Refine Search

New Search

Results in Journal Frontiers in Immunology: 20,684

(searched for: journal_id:(1136462))
Page of 414
Articles per Page
by
Show export options
  Select all
Liam J. O’Neil, Christopher B. Oliveira, Donavon Sandoval-Heglund, Ana Barrera-Vargas, Javier Merayo-Chalico, Eduardo Aguirre-Aguilar, ,
Published: 14 September 2021
Frontiers in Immunology, Volume 12; https://doi.org/10.3389/fimmu.2021.715997

Abstract:
Objective Antibodies against carbamylated proteins (anti-CarP) are associated with poor prognosis and the development of bone erosions in rheumatoid arthritis (RA). RA neutrophils externalize modified autoantigens through the formation of neutrophil extracellular traps (NETs). Increased levels of the cathelicidin LL37 have been documented in the synovium of RA patients, but the cellular source remains unclear. We sought to determine if post-translational modifications of LL37, specifically carbamylation, occur during NET formation, enhance this protein’s autoantigenicity, and contribute to drive bone erosion in the synovial joint. Methods ELISA and Western blot analyses were used to identify carbamylated LL37 (carLL37) in biological samples. Anti-carLL37 antibodies were measured in the serum of HLA-DRB1*04:01 transgenic mice and in human RA synovial fluid. Results Elevated levels of carLL37 were found in plasma and synovial fluid from RA patients, compared to healthy controls. RA NETs release carLL37 and fibroblast-like synoviocytes (FLS) internalized NET-bound carLL37 and loaded it into their MHCII compartment. HLA-DRB1*04:01 transgenic mice immunized with FLS containing NETs developed autoantibodies against carLL37. Anti-carLL37 antibodies were present in RA sera and synovial fluid and they correlated with radiologic bone erosion scores of the hands and feet in RA patients. CarLL37-IgG immune complexes enhanced the ability of monocytes to differentiate into osteoclasts and potentiated osteoclast-mediated extracellular matrix resorption. Conclusions NETs are a source of carLL37 leading to induction of anti-carbamylated autoantibody responses. Furthermore, carLL37-IgG immune complexes may be implicated in the bone damage characteristic of RA. These results support that dysregulated NET formation has pathogenic roles in RA.
Mingxing Tang, Shuo Li, Lan Wei, Zhaohua Hou, ,
Published: 14 September 2021
Frontiers in Immunology, Volume 12; https://doi.org/10.3389/fimmu.2021.684605

Abstract:
Engineered nanomaterials (ENMs) have been widely exploited in several industrial domains as well as our daily life, raising concern over their potential adverse effects. While in general ENMs do not seem to have detrimental effects on immunity or induce severe inflammation, their indirect effects on immunity are less known. In particular, since the gut microbiota has been tightly associated with human health and immunity, it is possible that ingested ENMs could affect intestinal immunity indirectly by modulating the microbial community composition and functions. In this perspective, we provide a few pieces of evidence and discuss a possible link connecting ENM exposure, gut microbiota and host immune response. Some experimental works suggest that excessive exposure to ENMs could reshape the gut microbiota, thereby modulating the epithelium integrity and the inflammatory state in the intestine. Within such microenvironment, numerous microbiota-derived components, including but not limited to SCFAs and LPS, may serve as important effectors responsible of the ENM effect on intestinal immunity. Therefore, the gut microbiota is implicated as a crucial regulator of the intestinal immunity upon ENM exposure. This calls for including gut microbiota analysis within future work to assess ENM biocompatibility and immunosafety. This also calls for refinement of future studies that should be designed more elaborately and realistically to mimic the human exposure situation.
Oliver F. Wirz, Katharina Röltgen, Bryan A. Stevens, Suchitra Pandey, Malaya K. Sahoo, Lorna Tolentino, Michelle Verghese, Khoa Nguyen, Molly Hunter, Theo Thomas Snow, et al.
Published: 14 September 2021
Frontiers in Immunology, Volume 12; https://doi.org/10.3389/fimmu.2021.739037

Abstract:
Background Transfusion of COVID-19 convalescent plasma (CCP) containing high titers of anti-SARS-CoV-2 antibodies serves as therapy for COVID-19 patients. Transfusions early during disease course was found to be beneficial. Lessons from the SARS-CoV-2 pandemic could inform early responses to future pandemics and may continue to be relevant in lower resource settings. We sought to identify factors correlating to high antibody titers in convalescent plasma donors and understand the magnitude and pharmacokinetic time course of both transfused antibody titers and the endogenous antibody titers in transfused recipients. Methods Plasma samples were collected up to 174 days after convalescence from 93 CCP donors with mild disease, and from 16 COVID-19 patients before and after transfusion. Using ELISA, anti-SARS-CoV-2 Spike RBD, S1, and N-protein antibodies, as well as capacity of antibodies to block ACE2 from binding to RBD was measured in an in vitro assay. As an estimate for viral load, viral RNA and N-protein plasma levels were assessed in COVID-19 patients. Results Anti-SARS-CoV-2 antibody levels and RBD-ACE2 blocking capacity were highest within the first 60 days after symptom resolution and markedly decreased after 120 days. Highest antibody titers were found in CCP donors that experienced fever. Effect of transfused CCP was detectable in COVID-19 patients who received high-titer CCP and had not seroconverted at the time of transfusion. Decrease in viral RNA was seen in two of these patients. Conclusion Our results suggest that high titer CCP should be collected within 60 days after recovery from donors with past fever. The much lower titers conferred by transfused antibodies compared to endogenous production in the patient underscore the importance of providing CCP prior to endogenous seroconversion.
, Catharina Schuetz, Ulrich Baumann, Christian Klemann, Dorothee Viemann, Simona Ursu, Eva-Maria Jacobsen, Klaus-Michael Debatin, Ansgar Schulz, Manfred Hoenig, et al.
Published: 14 September 2021
Frontiers in Immunology, Volume 12; https://doi.org/10.3389/fimmu.2021.739675

Abstract:
DNA damage occurs constantly in every cell triggered by endogenous processes of replication and metabolism, and external influences such as ionizing radiation and intercalating chemicals. Large sets of proteins are involved in sensing, stabilizing and repairing this damage including control of cell cycle and proliferation. Some of these factors are phosphorylated upon activation and can be used as biomarkers of DNA damage response (DDR) by flow and mass cytometry. Differential survival rates of lymphocyte subsets in response to DNA damage are well established, characterizing NK cells as most resistant and B cells as most sensitive to DNA damage. We investigated DDR to low dose gamma radiation (2Gy) in peripheral blood lymphocytes of 26 healthy donors and 3 patients with ataxia telangiectasia (AT) using mass cytometry. γH2AX, p-CHK2, p-ATM and p53 were analyzed as specific DDR biomarkers for functional readouts of DNA repair efficiency in combination with cell cycle and T, B and NK cell populations characterized by 20 surface markers. We identified significant differences in DDR among lymphocyte populations in healthy individuals. Whereas CD56+CD16+ NK cells showed a strong γH2AX response to low dose ionizing radiation, a reduced response rate could be observed in CD19+CD20+ B cells that was associated with reduced survival. Interestingly, γH2AX induction level correlated inversely with ATM-dependent p-CHK2 and p53 responses. Differential DDR could be further noticed in naïve compared to memory T and B cell subsets, characterized by reduced γH2AX, but increased p53 induction in naïve T cells. In contrast, DDR was abrogated in all lymphocyte populations of AT patients. Our results demonstrate differential DDR capacities in lymphocyte subsets that depend on maturation and correlate inversely with DNA damage-related survival. Importantly, DDR analysis of peripheral blood cells for diagnostic purposes should be stratified to lymphocyte subsets.
, Geoffrey R. Hill
Published: 14 September 2021
Frontiers in Immunology, Volume 12; https://doi.org/10.3389/fimmu.2021.715893

Abstract:
Allogeneic stem cell transplantation (alloSCT) is a curative therapy for hematopoietic malignancies. The therapeutic effect relies on donor T cells and NK cells to recognize and eliminate malignant cells, known as the graft-versus-leukemia (GVL) effect. However, off target immune pathology, known as graft-versus-host disease (GVHD) remains a major complication of alloSCT that limits the broad application of this therapy. The presentation of recipient-origin alloantigen to donor T cells is the primary process initiating GVHD and GVL. Therefore, the understanding of spatial and temporal characteristics of alloantigen presentation is pivotal to attempts to separate beneficial GVL effects from detrimental GVHD. In this review, we discuss mouse models and the tools therein, that permit the quantification of alloantigen presentation after alloSCT.
Hao Zhang, Zeyu Wang, Ziyu Dai, Wantao Wu, Hui Cao, Shuyu Li, Nan Zhang,
Published: 14 September 2021
Frontiers in Immunology, Volume 12; https://doi.org/10.3389/fimmu.2021.694490

