic disease observed in co-trimoxazole hypersensitivity patients.

42. NSP2 Is Important for Highly Pathogenic Porcine Reproductive and Respiratory Syndrome Virus to Trigger High Fever-Related COX-2-PGE2 Pathway in Pigs.

Front Immunol

2021 Apr 29

Du L, Wang H, Liu F

43. Next Generation Sequencing for Detecting Somatic FAS Mutations in Patients With Autoimmune Lymphoproliferative Syndrome.

Front Immunol

2021 Apr 29

López-Nevado M, Docampo-Cordeiro J, Ramos JT

44. NF-κB c-Rel Is Dispensable for the Development but Is Required for the Cytotoxic Function of NK Cells.

Front Immunol

2021 Apr 29

Vicioso Y, Wong DP, Roy NK

45. The Importance of Glycans of Viral and Host Proteins in Enveloped Virus Infection.

Front Immunol

2021 Apr 29

Li Y, Liu D, Wang Y

46. Melatonin Synergizes With Mesenchymal Stromal Cells Attenuates Chronic Allograft Vasculopathy.

Front Immunol

2021 Apr 29

Qin YF, Kong DJ, Qin H

47. Early Emergence of Adaptive Mechanisms Sustaining Ig Production: Application to Antibody Therapy.

Front Immunol

2021 Apr 29

Lemarié M, Chatonnet F, Caron G

48. Plasma Lectin Pathway Complement Proteins in Patients With COVID-19 and Renal Disease.

Front Immunol

2021 Apr 29

Medjeral-Thomas NR, Troldborg A, Hansen AG

49. Dietary Derived Micronutrients Modulate Immune Responses Through Innate Lymphoid Cells.

Front Immunol

2021 Apr 29

Shi Z, Ohno H, Satoh-Takayama N.

50. The Role of Proprotein Convertases in the Regulation of the Function of Immune Cells in the Oncoimmune Response.

Front Immunol

2021 Apr 29

Rose M, Duhamel M, Rodet F

51. Cold Agglutinins and Cryoglobulins Associate With Clinical and Laboratory Parameters of Cold Urticaria.

Front Immunol

2021 Apr 29

Bizjak M, Košnik M, Terhorst-Molawi D

52. Distinguishing Signal From Noise in Immunopeptidome Studies of Limiting-Abundance Biological Samples: Peptides Presented by I-A(b) in C57BL/6 Mouse Thymus.

Front Immunol

2021 Apr 29

Nanaware PP, Jurewicz MM, Clement CC

53. Role of Tonsillar Chronic Inflammation and Commensal Bacteria in the Pathogenesis of Pediatric OSA.

Front Immunol

2021 Apr 29

Sarmiento Varón L, De Rosa J, Rodriguez R

54. Case Report: Activating PIK3CD Mutation in Patients Presenting With Granulomatosis With Polyangiitis.

Front Immunol

2021 Apr 28

Lu M, Gu W, Sheng Y

55. SARS-CoV-2 Induces Lymphocytopenia by Promoting Inflammation and Decimates Secondary Lymphoid Organs.

Front Immunol

2021 Apr 28

Xiang Q, Feng Z, Diao B

56. Immune Phenotyping of Patients With Acute Vogt-Koyanagi-Harada Syndrome Before and After Glucocorticoids Therapy.

Front Immunol

2021 Apr 28

Jiang H, Li Z, Yu L

57. A Structural Landscape of Neutralizing Antibodies Against SARS-CoV-2 Receptor Binding Domain.

Front Immunol

2021 Apr 28

Niu L, Wittrock KN, Clabaugh GC

58. Stimulation of α7 Nicotinic Acetylcholine Receptor by Nicotine Suppresses Decidual M1 Macrophage Polarization Against Inflammation in Lipopolysaccharide-Induced Preeclampsia-Like Mouse Model.

Front Immunol

2021 Apr 28

Han X, Li W, Li P

Changes in decidual macrophage polarization affect local inflammatory microenvironment and lead to adverse pregnancy outcomes. However, the regulatory mechanism of macrophage polarization in preeclampsia (PE) remains unclear. In this study, we found that α7nAChR expression was significantly down-regulated in decidual macrophages in PE patients compared to normal pregnant women, accompanied by a reduced proportion of M2 phenotype and an increased proportion of M1 phenotype; these results suggested that the reduced α7nAChR activity might contribute to changes in the polarization of decidual macrophages. Then, we further investigated the regulatory role of α7nAChR activation by nicotine on decidual macrophage polarization and placental remodeling in the PE-like mouse model. The PE mice were obtained by i.p. injection of 10 µg/kg lipopolysaccharide (LPS) gestational day (GD) 13, and 40 µg/kg LPS daily until GD16. Subcutaneous injection of 1.0 mg/kg nicotine was administrated from GD14 to GD18. Nicotine treatment increased the decreased M2 phenotype and inhibited the increased M1 phenotype in decidua of pregnant mice induced by LPS. The levels of pro-inflammatory cytokines in decidua were higher but the levels of anti-inflammatory cytokines were lower in PE mice compared to the controls, nicotine reversed these changes. The level of choline acetyltransferase (CHAT) was reduced in the LPS-treated group, it was increased following nicotine treatment. Damage of spiral artery remodeling and down-regulation of markers related to trophoblast invasion in placentas were found in PE mice; nicotine improved these pathological structures of placentas. α-bungarotoxin (α-BGT) which is specific antagonist for α7nAChR could abolish the effects of nicotine on decidual macrophage polarization, trophoblast arrangement and vascular structure in placental tissue in PE mice. These results suggest that α7nAChR plays an important regulatory role in maternal-fetal inflammation and placental remodeling in preeclampsia and may provide a theoretical basis for the discovery of new strategies for preeclampsia.

59. Characterization of the Anti-Inflammatory Capacity of IL-10-Producing Neutrophils in Response to Streptococcus pneumoniae Infection.

Front Immunol

2021 Apr 28

González LA, Melo-González F, Sebastián VP

60. Aging-Induced Dysbiosis of Gut Microbiota as a Risk Factor for Increased Listeria monocytogenes Infection.

Front Immunol

2021 Apr 28

Alam MS, Gangiredla J, Hasan NA

Invasive foodborne Listeria monocytogenes infection causes gastroenteritis, septicemia, meningitis, and chorioamnionitis, and is associated with high case-fatality rates in the elderly. It is unclear how aging alters gut microbiota, increases risk of listeriosis, and causes dysbiosis post-infection. We used a geriatric murine model of listeriosis as human surrogate of listeriosis for aging individuals to study the effect of aging and L. monocytogenes infection. Aging and listeriosis-induced perturbation of gut microbiota and disease severity were compared between young-adult and old mice. Young-adult and old mice were dosed intragastrically with L. monocytogenes. Fecal pellets were collected pre- and post-infection for microbiome analysis. Infected old mice had higher Listeria colonization in liver, spleen, and feces. Metagenomics analyses of fecal DNA-sequences showed increase in α-diversity as mice aged, and infection reduced its diversity. The relative abundance of major bacterial phylum like, Bacteroidetes and Firmicutes remained stable over aging or infection, while the Verrucomicrobia phylum was significantly reduced only in infected old mice. Old mice showed a marked reduction in Clostridaiceae and Lactobacillaceae bacteria even before infection when compared to uninfected young-adult mice. L. monocytogenes infection increased the abundance of Porphyromonadaceae and Prevotellaceae in young-adult mice, while members of the Ruminococcaceae and Lachnospiraceae family were significantly increased in old mice. The abundance of the genera Blautia and Alistipes were significantly reduced post-infection in young-adult and in old mice as compared to their uninfected counterparts. Butyrate producing, immune-modulating bacterial species, like Pseudoflavonifractor and Faecalibacterium were significantly increased only in old infected mice, correlating with increased intestinal inflammatory mRNA up-regulation from old mice tissue. Histologic analyses of gastric tissues showed extensive lesions in the Listeria-infected old mice, more so in the non-glandular region and fundus than in the pylorus. Commensal species like Lactobacillus, Clostridiales, and Akkermansia were only abundant in infected young-adult mice but their abundance diminished in the infected old mice. Listeriosis in old mice enhances the abundance of butyrate-producing inflammatory members of the Ruminococcaceae/Lachnospiraceae bacteria while reducing/eliminating beneficial commensals in the gut. Results of this study indicate that, aging may affect the composition of gut microbiota and increase the risk of invasive L. monocytogenes infection.

61. Targeting Neutrophil Adhesive Events to Address Vaso-Occlusive Crisis in Sickle Cell Patients.

Front Immunol

2021 Apr 28

Morikis VA, Hernandez AA, Magnani JL

62. Diversity of Functionally Distinct Clonal Sets of Human Conventional Memory B Cells That Bind Staphylococcal Protein A.

Front Immunol

2021 Apr 28

Radke EE, Li Z, Hernandez DN

63. SARS-CoV-2-Seronegative Subjects Target CTL Epitopes in the SARS-CoV-2 Nucleoprotein Cross-Reactive to Common Cold Coronaviruses.

Front Immunol

2021 Apr 28

Schmidt KG, Nganou-Makamdop K, Tenbusch M

The beta-coronavirus SARS-CoV-2 induces severe disease (COVID-19) mainly in elderly persons with risk factors, whereas the majority of patients experience a mild course of infection. As the circulating common cold coronaviruses OC43 and HKU1 share some homologous sequences with SARS-CoV-2, beta-coronavirus cross-reactive T-cell responses could influence the susceptibility to SARS-CoV-2 infection and the course of COVID-19. To investigate the role of beta-coronavirus cross-reactive T-cells, we analyzed the T-cell response against a 15 amino acid long peptide (SCoV-DP15: DLSPRWYFYYLGTGP) from the SARS-CoV-2 nucleoprotein sequence with a high homology to the corresponding sequence (QLLPRWYFYYLGTGP) in OC43 and HKU1. SCoV-DP15-specific T-cells were detected in 4 out of 23 (17.4%) SARS-CoV-2-seronegative healthy donors. As HIV-1 infection is a potential risk factor for COVID-19, we also studied a cohort of HIV-1-infected patients on antiretroviral therapy. 44 out of these 116 HIV-1-infected patients (37.9%) showed a specific recognition of the SCoV-DP15 peptide or of shorter peptides within SCoV-DP15 by CD4+ T-cells and/or by CD8+ T-cells. We could define several new cross-reactive HLA-I-restricted epitopes in the SARS-CoV-2 nucleoprotein such as SPRWYFYYL (HLA-B*07, HLA-B*35), DLSPRWYFYY (HLA-A*02), LSPRWYFYY (HLA-A*29), WYFYYLGTGP and WYFYYLGT. Epitope specific CD8+ T-cell lines recognized corresponding epitopes within OC43 and HKU1 to a similar degree or even at lower peptide concentrations suggesting that they were induced by infection with OC43 or HKU1. Our results confirm that SARS-CoV-2-seronegative subjects can target SARS-CoV-2 not only by beta-coronavirus cross-reactive CD4+ T-cells but also by cross-reactive CD8+ cytotoxic T-cells (CTL). The delineation of cross-reactive T-cell epitopes contributes to an efficient epitope-specific immunomonitoring of SARS-CoV-2-specific T-cells. Further prospective studies are needed to prove a protective role of cross-reactive T-cells and their restricting HLA alleles for control of SARS-CoV-2 infection. The frequent observation of SARS-CoV-2-reactive T-cells in HIV-1-infected subjects could be a reason that treated HIV-1 infection does not seem to be a strong risk factor for the development of severe COVID-19.

64. A Pathogenic Missense Variant in NFKB1 Causes Common Variable Immunodeficiency Due to Detrimental Protein Damage.

Front Immunol

2021 Apr 27

Fliegauf M, Krüger R, Steiner S

In common variable immunodeficiency (CVID), heterozygous damaging NFKB1 variants represent the most frequent monogenic cause. NFKB1 encodes the precursor p105, which undergoes proteasomal processing to generate the mature NF-κB transcription factor subunit p50. The majority of NFKB1 sequence changes comprises missense variants of uncertain significance (VUS), each requiring functional evaluation to assess causality, particularly in families with multiple affected members presenting with different phenotypes. In four affected members of a German family, all diagnosed with CVID, we identified a previously uncharacterized heterozygous NFKB1 missense variant (c.1049A>G; p.Tyr350Cys). The clinical phenotypes varied markedly regarding onset, frequency and severity of infections. Consistent immunologic findings were hypogammaglobulinemia with normal specific antibody response to protein- and polysaccharide-based vaccinations, reduced switched memory B cells and decreased lymphocyte proliferation upon stimulation with the B cell mitogen SAC. To assess the pathogenicity of the NFKB1 missense variant, we employed immunophenotyping and functional analyses in a routine in vitro cell culture model. Following site-directed mutagenesis to introduce the variant into overexpression vectors encoding EGFP-fused p105 or p50, we analyzed transiently transfected HEK293T cells by confocal imaging and Western blotting. The cytoplasmic p105-Tyr350Cys precursor gained only weak expression levels indicating accelerated decay. The missense change disabled processing of the precursor to prevent the generation of mutant p50. Unlike the wildtype p50, the overexpressed mutant p50-Tyr350Cys was also not sustainable and showed a conspicuous subnuclear mislocalization with accumulation in dense aggregates instead of a homogenous distribution. Electrophoretic mobility shift assays, fluorescence-based reporter gene analyses and co-transfection experiments however demonstrated, that the DNA-binding activity of p50-Tyr350Cys and the interaction with RelA(p65), IκBα and wildtype p50 were preserved. Mutation carriers had reduced p105 and p50 levels, indicating insufficient protein amounts as the most likely primary defect. In conclusion, the missense variant c.1049A>G caused a detrimental defect, preventing the persistent expression of both, the p105-Tyr350Cys precursor and the mature p50-Tyr350Cys. The variable clinical phenotypes among affected family members sharing an identical pathogenic NFKB1 variant support a disease mechanism provoked by a p105/p50 (haplo)insufficient condition.

65. Overcoming Immunological Challenges Limiting Capsid-Mediated Gene Therapy With Machine Learning.

Front Immunol

2021 Apr 27

Wec AZ, Lin KS, Kwasnieski JC

66. Expression of Human Endogenous Retroviruses in Systemic Lupus Erythematosus: Multiomic Integration With Gene Expression.

Front Immunol

2021 Apr 27

Stearrett N, Dawson T, Rahnavard A

67. NK Cells and PMN-MDSCs in the Graft From G-CSF Mobilized Haploidentical Donors Display Distinct Gene Expression Profiles From Those of the Non-Mobilized Counterpart.

Front Immunol

2021 Apr 27

Pelosi A, Besi F, Tumino N

68. The Role of Tumor Necrosis Factor in Manipulating the Immunological Response of Tumor Microenvironment.

Front Immunol

2021 Apr 27

Laha D, Grant R, Mishra P

69. How Microbes Defend Themselves From Incoming Hydrogen Peroxide.

Front Immunol

2021 Apr 27

Sen A, Imlay JA.

70. Hidden in Plain View: Discovery of Chimeric Diabetogenic CD4 T Cell Neo-Epitopes.

Front Immunol

2021 Apr 27

Reed BK, Kappler JW.

71. Microphysiological Systems for Studying Cellular Crosstalk During the Neutrophil Response to Infection.

Front Immunol

2021 Apr 27

Richardson IM, Calo CJ, Hind LE.

72. Protein-Based Immunome Wide Association Studies (PIWAS) for the Discovery of Significant Disease-Associated Antigens.

Front Immunol

2021 Apr 27

Haynes WA, Kamath K, Waitz R

73. Regulation of Inflammatory Response by Transmembrane Adaptor Protein LST1.

Front Immunol

2021 Apr 27

Fabisik M, Tureckova J, Pavliuchenko N

74. Contribution of T Cell Receptor Alpha and Beta CDR3, MHC Typing, V and J Genes to Peptide Binding Prediction.

Front Immunol

2021 Apr 26

Springer I, Tickotsky N, Louzoun Y.

75. Optimization of T Cell Redirecting Strategies: Obtaining Inspirations From Natural Process of T Cell Activation.

Front Immunol

2021 Apr 26

Gao Y, Wang Y, Luo F

76. Nucleic Acid Immunity and DNA Damage Response: New Friends and Old Foes.

Front Immunol

2021 Apr 26

Taffoni C, Steer A, Marines J

77. Acute Transverse Myelitis (ATM):Clinical Review of 43 Patients With COVID-19-Associated ATM and 3 Post-Vaccination ATM Serious Adverse Events With the ChAdOx1 nCoV-19 Vaccine (AZD1222).