Abstract:
Tumor-infiltrating immune cells (TIICs) have become an important source of markers for predicting the clinical outcomes of cancer patients. However, measurements of cellular heterogeneity vary due to the frequently updated reference genomes and gene annotations. In this study, we systematically collected and evaluated the infiltration pattern of 65 immune cells. We constructed the Immune Cell Pair (ICP) score based on the cell pair algorithm in 3,715 samples and across 12 independent cancer types, among which, the ICP score from six cancer types was further validated in 2,228 GEO samples. An extensive tumorigenic and immunogenomic analysis was subsequently conducted. As a result, the ICP score showed a robust reliability and efficacy in predicting the survival of patients with gliomas, in pan-cancer samples, and six independent cancer types. Notably, the ICP score was correlated with the genomic alteration features in gliomas. Moreover, the ICP score exhibited a remarkable association with multiple immunomodulators that could potentially mediate immune escape. Finally, the ICP score predicted immunotherapeutic responses with a high sensitivity, allowing a useful tool for predicting the overall survival and guiding immunotherapy for cancer patients.
Zi Wang, Xinfang Xie, Jingyi Li, Xue Zhang, Jiawei He, Manliu Wang, , Hong Zhang
Published: 14 September 2021
Frontiers in Immunology, Volume 12; https://doi.org/10.3389/fimmu.2021.676919

Abstract:
Introduction Crescents, especially those found at a percentage greater than 50%, are often associated with rapid progression of kidney disease in IgA nephropathy (IgAN). The mechanism of crescents forming in IgAN is still unclear. In this study, we aimed to evaluate whether excess complement activation participates in the formation of crescents in IgAN. Methods One hundred IgAN patients with various proportions of crescents—24 with 1%–24%, 27 with 25%–49%, 21 with 50%–74% 12 with more than 75%, and 16 without crescents—were included. Urinary concentrations of mannose-binding lectin (MBL), Bb, C4d, C3a, C5a, and soluble C5b-9 (sC5b-9) were measured at the time of biopsy. Receiver operating characteristic (ROC) curves were performed to evaluate predictive ability of renal survival for urine complement activation. In addition, historical C4d, C5b-9, and C3d were stained by immunohistochemistry. Results IgAN patients with more than 50% crescent formation showed higher complement activation levels than the other patients (urinary C3a/creatinine (C3a/Cr): 6.7295 ng/mg, interquartile range (IQR) 1.4652–62.1086 ng/mg vs. 0.1055 ng/mg, IQR 0–1.4089 ng/mg; urinary C5a/Cr: 15.6202 ng/mg, 4.3127–66.7347 ng/mg vs. 0.3280 ng/mg, IQR 0.0859–2.4439 ng/mg; urinary sC5b-9/Cr: 98.6357 ng/mg, 8.8058–1,087.4578 ng/mg vs. 1.4262 ng/mg, 0.0916–11.0858 ng/mg, all p-values <0.001). The levels of urinary MBL and C4d representing lectin complement pathway showed a linear association with the proportion of crescents (r = 0.457 and 0.562, respectively, both p-values <0.001). Combined urine complement products could increase the predictive ability compared with crescents alone from 0.904 to 0.944 (p = 0.062) with borderline significance. Moreover, the glomerular C4d deposition rate elevated with the increase of proportions of crescents. Conclusion Excess complement activation may be involved in the formation of crescents, especially diffuse crescent formation, in patients with IgAN. Urinary C4d correlated with the proportion of crescents and was a potential biomarker for disease monitoring in crescentic IgAN.
Markus G. Klammer, Omar Dzaye, Thomas Wallach, Christina Krüger, Dorothea Gaessler, Alice Buonfiglioli, Katja Derkow, Helmut Kettenmann, Melanie M. Brinkmann,
Published: 13 September 2021
Frontiers in Immunology, Volume 12; https://doi.org/10.3389/fimmu.2021.715774

Abstract:
The chaperone protein Unc-93 homolog B1 (UNC93B1) regulates internalization, trafficking, and stabilization of nucleic acid-sensing Toll-like receptors (TLR) in peripheral immune cells. We sought to determine UNC93B1 expression and its functional relevance in inflammatory and injurious processes in the central nervous system (CNS). We found that UNC93B1 is expressed in various CNS cells including microglia, astrocytes, oligodendrocytes, and neurons, as assessed by PCR, immunocyto-/histochemistry, and flow cytometry. UNC93B1 expression in the murine brain increased during development. Exposure to the microRNA let-7b, a recently discovered endogenous TLR7 activator, but also to TLR3 and TLR4 agonists, led to increased UNC93B1 expression in microglia and neurons. Microglial activation by extracellular let-7b required functional UNC93B1, as assessed by TNF ELISA. Neuronal injury induced by extracellular let-7b was dependent on UNC93B1, as UNC93B1-deficient neurons were unaffected by the microRNA’s neurotoxicity in vitro. Intrathecal application of let-7b triggered neurodegeneration in wild-type mice, whereas mice deficient for UNC93B1 were protected against injurious effects on neurons and axons. In summary, our data demonstrate broad UNC93B1 expression in the murine brain and establish this chaperone as a modulator of neuroinflammation and neuronal injury triggered by extracellular microRNA and subsequent induction of TLR signaling.
Fabrice Cognasse, Hind Hamzeh-Cognasse, Patrick Mismetti, Thierry Thomas, David Eglin, Hubert Marotte
Published: 13 September 2021
Frontiers in Immunology, Volume 12; https://doi.org/10.3389/fimmu.2021.741988

Abstract:
The development of platelet lysate (PL) or platelet-rich plasma (PRP) products to stimulate tissue repair and regeneration has been an important research field in various indications for more than 30 years (1–4), resulting in considerable interest in their potential for regenerative medicine. Moreover, many in vitro, in vivo and ex vivo studies have recently focused on the mechanisms of action by which these growth factors affect the biological activities of cells, thus supporting tissue healing. We feel that it is worth emphasising 1/the still limited understanding of their biological effect in the context of musculoskeletal injuries and other diseases, and 2/the lack of standardization of PL or PRP products. We also want to highlight the scientific cornerstones that need to be addressed to ensure ultimately safe and efficacious PL or PRP. The vast majority of studies dealing with the efficacy of PL or PRP have focused only on the various growth factors - vascular endothelial growth factor (VEGF), insulin-like growth factor, fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), brain-derived neurotrophic factor, transforming growth factor-beta (TGF-β), epidermal growth factor and others - that could play a role in the putative healing properties of PL or PRP through angiogenesis and cell stimulation. Surprisingly, while blood platelets are universally known for their major haemostatic role, as they restore vascular epithelial damage, their ability to produce and secrete a variety of cytokines, chemokines and related pro/anti-inflammatory molecules including growth factors, which contribute to this process and its integrated immune reaction (Figures 1A, B), is rarely taken into account when deciphering the effects of PL or PRP administration. Figure 1 Platelet, platelet lysate (PL) or platelet-rich plasma (PRP) component (A), applied in different pathological contexts (B). We therefore believe that it is useful to draw a broader and ultimately more faithful picture of all the factors, platelets can release, with up to 1,100 proteins found in their secretome (5) that could trigger a mix of positive and negative effects on tissue healing, depending on the circumstances or local factors. Platelets tightly regulate the process of angiogenesis (6, 7) by releasing both pro-angiogenic [VEGF, fibroblast growth factor-2, hepatocyte growth factor, PDGF, interleukin (IL)-8 and many others] and anti-angiogenic (thrombospondin-1, TGF-β, plasminogen activator inhibitor-1, IL-1-β and others) factors in α-granules (8). Moreover, proangiogenic factors such as VEGF are released in high concentrations in haemostatic clots, causing the proliferation and migration of proliferating endothelial cells (9). However, secreted anti-angiogenic factors such as TGF-β1 inhibit the proliferation and migration of endothelial cells. Platelet factor 4 (PF4), also known as chemokine (C- X-C motif) ligand 4 (CXCL4), is a small cytokine belonging to the CXC chemokine family. This chemokine is also released from activated platelet α-granules. PF4 has two important functions in the vasculature. It not only plays a proatherogenic role, but also has anti-angiogenic effects. It is suggested that the molecules released from the α-granules (e.g., fibrinogen) and lysosomes of platelets participate in clot remodelling. Consequently, platelets and platelet-derived molecules participate in the natural process of wound healing and angiogenesis (8). Platelets are also the main source of circulating microparticles (PMPs) (10). Circulating PMPs, present in PL or PRP, can release phosphatidylserine, which provides a highly procoagulant external surface. In addition, PMPs also release tissue factor, the main molecule in the coagulation cascade, and can deliver immunomodulatory factors such as CCL5, IL-1β, and CD40L, which modulate the activation of inflammatory cells such as neutrophils and are capable of exerting their pro-inflammatory activity outside of the blood compartment, thus linking thrombosis and inflammation (11). Platelets also release chemotactic molecules (IL-8, CCL-5, etc.) and other substances (especially immunomodulatory substances such as sCD40L), and trigger the proliferation of fibroblasts, endothelial cells and progenitor cells, thus regulating the healing process. It is important to emphasize again that many of the proteins and components of platelets are mechanically and chemically activated, and therefore their preparation can affect their efficacy enormously (Figure 1A). Recently, Jaron Nazaroff et al. published (12) a systematic review and Meta-Analysis (Cochrane Database, PubMed, and EMBASE databases) for level I/II clinical studies on PRP injections across all medical specialties [cardiothoracic surgery, cosmetic, dermatology, musculoskeletal (MSK), neurology, oral maxillofacial surgery, ophthalmology, and plastic surgery]. Generally, 61% of the studies found PRP to be favorable over control treatment, with no difference across medical specialties. The authors pointed to the inconsistent report of PRP throughout the medical research literature. Because leukocyte is known to produce inflammation by driving the inflammatory phase of wound healing, research into leukocyte content in PRP formulations and the possible impact on osteoarthritis treatment has sparked some debate in the literature. However, José Fábio Lana et al. looked at the intriguing concept of leukocyte-rich platelet-rich plasma, or L-PRP, which may give benefits rather than drawbacks in terms of PRP’s regenerative potential (13). PPL or PRP are currently recognized as products that promote tissue healing and regeneration. PRP is used in numerous areas, for acute diseases as much as for chronic diseases, for its haemostatic and healing properties in bone or soft tissue, by delivering supraphysiological concentrations of autologous platelets and their contents at...
Corrigendum
Anna Gritsenko, Shi Yu, Fatima Martin-Sanchez, Ines Diaz-Del-Olmo, Eva-Maria Nichols, Daniel M. Davis, David Brough,
Published: 13 September 2021
Frontiers in Immunology, Volume 12; https://doi.org/10.3389/fimmu.2021.763899

Abstract:
A Corrigendum onPriming Is Dispensable for NLRP3 Inflammasome Activation in Human Monocytes In Vitro By Gritsenko A, Yu S, Martin-Sanchez F, Diaz-del-Olmo I, Nichols E-M, Davis DM, Brough D and Lopez-Castejon G (2020). Front. Immunol. 11:565924. doi: 10.3389/fimmu.2020.565924 In the original article, there was an error in the section Experimental Procedures, Cell Culture and Treatments, Paragraph 2. The incorrect guide RNA oligonucleotide sequences were given for GSDMD knockout in THP-1 cells: “GSDMD knockout THP-1 cells were lentivirally generated using guide RNA oligonucleotides sequence 5′-CACCGCTGCAAGCTGGCCAGGTACC-3′ and 5′ AAACGGTACCTGGCCAGCTTGCAGC-3′ (22) by utilizing the lentiCRISPR v2 plasmid system. lentiCRISPR v2 was a gift from Feng Zhang (Addgene plasmid # 52961; http://n2t.net/addgene:52961; RRID : Addgene_52961)”. A correction has been made to the above sentence, as follows: “GSDMD knockout THP-1 cells were lentivirally generated using guide RNA oligonucleotide sequences 5’-CACCGACCAGCCTGCAGAGCTCCAC-3’ and 5’-AAACGTGGAGCTCTGCAGGCTGGTC-3’ (22) by utilizing the lentiCRISPR v2 plasmid system. lentiCRISPR v2 was a gift from Feng Zhang (Addgene plasmid #52961; http://n2t.net/addgene:52961; RRID : Addgene_52961)”. The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated. All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. Keywords: macrophage, inflammasome, NLRP3, priming, monocytes, IL-18, GSDMD Citation: Gritsenko A, Yu S, Martin-Sanchez F, Diaz-del-Olmo I, Nichols E-M, Davis DM, Brough D and Lopez-Castejon G (2021) Corrigendum: Priming Is Dispensable for NLRP3 Inflammasome Activation in Human Monocytes In Vitro. Front. Immunol. 12:763899. doi: 10.3389/fimmu.2021.763899 Received: 24 August 2021; Accepted: 27 August 2021;Published: 13 September 2021. Edited and reviewed by: Copyright © 2021 Gritsenko, Yu, Martin-Sanchez, Diaz-del-Olmo, Nichols, Davis, Brough and Lopez-Castejon. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. *Correspondence: Gloria Lopez-Castejon, [email protected]
, Ioana Berindan-Neagoe,
Published: 13 September 2021
Frontiers in Immunology, Volume 12; https://doi.org/10.3389/fimmu.2021.764525

Abstract:
Editorial on the Research TopicRole of Macrophage MicroRNAs in Inflammatory Diseases and Cancer Macrophages are important players in immune pathogenesis and the miRNA macrophage involvement was proved to be central in various human diseases from hematologic malignancies and disorders, solid tumors, to allergy, asthma and autoimmune diseases. Indeed, MicroRNAs (miRNA) are short non-coding RNAs involved in regulating the differentiation between the pro-inflammatory type 1 macrophages (M1) and the anti-inflammatory type 2 macrophages (M2). Such effect can be direct (endogenous miRNA) or indirect when exogenous miRNA (including ones produce by macrophages) can influence the balance between type 1 and type 2 cytokines in their tissue environment (1). To this end it has been demonstrated that exosomal miRNA could be transferred from macrophages to other cell types, and vice versa, via extracellular vesicles influencing their phenotype and functions. This Research Topic papers (original research paper and reviews) provided knowledge on the role of miRNA macrophage in inflammatory diseases and cancer where monocyte/macrophage play an important role in their pathogenesis. In their review Iurca et al. present the involvement of tumor-associated macrophages (TAM) in the hallmarks of metastasis and their miRNA-related regulation with a focus on lung cancer Iurca et al. TAM have role in immunosuppression, angiogenesis and lymphangiogenesis, vessel intravasation and extravasation of cancer cells, and premetastatic niche formation. An indirect therapeutic approach on TAM can be also represented by regulation of miRNAs involved in their polarization and implicit oncogenic features such as studied miR-21 and miR-155, but also other miRNA less present in the current literature: miR-1207-5p, miR-193b, miR-320a, and others. Kwon et al. group’s review is focused on interactions between cancer cells and stromal cells specifically macrophages via exosome containing miRNA. Exosomes are lipid bilayer membrane vesicles derived from the luminal membrane of multivesicular bodies, which are constitutively released by fusion with the cell membrane. Exosomes protect miRNA from degradation, enabling them to be stably expressed in the extracellular space. In this review the role of several exosomal miRNAs from tumor cells in the polarization of macrophages are discussed and the targets of these miRNAs are presented. Tumor-derived exosomes miRNA play role in inducing the M1- or M2-like polarization of macrophages in the tumor microenvironment. For example, exosomal miRNA-146a from hepatic cancer cells and exosomal miRNA-203 from colorectal cancer cells have oncogenic activity and induce the pro-tumoral M2 polarization of macrophages and accelerated cancer progress (2, 3). On the other hand, exosomal miRNA-19a-3p by inducing M1-macrophages polarization, suppresses breast cancer progression (4). Conversely, the effects of exosomal miRNAs from TAMs on cancer cell invasion, growth, and anti-cancer drug resistance are presented. M2 phenotype TAMs-derived exosome miRNAs could affect tumor growth, invasion/metastasis, and anti-cancer drug resistance. A high number of TAMs has been associated with the poor prognosis of cancers. Exosomes from cancer cells carrying miRNAs proven to confer anti-cancer drug-resistance could be targeted. Conversion of immunosuppressive TAMs into M1 macrophages can be used in combination with current anti-cancer immunotherapies. Recent studies reported important role for the adaptator kinase Trib1 (Tribbles pseudokinase 1) in M2-like macrophage function, and its overexpression in prostate cancer. The original research article of Niespolo et al. is among the first to explore the Trib1 3’ UTR capacity to bind several miRNAs. Among them, miRNA-101-3p and miRNA-132-3p were found to regulate directly Trib1 expression and function, driving an inflammatory M1 phenotype in human macrophages. They also show that multiple miRNAs predicted to regulate Trib1 in prostate cancer show decreased expression leading to the hypothesis that this miRNA regulation leads to elevated Trib1 expression in this tumor. Following pathogen endocytosis, macrophages/dendritic cells instruct the adaptive immune response, in parallel to antigen-presentation, by providing cytokine production to promote an inflammatory response when macrophages are polarized in the classical M1 pathway or an anti-inflammatory response when they are polarized in the alternative M2 pathway. Polarization decision relies on two main metabolic pathways controlled by miRNAs as reviewed by Nelson and O’Connell. Indeed, the M1 pro-inflammatory macrophage profile triggered in vitro by lipopolysaccharide (LPS) and interferon (IFN)-γ drives an aerobic glycolysis signal, known as Warburg Effect, that helps to maintain a cellular redox state in the cells with the help of two master transcription factors: nuclear factor kappa B (NF-κB) and hypoxia inducible factor 1α (HIF1α). This leads to the production of interleukin (IL)1-β, tumor necrosis factor (TNF)-α, IL-6, IL-12, IL-23, reactive oxygen species (ROS), L-arginine conversion into citrulline, and nitric oxide (NO) production. At the opposite, IL-4 and IL-13 polarized M2 anti-inflammatory macrophage cells use oxidative phosphorylation through a janus kinase (Jak)-3/signal transducer and activator of transcription (STAT)-6 dependent axis to drive wound healing, humoral immunity, angiogenesis, tissue remodeling, and to produce the immunosuppressive IL-10, IL-13 and transforming growth factor (TGF)-β cytokines. Additional pathways are important in M2 polarized macrophages such as AMP-activated protein kinase (AMPK) that promote fatty acid oxidation (FA0). As a consequence, macrophage metabolic functions, polarization and cytokine production have to be tightly regulated, which can be achieved by miRNAs acting intracellularly or transport to distant cells...
, Fabian Schulte, Melissa Martins, Homa Sherzai, Constantinos Floros, Maryann Cugini, Chung-Jung Chiu, Markus Hardt, Thomas Van Dyke
Published: 13 September 2021
Frontiers in Immunology, Volume 12; https://doi.org/10.3389/fimmu.2021.704163