Front Immunol

2021 Apr 26

Román GC, Gracia F, Torres A

INTRODUCTION: Although acute transverse myelitis (ATM) is a rare neurological condition (1.34-4.6 cases per million/year) COVID-19-associated ATM cases have occurred during the pandemic. CASE-FINDING METHODS: We report a patient from Panama with SARS-CoV-2 infection complicated by ATM and present a comprehensive clinical review of 43 patients with COVID-19-associated ATM from 21 countries published from March 2020 to January 2021. In addition, 3 cases of ATM were reported as serious adverse events during the clinical trials of the COVID-19 vaccine ChAdOx1 nCoV-19 (AZD1222). RESULTS: All patients had typical features of ATM with acute onset of paralysis, sensory level and sphincter deficits due to spinal cord lesions demonstrated by imaging. There were 23 males (53%) and 20 females (47%) ranging from ages 21- to 73- years-old (mean age, 49 years), with two peaks at 29 and 58 years, excluding 3 pediatric cases. The main clinical manifestations were quadriplegia (58%) and paraplegia (42%). MRI reports were available in 40 patients; localized ATM lesions affected ≤3 cord segments (12 cases, 30%) at cervical (5 cases) and thoracic cord levels (7 cases); 28 cases (70%) had longitudinally-extensive ATM (LEATM) involving ≥4 spinal cord segments (cervicothoracic in 18 cases and thoracolumbar-sacral in 10 patients). Acute disseminated encephalomyelitis (ADEM) occurred in 8 patients, mainly women (67%) ranging from 27- to 64-years-old. Three ATM patients also had blindness from myeloneuritis optica (MNO) and two more also had acute motor axonal neuropathy (AMAN). CONCLUSIONS: We found ATM to be an unexpectedly frequent neurological complication of COVID-19. Most cases (68%) had a latency of 10 days to 6 weeks that may indicate post-infectious neurological complications mediated by the host's response to the virus. In 32% a brief latency (15 hours to 5 days) suggested a direct neurotropic effect of SARS-CoV-2. The occurrence of 3 reported ATM adverse effects among 11,636 participants in the AZD1222 vaccine trials is extremely high considering a worldwide incidence of 0.5/million COVID-19-associated ATM cases found in this report. The pathogenesis of ATM remains unknown, but it is conceivable that SARS-CoV-2 antigens -perhaps also present in the AZD1222 COVID-19 vaccine or its chimpanzee adenovirus adjuvant- may induce immune mechanisms leading to the myelitis.

78. Tumor-Intrinsic Mechanisms Regulating Immune Exclusion in Liver Cancers.

Front Immunol

2021 Apr 26

Lindblad KE, Ruiz de Galarreta M, Lujambio A.

79. Barriers and Facilitators Associated With Vaccine Acceptance and Uptake Among Pregnant Women in High Income Countries: A Mini-Review.

Front Immunol

2021 Apr 26

Qiu X, Bailey H, Thorne C.

80. Polyvalent Bacterial Lysate Protects Against Pneumonia Independently of Neutrophils, IL-17A or Caspase-1 Activation.

Front Immunol

2021 Apr 26

Ferrara F, Rial A, Suárez N

Polyvalent bacterial lysates have been in use for decades for prevention and treatment of respiratory infections with reported clinical benefits. However, besides claims of broad immune activation, the mode of action is still a matter of debate. The lysates, formulated with the main bacterial species involved in respiratory infections, are commonly prepared by chemical or mechanical disruption of bacterial cells, what is believed influences the biological activity of the product. Here, we prepared two polyvalent lysates with the same composition but different method of bacterial cell disruption and evaluated their biological activity in a comparative fashion. We found that both bacterial lysates induce NF-kB activation in a MyD88 dependent manner, suggesting they work as TLR agonists. Further, we found that a single intranasal dose of any of the two lysates, is sufficient to protect against pneumococcal pneumonia, suggesting that they exert similar biological activity. We have previously shown that protection against pneumococcal pneumonia can also be induced by prior S. pneumoniae sub lethal infection or therapeutic treatment with a TLR5 agonist. Protection in those cases depends on neutrophil recruitment to the lungs, and can be associated with increased local expression of IL-17A. Here, we show that bacterial lysates exert protection against pneumococcal pneumonia independently of neutrophils, IL-17A or Caspase-1/11 activation, suggesting the existence of redundant mechanisms of protection. Trypsin-treated lysates afford protection to the same extent, suggesting that just small peptides suffice to exert the protective effect or that the molecules responsible for the protective effect are not proteins. Understanding the mechanism of action of bacterial lysates and deciphering the active components shall allow redesigning them with more precisely defined formulations and expanding their range of action.

81. Corrigendum: Unveiling Interindividual Variability of Human Fibroblast Innate Immune Response Using Robust Cell-Based Protocols.

Front Immunol

2021 Apr 26

Chansard A, Dubrulle N, Poujol de Molliens M

82. γδ T/Interleukin-17A Contributes to the Effect of Maresin Conjugates in Tissue Regeneration 1 on Lipopolysaccharide-Induced Cardiac Injury.

Front Immunol

2021 Apr 26

Yang Y, Li XY, Li LC

83. Case Report: Novel Compound Heterozygous RNASEH2B Mutations Cause Aicardi-Goutières Syndrome.

Front Immunol

2021 Apr 26

Garau J, Masnada S, Dragoni F

84. Extracellular Vesicles: An Emerging Mechanism Governing the Secretion and Biological Roles of Tenascin-C.

Front Immunol

2021 Apr 26

Albacete-Albacete L, Sánchez-Álvarez M, Del Pozo MA.

85. Neurological Symptoms of COVID-19: The Zonulin Hypothesis.

Front Immunol

2021 Apr 26

Llorens S, Nava E, Muñoz-López M

86. Bactericidal/Permeability-Increasing Protein Preeminently Mediates Clearance of Pseudomonas aeruginosa In Vivo via CD18-Dependent Phagocytosis.

Front Immunol

2021 Apr 26

Theprungsirikul J, Skopelja-Gardner S, Burns AS

87. Islet Autoimmunity in Adults With Impaired Glucose Tolerance and Recently Diagnosed, Treatment Naïve Type 2 Diabetes in the Restoring Insulin SEcretion (RISE) Study.

Front Immunol

2021 Apr 26

Brooks-Worrell BM, Tjaden AH, Edelstein SL

88. Case Report: Non-episodic Angioedema With Eosinophilia in a Young Lactating Woman.

Front Immunol

2021 Apr 26

Hirmatsu-Ito M, Nakamura N, Miyabe M

89. Case Report: VEXAS Syndrome: From Mild Symptoms to Life-Threatening Macrophage Activation Syndrome.

Front Immunol

2021 Apr 23

Staels F, Betrains A, Woei-A-Jin FJSH

90. Case Report: Antibodies to the N-Methyl-D-Aspartate Receptor in a Patient With Multiple Sclerosis.

Front Immunol

2021 Apr 23

Zhou R, Jiang F, Cai H

91. Resolution-Based Therapies: The Potential of Lipoxins to Treat Human Diseases.

Front Immunol

2021 Apr 23

Jaén RI, Sánchez-García S, Fernández-Velasco M

92. Endometrial Cancer Suppresses CD8+ T Cell-Mediated Cytotoxicity in Postmenopausal Women.

Front Immunol

2021 Apr 23

Patel MV, Shen Z, Rodriguez-Garcia M

93. Platelets in HIV: A Guardian of Host Defence or Transient Reservoir of the Virus?

Front Immunol

2021 Apr 23

Pretorius E.

94. Ghrelin Alleviates Intestinal Dysfunction in Sepsis Through the KLF4/MMP2 Regulatory Axis by Activating SIRT1.

Front Immunol

2021 Apr 23

Li B, Dou Z, Zhang L

95. A Double-Antibody Sandwich ELISA for Sensitive and Specific Detection of Swine Fibrinogen-Like Protein 1.

Front Immunol

2021 Apr 23

Zhang X, Zhu H, Zheng X

96. A Quest for a Universal Plasma-Derived Antivenom Against All Elapid Neurotoxic Snake Venoms.

Front Immunol

2021 Apr 23

Ratanabanangkoon K.

This review describes the research aimed at the development of universal antivenom against elapid neurotoxic snake venoms. The antivenoms produced in Thailand in the 1980s were of low potency, especially against the elapid venoms. This was thought to be due to the low immunogenicity of the α-neurotoxins, which are the most lethal toxins in these venoms. Comparisons of various α-neurotoxin conjugates and polymers, and also different immunological adjuvants, showed that the adjuvant used is the major determinant in the antibody response in horses. The potent Freund's adjuvant was not used due to its severe local side-effect in horses. Therefore, a novel immunization protocol termed 'low dose, low volume multi-site' was developed for use in horses. This immunization protocol has led to the production of highly potent monospecific antivenoms against several elapid and viperid venoms, and two potent polyspecific antivenoms, one against 4 neurotoxic and another against 3 hematotoxic venoms. The immunization protocol has also led to other improvements in antivenom production including: several fold increases in antiserum potency, a reduction in the time required to reach therapeutically useful antibody titers, a 90% reduction in the amount of venom used, and 100% of the horses responding to the immunization program. This development is partly responsible for significant decrease in the Thailand's annual snakebite death toll from a few dozens to mostly nil in recent years. Finally, a simple and novel immunization strategy, using a 'diverse toxin repertoire' composed of numerous elapid toxin fractions as immunogen, was proposed and tested. This immunization procedure has resulted in the successful production of a widely paraspecific antiserum against at least 36 neurotoxic venoms of 28 species encompassing 10 genera and from 20 countries on four continents, and possibly against all elapid venoms with α-neurotoxins as the lethal toxins. These results indicate that, with optimizations of the composition of the 'diverse toxin repertoire', the immunization scheme and antibody fractionation to increase the antivenom neutralizing potency, an effective universal antivenom against the neurotoxic elapid snakes of the world can be produced.

97. Is It Feasible to Use CMV-Specific T-Cell Adoptive Transfer as Treatment Against Infection in SOT Recipients?

Front Immunol

2021 Apr 23

García-Ríos E, Nuévalos M, Mancebo FJ

98. From the Immune Profile to the Immunoscore: Signatures for Improving Postsurgical Prognostic Prediction of Pancreatic Neuroendocrine Tumors.

Front Immunol

2021 Apr 23

Wei M, Xu J, Hua J

OBJECTIVE: Immune infiltration plays an important role in tumor development and progression and shows promising prognostic value in numerous tumors. In this study, we aimed to identify the role of immune infiltration in pancreatic neuroendocrine tumors (Pan-NETs) and to establish an Immunoscore system to improve the prediction of postsurgical recurrence-free survival. METHODS: To derive transcriptional signatures and deconvolute specific immune populations, two GEO datasets containing 158 Pan-NET patients were reanalyzed to summarize the immune infiltration landscape and identify immune-related signatures. Using real-time reverse transcription-polymerase chain reaction, immunofluorescence and immunochemistry methods, candidate signatures were further detected. The least absolute shrinkage and selection operator (LASSO) logistic regression model used statistically significant survival predicators in the training cohort (n=125) to build an Immunoscore system. The prognostic and predictive accuracy was validated in an external independent cohort of 77 patients. RESULTS: The immune infiltration profile in Pan-NETs showed significant heterogeneity, among which accumulated immune cells, T lymphocytes and macrophages were predominant. Fourteen statistically significant immune-related signatures were further identified in the screening cohort. The Immunoscore system for Pan-NETs (ISpnet) consisting of six immune features (CCL19, IL-16, CD163, IRF4, CD8PT and CD8IT) was constructed to classify patients as high and low risk in the training cohort (cutoff value = 2.14). Low-risk patients demonstrated longer 5-year recurrence-free survival (HR, 0.061; 95% CI, 0.026 to 0.14; p < 0.0001), with fewer recurrences and better prognoses. To predict the individual risk of recurrence, a nomogram incorporating both immune signatures and clinicopathological characteristics was developed. CONCLUSION: Our model, ISpnet, captures immune feature-associated prognostic indicators in Pan-NETs and represents the first immune feature-based score for the postsurgical prognostic prediction. The nomogram based on the ISpnet and independent clinical risk factors might facilitate decision-making regarding early recurrence risk monitoring, identify high-risk patients in need of adjuvant therapy, and provide auxiliary guidance for patients with Pan-NETs that may benefit from immunotherapy in clinical trials.

99. Immunopathology of Acute Kidney Injury in Severe Malaria.

Front Immunol

2021 Apr 23

Katsoulis O, Georgiadou A, Cunnington AJ.

100. A Novel Resolution of Diabetes: C-C Chemokine Motif Ligand 4 Is a Common Target in Different Types of Diabetes by Protecting Pancreatic Islet Cell and Modulating Inflammation.

Front Immunol

2021 Apr 23

Chang TT, Lin LY, Chen JW.

101. Host-Specific Serum Factors Control the Development and Survival of Schistosoma mansoni.

Front Immunol

2021 Apr 23

Anisuzzaman, Frahm S, Prodjinotho UF

INTRODUCTION: Schistosomiasis is a neglected tropical disease (NTD) caused by blood-dwelling flatworms which develop from skin-penetrating cercariae, the freely swimming water-borne infective stage of Schistosoma mansoni, into adult worms. This natural course of infection can be mimicked in experimental mouse models of schistosomiasis. However, only a maximum of 20-30% of penetrated cercariae mature into fecund adults. The reasons for this are unknown but could potentially involve soluble factors of the innate immune system, such as complement factors and preexisting, natural antibodies. MATERIALS AND METHODS: Using our recently developed novel serum- and cell-free in vitro culture system for newly transformed schistosomula (NTS), which supports long-term larval survival, we investigated the effects of mouse serum and its major soluble complement factors C1q, C3, C4 as well as preexisting, natural IgM in vitro and assessed worm development in vivo by infecting complement and soluble (s)IgM-deficient animals. RESULTS: In contrast to sera from humans and a broad variety of mammalian species, serum from mice, surprisingly, killed parasites already at skin stage in vitro. Interestingly, the most efficient killing component(s) were heat-labile but did not include important members of the perhaps best known family of heat-labile serum factors, the complement system, nor consisted of complement-activating natural immunoglobulins. Infection of complement C1q and sIgM-deficient mice with S. mansoni as well as in vitro tests with sera from mice deficient in C3 and C4 revealed no major role for these soluble factors in vivo in regard to parasite maturation, fecundity and associated immunopathology. Rather, the reduction of parasite maturation from cercariae to adult worms was comparable to wild-type mice. CONCLUSION: This study reveals that not yet identified heat-labile serum factors are major selective determinants of the host-specificity of schistosomiasis, by directly controlling schistosomal development and survival.

102. Stochastic Episodes of Latent Cytomegalovirus Transcription Drive CD8 T-Cell "Memory Inflation" and Avoid Immune Evasion.

Front Immunol

2021 Apr 22

Griessl M, Renzaho A, Freitag K

Acute infection with murine cytomegalovirus (mCMV) is controlled by CD8+ T cells and develops into a state of latent infection, referred to as latency, which is defined by lifelong maintenance of viral genomes but absence of infectious virus in latently infected cell types. Latency is associated with an increase in numbers of viral epitope-specific CD8+ T cells over time, a phenomenon known as "memory inflation" (MI). The "inflationary" subset of CD8+ T cells has been phenotyped as KLRG1+CD62L- effector-memory T cells (iTEM). It is agreed upon that proliferation of iTEM requires repeated episodes of antigen presentation, which implies that antigen-encoding viral genes must be transcribed during latency. Evidence for this has been provided previously for the genes encoding the MI-driving antigenic peptides IE1-YPHFMPTNL and m164-AGPPRYSRI of mCMV in the H-2d haplotype. There exist two competing hypotheses for explaining MI-driving viral transcription. The "reactivation hypothesis" proposes frequent events of productive virus reactivation from latency. Reactivation involves a coordinated gene expression cascade from immediate-early (IE) to early (E) and late phase (L) transcripts, eventually leading to assembly and release of infectious virus. In contrast, the "stochastic transcription hypothesis" proposes that viral genes become transiently de-silenced in latent viral genomes in a stochastic fashion, not following the canonical IE-E-L temporal cascade of reactivation. The reactivation hypothesis, however, is incompatible with the finding that productive virus reactivation is exceedingly rare in immunocompetent mice and observed only under conditions of compromised immunity. In addition, the reactivation hypothesis fails to explain why immune evasion genes, which are regularly expressed during reactivation in the same cells in which epitope-encoding genes are expressed, do not prevent antigen presentation and thus MI. Here we show that IE, E, and L genes are transcribed during latency, though stochastically, not following the IE-E-L temporal cascade. Importantly, transcripts that encode MI-driving antigenic peptides rarely coincide with those that encode immune evasion proteins. As immune evasion can operate only in cis, that is, in a cell that simultaneously expresses antigenic peptides, the stochastic transcription hypothesis explains why immune evasion is not operative in latently infected cells and, therefore, does not interfere with MI.

103. HLA-A*11:01:01:01, HLA-C*12:02:02:01-HLA-B*52:01:02:02, Age and Sex Are Associated With Severity of Japanese COVID-19 With Respiratory Failure.