Abstract:
Background Periodontal disease is among the sixth most common inflammatory diseases worldwide with high risk to promote complications from other inflammatory diseases including diabetes, cardiovascular disease and Alzheimer’s Disease. Failure of active resolution of inflammation pathways is implicated in pathogenesis of periodontal diseases, including gingivitis. Lipoxin A4 (LXA4), a member of the specialized pro-resolving lipid mediators (SPMs) that drive resolution of inflammation via GPC-receptor mediated pathways, offered therapeutic advantages in preclinical models of periodontitis. Methods We conducted a randomized, placebo-controlled, parallel-group Phase 1 clinical trial to determine the safety and preliminary efficacy of an LXA4 analog in patients with gingival inflammation. One hundred twenty-seven (127) individuals were randomized to daily use of an oral rinse containing a LXA4 mimetic, methyl ester-benzo-lipoxin A4 (BLXA4), placebo rinse or a no-rinse control group for 28 days. Treatment emergent adverse events (TEAEs) were assessed for safety, the primary outcome. Secondary outcomes included the change in the level of gingival inflammation and periodontal pocket depth (PD). Serum SPMs were monitored using targeted lipid mediator lipidomics to assess potential systemic impact of BLXA4. Results The frequency of TEAEs was similar in BLXA4 and placebo-treated groups with no study-related SAEs. Once-daily rinsing with BLXA4 for 28-days resulted in a greater decrease in gingival inflammation compared to placebo rinse and no-rinse control groups (mean change: 0.26 GI unit vs 0.21 and 0.17, respectively). PD reduction was also greater with BLXA4 oral rinse compared to placebo and no-rinse groups (mean reduction: 1.23 mm vs. 0.71 mm and 0.46 mm, respectively). Topical application of BLXA4 increased serum levels of SPMs. Conclusion Treatment with BLXA4 reduces local inflammation, and increases abundance of pro-resolution molecules systemically, which may dampen inflammation that can mediate progression and course of inflammatory diseases beyond periodontitis. Clinical Trial Registration ClinicalTrials.gov, identifier (NCT02342691).
Lianlian Tian, Jun-Long Zhao, Jian-Qin Kang, Shi-Bo Guo, Nini Zhang, Lei Shang, Ya-Long Zhang, Jian Zhang, , Yan Lin
Published: 13 September 2021
Frontiers in Immunology, Volume 12; https://doi.org/10.3389/fimmu.2021.740565

Abstract:
Inflammatory bowel disease (IBD) is characterized by chronic and relapsing intestinal inflammation, which currently lacks safe and effective medicine. Some previous studies indicated that Astragaloside IV (AS-IV), a natural saponin extracted from the traditional Chinese medicine herb Ligusticum chuanxiong, alleviates the experimental colitis symptoms in vitro and in vivo. However, the mechanism of AS-IV on IBD remains unclear. Accumulating evidence suggests that M2-polarized intestinal macrophages play a pivotal role in IBD progression. Here, we found that AS-IV attenuated clinical activity of DSS-induced colitis that mimics human IBD and resulted in the phenotypic transition of macrophages from immature pro-inflammatory macrophages to mature pro-resolving macrophages. In vitro, the phenotype changes of macrophages were observed by qRT-PCR after bone marrow-derived macrophages (BMDMs) were induced to M1/M2 and incubated with AS-IV, respectively. In addition, AS-IV was effective in inhibiting pro-inflammatory macrophages and promoting the pro-resolving macrophages to ameliorate experimental colitis via the regulation of the STAT signaling pathway. Hence, we propose that AS-IV can ameliorate experimental colitis partially by modulating macrophage phenotype by remodeling the STAT signaling, which seems to have an essential function in the ability of AS-IV to alleviate the pathological progress of IBD.
Toni Herta, Aritra Bhattacharyya, Maciej Rosolowski, Claudia Conrad, Corinne Gurtner, Achim D. Gruber, Peter Ahnert, Birgitt Gutbier, Doris Frey, Norbert Suttorp, et al.
Published: 13 September 2021
Frontiers in Immunology, Volume 12; https://doi.org/10.3389/fimmu.2021.726135

Abstract:
The transcription factor Krueppel-like factor (KLF) 4 fosters the pro-inflammatory immune response in macrophages and polymorphonuclear neutrophils (PMNs) when stimulated with Streptococcus pneumoniae, the main causative pathogen of community-acquired pneumonia (CAP). Here, we investigated the impact of KLF4 expression in myeloid cells such as macrophages and PMNs on inflammatory response and disease severity in a pneumococcal pneumonia mouse model and in patients admitted to hospital with CAP. We found that mice with a myeloid-specific knockout of KLF4 mount an insufficient early immune response with reduced levels of pro-inflammatory cytokines and increased levels of the anti-inflammatory cytokine interleukin (IL) 10 in bronchoalveolar lavage fluid and plasma and an impaired bacterial clearance from the lungs 24 hours after infection with S. pneumoniae. This results in higher rates of bacteremia, increased lung tissue damage, more severe symptoms of infection and reduced survival. Higher KLF4 gene expression levels in the peripheral blood of patients with CAP at hospital admission correlate with a favourable clinical presentation (lower sequential organ failure assessment (SOFA) score), lower serum levels of IL-10 at admission, shorter hospital stay and lower mortality or requirement of intensive care unit treatment within 28 days after admission. Thus, KLF4 in myeloid cells such as macrophages and PMNs is an important regulator of the early pro-inflammatory immune response and, therefore, a potentially interesting target for therapeutic interventions in pneumococcal pneumonia.
Xing-Xing Zhen, Long Yang, Yan Gu, Qian Yang, Wen-Wen Gu, Ya-Ping He, Yan-Ling Wang,
Published: 13 September 2021
Frontiers in Immunology, Volume 12; https://doi.org/10.3389/fimmu.2021.691908

Abstract:
Decidual macrophages (dMϕ) are the second largest population of leukocytes at the maternal–fetal interface and play critical roles in maintaining pregnancy. Our previous studies demonstrated the active involvement of monoclonal nonspecific suppressor factor-β (MNSFβ) in embryonic implantation and pregnancy success. MNSFβ is a ubiquitously expressed ubiquitin-like protein that also exhibits immune regulatory potential, but its function in human dMϕ remains unknown. Here, we observed that the proportion of CD11chigh (CD11cHI) dMϕ was significantly increased in dMϕ derived from patients with recurrent pregnancy loss (RPL dMϕ) compared to those derived from normal pregnant women (Control dMϕ). The production of MNSFβ and TNFα by RPL dMϕ was also significantly increased compared to that by Control dMϕ. Conditioned medium from RPL dMϕ exerted an inhibitory effect on the invasiveness of human trophoblastic HTR8/SVneo cells, and this effect could be partially reversed by a neutralizing antibody against TNFα. Bioinformatics analysis indicated a potential interaction between MNSFβ and RC3H1, a suppressor of TNFα transcription. Immunoprecipitation experiments with human Mϕ differentiated from the human monocyte cell line Thp1 (Thp1-derived Mϕ) proved the binding of MNSFβ to RC3H1. Specific knockdown of MNSFβ in Thp1-derived Mϕ led to a marked decrease in TNFα production, which could be reversed by inhibiting RC3H1 expression. Interestingly, a significant decrease in the protein level of RC3H1 was observed in RPL dMϕ. Together, our findings indicate that aberrantly increased MNSFβ expression in dMϕ may promote TNFα production via its interaction with RC3H1, and these phenomena could result in the disruption of the immune balance at the maternal–fetal interface and thus pregnancy loss.
Fang Huang, Ning Pan, Yiting Wei, Jinjin Zhao, Mohanad Aldarouish, Xuru Wang, Xiaotong Sun, Zhifa Wen, Yongqiang Chen,
Published: 13 September 2021
Frontiers in Immunology, Volume 12; https://doi.org/10.3389/fimmu.2021.707298

Abstract:
We previously reported that enriched ubiquitinated proteins (UPs) from tumor cells have the potential to be used as immunotherapy vaccine against cancer. Here we enriched UPs from epirubicin (EPB)-induced multi-drug-resistant cancer stem-like breast cancer cell line (4T1/EPB) and tested the efficacy of α-Al2O3-UPs-4T1/EPB (short for UPs-4T1/EPB) as therapeutic vaccine alone and in combination with the stimulator of interferon genes (STING) agonist in mice with drug-resistant and metastatic breast cancer. Vaccination with UPs-4T1/EPB exerted profound anti-tumor effects through augmented specific CD8+ T cell responses and amplified T cell receptor diversity of tumor-infiltrating lymphocytes (TILs). Importantly, the combination with STING agonist further facilitated the migration of mature CD8α+ dendritic cells to the lymph nodes and the infiltration of TILs within tumors, resulting in primary tumor regression and pulmonary metastasis eradication in mice. Moreover, the cured mice were completely resistant against a subsequent rechallenge with the same tumor. Our study indicates that this novel combinatorial immunotherapy with UPs-4T1/EPB vaccine and STING agonist is effective in mice with drug-resistant and metastatic breast cancer.
, Angie Snell Bennett, Elisabete Lino, Adam J. Gehring, Jordan Feld, Harry L. A. Janssen, Scott H. Robbins
Published: 13 September 2021
Frontiers in Immunology, Volume 12; https://doi.org/10.3389/fimmu.2021.648420