Front Immunol

2021 Apr 22

Khor SS, Omae Y, Nishida N

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus causing coronavirus disease 2019 (COVID-19) was announced as an outbreak by the World Health Organization (WHO) in January 2020 and as a pandemic in March 2020. The majority of infected individuals have experienced no or only mild symptoms, ranging from fully asymptomatic cases to mild pneumonic disease. However, a minority of infected individuals develop severe respiratory symptoms. The objective of this study was to identify susceptible HLA alleles and clinical markers that can be used in risk prediction model for the early identification of severe COVID-19 among hospitalized COVID-19 patients. A total of 137 patients with mild COVID-19 (mCOVID-19) and 53 patients with severe COVID-19 (sCOVID-19) were recruited from the Center Hospital of the National Center for Global Health and Medicine (NCGM), Tokyo, Japan for the period of February-August 2020. High-resolution sequencing-based typing for eight HLA genes was performed using next-generation sequencing. In the HLA association studies, HLA-A*11:01:01:01 [Pc = 0.013, OR = 2.26 (1.27-3.91)] and HLA-C*12:02:02:01-HLA-B*52:01:01:02 [Pc = 0.020, OR = 2.25 (1.24-3.92)] were found to be significantly associated with the severity of COVID-19. After multivariate analysis controlling for other confounding factors and comorbidities, HLA-A*11:01:01:01 [P = 3.34E-03, OR = 3.41 (1.50-7.73)], age at diagnosis [P = 1.29E-02, OR = 1.04 (1.01-1.07)] and sex at birth [P = 8.88E-03, OR = 2.92 (1.31-6.54)] remained significant. The area under the curve of the risk prediction model utilizing HLA-A*11:01:01:01, age at diagnosis, and sex at birth was 0.772, with sensitivity of 0.715 and specificity of 0.717. To the best of our knowledge, this is the first article that describes associations of HLA alleles with COVID-19 at the 4-field (highest) resolution level. Early identification of potential sCOVID-19 could help clinicians prioritize medical utility and significantly decrease mortality from COVID-19.

104. Rhinovirus C Infection Induces Type 2 Innate Lymphoid Cell Expansion and Eosinophilic Airway Inflammation.

Front Immunol

2021 Apr 22

Rajput C, Han M, Ishikawa T

105. Association of CD40 Gene Polymorphisms With Systemic Lupus Erythematosus and Rheumatoid Arthritis in a Chinese Han Population.

Front Immunol

2021 Apr 22

Huang Q, Xu WD, Su LC

106. Bile Acids Elevated in Chronic Periaortitis Could Activate Farnesoid-X-Receptor to Suppress IL-6 Production by Macrophages.

Front Immunol

2021 Apr 22

Cao S, Meng X, Li Y

107. Investigation of Extracellular Vesicles From SARS-CoV-2 Infected Specimens: A Safety Perspective.

Front Immunol

2021 Apr 22

Nunez Lopez YO, Casu A, Pratley RE.

108. OCT Hyperreflective Retinal Foci in Diabetic Retinopathy: A Semi-Automatic Detection Comparative Study.

Front Immunol

2021 Apr 22

Midena E, Torresin T, Velotta E

Optical coherence tomography (OCT) allows us to identify, into retinal layers, new morphological entities, which can be considered clinical biomarkers of retinal diseases. According to the literature, solitary, small (<30 µm), medium level hyperreflective (similar to retinal fiber layer) retinal foci (HRF) may represent aggregates of activated microglial cells and an in vivo biomarker of retinal inflammation. The identification and quantification of this imaging biomarker allows for estimating the level and possibly the amount of intraretinal inflammation in major degenerative retinal disorders, whose inflammatory component has already been demonstrated (diabetic retinopathy, age-related macular degeneration, radiation retinopathy). Currently, diabetic retinopathy (DR) probably represents the best clinical model to apply this analysis in the definition of this clinical biomarker. However, the main limitation to the clinical use of HRF is related to the technical difficulty of counting them: a time-consuming methodology, which also needs trained examiners. To contribute to solve this limitation, we developed and validated a new method for the semi-automatic detection of HRF in OCT scans. OCT scans of patients affected by DR, were analyzed. HRF were manually counted in High Resolution spectral domain OCT images. Then, the same OCT scans underwent semi-automatic HRF counting, using an ImageJ software with four different settings profiles. Statistical analysis showed an excellent intraclass correlation coefficient (ICC) between the manual count and each of the four semi-automated methods. The use of the second setting profile allows to obtain at the Bland-Altman graph a bias of -0.2 foci and a limit of agreement of ±16.3 foci. This validation approach opens the way not only to the reliable and daily clinical applicable quantification of HRF, but also to a better knowledge of the inflammatory component-including its progression and regression changes-of diabetic retinopathy.

109. Editorial: Advances in Immunotherapeutic Approaches to Tuberculosis.

Front Immunol

2021 Apr 22

Estrada García I, Hernández Pando R, Ivanyi J.

Front Immunol

2021 Apr 22

Srinivasan J, Lancaster JN, Singarapu N

111. Partners in Leaky Gut Syndrome: Intestinal Dysbiosis and Autoimmunity.

Front Immunol

2021 Apr 22

Kinashi Y, Hase K.

112. BTLA Expression and Function Are Impaired on SLE B Cells.

Front Immunol

2021 Apr 22

Wiedemann A, Lettau M, Weißenberg SY

113. The Synergistic Effects of Polysaccharides and Ginsenosides From American Ginseng (Panax quinquefolius L.) Ameliorating Cyclophosphamide-Induced Intestinal Immune Disorders and Gut Barrier Dysfunctions Based on Microbiome-Metabolomics Analysis.

Front Immunol

2021 Apr 22

Zhou R, He D, Xie J

Cyclophosphamide (CTX), used in cancer chemotherapy, a high dose of which would cause immunosuppressive effect and intestinal mucosa damage. American ginseng (Panax quinquefolius L.) has a long history of functional food use for immunological disorder, colitis, cancer, and so on. This study aimed to illustrate the underlying mechanism of American ginseng's immunomodulatory effect in CTX-induced mice. In this study, all groups of American ginseng (American ginseng polysaccharide [AGP], American ginseng ginsenoside [AGG], co-treated with American ginseng polysaccharide and ginsenoside [AGP_AGG]) have relieve the immune disorder by reversing the lymphocyte subsets ratio in spleen and peripheral blood, as well as stimulating CD4+T cells and IgA-secreting cells in small intestine. These three treatment groups, especially AGP_AGG co-treated group recovered the intestine morphology that up-regulated villus height (VH)/crypt depth (CD) ratio, areas of mucins expression, quantity of goblet cells, and expression of tight junction proteins (ZO-1, occludin). Importantly, the microbiome-metabolomics analysis was applied in this study to illustrate the possible immuno-modulating mechanism. The synergistic effect of polysaccharides and ginsenosides (AGP_AGG group) restored the gut microbiota composition and increased various beneficial mucosa-associated bacterial taxa Clostridiales, Bifidobacterium, and Lachnospiraceae, while decreased harmful bacteria Escherichia-Shigella and Peptococcaceae. Also, AGP_AGG group altered various fecal metabolites such as uric acid, xanthurenic acid, acylcarnitine, 9,10-DHOME, 13-HDoHE, LysoPE15:0, LysoPC 16:0, LysoPI 18:0, and so on, that associated with immunometabolism or protective effect of gut barrier. These results suggest AG, particularly co-treated of polysaccharide and ginsenoside may be used as immunostimulants targeting microbiome-metabolomics axis to prevent CTX-induced side effects in cancer patients.

114. Perillaldehyde Inhibition of cGAS Reduces dsDNA-Induced Interferon Response.

Front Immunol

2021 Apr 22

Chu L, Li C, Li Y

115. Neutrophil Elastase Defects in Congenital Neutropenia.

Front Immunol

2021 Apr 22

Rydzynska Z, Pawlik B, Krzyzanowski D

116. Factors Predicting the Presence of Maternal Cells in Cord Blood and Associated Changes in Immune Cell Composition.

Front Immunol

2021 Apr 22

Haddad ME, Karlmark KR, Donato XC

117. Increased Serum Levels of Soluble TNF-α Receptor Is Associated With ICU Mortality in COVID-19 Patients.

Front Immunol

2021 Apr 22

Mortaz E, Tabarsi P, Jamaati H

118. Vaccine-Induced Immunological Memory in Invasive Fungal Infections - A Dream so Close yet so Far.

Front Immunol

2021 Apr 21

Biswas PS.

119. Tumor Mutation Burden and Immune Invasion Characteristics in Triple Negative Breast Cancer: Genome High-Throughput Data Analysis.

Front Immunol

2021 Apr 21

Gao C, Li H, Liu C

120. Current Challenges for IDO2 as Target in Cancer Immunotherapy.

Front Immunol

2021 Apr 21

Mondanelli G, Mandarano M, Belladonna ML

121. Genetic Background but Not Intestinal Microbiota After Co-Housing Determines Hyperoxaluria-Related Nephrocalcinosis in Common Inbred Mouse Strains.

Front Immunol

2021 Apr 21

Ma Q, Grigorescu M, Schreiber A

Calcium oxalate (CaOx) crystal formation, aggregation and growth is a common cause of kidney stone disease and nephrocalcinosis-related chronic kidney disease (CKD). Genetically modified mouse strains are frequently used as an experimental tool in this context but observed phenotypes may also relate to the genetic background or intestinal microbiota. We hypothesized that the genetic background or intestinal microbiota of mice determine CaOx crystal deposition and thus the outcome of nephrocalcinosis. Indeed, Casp1-/-, Cybb-/- or Casp1-/-/Cybb-/- knockout mice on a 129/C57BL/6J (B6J) background that were fed an oxalate-rich diet for 14 days did neither encounter intrarenal CaOx crystal deposits nor nephrocalcinosis-related CKD. To test our assumption, we fed C57BL/6N (B6N), 129, B6J and Balb/c mice an oxalate-rich diet for 14 days. Only B6N mice displayed CaOx crystal deposits and developed CKD associated with tubular injury, inflammation and interstitial fibrosis. Intrarenal mRNA expression profiling of 64 known nephrocalcinosis-related genes revealed that healthy B6N mice had lower mRNA levels of uromodulin (Umod) compared to the other three strains. Feeding an oxalate-rich diet caused an increase in uromodulin protein expression and CaOx crystal deposition in the kidney as well as in urinary uromodulin excretion in B6N mice but not 129, B6J and Balb/c mice. However, backcrossing 129 mice on a B6N background resulted in a gradual increase in CaOx crystal deposits from F2 to F7, of which all B6N/129 mice from the 7th generation developed CaOx-related nephropathy similar to B6N mice. Co-housing experiments tested for a putative role of the intestinal microbiota but B6N co-housed with 129 mice or B6N/129 (3rd and 6th generation) mice did not affect nephrocalcinosis. In summary, genetic background but not the intestinal microbiome account for strain-specific crystal formation and, the levels of uromodulin secretion may contribute to this phenomenon. Our results imply that only littermate controls of the identical genetic background strain are appropriate when performing knockout mouse studies in this context, while co-housing is optional.

122. Case Report: Leishmania and HIV Co-Diagnosis: How to Understand Medical History?

Front Immunol

2021 Apr 21

Dujardin A, de La Blanchardière A, Dina J

123. Metformin Modulates T Cell Function and Alleviates Liver Injury Through Bioenergetic Regulation in Viral Hepatitis.

Front Immunol

2021 Apr 21

Xu L, Wang X, Chen Y

124. Tetraspanins as Potential Therapeutic Candidates for Targeting Flaviviruses.

Front Immunol

2021 Apr 21

Ahmed W, Neelakanta G, Sultana H.

125. The Immunoproteasome Subunits LMP2, LMP7 and MECL-1 Are Crucial Along the Induction of Cerebral Toxoplasmosis.

Front Immunol

2021 Apr 21

French T, Israel N, Düsedau HP

126. The Role of CD4(+) Resident Memory T Cells in Local Immunity in the Mucosal Tissue - Protection Versus Pathology.

Front Immunol

2021 Apr 21

Hirahara K, Kokubo K, Aoki A

127. Fish Oil Improves Pathway-Oriented Profiling of Lipid Mediators for Maintaining Metabolic Homeostasis in Adipose Tissue of Prediabetic Rats.

Front Immunol

2021 Apr 21

Dasilva G, Lois S, Méndez L

Adipose tissue is now recognized as an active organ with an important homeostatic function in glucose and lipid metabolism and the development of insulin resistance. The present research investigates the role of lipid mediators and lipid profiling for controlling inflammation and the metabolic normal function of white adipose tissue from rats suffering from diet-induced prediabetes. Additionally, the contribution to the adipose lipidome induced by the consumption of marine ω-3 PUFAs as potential regulators of inflammation is addressed. For that, the effects on the inflammatory response triggered by high-fat high-sucrose (HFHS) diets were studied in male Sprague-Dawley rats. Using SPE-LC-MS/MS-based metabolo-lipidomics, a range of eicosanoids, docosanoids and specialized pro-resolving mediators (SPMs) were measured in white adipose tissue. The inflammatory response occurring in prediabetic adipose tissue was associated with the decomposition of ARA epoxides to ARA-dihydroxides, the reduction of oxo-derivatives and the formation of prostaglandins (PGs). In an attempt to control the inflammatory response initiated, LOX and non-enzymatic oxidation shifted toward the production of the less pro-inflammatory EPA and DHA metabolites rather than the high pro-inflammatory ARA hydroxides. Additionally, the change in LOX activity induced the production of intermediate hydroxides precursors of SPMs as protectins (PDs), resolvins (Rvs) and maresins (MaRs). This compensatory mechanism to achieve the restoration of tissue homeostasis was significantly strengthened through supplementation with fish oils. Increasing proportions of ω-3 PUFAs in adipose tissue significantly stimulated the formation of DHA-epoxides by cytochrome P450, the production of non-enzymatic EPA-metabolites and prompted the activity of 12LOX. Finally, protectin PDX was significantly reduced in the adipose tissue of prediabetic rats and highly enhanced through ω-3 PUFAs supplementation. Taken together, these actively coordinated modifications constitute key mechanisms to restore adipose tissue homeostasis with an important role of lipid mediators. This compensatory mechanism is reinforced through the supplementation of the diet with fish oils with high and balanced contents of EPA and DHA. The study highlights new insides on the targets for effective treatment of incipient diet-induced diabetes and the mechanism underlying the potential anti-inflammatory action of marine lipids.

128. Corrigendum: IL-7 During Antigenic Stimulation Using Allogeneic Dendritic Cells Promotes Expansion of CD45RA(-)CD62L(+)CD4(+) Invariant NKT Cells With Th-2 Biased Cytokine Production Profile.

Front Immunol

2021 Apr 20

Trujillo-Ocampo A, Cho HW, Pareek S

129. Intravacuolar Pathogens Hijack Host Extracellular Vesicle Biogenesis to Secrete Virulence Factors.

Front Immunol

2021 Apr 20

Gioseffi A, Edelmann MJ, Kima PE.

130. Cellular Responses to the Efferocytosis of Apoptotic Cells.

Front Immunol

2021 Apr 20

Yin C, Heit B.

131. Gene Expression Classifier Reveals Prognostic Osteosarcoma Microenvironment Molecular Subtypes.

Front Immunol

2021 Apr 20

Song YJ, Xu Y, Deng C

132. Fit-For-All iPSC-Derived Cell Therapies and Their Evaluation in Humanized Mice With NK Cell Immunity.

Front Immunol

2021 Apr 2

Flahou C, Morishima T, Takizawa H

Human induced pluripotent stem cells (iPSCs) can be limitlessly expanded and differentiated into almost all cell types. Moreover, they are amenable to gene manipulation and, because they are established from somatic cells, can be established from essentially any person. Based on these characteristics, iPSCs have been extensively studied as cell sources for tissue grafts, blood transfusions and cancer immunotherapies, and related clinical trials have started. From an immune-matching perspective, autologous iPSCs are perfectly compatible in principle, but also require a prolonged time for reaching the final products, have high cost, and person-to-person variation hindering their common use. Therefore, certified iPSCs with reduced immunogenicity are expected to become off-the-shelf sources, such as those made from human leukocyte antigen (HLA)-homozygous individuals or genetically modified for HLA depletion. Preclinical tests using immunodeficient mice reconstituted with a human immune system (HIS) serve as an important tool to assess the human alloresponse against iPSC-derived cells. Especially, HIS mice reconstituted with not only human T cells but also human natural killer (NK) cells are considered crucial. NK cells attack so-called "missing self" cells that do not express self HLA class I, which include HLA-homozygous cells that express only one allele type and HLA-depleted cells. However, conventional HIS mice lack enough reconstituted human NK cells for these tests. Several measures have been developed to overcome this issue including the administration of cytokines that enhance NK cell expansion, such as IL-2 and IL-15, the administration of vectors that express those cytokines, and genetic manipulation to express the cytokines or to enhance the reconstitution of human myeloid cells that express IL15R-alpha. Using such HIS mice with enhanced human NK cell reconstitution, alloresponses against HLA-homozygous and HLA-depleted cells have been studied. However, most studies used HLA-downregulated tumor cells as the target cells and tested in vitro after purifying human cells from HIS mice. In this review, we give an overview of the current state of iPSCs in cell therapies, strategies to lessen their immunogenic potential, and then expound on the development of HIS mice with reconstituted NK cells, followed by their utilization in evaluating future universal HLA-engineered iPSC-derived cells.

133. Metabolic Control of Autoimmunity and Tissue Inflammation in Rheumatoid Arthritis.

Front Immunol

2021 Apr 2

Qiu J, Wu B, Goodman SB

Like other autoimmune diseases, rheumatoid arthritis (RA) develops in distinct stages, with each phase of disease linked to immune cell dysfunction. HLA class II genes confer the strongest genetic risk to develop RA. They encode for molecules essential in the activation and differentiation of T cells, placing T cells upstream in the immunopathology. In Phase 1 of the RA disease process, T cells lose a fundamental function, their ability to be self-tolerant, and provide help for autoantibody-producing B cells. Phase 2 begins many years later, when mis-differentiated T cells gain tissue-invasive effector functions, enter the joint, promote non-resolving inflammation, and give rise to clinically relevant arthritis. In Phase 3 of the RA disease process, abnormal innate immune functions are added to adaptive autoimmunity, converting synovial inflammation into a tissue-destructive process that erodes cartilage and bone. Emerging data have implicated metabolic mis-regulation as a fundamental pathogenic pathway in all phases of RA. Early in their life cycle, RA T cells fail to repair mitochondrial DNA, resulting in a malfunctioning metabolic machinery. Mitochondrial insufficiency is aggravated by the mis-trafficking of the energy sensor AMPK away from the lysosomal surface. The metabolic signature of RA T cells is characterized by the shunting of glucose toward the pentose phosphate pathway and toward biosynthetic activity. During the intermediate and terminal phase of RA-imposed tissue inflammation, tissue-residing macrophages, T cells, B cells and stromal cells are chronically activated and under high metabolic stress, creating a microenvironment poor in oxygen and glucose, but rich in metabolic intermediates, such as lactate. By sensing tissue lactate, synovial T cells lose their mobility and are trapped in the tissue niche. The linkage of defective DNA repair, misbalanced metabolic pathways, autoimmunity, and tissue inflammation in RA encourages metabolic interference as a novel treatment strategy during both the early stages of tolerance breakdown and the late stages of tissue inflammation. Defining and targeting metabolic abnormalities provides a new paradigm to treat, or even prevent, the cellular defects underlying autoimmune disease.

134. Evaluation of the Immunogenic Response of a Novel Enterobactin Conjugate Vaccine in Chickens for the Production of Enterobactin-Specific Egg Yolk Antibodies.

Front Immunol

2021 Apr 2

Zeng X, Wang H, Huang C

Passive immunization with specific egg yolk antibodies (immunoglobulin Y, IgY) is emerging as a promising alternative to antibiotics to control bacterial infections. Recently, we developed a novel conjugate vaccine that could trigger a strong immune response in rabbits directed against enterobactin (Ent), a highly conserved siderophore molecule utilized by different Gram-negative pathogens. However, induction of Ent-specific antibodies appeared to be affected by the choice of animal host and vaccination regimen. It is still unknown if the Ent conjugate vaccine can trigger a specific immune response in layers for the purpose of production of anti-Ent egg yolk IgY. In this study, three chicken vaccination trials with different regimens were performed to determine conditions for efficient production of anti-Ent egg yolk IgY. Purified Ent was conjugated to three carrier proteins, keyhole limpet hemocyanin (KLH), bovine serum albumin (BSA) and CmeC (a subunit vaccine candidate), respectively. Intramuscular immunization of Barred Rock layers with KLH-Ent conjugate four times induced strong immune response against whole conjugate vaccine but the titer of Ent-specific IgY did not change in yolk with only a 4 fold increase detected in serum. In the second trial, three different Ent conjugate vaccines were evaluated in Rhode Island Red pullets with four subcutaneous injections. The KLH-Ent or CmeC-Ent conjugate consistently induced high level of Ent-specific IgY in both serum (up to 2,048 fold) and yolk (up to 1,024 fold) in each individual chicken. However, the Ent-specific immune response was only temporarily and moderately induced using a BSA-Ent vaccination. In the third trial, ten White Leghorn layers were subcutaneously immunized three times with KLH-Ent, leading to consistent and strong immune response against both whole conjugate and the Ent molecule in each chicken; the mean titer of Ent-specific IgY increased approximately 32 and 256 fold in serum and yolk, respectively. Consistent with its potent binding to various Ent derivatives, the Ent-specific egg yolk IgY also inhibited in vitro growth of a representative Escherichia coli strain. Together, this study demonstrated that the novel Ent conjugate vaccine could induce strong, specific, and robust immune response in chickens. The Ent-specific hyperimmune egg yolk IgY has potential for passive immune intervention against Gram-negative infections.

135. Cells of the Immune System in Cardiac Remodeling: Main Players in Resolution of Inflammation and Repair After Myocardial Infarction.

Front Immunol

2021 Apr 2

Kologrivova I, Shtatolkina M, Suslova T

136. Macrophages in Chronic Liver Failure: Diversity, Plasticity and Therapeutic Targeting.

Front Immunol

2021 Apr 2

Singanayagam A, Triantafyllou E.

137. Posttranslational and Therapeutic Control of Gasdermin-Mediated Pyroptosis and Inflammation.

Front Immunol

2021 Apr 2

Fischer FA, Chen KW, Bezbradica JS.

138. Oxidative Stress-Mediated YAP Dysregulation Contributes to the Pathogenesis of Pemphigus Vulgaris.

Front Immunol

2021 Apr 19

Huang Y, Jedličková H, Cai Y

Pemphigus Vulgaris (PV) is a life-threatening autoimmune disease manifested with blisters in the skin and mucosa and caused by autoantibodies against adhesion protein desmoglein-3 (Dsg3) expressed in epithelial membrane linings of these tissues. Despite many studies, the pathogenesis of PV remains incompletely understood. Recently we have shown Dsg3 plays a role in regulating the yes-associated protein (YAP), a co-transcription factor and mechanical sensor, and constraining reactive oxygen species (ROS). This study investigated the effect of PV sera as well as the anti-Dsg3 antibody AK23 on these molecules. We detected elevated YAP steady-state protein levels in PV cells surrounding blisters and perilesional regions and in keratinocytes treated with PV sera and AK23 with concomitant transient ROS overproduction. Cells treated with hydrogen peroxide also exhibited augmented nuclear YAP accompanied by reduction of Dsg3 and α-catenin, a negative regulator of YAP. As expected, transfection of α-catenin-GFP plasmid rendered YAP export from the nucleus evoked by hydrogen peroxide. In addition, suppression of total YAP was observed in hydrogen peroxide treated cells exposed to antioxidants with enhanced cell-cell adhesion being confirmed by decreased fragmentation in the dispase assay compared to hydrogen peroxide treatment alone. On the other hand, the expression of exogenous YAP disrupted intercellular junction assembly. In contrast, YAP depletion resulted in an inverse effect with augmented expression of junction assembly proteins, including Dsg3 and α-catenin capable of abolishing the effect of AK23 on Dsg3 expression. Finally, inhibition of other kinase pathways, including p38MAPK, also demonstrated suppression of YAP induced by hydrogen peroxide. Furthermore, antioxidant treatment of keratinocytes suppressed PV sera-induced total YAP accumulation. In conclusion, this study suggests that oxidative stress coupled with YAP dysregulation attributes to PV blistering, implying antioxidants may be beneficial in the treatment of PV.

139. Role of ILC2 in Viral-Induced Lung Pathogenesis.

Front Immunol

2021 Apr 19

Fonseca W, Lukacs NW, Elesela S

140. Targeting Enclysis in Liver Autoimmunity, Transplantation, Viral Infection and Cancer.

Front Immunol

2021 Apr 19

Aghabi YO, Yasin A, Kennedy JI

141. The Architecture of Circulating Immune Cells Is Dysregulated in People Living With HIV on Long Term Antiretroviral Treatment and Relates With Markers of the HIV-1 Reservoir, Cytomegalovirus, and Microbial Translocation.

Front Immunol

2021 Apr 19

Van de Wijer L, van der Heijden WA, Ter Horst R

142. Modular Organization of Engulfment Receptors and Proximal Signaling Networks: Avenues to Reprogram Phagocytosis.

Front Immunol

2021 Apr 19

Britt EA, Gitau V, Saha A

143. Host-Directed Therapies: Modulating Inflammation to Treat Tuberculosis.

Front Immunol

2021 Apr 19

Krug S, Parveen S, Bishai WR.

144. LUBAC Suppresses IL-21-Induced Apoptosis in CD40-Activated Murine B Cells and Promotes Germinal Center B Cell Survival and the T-Dependent Antibody Response.

Front Immunol

2021 Apr 19

Wang J, Li T, Zan H

145. Schistosomes in the Lung: Immunobiology and Opportunity.

Front Immunol

2021 Apr 19

Houlder EL, Costain AH, Cook PC

146. Tregitopes Improve Asthma by Promoting Highly Suppressive and Antigen-Specific Tregs.

Front Immunol

2021 Apr 19

Dembele M, Tao S, Massoud AH

Tregitopes (T regulatory epitopes) are IgG-derived peptides with high affinity to major histocompatibility complex class II (MHCII), that are known to promote tolerance by activating T regulatory cell (Treg) activity. Here we characterized the effect of IgG Tregitopes in a well-established murine model of allergic asthma, demonstrating in vivo antigen-specific tolerance via adoptive transfer of Tregitope-and-allergen-activated Tregs. Asthma is a heterogeneous chronic inflammatory condition affecting the airways and impacting over 300 million individuals worldwide. Treatment is suppressive, and no current therapy addresses immune regulation in severely affected asthmatics. Although high dose intra-venous immunoglobulin (IVIg) is not commonly used in the asthma clinic setting, it has been shown to improve severe asthma in children and in adults. In our laboratory, we previously demonstrated that IVIg abrogates airway hyperresponsiveness (AHR) in a murine model of asthma and induces suppressive antigen-specific T-regulatory cells. We hypothesized that IgG-derived Tregitopes would modulate allergic airway disease by inducing highly suppressive antigen-specific Tregs capable of diminishing T effector cell responses and establishing antigen-specific tolerance. Using ovalbumin (OVA-) and ragweed-driven murine models of allergic airway disease, we characterized the immunoregulatory properties of Tregitopes and performed Treg adoptive transfer to OVA- and ragweed-allergic mice to test for allergen specificity. Treatment with Tregitopes attenuated allergen-induced airway hyperresponsiveness and lung inflammation. We demonstrated that Tregitopes induce highly suppressive allergen-specific Tregs. The tolerogenic action of IgG Tregitopes in our model is very similar to that of IVIg, so we foresee that IgG Tregitopes could potentially replace steroid-based treatment and can offer a synthetic alternative to IVIg in a range of inflammatory and allergic conditions.

147. Co-Isolation of Cytokines and Exosomes: Implications for Immunomodulation Studies.

Front Immunol

2021 Apr 19

Benjamin-Davalos S, Koroleva M, Allen CL

148. Cytotoxic Lymphocytes Target HIV-1 Gag Through Granzyme M-Mediated Cleavage.

Front Immunol

2021 Apr 19

Saccon E, Mikaeloff F, Figueras Ivern P

149. Innate Immune Modulation Induced by EBV Lytic Infection Promotes Endothelial Cell Inflammation and Vascular Injury in Scleroderma.

Front Immunol

2021 Apr 19

Farina A, Rosato E, York M

150. pH-Controlled Release of Antigens Using Mesoporous Silica Nanoparticles Delivery System for Developing a Fish Oral Vaccine.

Front Immunol

2021 Apr 19

Zhang W, Zhu C, Xiao F

151. Therapeutic Approaches Targeting the Natural Killer-Myeloid Cell Axis in the Tumor Microenvironment.

Front Immunol

2021 Apr 19

Carnevalli LS, Ghadially H, Barry ST.

152. A Comparison Between Recombinant Listeria GAPDH Proteins and GAPDH Encoding mRNA Conjugated to Lipids as Cross-Reactive Vaccines for Listeria, Mycobacterium, and Streptococcus.

Front Immunol

2021 Apr 19

Teran-Navarro H, Salcines-Cuevas D, Calderon-Gonzalez R

Cross-reactive vaccines recognize common molecular patterns in pathogens and are able to confer broad spectrum protection against different infections. Antigens common to pathogenic bacteria that induce broad immune responses, such as the glyceraldehyde-3-phosphate dehydrogenase (GAPDH) of the genera Listeria, Mycobacterium, or Streptococcus, whose sequences present more than 95% homology at the N-terminal GAPDH1-22 peptide, are putative candidates for universal vaccines. Here, we explore vaccine formulations based on dendritic cells (DC) loaded with two molecular forms of Listeria monocytogenes GAPDH (LM-GAPDH), such as mRNA carriers or recombinant proteins, and compare them with the same molecular forms of three other antigens used in experimental vaccines, listeriolysin O of Listeria monocytogeness, Ag85A of Mycobacterium marinum, and pneumolysin of Streptococcus pneumoniae. DC loaded with LM-GAPDH recombinant proteins proved to be the safest and most immunogenic vaccine vectors, followed by mRNA encoding LM-GAPDH conjugated to lipid carriers. In addition, macrophages lacked sufficient safety as vaccines for all LM-GAPDH molecular forms. The ability of DC loaded with LM-GAPDH recombinant proteins to induce non-specific DC activation explains their adjuvant potency and their capacity to trigger strong CD4+ and CD8+ T cell responses explains their high immunogenicity. Moreover, their capacity to confer protection in vaccinated mice against challenges with L. monocytogenes, M. marinum, or S. pneumoniae validated their efficiency as cross-reactive vaccines. Cross-protection appears to involve the induction of high percentages of GAPDH1-22 specific CD4+ and CD8+ T cells stained for intracellular IFN-γ, and significant levels of peptide-specific antibodies in vaccinated mice. We concluded that DC vaccines loaded with L. monocytogenes GAPDH recombinant proteins are cross-reactive vaccines that seem to be valuable tools in adult vaccination against Listeria, Mycobacterium, and Streptococcus taxonomic groups.

153. Glycolytic Metabolism Is Critical for the Innate Antibacterial Defense in Acute Streptococcus pneumoniae Otitis Media.

Front Immunol

2021 Apr 19

Fan F, Ma Y, Ai R

154. Lung Marginated and Splenic Murine Resident Neutrophils Constitute Pioneers in Tissue-Defense During Systemic E. coli Challenge.

Front Immunol

2021 Apr 19

Juzenaite G, Secklehner J, Vuononvirta J

155. Metformin Attenuates ROS via FOXO3 Activation in Immune Cells.

Front Immunol

2021 Apr 19

Hartwig J, Loebel M, Steiner S

156. The Predictive Value of Monocytes in Immune Microenvironment and Prognosis of Glioma Patients Based on Machine Learning.

Front Immunol

2021 Apr 16

Zhang N, Dai Z, Wu W

157. Case Report: Hypomorphic Function and Somatic Reversion in DOCK8 Deficiency in One Patient With Two Novel Variants and Sclerosing Cholangitis.

Front Immunol

2021 Apr 16

Saettini F, Fazio G, Moratto D

158. Case Report: Complete and Fast Recovery From Severe COVID-19 in a Pemphigus Patient Treated With Rituximab.

Front Immunol

2021 Apr 16

Sinagra JL, Vedovelli C, Binazzi R

159. AhR Ligands Modulate the Differentiation of Innate Lymphoid Cells and T Helper Cell Subsets That Control the Severity of a Pulmonary Fungal Infection.

Front Immunol

2021 Apr 16

de Araújo EF, Loures FV, Preite NW

In agreement with other fungal infections, immunoprotection in pulmonary paracoccidioidomycosis (PCM) is mediated by Th1/Th17 cells whereas disease progression by prevalent Th2/Th9 immunity. Treg cells play a dual role, suppressing immunity but also controlling excessive tissue inflammation. Our recent studies have demonstrated that the enzyme indoleamine 2,3 dioxygenase (IDO) and the transcription factor aryl hydrocarbon receptor (AhR) play an important role in the immunoregulation of PCM. To further evaluate the immunomodulatory activity of AhR in this fungal infection, Paracoccidioides brasiliensis infected mice were treated with two different AhR agonists, L-Kynurenin (L-Kyn) or 6-formylindole [3,2-b] carbazole (FICZ), and one AhR specific antagonist (CH223191). The disease severity and immune response of treated and untreated mice were assessed 96 hours and 2 weeks after infection. Some similar effects on host response were shared by FICZ and L-Kyn, such as the reduced fungal loads, decreased numbers of CD11c+ lung myeloid cells expressing activation markers (IA, CD40, CD80, CD86), and early increased expression of IDO and AhR. In contrast, the AhR antagonist CH223191 induced increased fungal loads, increased number of pulmonary CD11c+ leukocytes expressing activation markers, and a reduction in AhR and IDO production. While FICZ treatment promoted large increases in ILC3, L-Kyn and CH223191 significantly reduced this cell population. Each of these AhR ligands induced a characteristic adaptive immunity. The large expansion of FICZ-induced myeloid, lymphoid, and plasmacytoid dendritic cells (DCs) led to the increased expansion of all CD4+ T cell subpopulations (Th1, Th2, Th17, Th22, and Treg), but with a clear predominance of Th17 and Th22 subsets. On the other hand, L-Kyn, that preferentially activated plasmacytoid DCs, reduced Th1/Th22 development but caused a robust expansion of Treg cells. The AhR antagonist CH223191 induced a preferential expansion of myeloid DCs, reduced the number of Th1, Th22, and Treg cells, but increased Th17 differentiation. In conclusion, the present study showed that the pathogen loads and the immune response in pulmonary PCM can be modulated by AhR ligands. However, further studies are needed to define the possible use of these compounds as adjuvant therapy for this fungal infection.