Abstract:
Background A functional cure for chronic HBV could be achieved by boosting HBV-specific immunity. In vitro studies show that immunotherapy could be an effective strategy. However, these studies include strategies to enrich HBV-specific CD8 T cells, which could alter the expression of the anti-PD-1/anti-PD-L1 antibody targets. Our aim was to determine the efficacy of PD-L1 blockade ex vivo. Methods HBV-specific CD8 T cells were characterized ex vivo by flow cytometry for the simultaneous analysis of six immune populations and 14 activating and inhibitory receptors. Ex vivo functionality was quantified by ELISpot and by combining peptide pool stimulation, dextramers and intracellular flow cytometry staining. Results The functionality of HBV-specific CD8 T cells is associated with a higher frequency of cells with low exhaustion phenotype (LAG3-TIM3-PD-1+), independently of the clinical parameters. The accumulation of HBV-specific CD8 T cells with a functionally exhausted phenotype (LAG3+TIM3+PD-1+) is associated with lack of ex vivo functionality. PD-L1 blockade enhanced the HBV-specific CD8 T cell response only in patients with lower exhaustion levels, while response to PD-L1 blockade was abrogated in patients with higher frequencies of exhausted HBV-specific CD8 T cells. Conclusion Higher levels of functionally exhausted HBV-specific CD8 T cells are associated with a lack of response that cannot be restored by blocking the PD-1:PD-L1 axis. This suggests that the clinical effectiveness of blocking the PD-1:PD-L1 axis as a monotherapy may be restricted. Combination strategies, potentially including the combination of anti-LAG-3 with other anti-iR antibodies, will likely be required to elicit a functional cure for patients with high levels of functionally exhausted HBV-specific CD8 T cells.
Zeyu Wang, Yuze Liu, Yuyao Mo, Hao Zhang, Ziyu Dai, Xun Zhang, Weijie Ye, Hui Cao, ,
Published: 13 September 2021
Frontiers in Immunology, Volume 12; https://doi.org/10.3389/fimmu.2021.731751

Abstract:
Gliomas are a type of malignant central nervous system tumor with poor prognosis. Molecular biomarkers of gliomas can predict glioma patient’s clinical outcome, but their limitations are also emerging. C-X-C motif chemokine ligand family plays a critical role in shaping tumor immune landscape and modulating tumor progression, but its role in gliomas is elusive. In this work, samples of TCGA were treated as the training cohort, and as for validation cohort, two CGGA datasets, four datasets from GEO database, and our own clinical samples were enrolled. Consensus clustering analysis was first introduced to classify samples based on CXCL expression profile, and the support vector machine was applied to construct the cluster model in validation cohort based on training cohort. Next, the elastic net analysis was applied to calculate the risk score of each sample based on CXCL expression. High-risk samples associated with more malignant clinical features, worse survival outcome, and more complicated immune landscape than low-risk samples. Besides, higher immune checkpoint gene expression was also noticed in high-risk samples, suggesting CXCL may participate in tumor evasion from immune surveillance. Notably, high-risk samples also manifested higher chemotherapy resistance than low-risk samples. Therefore, we predicted potential compounds that target high-risk samples. Two novel drugs, LCL-161 and ADZ5582, were firstly identified as gliomas’ potential compounds, and five compounds from PubChem database were filtered out. Taken together, we constructed a prognostic model based on CXCL expression, and predicted that CXCL may affect tumor progression by modulating tumor immune landscape and tumor immune escape. Novel potential compounds were also proposed, which may improve malignant glioma prognosis.
Sun Koo Yoo, Syed Faizan Mehdi, Suma Pusapati, Nimisha Mathur, Manasa Anipindi, Bruno Lunenfeld, Barbara Lowell, Huan Yang, Christine Noel Metz, Sawleha Arshi Khan, et al.
Published: 13 September 2021
Frontiers in Immunology, Volume 12; https://doi.org/10.3389/fimmu.2021.714177

Abstract:
Sepsis continues to be a major cause of morbidity, mortality, and post-recovery disability in patients with a wide range of non-infectious and infectious inflammatory disorders, including COVID-19. The clinical onset of sepsis is often marked by the explosive release into the extracellular fluids of a multiplicity of host-derived cytokines and other pro-inflammatory hormone-like messengers from endogenous sources (“cytokine storm”). In patients with sepsis, therapies to counter the pro-inflammatory torrent, even when administered early, typically fall short. The major focus of our proposed essay is to promote pre-clinical studies with hCG (human chorionic gonadotropin) as a potential anti-inflammatory therapy for sepsis.
Luka Krampert, Katharina Bauer, Stefan Ebner, Patrick Neubert, Thomas Ossner, Anna Weigert, Valentin Schatz, Martina Toelge, Agnes Schröder, Martin Herrmann, et al.
Published: 10 September 2021
Frontiers in Immunology, Volume 12; https://doi.org/10.3389/fimmu.2021.712948

Abstract:
Infection and inflammation can augment local Na+ abundance. These increases in local Na+ levels boost proinflammatory and antimicrobial macrophage activity and can favor polarization of T cells towards a proinflammatory Th17 phenotype. Although neutrophils play an important role in fighting intruding invaders, the impact of increased Na+ on the antimicrobial activity of neutrophils remains elusive. Here we show that, in neutrophils, increases in Na+ (high salt, HS) impair the ability of human and murine neutrophils to eliminate Escherichia coli and Staphylococcus aureus. High salt caused reduced spontaneous movement, degranulation and impaired production of reactive oxygen species (ROS) while leaving neutrophil viability unchanged. High salt enhanced the activity of the p38 mitogen-activated protein kinase (p38/MAPK) and increased the interleukin (IL)-8 release in a p38/MAPK-dependent manner. Whereas inhibition of p38/MAPK did not result in improved neutrophil defense, pharmacological blockade of the phagocyte oxidase (PHOX) or its genetic ablation mimicked the impaired antimicrobial activity detected under high salt conditions. Stimulation of neutrophils with phorbol-12-myristate-13-acetate (PMA) overcame high salt-induced impairment in ROS production and restored antimicrobial activity of neutrophils. Hence, we conclude that high salt-impaired PHOX activity results in diminished antimicrobial activity. Our findings suggest that increases in local Na+ represent an ionic checkpoint that prevents excessive ROS production of neutrophils, which decreases their antimicrobial potential and could potentially curtail ROS-mediated tissue damage.
Joy Manohar Sibi, Viswanathan Mohan, Saravanan Munisankar, Subash Babu,
Published: 10 September 2021
Frontiers in Immunology, Volume 12; https://doi.org/10.3389/fimmu.2021.716515

Abstract:
Metainflammation, as seen in chronic diabetes subjects, impairs immunity and increases the susceptibility to infections. In the present study, the effect of diabetes on immune response against filariasis was studied. Both toll-like receptor (TLR)-mediated and crude antigen-induced immune responses were quantified, in whole blood cultures from filariasis-infected subjects (LF+), with and without diabetes. Blood cultures were stimulated with TLR ligands (TLR2 and TLR4) or filarial antigen or were left unstimulated (control) for 18 h. Cytokine, chemokine, and defensin secretion was quantified by ELISA. Expression of HLA-DR, B7-1, B7-2, activation marker (CD69), and Th (Th1, Th2, Th17, and Th9) phenotypes was quantified by flow cytometry. Expression of immunomodulatory effectors (Cox-2, HO-1, IDO-1, and p47Phox) and Th-polarizing transcription factors (T-bet, GATA3, and ROR-γt) was quantified by quantitative PCR. Secretion of IL-27, IL-1Ra, IL-12, IL-33, IL-9, and SDF-1 was increased under diabetes conditions with increased Th9 polarization and increased expression of Cox-2 and IDO. Overall, diabetes was found to augment both TLR-mediated and antigen-induced inflammation, which can promote chronic pathology in LF+ subjects.
Simone I. Richardson, Frances Ayres, Nelia P. Manamela, Brent Oosthuysen, Zanele Makhado, Bronwen E. Lambson, Lynn Morris,
Published: 10 September 2021
Frontiers in Immunology, Volume 12; https://doi.org/10.3389/fimmu.2021.733958

Abstract:
The ability of several broadly neutralizing antibodies (bNAbs) to protect against HIV infection is enhanced through Fc receptor binding. Antibody isotype modulates this effect, with IgG3 associated with improved HIV control and vaccine efficacy. We recently showed that an IgG3 variant of bNAb CAP256-VRC26.25 exhibited more potent neutralization and phagocytosis than its IgG1 counterpart. Here, we expanded this analysis to include additional bNAbs targeting all major epitopes. A total of 15 bNAbs were expressed as IgG1 or IgG3, and pairs were assessed for neutralization potency against the multi-subtype global panel of 11 HIV strains. Binding to the neonatal Fc receptor (FcRn) and Fcγ receptors were measured using ELISA and antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis were measured using infectious viruses and global panel Env SOSIP trimers, respectively. IgG3 bNAbs generally showed similar or increased (up to 60 fold) neutralization potency than IgG1 versions, though the effect was virus-specific. This improvement was statistically significant for CAP256-VRC26.25, 35022, PGT135 and CAP255.G3. IgG3 bNAbs also showed significantly improved binding to FcγRIIa which correlated with enhanced phagocytosis of all trimeric Env antigens. Differences in ADCC were epitope-specific, with IgG3 bNAbs to the MPER, CD4 binding site and gp120-gp41 interface showing increased ADCC. We also explored the pH dependence of IgG1 and IgG3 variants for FcRn binding, as this determines the half-life of antibodies. We observed reduced pH dependence, associated with shorter half-lives for IgG3 bNAbs, with κ-light chains. However, IgG3 bNAbs that use λ-light chains showed similar pH dependence to their IgG1 counterparts. This study supports the manipulation of the constant region to improve both the neutralizing and Fc effector activity of bNAbs, and suggests that IgG3 versions of bNAbs may be preferable for passive immunity given their polyfunctionality.
Chih-Chung Chen, Yao-Min Hung, Lu-Ting Chiu, Mei-Chia Chou, Renin Chang,
Published: 10 September 2021
Frontiers in Immunology, Volume 12; https://doi.org/10.3389/fimmu.2021.721752