160. Establishing a Risk Prediction Model for Atherosclerosis in Systemic Lupus Erythematosus.

Front Immunol

2021 Apr 16

Xing H, Pang H, Du T

Background and aims: Patients with systemic lupus erythematosus (SLE) have a significantly higher incidence of atherosclerosis than the general population. Studies on atherosclerosis prediction models specific for SLE patients are very limited. This study aimed to build a risk prediction model for atherosclerosis in SLE. Methods: RNA sequencing was performed on 67 SLE patients. Subsequently, differential expression analysis was carried out on 19 pairs of age-matched SLE patients with (AT group) or without (Non-AT group) atherosclerosis using peripheral venous blood. We used logistic least absolute shrinkage and selection operator regression to select variables among differentially expressed (DE) genes and clinical features and utilized backward stepwise logistic regression to build an atherosclerosis risk prediction model with all 67 patients. The performance of the prediction model was evaluated by area under the curve (AUC), calibration curve, and decision curve analyses. Results: The 67 patients had a median age of 42.7 (Q1-Q3: 36.6-51.2) years, and 20 (29.9%) had atherosclerosis. A total of 106 DE genes were identified between the age-matched AT and Non-AT groups. Pathway analyses revealed that the AT group had upregulated atherosclerosis signaling, oxidative phosphorylation, and interleukin (IL)-17-related pathways but downregulated T cell and B cell receptor signaling. Keratin 10, age, and hyperlipidemia were selected as variables for the risk prediction model. The AUC and Hosmer-Lemeshow test p-value of the model were 0.922 and 0.666, respectively, suggesting a relatively high discrimination and calibration performance. The prediction model had a higher net benefit in the decision curve analysis than that when predicting with age or hyperlipidemia only. Conclusions: We built an atherosclerotic risk prediction model with one gene and two clinical factors. This model may greatly assist clinicians to identify SLE patients with atherosclerosis, especially asymptomatic atherosclerosis.

161. PRAK Promotes the Pathogen Clearance by Macrophage Through Regulating Autophagy and Inflammasome Activation.

Front Immunol

2021 Apr 16

Mi L, Wang Y, Xu H

162. IDO1 Expression in Ovarian Cancer Induces PD-1 in T Cells via Aryl Hydrocarbon Receptor Activation.

Front Immunol

2021 Apr 16

Amobi-McCloud A, Muthuswamy R, Battaglia S

163. Role of Circulating T Follicular Helper Cells and Stem-Like Memory CD4(+) T Cells in the Pathogenesis of HIV-2 Infection and Disease Progression.

Front Immunol

2021 Apr 16

Ponnan SM, Vidyavijayan KK, Thiruvengadam K

CD4+ T cells are critical players in the host adaptive immune response. Emerging evidence suggests that certain CD4+ T cell subsets contribute significantly to the production of neutralizing antibodies and help in the control of virus replication. Circulating T follicular helper cells (Tfh) constitute a key T cell subset that triggers the adaptive immune response and stimulates the production of neutralizing antibodies (NAbs). T cells having stem cell-like property, called stem-like memory T cells (Tscm), constitute another important subset of T cells that play a critical role in slowing the rate of disease progression through the differentiation and expansion of different types of memory cell subsets. However, the role of these immune cell subsets in T cell homeostasis, CD4+ T cell proliferation, and progression of disease, particularly in HIV-2 infection, has not yet been elucidated. The present study involved a detailed evaluation of the different CD4+ T cell subsets in HIV-2 infected persons with a view to understanding the role of these immune cell subsets in the better control of virus replication and delayed disease progression that is characteristic of HIV-2 infection. We observed elevated levels of CD4+ Tfh and CD4+ Tscm cells along with memory and effector T cell abundance in HIV-2 infected individuals. We also found increased frequencies of CXCR5+ CD8+ T cells and CD8+ Tscm cells, as well as memory B cells that are responsible for NAb development in HIV-2 infected persons. Interestingly, we found that the frequency of memory CD4+ T cells as well as memory B cells correlated significantly with neutralizing antibody titers in HIV-2 infected persons. These observations point to a more robust CD4+ T cell response that supports B cell differentiation, antibody production, and CD8+ T cell development in HIV-2 infected persons and contributes to better control of the virus and slower rate of disease progression in these individuals.

164. High Dimensional Imaging Mass Cytometry Panel to Visualize the Tumor Immune Microenvironment Contexture.

Front Immunol

2021 Apr 16

Elaldi R, Hemon P, Petti L

165. Airway Telomere Length in Lung Transplant Recipients.

Front Immunol

2021 Apr 16

Mackintosh JA, Yerkovich ST, Tan ME

INTRODUCTION: Chronic lung allograft dysfunction (CLAD) represents the major impediment to long term survival following lung transplantation. Donor and recipient telomere length have been shown to associate with lung transplant outcomes, including CLAD. In this study we aimed to measure the telomere lengths of bronchial and bronchiolar airway cells in lung allografts early after transplantation and to investigate associations with CLAD and all-cause mortality. METHODS: This prospective, longitudinal study was performed at The Prince Charles Hospital, Australia. Airway cells were collected via bronchial and bronchiolar airway brushings at post-transplant bronchoscopies. The relative telomere length in airway cells was determined by quantitative PCR based on the T/S ratio. All patients were censored for CLAD and all-cause mortality in August 2020. RESULTS: In total 231 bronchoscopies incorporating transbronchial brush and bronchial brush were performed in 120 patients. At the time of censoring, 43% and 35% of patients, respectively, had developed CLAD and had died. Airway bronchiolar and bronchial telomere lengths were strongly correlated (r=0.78, p<0.001), confirming conservation of telomere length with airway branch generation. Both the bronchiolar (r = -0.34, p<0.001) and bronchial (r = -0.31, p<0.001) telomere length decreased with age. Shorter airway telomere length was associated with older donor age and higher donor pack-year smoking history. Neither the bronchiolar nor the bronchial airway telomere length were associated with the development of CLAD (HR 0.39 (0.06-2.3), p=0.30; HR 0.66 (0.2-1.7), p=0.39, respectively) or all-cause mortality (HR 0.92 (0.2-4.5), p=0.92; HR 0.47 (0.1-1.9), p=0.28, respectively). CONCLUSIONS: In this cohort, airway telomere length was associated with donor age and smoking history but was not associated with the future development of CLAD or all-cause mortality.

166. Genome-Wide Gene Expression Analysis of Mtb-Infected DC Highlights the Rapamycin-Driven Modulation of Regulatory Cytokines via the mTOR/GSK-3β Axis.

Front Immunol

2021 Apr 16

Etna MP, Severa M, Licursi V

167. Diagnostic and Predictive Value of Immune-Related Genes in Crohn's Disease.

Front Immunol

2021 Apr 16

Yu B, Yin YX, Tang YP

168. Case Report: Splenic Irradiation for the Treatment of Chronic Active Antibody-Mediated Rejection in Kidney Allograft Recipients With De Novo Donor-Specific Antibodies.

Front Immunol

2021 Apr 15

Zhu L, Guo Z, Sa R

169. Cholinergic System and Its Therapeutic Importance in Inflammation and Autoimmunity.

Front Immunol

2021 Apr 15

Halder N, Lal G.

170. C5a-C5aR1 Axis Activation Drives Envenomation Immunopathology by the Snake Naja annulifera.

Front Immunol

2021 Apr 15

Silva de França F, Villas-Boas IM, Cogliati B

171. Circulating Interleukins and Risk of Multiple Sclerosis: A Mendelian Randomization Study.

Front Immunol

2021 Apr 15

Lu H, Wu PF, Zhang W

172. Immune Polarization Potential of the S. aureus Virulence Factors SplB and GlpQ and Modulation by Adjuvants.

Front Immunol

2021 Apr 15

Mrochen DM, Trübe P, Jorde I

173. Mesenchymal Stromal Cell-Derived Extracellular Vesicles Restore Thymic Architecture and T Cell Function Disrupted by Neonatal Hyperoxia.

Front Immunol

2021 Apr 15

Reis M, Willis GR, Fernandez-Gonzalez A

174. Identification of a Sensitive Human Immunological Target of Aryl Hydrocarbon Receptor Activation: CD5(+) Innate-Like B Cells.

Front Immunol

2021 Apr 15

Blevins LK, Zhou J, Crawford RB

175. Variant to Gene Mapping to Discover New Targets for Immune Tolerance.

Front Immunol

2021 Apr 15

Mehra P, Wells AD.

176. Impact of Treatment Regimens on Antibody Response to the SARS-CoV-2 Coronavirus.

Front Immunol

2021 Apr 15

Shang Y, Liu T, Li J

177. PD-L1 Improves Motor Function and Alleviates Neuropathic Pain in Male Mice After Spinal Cord Injury by Inhibiting MAPK Pathway.

Front Immunol

2021 Apr 15

Kong F, Sun K, Zhu J

178. Chlamydia trachomatis Infection Impairs MHC-I Intracellular Trafficking and Antigen Cross-Presentation by Dendritic Cells.

Front Immunol

2021 Apr 15

Del Balzo D, Capmany A, Cebrian I

179. The Key Role of NAD(+) in Anti-Tumor Immune Response: An Update.

Front Immunol

2021 Apr 15

Morandi F, Horenstein AL, Malavasi F.

180. Potential Mimicry of Viral and Pancreatic β Cell Antigens Through Non-Spliced and cis-Spliced Zwitter Epitope Candidates in Type 1 Diabetes.

Front Immunol

2021 Apr 15

Mishto M, Mansurkhodzhaev A, Rodriguez-Calvo T

Increasing evidence suggests that post-translational peptide splicing can play a role in the immune response under pathological conditions. This seems to be particularly relevant in Type 1 Diabetes (T1D) since post-translationally spliced epitopes derived from T1D-associated antigens have been identified among those peptides bound to Human Leucocyte Antigen (HLA) class I and II complexes. Their immunogenicity has been confirmed through CD4+ and CD8+ T cell-mediated responses in T1D patients. Spliced peptides theoretically have a large sequence variability. This might increase the frequency of viral-human zwitter peptides, i.e. peptides that share a complete sequence homology irrespective of whether they originate from human or viral antigens, thereby impinging upon the discrimination between self and non-self antigens by T cells. This might increase the risk of autoimmune responses triggered by viral infections. Since enteroviruses and other viral infections have historically been associated with T1D, we investigated whether cis-spliced peptides derived from selected viruses might be able to trigger CD8+ T cell-mediated autoimmunity. We computed in silico viral-human non-spliced and cis-spliced zwitter epitope candidates, and prioritized peptide candidates based on: (i) their binding affinity to HLA class I complexes, (ii) human pancreatic β cell and medullary thymic epithelial cell (mTEC) antigens' mRNA expression, (iii) antigen association with T1D, and (iv) potential hotspot regions in those antigens. Neglecting potential T cell receptor (TCR) degeneracy, no viral-human zwitter non-spliced peptide was found to be an optimal candidate to trigger a virus-induced CD8+ T cell response against human pancreatic β cells. Conversely, we identified some zwitter peptide candidates, which may be produced by proteasome-catalyzed peptide splicing, and might increase the likelihood of pancreatic β cells recognition by virus-specific CD8+ T cell clones, therefore promoting β cell destruction in the context of viral infections.

181. Interleukin-33-Dependent Accumulation of Regulatory T Cells Mediates Pulmonary Epithelial Regeneration During Acute Respiratory Distress Syndrome.

Front Immunol

2021 Apr 15

Tan W, Zhang B, Liu X

182. IFNγ, and to a Lesser Extent TNFα, Provokes a Sustained Endothelial Costimulatory Phenotype.

Front Immunol

2021 Apr 15

Valenzuela NM.

BACKGROUND: Vascular endothelial cells (EC) are critical for regulation of local immune responses, through coordination of leukocyte recruitment from the blood and egress into the tissue. Growing evidence supports an additional role for endothelium in activation and costimulation of adaptive immune cells. However, this function remains somewhat controversial, and the full repertoire and durability of an enhanced endothelial costimulatory phenotype has not been wholly defined. METHODS: Human endothelium was stimulated with continuous TNFα or IFNγ for 1-48hr; or primed with TNFα or IFNγ for only 3hr, before withdrawal of stimulus for up to 45hr. Gene expression of cytokines, costimulatory molecules and antigen presentation molecules was measured by Nanostring, and publicly available datasets of EC stimulation with TNFα or IFNγ were leveraged to further corroborate the results. Cell surface protein expression was detected by flow cytometry, and secretion of cytokines was assessed by Luminex and ELISA. Key findings were confirmed in primary human endothelial cells from 4-6 different vascular beds. RESULTS: TNFα triggered mostly positive immune checkpoint molecule expression on endothelium, including CD40, 4-1BB, and ICOSLG but in the context of only HLA class I and immunoproteasome subunits. IFNγ promoted a more tolerogenic phenotype of high PD-L1 and PD-L2 expression with both HLA class I and class II molecules and antigen processing genes. Both cytokines elicited secretion of IL-15 and BAFF/BLyS, with TNFα stimulated EC additionally producing IL-6, TL1A and IL-1β. Moreover, endothelium primed for a short period (3hr) with TNFα mostly failed to alter the costimulatory phenotype 24-48hr later, with only somewhat augmented expression of HLA class I. In contrast, brief exposure to IFNγ was sufficient to cause late expression of antigen presentation, cytokines and costimulatory molecules. In particular HLA class I, PD-1 ligand and cytokine expression was markedly high on endothelium two days after IFNγ was last present. CONCLUSIONS: Endothelia from multiple vascular beds possess a wide range of other immune checkpoint molecules and cytokines that can shape the adaptive immune response. Our results further demonstrate that IFNγ elicits prolonged signaling that persists days after initiation and is sufficient to trigger substantial gene expression changes and immune phenotype in vascular endothelium.

183. Immunological Consequences of In Utero Exposure to Foreign Antigens.

Front Immunol

2021 Apr 15

Chen JC.

Immunologic tolerance refers to a state of immune nonreactivity specific to particular antigens as an important issue in the field of transplantation and the management of autoimmune diseases. Tolerance conceptually originated from Owen's observation of blood cell sharing in twin calves. Owen's conceptual framework subsequently constituted the backbone of Medawar's "actively acquired tolerance" as the major tenet of modern immunology. Based upon this knowledge, the delivery of genetically distinct hematopoietic stem cells into pre-immune fetuses represented a novel and unique approach to their engraftment without the requirement of myeloablation or immunosuppression. It might also make fetal recipients commit donor alloantigens to memory of their patterns as "self" so as to create a state of donor-specific tolerance. Over the years, the effort made experimentally or clinically toward in utero marrow transplantation could not reliably yield sufficient hematopoietic chimerism for curing candidate diseases as anticipated, nor did allogeneic graft tolerance universally develop as envisaged by Medawar following in utero exposure to various forms of alloantigens from exosomes, lymphocytes or marrow cells. Enduring graft tolerance was only conditional on a state of significant hematopoietic chimerism conferred by marrow inocula. Notably, fetal exposure to ovalbumin, oncoprotein and microbial antigens did not elicit immune tolerance, but instead triggered an event of sensitization to the antigens inoculated. These fetal immunogenic events might be clinically relevant to prenatal imprinting of atopy, immune surveillance against developmental tumorigenesis, and prenatal immunization against infectious diseases. Briefly, the immunological consequences of fetal exposure to foreign antigens could be tolerogenic or immunogenic, relying upon the type or nature of antigens introduced. Thus, the classical school of "actively acquired tolerance" might oversimplify the interactions between developing fetal immune system and antigens. Such interactions might rely upon fetal macrophages, which showed up earlier than lymphocytes and were competent to phagocytose foreign antigens so as to bridge toward antigen-specific adaptive immunity later on in life. Thus, innate fetal macrophages may be the potential basis for exploring how the immunological outcome of fetal exposure to foreign antigens is determined to improve the likelihood and reliability of manipulating fetal immune system toward tolerization or immunization to antigens.

184. Lipoxin A4 Restores Septic Renal Function via Blocking Crosstalk Between Inflammation and Premature Senescence.

Front Immunol

2021 Apr 15

Chen C, Qiu R, Yang J

185. Immune-Therapy-Related Toxicity Events and Dramatic Remission After a Single Dose of Pembrolizumab Treatment in Metastatic Thymoma: A Case Report.

Front Immunol

2021 Apr 15

Shen L, Chen H, Wei Q.