Abstract:
Introduction Infections play a role in autoimmune diseases (AD). Leptospirosis has been linked to the trigger of systemic lupus erythematosus. Objective To investigate subsequent risk of major AD in hospitalized Taiwanese for Leptospirosis. Methods Retrospective observational cohort study was employed. The enrolled period was from 2000 to 2012. In the main model, we extracted 4026 inpatients with leptospirosis from the Taiwan National Health Insurance Research Database (NHIRD) and 16,104 participants without leptospirosis at a 1:4 ratio propensity-score matched (PSM) by age, gender, index year, and comorbidities. The follow-up period was defined as the time from the initial diagnosis of leptospirosis to major AD occurrence or 2013. This study was re-analyzed by frequency-matching as a sensitivity analysis for cross-validation. Univariable and multivariable Cox proportional hazards regression models were applied to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Results The adjusted HR (95% CI) of major ADs for the leptospirosis group was 4.45 (3.25–6.79) (p < 0.001) compared to the controls after full adjustment. The risk of major ADs was 5.52-fold (95% CI, 3.82–7.99) higher in leptospirosis patients hospitalized for seven days and above than the controls, while 2.80-fold (95% CI, 1.68–5.61) in those hospitalized less than seven days. The sensitivity analysis yields consistent findings. Stratified analysis revealed that the association between leptospirosis and major ADs was generalized in both genders, and all age groups. Conclusions Symptomatic leptospirosis is associated with increased rate of subsequent major ADs, and the risk seems to be higher in severe cases.
, Lauren E. Hein, Carole A. Parent
Published: 10 September 2021
Frontiers in Immunology, Volume 12; https://doi.org/10.3389/fimmu.2021.734188

Abstract:
Neutrophils sense and migrate towards chemotactic factors released at sites of infection/inflammation and contain the affected area using a variety of effector mechanisms. Aside from these established immune defense functions, neutrophils are emerging as one of the key tumor-infiltrating immune cells that influence cancer progression and metastasis. Neutrophil recruitment to the tumor microenvironment (TME) is mediated by multiple mediators including cytokines, chemokines, lipids, and growth factors that are secreted from cancer cells and cancer-associated stromal cells. However, the molecular mechanisms that underlie the expression and secretion of the different mediators from cancer cells and how neutrophils integrate these signals to reach and invade tumors remain unclear. Here, we discuss the possible role of the epithelial to mesenchymal transition (EMT) program, which is a well-established promoter of malignant potential in cancer, in regulating the expression and secretion of these key mediators. We also summarize and review our current understanding of the machineries that potentially control the secretion of the mediators from cancer cells, including the exocytic trafficking pathways, secretory autophagy, and extracellular vesicle-mediated secretion. We further reflect on possible mechanisms by which different mediators collaborate by integrating their signaling network, and particularly focus on TGF-β, a cytokine that is highly expressed in invasive tumors, and CXCR2 ligands, which are crucial neutrophil recruiting chemokines. Finally, we highlight gaps in the field and the need to expand current knowledge of the secretory machineries and cross-talks among mediators to develop novel neutrophil targeting strategies as effective therapeutic options in the treatment of cancer.
Yue Qiu, Yirui Cao, Guowei Tu, Jiawei Li, Ying Su, Fang Fang, Xuepeng Zhang, , ,
Published: 10 September 2021
Frontiers in Immunology, Volume 12; https://doi.org/10.3389/fimmu.2021.698894

Abstract:
Background Renal fibrosis is inevitable in all progressive chronic kidney diseases (CKDs) and represents a serious public health problem. Immune factors contribute to the progression of renal fibrosis. Thus, it is very possible that immunosuppression cells, such as myeloid-derived suppressor cells (MDSCs), could bring benefits to renal fibrosis. Herein, this study investigated the antifibrotic and reno-protective effect of MDSCs and the possible mechanisms. Methods Murine and cell models of unilateral ureter obstruction (UUO) renal fibrosis were used. Bone marrow-induced MDSCs and granulocyte–macrophage colony-stimulating factor (GM-CSF) were pretreated before surgery. Kidney weight, pathological injury, extracellular matrix deposition, and epithelial–mesenchymal transition progression were examined. Transforming growth factor (TGF)-β1)/Smad/Snail signaling pathway involvement was investigated through Western blotting and quantitative PCR (qPCR). Accumulation of MDSC, CD4+ T cell, regulatory T (Treg), and T helper 1 (TH1) cell accumulation, and CCL5 and CCR5 expression level in MDSCs and non-MDSCs were evaluated using flow cytometry. Results In vitro- and in vivo-induced MDSCs significantly ameliorated UUO-induced tubulointerstitial fibrosis, inhibited the TGF-β1/Smad/Snail signaling pathway, and enhanced MDSC and Treg infiltration in the kidney while downregulating the TH1 cells. Both in vitro and in vivo experiments confirmed CCL5 elevation in the two MDSC-treated groups. Conclusion In vitro- and in vivo-induced MDSCs alleviated renal fibrosis similarly through promoting the CCL5–CCR5 axis interaction and TGF-β1/Smad/Snail signaling pathway inhibition. Our results indicate an alternative treatment for renal fibrosis.
Nóra Garam, Marcell Cserhalmi, , Ágnes Szilágyi, Nóra Veszeli, Edina Szabó, Barbara Uzonyi, Attila Iliás, Christof Aigner, Alice Schmidt, et al.
Published: 10 September 2021
Frontiers in Immunology, Volume 12; https://doi.org/10.3389/fimmu.2021.720183

Abstract:
Background Factor H-related protein 5 (FHR-5) is a member of the complement Factor H protein family. Due to the homology to Factor H, the main complement regulator of the alternative pathway, it may also be implicated in the pathomechanism of kidney diseases where Factor H and alternative pathway dysregulation play a role. Here, we report the first observational study on CFHR5 variations along with serum FHR-5 levels in immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) and C3 glomerulopathy (C3G) patients together with the clinical, genetic, complement, and follow-up data. Methods A total of 120 patients with a histologically proven diagnosis of IC-MPGN/C3G were enrolled in the study. FHR-5 serum levels were measured in ELISA, the CFHR5 gene was analyzed by Sanger sequencing, and selected variants were studied as recombinant proteins in ELISA and surface plasmon resonance (SPR). Results Eight exonic CFHR5 variations in 14 patients (12.6%) were observed. Serum FHR-5 levels were lower in patients compared to controls. Low serum FHR-5 concentration at presentation associated with better renal survival during the follow-up period; furthermore, it showed clear association with signs of complement overactivation and clinically meaningful clusters. Conclusions Our observations raise the possibility that the FHR-5 protein plays a fine-tuning role in the pathogenesis of IC-MPGN/C3G.
, Carine Truyens, Eric Muraille
Published: 10 September 2021
Frontiers in Immunology, Volume 12; https://doi.org/10.3389/fimmu.2021.723516

Abstract:
The newborns of women infected with the parasite Trypanosoma cruzi (the agent of Chagas disease) can be infected either before birth (congenitally), or after birth (as e.g., by vector route). Congenital Chagas disease can induce high levels of neonatal morbidity and mortality. Parasite-infected pregnant women transmit antibodies to their fetus. Antibodies, by opsonizing parasites, can promote phagocytosis and killing of T. cruzi by cells expressing FcγR, on the mandatory condition that such cells are sufficiently activated in an inflammatory context. Antibody-dependent enhancement (ADE) is a mechanism well described in viral infections, by which antibodies enhance entry of infectious agents into host cells by exploiting the phagocytic FcγR pathway. Previously reported Chagas disease studies highlighted a severe reduction of the maternal-fetal/neonatal inflammatory context in parasite-transmitting pregnant women and their congenitally infected newborns. Otherwise, experimental observations brought to light ADE of T. cruzi infection (involving FcγR) in mouse pups displaying maternally transferred antibodies, out of an inflammatory context. Herein, based on such data, we discuss the previously unconsidered possibility of a role of ADE in the trans-placental parasite transmission, and/or the development of severe and mortal clinical forms of congenital/neonatal Chagas disease in newborns of T. cruzi-infected mothers.
Siqi Ming, Huan Yin, Xingyu Li, Sitang Gong, Guoliang Zhang,
Published: 10 September 2021
Frontiers in Immunology, Volume 12; https://doi.org/10.3389/fimmu.2021.736269