186. Elevated microRNA-21 Is a Brake of Inflammation Involved in the Development of Nasal Polyps.

Front Immunol

2021 Apr 15

Liu R, Du J, Zhou J

BACKGROUND: CRSwNP is an inflammatory disease but the mechanism is not yet fully understood. MiR-21, a member of miRNAs, has been reported to play roles in mediating inflammation. However, the expression of miR-21 and its role in patients with CRSwNP remain elusive. METHODS: Turbinates from control subjects, uncinate processes from CRSsNP, polyp tissues from CRSwNP, and nasal epithelial cells brushed from nasal mucosa were collected. The expression of miR-21 and cytokines in nasal tissues and epithelial cells were detected by qPCR. The localization of miR-21 was detected by ISH, and its target was identified by bioinformation analysis, qPCR, IHC, WB, and luciferase reporter system. The protein and mRNA of PDCD4 and NF-κB P65 were determined by WB and qPCR after miR-21 transfection in HNEpC. The role of miR-21 on cytokines was analyzed in HNEpC and nasal polyp explants. RESULTS: MiR-21 was upregulated in CRSwNP relative to control subjects by qPCR, which was determined mainly in nasal epithelial cells of CRSwNP by ISH. Both pro-inflammation cytokines (IL-1β, IL-6, IL-8, IL-25, and TSLP) and a suppressive cytokine (IL-10) were overexpressed in the epithelial cells of CRSwNP. The expression of miR-21 was positively correlated with IL-10 and negatively correlated with IL-6, IL-8, IL-33, and TSLP in the epithelial cells of CRSwNP. As a potential target of miR-21, the expression of PDCD4 was negatively correlated with miR-21 in CRSwNP. In HNEpC, miR-21 could reduce the expression of PDCD4 at both mRNA and protein levels, and bioinformation analysis and luciferase reporter system confirmed PDCD4 as one target of miR-21. Furthermore, miR-21 could decrease the activation of NF-κB and increase IL-10 mRNA. Both SEB and LPS could elevate miR-21, with IL-25, IL-33, TSLP induced by SEB and IL-1β, IL-6, IL-8 induced by LPS, while the miR-21 could regulate the expression of IL-33, TSLP, IL-1β, IL- 6 and IL-8 in vitro and ex vivo. Clinically, miR-21 expression was inversely correlated with the Lund-Mackay CT scores and the Lund-Kennedy scores in CRSwNP. CONCLUSION: MiR-21 could be a prominent negative feedback factor in the inflammation process to attenuate the expression of pro-inflammatory cytokines, thereby playing an anti-inflammation role in CRSwNP.

187. Epigenetic Dynamics in the Function of T-Lineage Regulatory Factor Bcl11b.

Front Immunol

2021 Apr 14

Sidwell T, Rothenberg EV.

188. Independent Associations of Tumor Necrosis Factor-Alpha and Interleukin-1 Beta With Radiographic Emphysema in People Living With HIV.

Front Immunol

2021 Apr 14

Thudium RF, Ringheim H, Ronit A

BACKGROUND: People living with HIV (PLWH) have increased systemic inflammation, and inflammation has been suggested to contribute to the pathogenesis of emphysema. We investigated whether elevated cytokine concentrations (interleukin (IL)-1β, IL-1 receptor antagonist (IL-1RA), IL-2, IL-4, IL-6, IL-10, IL-17A, tumor necrosis factor-alpha (TNFα), interferon-gamma (IFNγ), soluble CD14 (sCD14) and sCD163 were independently associated with radiographic emphysema in PLWH. METHODS: We included PLWH from the Copenhagen Comorbidity in HIV Infection (COCOMO) Study without hepatitis B and C co-infection and with a plasma sample and a chest computed tomography scan available. Emphysema plus trace emphysema was defined as the percentage of low attenuation area under -950 Houndsfield Unit (%LAA-950) using a cut-off at 5%. Cytokine concentrations were measured by ELISA or Luminex immunoassays. An elevated cytokine concentration was defined as above the 75th percentile. RESULTS: Of 783 PLWH, 147 (18.8%) had emphysema. PLWH were predominantly male (86.0%) and 743 (94.9%) had undetectable viral replication. PLWH with emphysema had higher concentrations of TNFα (median (IQR): 8.2 (6.4-9.8) versus 7.1 (5.7-8.6) pg/ml, p<0.001), IL-1β (0.21 (0.1-0.4) versus 0.17 (0.1-0.3) pg/ml, p=0.004) and IL-6 (3.6 (2.6-4.9) versus 3.1 (2.0-4.3) pg/ml, p=0.023) than PLWH without. In a logistic regression model adjusted for age, sex, ethnicity, smoking status, BMI and CD4 nadir, elevated TNFα (adjusted odds ratio (aOR): 1.78 [95%CI: 1.14-2.76], p=0.011) and IL-1β (aOR: 1.81 [95%CI: 1.16-2.81], p=0.009) were independently associated with emphysema. The association between IL-1β and emphysema was modified by smoking (p-interaction=0.020) with a more pronounced association in never-smokers (aOR: 4.53 [95%CI: 2.05-9.98], p<0.001). CONCLUSION: Two markers of systemic inflammation, TNFα and IL-1β, were independently associated with emphysema in PLWH and may contribute to the pathogenesis of emphysema. Importantly, the effect of IL-1β seems to be mediated through pathways that are independent of excessive smoking. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov, identifier NCT02382822.

189. Bispecific T-Cell Engaging Antibodies Against MUC16 Demonstrate Efficacy Against Ovarian Cancer in Monotherapy and in Combination With PD-1 and VEGF Inhibition.

Front Immunol

2021 Apr 14

Yeku OO, Rao TD, Laster I

190. The Mechanism of Action of Antigen Processing Independent T Cell Epitopes Designed for Immunotherapy of Autoimmune Diseases.

Front Immunol

2021 Apr 14

Shepard ER, Wegner A, Hill EV

191. Bispecific NKG2D-CD3 and NKG2D-CD16 Fusion Proteins as Novel Treatment Option in Advanced Soft Tissue Sarcomas.

Front Immunol

2021 Apr 14

Hagelstein I, Lutz MS, Schmidt M

192. Hydroxychloroquine Inhibits Macrophage Activation and Attenuates Renal Fibrosis After Ischemia-Reperfusion Injury.

Front Immunol

2021 Apr 14

Zheng H, Zhang Y, He J

193. Regulation of Intrinsic and Bystander T Follicular Helper Cell Differentiation and Autoimmunity by Tsc1.

Front Immunol

2021 Apr 14

Zhang S, Li L, Xie D

194. Corrigendum: Immunological Impact of Intestinal T Cells on Metabolic Diseases.

Front Immunol

2021 Apr 14

Zhou H, Wang L, Liu F.

195. The Role of B Cells and B Cell Therapies in Immune-Mediated Liver Diseases.

Front Immunol

2021 Apr 14

Cargill T, Culver EL.

196. Corrigendum: Blocking of the High-Affinity Interaction-Synapse Between SARS-CoV-2 Spike and Human ACE2 Proteins Likely Requires Multiple High-Affinity Antibodies: An Immune Perspective.

Front Immunol

2021 Apr 14

Khatri I, Staal FJT, van Dongen JJM.

197. The Impact of Acute and Chronic Exercise on Immunoglobulins and Cytokines in Elderly: Insights From a Critical Review of the Literature.

Front Immunol

2021 Apr 14

Sellami M, Bragazzi NL, Aboghaba B

198. Predicted Disease-Specific Immune Infiltration Patterns Decode the Potential Mechanisms of Long Non-Coding RNAs in Primary Sjogren's Syndrome.

Front Immunol

2021 Apr 14

Cheng C, Zhou J, Chen R

199. Case Report: Expanding Clinical, Immunological and Genetic Findings in Sideroblastic Anemia With Immunodeficiency, Fevers and Development Delay (SIFD) Syndrome.

Front Immunol

2021 Apr 14

Mendonca LO, Prado AI, Costa IMC

200. Corrigendum: Galectin-9: A Suppressor of Atherosclerosis?

Front Immunol

2021 Apr 13

Yu J, Zhu R, Yu K

201. Editorial: Novel Advances in Allergy Diagnosis and Treatment.

Front Immunol

2021 Apr 13

Blank S, Hilger C.

202. Impaired ATG16L-Dependent Autophagy Promotes Renal Interstitial Fibrosis in Chronic Renal Graft Dysfunction Through Inducing EndMT by NF-κB Signal Pathway.

Front Immunol

2021 Apr 13

Gui Z, Suo C, Wang Z

Chronic renal graft dysfunction (CAD) is caused by multiple factors, including glomerular sclerosis, inflammation, interstitial fibrosis and tubular atrophy (IF/TA). However, the most prominent elements of CAD are IF/TA. Our studies have confirmed that endothelial-mesenchymal transition (EndMT) is an important source to allograft IF/TA. The characteristic of EndMT is the loss of endothelial marker and the acquisition of mesenchymal or fibroblastic phenotypes. Autophagy is an intracellular degradation pathway that is regulated by autophagy-related proteins and plays a vital role in many fibrotic conditions. However, whether or not autophagy contributes to fibrosis of renal allograft and how such mechanism occurs still remains unclear. Autophagy related 16 like gene (ATG16L) is a critical autophagy-related gene (ARG) necessary for autophagosome formation. Here, we first analyzed kidney transplant patient tissues from Gene Expression Omnibus (GEO) datasets and 60 transplant patients from our center. Recipients with stable kidney function were defined as non-CAD group and all patients in CAD group were histopathologically diagnosed with CAD. Results showed that ATG16L, as one significant differential ARG, was less expressed in CAD group compared to the non-CAD group. Furthermore, we found there were less autophagosomes and autolysosomes in transplanted kidneys of CAD patients, and downregulation of autophagy is a poor prognostic factor. In vitro, we found out that the knockdown of ATG16L enhanced the process of EndMT in human renal glomerular endothelial cells (HRGECs). In vivo, the changes of EndMT and autophagic flux were then detected in rat renal transplant models of CAD. We demonstrated the occurrence of EndMT, and indicated that abundance of ATG16L was accompanied by the dynamic autophagic flux change along different stages of kidney transplantation. Mechanistically, knockdown of ATG16L, specifically in endothelial cells, reduced of NF-κB degradation and excreted inflammatory cytokines (IL-1β, IL-6 and TNF-α), which could facilitate EndMT. In conclusion, ATG16L-dependent autophagic flux causing by transplant showed progressive loss increase over time. Inflammatory cytokines from this process promoted EndMT, thereby leading to progression of CAD. ATG16L served as a negative regulator of EndMT and development of renal graft fibrosis, and autophagy can be explored as a potential therapeutic target for chronic renal graft dysfunction.

203. Metabolites in the Tumor Microenvironment Reprogram Functions of Immune Effector Cells Through Epigenetic Modifications.

Front Immunol

2021 Apr 13

Li Y, Wu Y, Hu Y.

204. Comprehensive Analysis of CDR3 Sequences in Gluten-Specific T-Cell Receptors Reveals a Dominant R-Motif and Several New Minor Motifs.

Front Immunol

2021 Apr 13

Dahal-Koirala S, Risnes LF, Neumann RS

Gluten-specific CD4+ T cells are drivers of celiac disease (CeD). Previous studies of gluten-specific T-cell receptor (TCR) repertoires have found public TCRs shared across multiple individuals, biased usage of particular V-genes and conserved CDR3 motifs. The CDR3 motifs within the gluten-specific TCR repertoire, however, have not been systematically investigated. In the current study, we analyzed the largest TCR database of gluten-specific CD4+ T cells studied so far consisting of TCRs of 3122 clonotypes from 63 CeD patients. We established a TCR database from CD4+ T cells isolated with a mix of HLA-DQ2.5:gluten tetramers representing four immunodominant gluten epitopes. In an unbiased fashion we searched by hierarchical clustering for common CDR3 motifs among 2764 clonotypes. We identified multiple CDR3α, CDR3β, and paired CDR3α:CDR3β motif candidates. Among these, a previously known conserved CDR3β R-motif used by TRAV26-1/TRBV7-2 TCRs specific for the DQ2.5-glia-α2 epitope was the most prominent motif. Furthermore, we identified the epitope specificity of altogether 16 new CDR3α:CDR3β motifs by comparing with TCR sequences of 231 T-cell clones with known specificity and TCR sequences of cells sorted with single HLA-DQ2.5:gluten tetramers. We identified 325 public TCRα and TCRβ sequences of which 145, 102 and 78 belonged to TCRα, TCRβ and paired TCRαβ sequences, respectively. While the number of public sequences was depended on the number of clonotypes in each patient, we found that the proportion of public clonotypes from the gluten-specific TCR repertoire of given CeD patients appeared to be stable (median 37%). Taken together, we here demonstrate that the TCR repertoire of CD4+ T cells specific to immunodominant gluten epitopes in CeD is diverse, yet there is clearly biased V-gene usage, presence of public TCRs and existence of conserved motifs of which R-motif is the most prominent.

205. T-Cell Receptor Therapy in the Treatment of Ovarian Cancer: A Mini Review.

Front Immunol

2021 Apr 13

Wu JWY, Dand S, Doig L

206. T Cell-Mediated Immune Responses to AAV and AAV Vectors.

Front Immunol

2021 Apr 13

Ertl HCJ.

207. Robust Prediction of Immune Checkpoint Inhibition Therapy for Non-Small Cell Lung Cancer.

Front Immunol

2021 Apr 13

Jiang J, Jin Z, Zhang Y

BACKGROUND: The development of immune checkpoint inhibitors (ICIs) is a revolutionary milestone in the field of immune-oncology. However, the low response rate is the major problem of ICI treatment. The recent studies showed that response rate to single-agent programmed cell death protein 1 (PD-1)/programmed cell death-ligand 1 (PD-L1) inhibition in unselected non-small cell lung cancer (NSCLC) patients is 25% so that researchers defined several biomarkers to predict the response of immunotherapy in ICIs treatment. Common biomarkers like tumor mutational burden (TMB) and PD-L1 expression have several limitations, such as low accuracy and inadequately validated cutoff value. METHODS: Two published and an unpublished ICIs treatment NSCLC cohorts with 129 patients were collected and divided into a training cohort (n = 53), a validation cohort (n = 22), and two independent test cohorts (n = 34 and n = 20). We identified six immune-related pathways whose mutational status was significantly associated with overall survival after ICIs treatment. Then these pathways mutational status combined with TMB, PD-L1 expression and intratumor heterogeneity were incorporated to build a Bayesian-regularization neural networks (BRNN) model to predict the ICIs treatment response. RESULTS: We firstly proved that TMB, PD-L1, and mutant-allele tumor heterogeneity (MATH) were independent biomarkers. The survival analysis of six immune-related pathways revealed the mutational status could distinguish overall survival after ICIs treatment. When predicting immunotherapy efficacy, the overall accuracy of area under curve (AUC) in validation cohort reaches 0.85, outperforming previous predictors in either sensitivity or specificity. And the AUC in two independent test cohorts reach 0.74 and 0.80. CONCLUSION: We developed a pathway-model that could predict the efficacy of ICIs in NSCLC patients. Our study made a significant contribution to solving the low prediction accuracy of immunotherapy of single biomarker. With the accumulation of larger data sets, further studies are warranted to refine the predictive performance of the approach.

208. Repurposing Immunomodulatory Drugs to Combat Tuberculosis.

Front Immunol

2021 Apr 13

Fatima S, Bhaskar A, Dwivedi VP.

Tuberculosis (TB) is an infectious disease caused by an obligate intracellular pathogen, Mycobacterium tuberculosis (M.tb) and is responsible for the maximum number of deaths due to a single infectious agent. Current therapy for TB, Directly Observed Treatment Short-course (DOTS) comprises multiple antibiotics administered in combination for 6 months, which eliminates the bacteria and prevents the emergence of drug-resistance in patients if followed as prescribed. However, due to various limitations viz., severe toxicity, low efficacy and long duration; patients struggle to comply with the prescribed therapy, which leads to the development of drug resistance (DR). The emergence of resistance to various front-line anti-TB drugs urgently require the introduction of new TB drugs, to cure DR patients and to shorten the treatment course for both drug-susceptible and resistant populations of bacteria. However, the development of a novel drug regimen involving 2-3 new and effective drugs will require approximately 20-30 years and huge expenditure, as seen during the discovery of bedaquiline and delamanid. These limitations make the field of drug-repurposing indispensable and repurposing of pre-existing drugs licensed for other diseases has tremendous scope in anti-DR-TB therapy. These repurposed drugs target multiple pathways, thus reducing the risk of development of drug resistance. In this review, we have discussed some of the repurposed drugs that have shown very promising results against TB. The list includes sulfonamides, sulfanilamide, sulfadiazine, clofazimine, linezolid, amoxicillin/clavulanic acid, carbapenems, metformin, verapamil, fluoroquinolones, statins and NSAIDs and their mechanism of action with special emphasis on their immunomodulatory effects on the host to attain both host-directed and pathogen-targeted therapy. We have also focused on the studies involving the synergistic effect of these drugs with existing TB drugs in order to translate their potential as adjunct therapies against TB.

209. NEPdb: A Database of T-Cell Experimentally-Validated Neoantigens and Pan-Cancer Predicted Neoepitopes for Cancer Immunotherapy.

Front Immunol

2021 Apr 13

Xia J, Bai P, Fan W

210. Extracellular Vesicles Secreted by Mesenchymal Stromal Cells Exert Opposite Effects to Their Cells of Origin in Murine Sodium Dextran Sulfate-Induced Colitis.

Front Immunol

2021 Apr 13

Tolomeo AM, Castagliuolo I, Piccoli M

211. Case Report: Resetting the Humoral Immune Response by Targeting Plasma Cells With Daratumumab in Anti-Phospholipid Syndrome.

Front Immunol

2021 Apr 12

Pleguezuelo DE, Díaz-Simón R, Cabrera-Marante O

INTRODUCTION: Monoclonal antibodies (mAb) targeting plasma cells are malignant gammopathy designed and approved therapies. In recent years, these antibodies have also been increasingly introduced for non-malignant conditions such as autoimmune-mediated diseases. The Anti-Phospholipid Syndrome (APS) is an immune-mediated disorder in which autoantibodies against phospholipid associated proteins could elicit the activation of the coagulation cascade in specific situations. Therefore, the mainstream treatment for APS patients is the use of anticoagulant therapy. However, there are refractory patients who would benefit from targeting the antibodies rather than their effects. Rituximab, a B-cell depleting mAb, and intravenous immunoglobulins (IVIG) have been used in APS patients without showing a clear beneficial effect or a significant drop in anti-phospholipid antibody (aPL) levels. CLINICAL CASE: We present our first APS case treated with daratumumab, an anti-CD38 mAb, in a 21-year-old patient with APS who presented with recurrent venous thromboembolic events despite adequate anticoagulant therapy. She tested positive for lupus anticoagulant, anti-cardiolipin IgG, anti-beta-2-glycoprotein-I IgG and anti-phosphatidylserine/prothrombin IgG and IgM. She was administered one dose weekly of daratumumab for 4 weeks. The treatment showed an adequate safety profile and was well tolerated. The patient was discharged after undergoing a clinically significant improvement. After the therapy, her levels of positive aPL declined significantly and most continued to decrease during the next three months. The patient experienced a new thrombotic episode two years after the therapy associated with poor adherence to antithrombotic therapy. CONCLUSIONS: The treatment with daratumumab showed an adequate safety profile, was well tolerated and led to a significant clinical improvement. Levels of aPL lowered on therapy and the next three months and then rose again during follow-up. Further investigation is needed to better elucidate the role and optimal timing and doses of daratumumab in treatment of refractory APS.

212. Paroxysmal Sympathetic Hyperactivity in Severe Anti-N-Methyl-d-Aspartate Receptor Encephalitis: A Single Center Retrospective Observational Study.

Front Immunol

2021 Apr 12

Wang D, Su S, Tan M

BACKGROUND: Paroxysmal sympathetic hyperactivity (PSH) is a disorder with excessive sympathetic activity commonly recognized in patients with acquired brain injury. Autonomic instability is frequent in anti-N-methyl-d-aspartate receptor encephalitis (anti-NMDARE). However, PSH in anti-NMDARE has gained little attention. METHODS: We retrospectively reviewed 24 patients diagnosed with severe anti-NMDARE in the neuro-intensive care unit (NICU) between 2014 and 2019. Patients were assessed with the PSH assessment measure (PSH-AM) scale, and categorized into "PSH+" group and "PSH-" group. The clinical characteristics, hospital mortality, and functional outcome by modified Rankin Scale (mRS) score at six months after discharge were compared between the two groups. Among patients with PSH+, the clinical features and pharmacotherapy of PSH were summarized and compared. RESULTS: Twenty-four patients were included in the study. Twelve of them (50%) were categorized as PSH+ based on PSH-AM scores. There were no significant differences in the demographic characteristic, GCS scores upon admission, incidence of status epilepticus, teratoma occurrence, hospital mortality, and 6-month mRS between PSH+ and PSH- groups. Patients with PSH+ had increased length of NICU stay, hospital stay and duration of mechanical ventilation. The most prominent clinical features of PSH in severe anti-NMDARE were tachycardia and hyperthermia, while posturing was the relatively mildest clinical feature. Propranolol and clonazepam were more commonly used than gabapentin in pharmacotherapy of PSH in severe anti-NMDARE. CONCLUSIONS: The incidence of PSH in severe anti-NMDARE patients was as high as 50%. Patients with PSH demonstrated prolonged NICU stay, hospital stay and increased duration of mechanical ventilation, while no effect on hospital mortality and functional outcome. Clinicians should be aware of the distinctive characteristics and treatment options of PSH in severe anti-NMDARE.

213. In Ovo and Oral Administration of Probiotic Lactobacilli Modulate Cell- and Antibody-Mediated Immune Responses in Newly Hatched Chicks.

Front Immunol

2021 Apr 12

Alizadeh M, Bavananthasivam J, Shojadoost B

214. Fasciola gigantica-Derived Excretory-Secretory Products Alter the Expression of mRNAs, miRNAs, lncRNAs, and circRNAs Involved in the Immune Response and Metabolism in Goat Peripheral Blood Mononuclear Cells.

Front Immunol

2021 Apr 12

Wang SS, Chen D, He JJ

215. Aberrant Gut Microbiome Contributes to Intestinal Oxidative Stress, Barrier Dysfunction, Inflammation and Systemic Autoimmune Responses in MRL/lpr Mice.

Front Immunol

2021 Apr 12

Wang H, Wang G, Banerjee N

Microbiome composition and function have been implicated as contributing factors in the pathogenesis of autoimmune diseases (ADs), including systemic lupus erythematosus (SLE), rheumatoid arthritis and autoimmune hepatitis (AIH). Furthermore, dysbiosis of gut microbiome is associated with impaired barrier function and mucosal immune dysregulation. However, mechanisms by which gut microbiome contributes to the ADs and whether antioxidant treatment can restore gut homeostasis and ameliorate the disease outcome are not known. This study was, therefore, focused on examining the involvement of gut microbiome and host responses in the pathogenesis of SLE using unique female mouse models (C57BL/6, MRL+/+ and MRL/lpr) of 6 and 18 weeks with varying degrees of disease progression. Fecal microbiome diversity and composition, gut oxidative stress (OS), barrier function and inflammation, as well as systemic autoimmunity were determined. Interestingly, each mouse strain had distinct bacterial community as revealed by β-diversity. A lower Firmicutes/Bacteroidetes ratio in 6-week-old MRL/lpr mice was observed, evidenced by decrease in Peptostreptococcaceae under Firmicutes phylum along with enrichment of Rikenellaceae under Bacteroidetes phylum. Additionally, we observed increases in colonic OS [4-hydroxynonenal (HNE)-adducts and HNE-specific immune complexes], permeability changes (lower tight junction protein ZO-2; increased fecal albumin and IgA levels) and inflammatory responses (increased phos-NF-κB, IL-6 and IgG levels) in 18-week-old MRL/lpr mice. These changes were associated with markedly elevated AD markers (antinuclear and anti-smooth muscle antibodies) along with hepatic portal inflammation and severe glomerulonephritis. Notably, antioxidant N-acetylcysteine treatment influenced the microbial composition (decreased Rikenellaceae; increased Akkeransiaceae, Erysipelotrichaceae and Muribaculaceae) and attenuated the systemic autoimmunity in MRL/lpr mice. Our data thus show that gut microbiome dysbiosis is associated with increased colonic OS, barrier dysfunction, inflammatory responses and systemic autoimmunity markers. These findings apart from delineating a role for gut microbiome dysbiosis, also support the contribution of gut OS, permeability changes and inflammatory responses in the pathogenesis of ADs.

216. Human Milk Drives the Intimate Interplay Between Gut Immunity and Adipose Tissue for Healthy Growth.

Front Immunol

2021 Apr 12

van den Elsen LWJ, Verhasselt V.

217. Increased Pentraxin 3 Levels Correlate With IVIG Responsiveness and Coronary Artery Aneurysm Formation in Kawasaki Disease.

Front Immunol

2021 Apr 12

Kitoh T, Ohara T, Muto T

Kawasaki disease (KD) is a febrile disease of childhood characterized by systemic vasculitis that can lead to coronary artery lesions (CAL). This was a prospective cohort study to determine the levels of the pentraxin 3 (PTX3), soluble CD24-Subtype (Presepsin) and N-terminal pro-brain natriuretic peptide (NT-pro BNP) in consecutive KD patients. From January 2013 to March 2015, all patients with KD admitted to Aichi Medical University Hospital who provided consent had their plasma saved before IVIG administration. In total, 97 cases were registered. 22 cases of incomplete KD were excluded from the outcome analysis. The total 75 cases were used for statistical analyses. A PTX3 threshold of >7.92 ng/ml provided a specificity of 88.5 %, a sensitivity of 94.4 %, and a likelihood ratio as high as 15.92 for the diagnosis of KD compared with febrile non-KD controls. Although an echocardiographic diagnosis of CAL in the early course of the disease was confirmed in 24 cases, it was not in the remaining 51 cases. Neither NT-proBNP nor Presepsin had statistical significance for the prediction of the echocardiographic CAL diagnosis. Only PTX3 was significantly predictive of the echocardiographic CAL diagnosis (p=0.01). The PTX3 level was significantly higher in the intravenous immunoglobulin (IVIG) non-responders (45.9±7.45) than in the IVIG responders (17.0 ± 1.46 ng/ml) (p< 0.001). The PTX3 level also correlated with the number of IVIG treatment courses needed to resolve fever (R² =0.64). Persistent CAL (pCAL) formation was observed in three cases; one of aneurysm only and two aneurysms with dilatations. The patients with pCAL had significantly higher PTX3 levels (85 ± 8.4 ng/ml) than patients without pCAL (22 ± 2.2 ng/ml) (p< 0.0001). In terms of pCAL prediction, the area under the curve (AUC) of receiver operating characteristic ROC curve of PTX3 was 0.99, and it was significantly greater than that of Presepsin (0.67) or NT-proBNP (0.75). PTX3 is a soluble pattern recognition molecule that acts as a main component of the innate immune system. These data suggest that PTX3 can be utilized as a definitive biomarker for the prediction of IVIG resistance and subsequent CAL formation in patients with KD.

218. Case Report: Infantile-Onset Fulminant Type 1 Diabetes Mellitus Caused by Novel Compound Heterozygous LRBA Variants.

Front Immunol

2021 Apr 12

Totsune E, Nakano T, Moriya K

219. The Ratio of IP10 to IL-8 in Plasma Reflects and Predicts the Response of Patients With Lung Cancer to Anti-PD-1 Immunotherapy Combined With Chemotherapy.

Front Immunol

2021 Apr 12

Wu L, Xie S, Wang L

220. Latent Cytomegalovirus-Driven Recruitment of Activated CD4+ T Cells Promotes Virus Reactivation.

Front Immunol

2021 Apr 12

Jackson SE, Chen KC, Groves IJ

221. ILC3, a Central Innate Immune Component of the Gut-Brain Axis in Multiple Sclerosis.

Front Immunol

2021 Apr 12

Miljković Đ, Jevtić B, Stojanović I

222. A Novel Image Analysis Approach Reveals a Role for Complement Receptors 1 and 2 in Follicular Dendritic Cell Organization in Germinal Centers.

Front Immunol

2021 Apr 12

Anania JC, Westin A, Adler J

Follicular dendritic cells (FDCs) are rare and enigmatic cells that mainly reside in germinal centers (GCs). They are capable of capturing immune complexes, via their Fc (FcRs) and complement receptors (CRs) and storing them for long periods in non-degradative vesicles. Presentation of ICs on FDCs to B cells is believed to drive affinity maturation. CR1 and CR2 are expressed on B cells and FDCs. Cr2 knock out (KO) mice, lacking both receptors, have impaired antibody and GC responses. Utilizing a novel ImageJ macro to analyze confocal fluorescence microscopy images of spleen sections, we here investigate how FDCs in wild type (WT) and Cr2 KO mice behave during the first two weeks after immunization with sheep red blood cells (SRBC). Mice were immunized with SRBC i.v. and spleen and serum samples harvested at various time points. As expected, antibody and GC responses in Cr2 KO mice were impaired in comparison to WT mice. Fewer FDCs were identified in Cr2 KO mice, and these exhibited differential localization and organization in comparison to WT mice. WT FDCs were primarily located within GCs at the light zone/dark zone border. FDCs from WT but not Cr2 KO mice were actively dispersed in GCs, i.e. tended to move away from each other, presumably to increase their surface area for B cell interaction. FDCs from Cr2 KO mice were more often found on follicles outside of the GCs and those within the GCs were closer to the periphery in comparison to WT FDCs. Expression of CR1 and CR2, FcγRIIB, and FcµR increased in FDCs from WT mice during the course of immunization. The results suggest that decreased ability to capture ICs by FDCs lacking CR1 and CR2 may not be the only explanation for the impaired GC and antibody responses in Cr2 KO mice. Poor FDC organization in GCs and failure to increase receptor expression after immunization may further contribute to the inefficient immune responses observed.

223. Regulatory B Cells Dysregulated T Cell Function in an IL-35-Dependent Way in Patients With Chronic Hepatitis B.

Front Immunol

2021 Apr 12

Liu Y, Luo Y, Zhu T

224. Tributyrin Plays an Important Role in Regulating the Growth and Health Status of Juvenile Blunt Snout Bream (Megalobrama amblycephala), as Evidenced by Pathological Examination.

Front Immunol

2021 Apr 12

Liang H, Ji K, Ge X

The present study aimed to assess the role of tributyrin (TB) in regulating the growth and health status of juvenile blunt snout bream (Megalobrama amblycephala) through an 8-week feeding experiment. Six groups were fed experimental diets with added TB percentages of 0% (control group), 0.03%, 0.06%, 0.09%, 0.12% and 0.15%. The present results showed that TB supplementation in feed had some positive impacts on FW, WG, FCR and SGR, and the best results were found in the 0.06% TB group (P<0.05). However, TB supplementation in feed had no significant effects on SR, CF, VSI or whole-body composition (P>0.05). TB supplementation in feed increased antioxidant capacity and immunological capacity and attenuated the inflammatory response by increasing the activity of T-SOD, GPx, CAT and the levels of anti-inflammatory cytokines (IL-10 and TGF-β) and decreasing the levels of MDA and anti-inflammatory cytokines (TNF-α) (P<0.05). Furthermore, TB supplementation improved immunity by increasing the levels of immunoglobulins (IgM and IgG), C3 and IFN-γ (P<0.05). Surprisingly, 0.06%-0.12% TB supplementation significantly increased the content of IL-1β (P<0.05). However, TB supplementation in feed had no significant effects on the plasma content of GSH, HSP70, IL-8 and the activity of T-AOC (P>0.05). The possible mechanism was that TB activated PI3K/Akt/Nrf2 and inhibits the NF-κB signaling pathway, further regulating the mRNA levels of key genes with antioxidant capacity and the inflammatory response; for example, it increased the mRNA levels of Nrf2, Cu/Zn-SOD, HO-1, CAT, Akt, PI3K, GPx, IL-10, and TGF-β and decreased the mRNA levels of NF-κB and TNF-α (P<0.05). In addition, 0.06%-0.15% TB supplementation significantly increased the mRNA levels of IL-1β (P<0.05). TB supplementation in feed had no significant effects on the mRNA levels of HSP70, Mn-SOD and IL-8 (P>0.05). Evidence was presented that TB supplementation decreased the mortality rate caused by Aeromonas hydrophila challenge. In pathological examination, TB supplementation prevented hepatic and intestinal damage. Generally, TB supplementation improved the growth performance of juvenile blunt snout bream. Furthermore, TB supplementation activated PI3K/Akt/Nrf2 and inhibited the NF-κB signaling pathway, regulating health status and preventing hepatic and intestinal damage.

225. Improvement of Myelopoiesis in Cyclophosphamide-Immunosuppressed Mice by Oral Administration of Viable or Non-Viable Lactobacillus Strains.

Front Immunol

2021 Apr 12

Gramajo Lopez A, Gutiérrez F, Saavedra L

Myelosuppression is the major dose-limiting toxicity of cancer chemotherapy. There have been many attempts to find new strategies that reduce myelosuppression. The dietary supplementation with lactic acid bacteria (LAB) improved respiratory innate immune response and the resistance against respiratory pathogens in immunosupressed hosts. Although LAB viability is an important factor in achieving optimal protective effects, non-viable LAB are capable of stimulating immunity. In this work, we studied the ability of oral preventive administration of viable and non-viable Lactobacillus rhamnosus CRL1505 or L. plantarum CRL1506 (Lr05, Lr05NV, Lp06V or Lp06NV, respectively) to minimize myelosuppressive and immunosuppressive effects derived from chemotherapy. Cyclophosphamide (Cy) impaired steady-state myelopoiesis in lactobacilli-treated and untreated control mice. Lr05V, Lr05NV and Lp06V treatments were the most effective to induce the early recovery of bone marrow (BM) tissue architecture, leukocytes, myeloid, pool mitotic and post-mitotic, peroxidase positive, and Gr-1Low/High cells in BM. We selected the CRL1505 strain for being the one capable of maintaining its myelopoiesis-enhancing properties in its non-viable form. Although the CRL1505 treatments do not modify the Cy ability to induce apoptosis, both increased the incorporation of BrdU in BM cells. Consequently, Lr05NV and Lr05V treatments were able to promote early recovery of LSK cells (Lin-Sca-1+c-Kit+ cells), multipotent progenitors (Lin-Sca-1+c-Kit+CD34+ cells), and myeloid cells (Gr-1+Ly6G+Ly6C- cells) with respect to the untreated Cy control. In addition, these treatments were able to increase the frequency of IL17A-producing innate lymphoid cells in the intestinal lamina propria (IL-17A+RORγt+CD4-NKp46+ cells) after Cy injection. These results were correlated with an increase in the IL-17A serum levels, a GM-CSF high expression and a CXCL12 lower expression in BM. Therefore, both Lr05V and Lr05NV treatments are able to activate beneficially the IL-17A/GM-CSF axis and accelerate the recovery of Cy-induced immunosuppression by increasing BM myeloid precursors. We demonstrated for the first time the beneficial effect of CRL1505 strain on myelopoiesis affected by a chemotherapeutic drug. Furthermore, Lr05NV could be a good and safe resource for reducing chemotherapy-induced leukopenia. The results are a starting point for future research and open up broad prospects for future applications of the immunobiotics.