Abstract:
Gastric CD4+T cells contribute to Helicobacter pylori (H. pylori)-induced gastritis by amplifying mucosal inflammation and exacerbating mucosal injuries. However, the pathogenic CD4+ T cell subset involved in gastritis and the potential regulators are still unclear. Here we identified an IL-21-producing gastric CD4+T cell subset, which exhibited tissue-resident CXCR5−BTLA−PD-1hi TFH-like phenotype in H. pylori-positive gastritis patients. Meanwhile, we identified glucocorticoid-induced tumor necrosis factor receptor (GITR) as an important regulator to facilitate IL-21 production by CD4+T cells and accelerate mucosal inflammation in gastritis patients with H. pylori infection. Moreover, GITR expression was increased in gastric CD4+T cells of gastritis patients compared to healthy controls, along with the upregulated expression of its ligand GITRL in mucosal macrophages (Mϕ) of gastritis patients. Further observations showed that the activation of GITR/GITRL signal promoted the IL-21 production of CD4+T cells via the STAT3 pathway. Besides this, IL-21 from CD4+T cells induced the proliferation of B cell and promoted the production of inflammatory cytokines IL-1β and IL-6 and chemokines MIP-3α and CCL-25 as well as matrix metalloproteinase (MMP)-3 and MMP-9 by human gastric epithelial cells, suggesting the facilitating effect of IL-21-producing CD4+T cells on mucosal inflammation and injuries. Taking these data together, we revealed that GITR/GITRL signal promoted the polarization of mucosal IL-21-producing CD4+T cells in H. pylori-positive gastritis, which may provide therapeutic strategies for the clinical treatment of H. pylori-induced gastritis.
Yicun Wang, Jiyao Sheng, Jin Chai, Cuilin Zhu, Xin Li, Wei Yang, Ranji Cui,
Published: 10 September 2021
Frontiers in Immunology, Volume 12; https://doi.org/10.3389/fimmu.2021.729336

Abstract:
Glioma is a life-threatening malignant tumor. Resistance to traditional treatments and tumor recurrence present major challenges in treating and managing this disease, consequently, new therapeutic strategies must be developed. Crossing the blood-brain barrier (BBB) is another challenge for most drug vectors and therapy medications. Filamentous bacteriophage can enter the brain across the BBB. Compared to traditional drug vectors, phage-based drugs offer thermodynamic stability, biocompatibility, homogeneity, high carrying capacity, self-assembly, scalability, and low toxicity. Tumor-targeting peptides from phage library and phages displaying targeting peptides are ideal drug delivery agents. This review summarized recent studies on phage-based glioma therapy and shed light on the developing therapeutics phage in the personalized treatment of glioma.
Diana C. Yánez, Eleftheria Papaioannou, Mira M. Chawda, Jasmine Rowell, Susan Ross, Ching-In Lau,
Published: 10 September 2021
Frontiers in Immunology, Volume 12; https://doi.org/10.3389/fimmu.2021.737245

Abstract:
Allergic asthma is a common inflammatory airway disease in which Th2 immune response and inflammation are thought to be triggered by inhalation of environmental allergens. Many studies using mouse models and human tissues and genome-wide association have indicated that Sonic Hedgehog (Shh) and the Hedgehog (Hh) signaling pathway are involved in allergic asthma and that Shh is upregulated in the lung on disease induction. We used a papain-induced mouse model of allergic airway inflammation to investigate the impact of systemic pharmacological inhibition of the Hh signal transduction molecule smoothened on allergic airway disease induction and severity. Smoothened-inhibitor treatment reduced the induction of Shh, IL-4, and IL-13 in the lung and decreased serum IgE, as well as the expression of Smo, Il4, Il13, and the mucin gene Muc5ac in lung tissue. Smoothened inhibitor treatment reduced cellular infiltration of eosinophils, mast cells, basophils, and CD4+ T-cells to the lung, and eosinophils and CD4+ T-cells in the bronchoalveolar lavage. In the mediastinal lymph nodes, smoothened inhibitor treatment reduced the number of CD4+ T-cells, and the cell surface expression of Th2 markers ST2 and IL-4rα and expression of Th2 cytokines. Thus, overall pharmacological smoothened inhibition attenuated T-cell infiltration to the lung and Th2 function and reduced disease severity and inflammation in the airway.
Xiaoxiao Du, Weitao Que, Xin Hu, Xiao Yu, Wen-Zhi Guo, Shuijun Zhang,
Published: 10 September 2021
Frontiers in Immunology, Volume 12; https://doi.org/10.3389/fimmu.2021.719574

Abstract:
Background Oridonin (Ori), the main bioactive ingredient of the natural anti-inflammatory herb Rabdosia rubescens, could be a covalent inhibitor of the NLRP3 inflammasome. Solid organ transplantation provides a life-saving optional therapy for patients with end-stage organ dysfunction. The long-term survival of solid organ transplantation remains restricted because of the possibility of rejection and the toxicity, infection, cardiovascular disease, and malignancy related to immunosuppressive (IS) drugs. However, the pathogenic mechanisms involved remain unclear. The ideal IS drugs to prevent allograft rejection have not been identified. Here, we investigated whether Ori could prolong the in vivo survival of completely mismatched cardiac allografts. Methods The cardiac transplantation models were conducted among three groups of mice from C57BL/6NCrSlc (B6/N) or C3H/HeNSlc (C3H) to C3H: the syngeneic and the allogeneic group, whose recipients were treated with vehicle of Ori, and the Ori treatment group, in which the recipients were transplanted hearts from MHC-I mismatched donors and treated with different dosages of Ori from post-operative day (POD) 0 to 7. Then, we investigated the effect of Ori on bone marrow-derived dendritic cell (BMDC) and allogeneic mixed lymphocyte reaction in vitro. Results Ori with 3, 10, and 15 mg/kg Ori could prolong the survival (MST = 22.8, 49.2, and 65.3 days, respectively). We found that infiltrating CD8+ T cells and macrophages were decreased, and regulatory T cells (Tregs) were expanded in allografts on POD7. The mRNA level of IL-1β and IFN-γ of allografts was downregulated. Mechanistically, Ori-treated BMDCs suppressed T-cell proliferation and IFN-γ+CD4+ T-cell differentiation, along with the expansion of Tregs and IL-10+CD4+ T cells. Ori inhibited NOD, LRR-, and pyrin domain-containing protein 3 (NLRP3) expression; attenuated NF-κB and IκBα phosphorylation in LPS-activated BMDCs; downregulated NLRP3, Caspase-1, IL-1β, IL-18, and IFN-γ; and upregulated IL-10 expression. Conclusions Our findings highlight the potential of Ori as a novel and natural IS agent to improve transplant tolerance. Ori could exert IS activity through decreasing IL-1β and IL-18 production and Th1 differentiation and proliferation and expanding Tregs via inhibiting the NF-κB/NLRP3 signaling pathway.
, Giacomo Ramponi, Marco Folci, Maria De Santis, Emanuela Morenghi, Elena Vanni, Elena Bredi, Raffaello Furlan, Claudio Angelini, Carlo Selmi
Published: 10 September 2021
Frontiers in Immunology, Volume 12; https://doi.org/10.3389/fimmu.2021.714174

Abstract:
Background Antineutrophil cytoplasmic antibodies (ANCA) are primarily involved in the pathogenesis of ANCA-associated vasculitides (AAV). However, ANCA may also be present in healthy subjects and in patients with autoimmune disorders different from AAV. We hypothesized that serum ANCA are associated with a worse prognosis in disorders other than AAV. Objective We investigated the association between the overall survival and the presence of serum ANCA in 1,024 Italian subjects with various testing indications in a 10-year interval. Methods In this retrospective cohort study, a population of 6,285 patients (many of whom were subsequently excluded due to our criteria) who tested for ANCA at a single center in 10 years was considered, and life status and comorbidities of subjects were collected. We compared the overall survival of ANCA-positive and ANCA-negative patients by means of Kaplan-Meier curves, while a multivariable adjusted Cox regression was used to evaluate the association between the ANCA status and the outcome (death) in terms of hazard ratios (HR) with 95% confidence intervals (CI). Results The positivity of perinuclear ANCA (pANCA) increased significantly mortality (HR, 1.60; 95% CI, 1.10–2.32), while cytoplasmic ANCA (cANCA) positivity failed to show a significant association (HR, 1.43; 95% CI, 0.77–2.68). The increased mortality rate was observed for both pANCA and cANCA in patients suffering from rheumatic disorders. No association was found between mortality and anti-MPO (HR, 0.63; 95% CI, 0.20–2.00) or anti-PR3 (HR, 0.98; 95% CI, 0.24–3.96) after adjusting for confounders. Conclusions Serum pANCA and cANCA are independent negative prognostic factors in patients with concurrent autoimmune diseases.
Biao Chen, Yuhai Chen, Kul Raj Rai, Xuefei Wang, Shasha Liu, Yingying Li, Meng Xiao, Yun Ma, Guoqing Wang, Guijie Guo, et al.
Published: 10 September 2021
Frontiers in Immunology, Volume 12; https://doi.org/10.3389/fimmu.2021.723885

Abstract:
Eukaryotic translation initiation factor 4B (eIF4B) plays an important role in mRNA translation initiation, cell survival and proliferation in vitro. However, its function in vivo is poorly understood. Here, we identified that eIF4B knockout (KO) in mice led to embryonic lethality, and the embryos displayed severe liver damage. Conditional KO (CKO) of eIF4B in adulthood profoundly increased the mortality of mice, characterized by severe pathological changes in several organs and reduced number of peripheral blood lymphocytes. Strikingly, eIF4B CKO mice were highly susceptible to viral infection with severe pulmonary inflammation. Selective deletion of eIF4B in lung epithelium also markedly promoted replication of influenza A virus (IAV) in the lung of infected animals. Furthermore, we observed that eIF4B deficiency significantly enhanced the expression of several important inflammation-associated factors and chemokines, including serum amyloid A1 (Saa1), Marco, Cxcr1, Ccl6, Ccl8, Ccl20, Cxcl2, Cxcl17 that are implicated in recruitment and activation of neutrophiles and macrophages. Moreover, the eIF4B-deficient mice exhibited impaired natural killer (NK) cell-mediated cytotoxicity during the IAV infection. Collectively, the results reveal that eIF4B is essential for mouse survival and host antiviral responses, and establish previously uncharacterized roles for eIF4B in regulating normal animal development and antiviral immunity in vivo.
Hang Ji, Yixu Ba, Shuai Ma, Kuiyuan Hou, Shan Mi, Xin Gao, Jiaqi Jin, Qin Gong, Ting Liu, Fang Wang, et al.
Published: 10 September 2021
Frontiers in Immunology, Volume 12; https://doi.org/10.3389/fimmu.2021.729359