226. Neuroimmune Consequences of eIF4E Phosphorylation on Chemotherapy-Induced Peripheral Neuropathy.

Front Immunol

2021 Apr 12

Agalave NM, Mody PH, Szabo-Pardi TA

227. Illumination of Molecular Pathways in Multiple Sclerosis Lesions and the Immune Mechanism of Matrine Treatment in EAE, a Mouse Model of MS.

Front Immunol

2021 Apr 12

Dou M, Zhou X, Li L

The etiology of multiple sclerosis (MS) is not clear, and the treatment of MS presents a great challenge. This study aimed to investigate the pathogenesis and potential therapeutic targets of MS and to define target genes of matrine, a quinolizidine alkaloid component derived from the root of Sophorae flavescens that effectively suppressed experimental autoimmune encephalomyelitis (EAE), an animal model of MS. To this end, the GSE108000 gene data set in the Gene Expression Omnibus Database, which included 7 chronic active MS lesions and 10 control samples of white matter, was analyzed for differentially expressed genes (DEGs). X cell was used to analyze the microenvironmental differences in brain tissue samples of MS patients, including 64 types of immune cells and stromal cells. The biological functions and enriched signaling pathways of DEGs were analyzed by multiple approaches, including GO, KEGG, GSEA, and GSVA. The results by X cell showed significantly increased numbers of immune cell populations in the MS lesions, with decreased erythrocytes, megakaryocytes, adipocytes, keratinocytes, endothelial cells, Th1 cells and Tregs. In GSE108000, there were 637 DEGs, including 428 up-regulated and 209 down-regulated genes. Potential target genes of matrine were then predicted by the network pharmacology method of Traditional Chinese medicine, and 12 key genes were obtained by cross analysis of the target genes of matrine and DEGs in MS lesions. Finally, we confirmed by RT-PCR the predicted expression of these genes in brain tissues of matrine-treated EAE mice. Among these genes, 2 were significantly downregulated and 6 upregulated by matrine treatment, and the significance of this gene regulation was further investigated. In conclusion, our study defined several possible matrine target genes, which can be further elucidated as mechanism(s) of matrine action, and novel targets in the treatment of MS.

228. Regulation of B Lymphocyte Development by Histone H2A Deubiquitinase BAP1.

Front Immunol

2021 Apr 12

Lin YH, Liang Y, Wang H

229. Post-Translational Regulations of Foxp3 in Treg Cells and Their Therapeutic Applications.

Front Immunol

2021 Apr 12

Dong Y, Yang C, Pan F.

230. Phenotypic and Epigenetic Adaptations of Cord Blood CD4+ T Cells to Maternal Obesity.

Front Immunol

2021 Apr 12

Sureshchandra S, Mendoza N, Jankeel A

231. Editorial: Brain-Targeted Autoimmunity: Beyond Multiple Sclerosis.

Front Immunol

2021 Apr 1

Nataf S, Hunot S, Dorothée G

232. Examining the Underappreciated Role of S-Acylated Proteins as Critical Regulators of Phagocytosis and Phagosome Maturation in Macrophages.

Front Immunol

2021 Apr 1

Dixon CL, Mekhail K, Fairn GD.

233. Complement Initiation Varies by Sex in Intestinal Ischemia Reperfusion Injury.

Front Immunol

2021 Apr 1

Wu M, Rowe JM, Fleming SD.

234. Tremella fuciformis Polysaccharides Inhibited Colonic Inflammation in Dextran Sulfate Sodium-Treated Mice via Foxp3+ T Cells, Gut Microbiota, and Bacterial Metabolites.

Front Immunol

2021 Apr 1

Xu Y, Xie L, Zhang Z

235. Using Deep Learning in a Monocentric Study to Characterize Maternal Immune Environment for Predicting Pregnancy Outcomes in the Recurrent Reproductive Failure Patients.

Front Immunol

2021 Apr 1

Huang C, Xiang Z, Zhang Y

Recurrent reproductive failure (RRF), such as recurrent pregnancy loss and repeated implantation failure, is characterized by complex etiologies and particularly associated with diverse maternal factors. It is currently believed that RRF is closely associated with the maternal environment, which is, in turn, affected by complex immune factors. Without the use of automated tools, it is often difficult to assess the interaction and synergistic effects of the various immune factors on the pregnancy outcome. As a result, the application of Artificial Intelligence (A.I.) has been explored in the field of assisted reproductive technology (ART). In this study, we reviewed studies on the use of A.I. to develop prediction models for pregnancy outcomes of patients who underwent ART treatment. A limited amount of models based on genetic markers or common indices have been established for prediction of pregnancy outcome of patients with RRF. In this study, we applied A.I. to analyze the medical information of patients with RRF, including immune indicators. The entire clinical samples set (561 samples) was divided into two sets: 90% of the set was used for training and 10% for testing. Different data panels were established to predict pregnancy outcomes at four different gestational nodes, including biochemical pregnancy, clinical pregnancy, ongoing pregnancy, and live birth, respectively. The prediction models of pregnancy outcomes were established using sparse coding, based on six data panels: basic patient characteristics, hormone levels, autoantibodies, peripheral immunology, endometrial immunology, and embryo parameters. The six data panels covered 64 variables. In terms of biochemical pregnancy prediction, the area under curve (AUC) using the endometrial immunology panel was the largest (AUC = 0.766, accuracy: 73.0%). The AUC using the autoantibodies panel was the largest in predicting clinical pregnancy (AUC = 0.688, accuracy: 78.4%), ongoing pregnancy (AUC = 0.802, accuracy: 75.0%), and live birth (AUC = 0.909, accuracy: 89.7%). Combining the data panels did not significantly enhance the effect on prediction of all the four pregnancy outcomes. These results give us a new insight on reproductive immunology and establish the basis for assisting clinicians to plan more precise and personalized diagnosis and treatment for patients with RRF.

236. Case Report: Combination Therapy With PD-1 Blockade for Acute Myeloid Leukemia After Allogeneic Hematopoietic Stem Cell Transplantation Resulted in Fatal GVHD.

Front Immunol

2021 Apr 1

Yao S, Jianlin C, Zhuoqing Q

237. Humanized Mice for the Evaluation of Novel HIV-1 Therapies.

Front Immunol

2021 Apr 1

Abeynaike S, Paust S.

238. In vitro Evaluation of Programmed Cell Death in the Immune System of Pacific Oyster Crassostrea gigas by the Effect of Marine Toxins.

Front Immunol

2021 Apr 1

Estrada N, Núñez-Vázquez EJ, Palacios A

Programmed cell death (PCD) is an essential process for the immune system's development and homeostasis, enabling the remotion of infected or unnecessary cells. There are several PCD's types, depending on the molecular mechanisms, such as non-inflammatory or pro-inflammatory. Hemocytes are the main component of cellular immunity in bivalve mollusks. Numerous infectious microorganisms produce toxins that impair hemocytes functions, but there is little knowledge on the role of PCD in these cells. This study aims to evaluate in vitro whether marine toxins induce a particular type of PCD in hemocytes of the bivalve mollusk Crassostrea gigas during 4 h at 25°C. Hemocytes were incubated with two types of marine toxins: non-proteinaceous toxins from microalgae (saxitoxin, STX; gonyautoxins 2 and 3, GTX2/3; okadaic acid/dynophysistoxin-1, OA/DTX-1; brevetoxins 2 and 3, PbTx-2,-3; brevetoxin 2, PbTx-2), and proteinaceous extracts from bacteria (Vibrio parahaemolyticus, Vp; V. campbellii, Vc). Also, we used the apoptosis inducers, staurosporine (STP), and camptothecin (CPT). STP, CPT, STX, and GTX 2/3, provoked high hemocyte mortality characterized by apoptosis hallmarks such as phosphatidylserine translocation into the outer leaflet of the cell membrane, exacerbated chromatin condensation, DNA oligonucleosomal fragments, and variation in gene expression levels of apoptotic caspases 2, 3, 7, and 8. The mixture of PbTx-2,-3 also showed many apoptosis features; however, they did not show apoptotic DNA oligonucleosomal fragments. Likewise, PbTx-2, OA/DTX-1, and proteinaceous extracts from bacteria Vp, and Vc, induced a minor degree of cell death with high gene expression of the pro-inflammatory initiator caspase-1, which could indicate a process of pyroptosis-like PCD. Hemocytes could carry out both PCD types simultaneously. Therefore, marine toxins trigger PCD's signaling pathways in C. gigas hemocytes, depending on the toxin's nature, which appears to be highly conserved both structurally and functionally.

239. RNA-Seq Identifies Marked Th17 Cell Activation and Altered CFTR Expression in Different Atopic Dermatitis Subtypes in Chinese Han Populations.

Front Immunol

2021 Apr 1

Tian X, Liu B, Chen L

BACKGROUND: Patients with atopic dermatitis (AD) exhibit phenotypic variability in ethnicity and IgE status. In addition, some patients develop other allergic conditions, such as allergic rhinitis (AR), in subsequent life. Understanding the heterogeneity of AD would be beneficial to phenotype-specific therapies. METHODS: Twenty-eight Chinese AD patients and 8 healthy volunteers were enrolled in the study. High-throughput transcriptome sequencing was conducted on lesional and nonlesional skin samples from 10 AD patients and matched normal skin samples from 5 healthy volunteers. Identification of differentially expressed genes (DEGs), KEGG pathway analyses, and sample cluster analyses were conducted in the R software environment using the DEseq2, ClusterProfiler, and pheatmap R packages, respectively. qRT-PCR, Western blotting, and ELISA were used to detect gene expression levels among subtypes. Correlation analysis was performed to further investigate their correlation with disease severity. RESULTS: A total of 25,798 genes were detected per sample. Subgroup differential expression analysis and functional enrichment analysis revealed significant changes in the IL17 signaling pathway in Chinese EAD patients but not in IAD patients. DEGs enriched in cytokine-cytokine receptor interactions and gland secretion were considered to be associated with atopic march. Further investigations confirmed a marked IL17A upregulation in Chinese EAD with a positive relationship with total IgE level and AD severity. In addition, increased IL17A in AD patients with AR demonstrated a closer association with AR severity than IL4R. Moreover, AQP5 and CFTR were decreased in the lesions of AD patients with AR. The CFTR mRNA expression level was negatively associated with the skin IL17A level and AR severity. CONCLUSION: Our research characterized marked Th17 activation in Chinese EAD patients, and altered expression of IL17A, IL4R, AQP5, and CFTR in AD patients with AR was associated with AR severity. It partially explained the phenotypic differences of AD subtypes and provided potential references for endotype-targeted therapy.

240. Genetics Insight for COVID-19 Susceptibility and Severity: A Review.

Front Immunol

2021 Apr 1

Fricke-Galindo I, Falfán-Valencia R.

241. PMMA-Based Continuous Hemofiltration Modulated Complement Activation and Renal Dysfunction in LPS-Induced Acute Kidney Injury.

Front Immunol

2021 Apr 1

Stasi A, Franzin R, Divella C

242. Diagnostic and Predictive Contribution of Autoantibodies Screening in a Large Series of Patients With Primary Immunodeficiencies.

Front Immunol

2021 Apr 1

Tahiat A, Yagoubi A, Ladj MS

OBJECTIVES: To evaluate the diagnostic and predictive contribution of autoantibodies screening in patients with primary immunodeficiencies (PIDs). METHODS: In the present study, PID patients and healthy controls have been screened for 54 different autoantibodies. The results of autoantibodies screening in PID patients were correlated to the presence of autoimmune diseases. RESULTS: A total of 299 PID patients were included in this study with a predominance of antibody deficiencies (27.8%) followed by immunodeficiencies affecting cellular and humoral immunity (26.1%) and complement deficiencies (22.7%). Autoimmune manifestations were present in 82 (27.4%) patients. Autoimmune cytopenia (10.4%) was the most common autoimmune disease followed by gastrointestinal disorders (10.0%), rheumatologic diseases (3.7%), and endocrine disorders (3.3%). Autoantibodies were found in 32.4% of PID patients and 15.8% of healthy controls (P < 0.0005). Anti-nuclear antibodies (ANA) (10.0%), transglutaminase antibody (TGA) (8.4%), RBC antibodies (6.7%), anti-smooth muscle antibody (ASMA) (5.4%), and ASCA (5.0%) were the most common autoantibodies in our series. Sixty-seven out of the 82 patients with autoimmune manifestations (81.7%) were positive for one or more autoantibodies. Eleven out of the 14 patients (78.6%) with immune thrombocytopenia had positive platelet-bound IgM. The frequencies of ASCA and ANCA among patients with IBD were 47.4% and 21.0% respectively. All patients with celiac disease had TGA-IgA, while six out of the 11 patients with rheumatologic diseases had ANA (54.5%). Almost one third of patients (30/97) with positive autoantibodies had no autoimmune manifestations. ANA, rheumatoid factor, ASMA, anti-phospholipid antibodies and ANCA were often detected while specific AID was absent. Despite the low positive predictive value of TGA-IgA and ASCA for celiac disease and inflammatory bowel disease respectively, screening for these antibodies identified undiagnosed disease in four patients with positive TGA-IgA and two others with positive ASCA. CONCLUSION: The present study provides valuable information about the frequency and the diagnostic/predictive value of a large panel of autoantibodies in PIDs. Given the frequent association of some AIDs with certain PIDs, screening for corresponding autoantibodies would be recommended. However, positivity for autoantibodies should be interpreted with caution in patients with PIDs due to their low positive predictive value.

243. TREX1 as a Novel Immunotherapeutic Target.

Front Immunol

2021 Apr 1

Hemphill WO, Simpson SR, Liu M

244. Proteomic Analysis of the Hemolymph After Metschnikowia bicuspidata Infection in the Chinese Mitten Crab Eriocheir sinensis.

Front Immunol

2021 Apr 1

Jiang H, Bao J, Xing Y

The "milky disease" of the Chinese mitten crab, Eriocheir sinensis, is a highly lethal fungal disease caused by Metschnikowia bicuspidata infection. To elucidate the immune responses of the hemolymph of E. sinensis to M. bicuspidata infection, a comparative analysis of the hemolymph of E. sinensis infected with M. bicuspidata and that treated with phosphate buffered saline was performed using label-free quantitative proteomics. A total of 429 proteins were identified. Using a 1.5-fold change in expression as a physiologically significant benchmark, 62 differentially expressed proteins were identified, of which 38 were significantly upregulated and 24 were significantly downregulated. The upregulated proteins mainly included cytoskeleton-related proteins (myosin regulatory light chain 2, myosin light chain alkali, tubulin α-2 chain, and tubulin β-1 chain), serine protease and serine protease inhibitor (clip domain-containing serine protease, leukocyte elastase inhibitor, serine protein inhibitor 42Dd), catalase, transferrin, and heat shock protein 70. Upregulation of these proteins indicated that phenoloxidase system, phagocytosis and the ROS systems were induced by M. bicuspidata. The downregulated proteins were mainly organ and tissue regeneration proteins (PDGF/VEGF-related factor protein, integrin-linked protein kinase homing pat-4 gene) and hemagglutination-associated proteins (hemolymph clottable protein, hemocyte protein-glutamine gamma-glutamyltransferase). Downregulation of these proteins indicated that M. bicuspidata inhibited hemocyte regeneration and hemolymph agglutination. Fifteen differentially expressed proteins related to immunity were verified using a parallel reaction monitoring method. The expression trend of these proteins was similar to that of the proteome. To the best of our knowledge, this is the first report on the proteome of E. sinensis in response to M. bicuspidata infection. These results not only provide new and important information on the immune response of crustaceans to yeast infection but also provide a basis for further understanding the molecular mechanism of complex host pathogen interactions between crustaceans and fungi.

245. Using Domain Based Latent Personal Analysis of B Cell Clone Diversity Patterns to Identify Novel Relationships Between the B Cell Clone Populations in Different Tissues.

Front Immunol

2021 Apr 1

Alon U, Mokryn O, Hershberg U.

246. Double Insurance for OC: miRNA-Mediated Platinum Resistance and Immune Escape.

Front Immunol

2021 Apr 1

Zou X, Zhao Y, Liang X

247. New Insights Into Biomphalysin Gene Family Diversification in the Vector Snail Biomphalaria glabrata.

Front Immunol

2021 Apr 1

Pinaud S, Tetreau G, Poteaux P