Abstract:
Interferon-gamma (IFNG) has profound impacts on tumor-immune interaction and is of great clinical significance for multiple cancers. Exploring the role of IFNG in glioblastoma (GBM) may optimize the current treatment paradigm of this disease. Here, multi-dimensional data of 429 GBM samples were collected. Various bioinformatics algorithms were employed to establish a gene signature that characterizes immunological features, genomic alterations, and clinical characteristics associated with the IFNG response. In this way, a novel IFNG-related gene signature (IFNGrGS, including TGFBI, IL4I1, ACP5, and LUM) has been constructed and validated. Samples with increased IFNGrGS scores were characterized by increased neutrophil and macrophage infiltration and exuberant innate immune responses, while the activated adaptive immune response may be frustrated by multiple immunosuppressive mechanisms. Notably, the IFNG pathway as well as its antagonistic pathways including IL4, IL10, TGF-beta, and VEGF converged on the expression of immune checkpoints. Besides, gene mutations involved in the microenvironment were associated with the IFNGrGS-based stratification, where the heterogeneous prognostic significance of EGFR mutation may be related to the different degrees of IFNG response. Moreover, the IFNGrGS score had solid prognostic value and the potential to screen ICB and radiotherapy sensitive populations. Collectively, our study provided insights into the role of IFNG on the GBM immune microenvironment and offered feasible information for optimizing the treatment of GBM.
Xavier Bosch-Amate, Pilar Iranzo, Marta Ivars, José Manuel Mascaró Galy,
Published: 10 September 2021
Frontiers in Immunology, Volume 12; https://doi.org/10.3389/fimmu.2021.740820

Abstract:
The presence of anti-desmocollin (Dsc) antibodies is rarely described in autoimmune blistering diseases patients. Moreover, several clinical phenotypes of pemphigus may be associated with these antibodies. In this review we analyze clinicopathological, immunologic and outcome features of anti-Dsc autoimmune blistering diseases patients, to improve their diagnosis and management. We conducted a systematic search of PubMed and Embase (1990-present) for studies reporting cases of autoimmune blistering diseases with anti-Dsc antibodies. We classified the selected patients as patients with exclusively anti-Dsc autoantibodies, and patients with anti-Dsc and other autoantibodies. Of 93 cases with anti-Dsc autoantibodies included, 38 (41%) had exclusively these antibodies. Only 18% of patients presented with the typical clinicopathological phenotype of pemphigus vulgaris or pemphigus foliaceous. Mucosal involvement was seen in approximately half of the patients. Up to 18% of cases were associated with neoplasms. Acantholysis was described in 54% of cases with histopathological information. Treatments and outcomes vary in the different clinical phenotypes. The presence of anti-Dsc antibodies must be suspected mainly in those patients with either atypical pemphigus, in special with clinical pustules, or in cases showing intraepithelial or dermal neutrophilic/eosinophilic infiltrate on histological examination and dual pattern by direct immunofluorescence examination.
Giuseppe Gianini Figueirêdo Leite, Bianca Lima Ferreira, Alexandre Keiji Tashima, Erika Sayuri Nishiduka, Edecio Cunha-Neto, Milena Karina Colo Brunialti, Murillo Assuncao, Luciano Cesar Pontes Azevedo, Flávio Freitas, Tom van der Poll, et al.
Published: 10 September 2021
Frontiers in Immunology, Volume 12; https://doi.org/10.3389/fimmu.2021.744799

Abstract:
Sepsis is a global health emergency, which is caused by various sources of infection that lead to changes in gene expression, protein-coding, and metabolism. Advancements in “omics” technologies have provided valuable tools to unravel the mechanisms involved in the pathogenesis of this disease. In this study, we performed shotgun mass spectrometry in peripheral blood mononuclear cells (PBMC) from septic patients (N=24) and healthy controls (N=9) and combined these results with two public microarray leukocytes datasets. Through combination of transcriptome and proteome profiling, we identified 170 co‐differentially expressed genes/proteins. Among these, 122 genes/proteins displayed the same expression trend. Ingenuity Pathway Analysis revealed pathways related to lymphocyte functions with decreased status, and defense processes that were predicted to be strongly increased. Protein-protein interaction network analyses revealed two densely connected regions, which mainly included down‐regulated genes/proteins that were related to the transcription of RNA, translation of proteins, and mitochondrial translation. Additionally, we identified one module comprising of up‐regulated genes/proteins, which were mainly related to low-density neutrophils (LDNs). LDNs were reported in sepsis and in COVID-19. Changes in gene expression level were validated using quantitative real-time PCR in PBMCs from patients with sepsis. To further support that the source of the upregulated module of genes/proteins found in our results were derived from LDNs, we identified an increase of this population by flow cytometry in PBMC samples obtained from the same cohort of septic patients included in the proteomic analysis. This study provides new insights into a reprioritization of biological functions in response to sepsis that involved a transcriptional and translational shutdown of genes/proteins, with exception of a set of genes/proteins related to LDNs and host‐defense system.
Zili Lin, Ziyi Wu,
Published: 10 September 2021
Frontiers in Immunology, Volume 12; https://doi.org/10.3389/fimmu.2021.707211

Abstract:
Ewing’s sarcoma (EWS) is a malignant and aggressive tumor type that predominantly occurs in children and adolescents. Traditional treatments such as surgery, radiotherapy and chemotherapy, while successful in the early disease stages, are ineffective in patients with metastases and relapses who often have poor prognosis. Therefore, new treatments for EWS are needed to improve patient’s outcomes. Chimeric antigen receptor (CAR)-T cells therapy, a novel adoptive immunotherapy, has been developing over the past few decades, and is increasingly popular in researches and treatments of various cancers. CAR-T cell therapy has been approved by the Food and Drug Administration (FDA) for the treatment of leukemia and lymphoma. Recently, this therapeutic approach has been employed for solid tumors including EWS. In this review, we summarize the safety, specificity and clinical transformation of the treatment targets of EWS, and point out the directions for further research.
Chaojun Hu, Siting Li, Zhijuan Xie, Hanxiao You, Hui Jiang, Yu Shi, Wanting Qi, Jiuliang Zhao, Qian Wang, Xinping Tian, et al.
Published: 10 September 2021
Frontiers in Immunology, Volume 12; https://doi.org/10.3389/fimmu.2021.741369

Abstract:
Objective Although specific anti-phospholipid antibodies (aPLs) have been used in the diagnosis of the antiphospholipid syndrome (APS) for years, new biomarkers are required to increase its diagnostic and risk-predictive power. This study aimed to explore the value of several non-criteria aPLs in a Chinese cohort. Methods A total of 312 subjects, namely, 100 patients diagnosed with primary APS, 51 with APS secondary to SLE, 71 with SLE, and 90 healthy controls, were recruited. Serum anticardiolipin (aCL) IgG/IgM/IgA, anti-β2-glycoprotein I (aβ2GPI) IgG/IgM/IgA, anti-phosphatidylserine/prothrombin antibodies (aPS/PT) IgG/IgM, and anti-annexin A5 antibodies (aAnxV) IgG/IgM were tested using ELISA kits. Results Of the total number of patients, 30.46% and 6.62% with APS were positive for aCL or aβ2GPI IgA, respectively, while 39.07% and 24.50% were positive for aAnxV or aPS/PT for at least one antibody (IgG or IgM). The addition test of aCL IgA and aAnxV IgM assists in identifying seronegative APS patients, and IgG aPS/PT was linked to stroke. Conclusion Detection of aCL IgA, aβ2GPI IgA, aAnxV IgG/M, and aPS/PT IgG/M as a biomarker provides additive value in APS diagnosis and would help in risk prediction for APS patients in medical practice.
Natalia Adamiak, Krzysztof T. Krawczyk, Camille Locht,
Published: 10 September 2021
Frontiers in Immunology, Volume 12; https://doi.org/10.3389/fimmu.2021.746235

Abstract:
Archaea are prokaryotic organisms that were classified as a new domain in 1990. Archaeal cellular components and metabolites have found various applications in the pharmaceutical industry. Some archaeal lipids can be used to produce archaeosomes, a new family of liposomes that exhibit high stability to temperatures, pH and oxidative conditions. Additionally, archaeosomes can be efficient antigen carriers and adjuvants promoting humoral and cellular immune responses. Some archaea produce gas vesicles, which are nanoparticles released by the archaea that increase the buoyancy of the cells and facilitate an upward flotation in water columns. Purified gas vesicles display a great potential for bioengineering, due to their high stability, immunostimulatory properties and uptake across cell membranes. Both archaeosomes and archaeal gas vesicles are attractive tools for the development of novel drug and vaccine carriers to control various diseases. In this review we discuss the current knowledge on production, preparation methods and potential applications of archaeosomes and gas vesicles as carriers for vaccines. We give an overview of the traditional structures of these carriers and their modifications. A comparative analysis of both vaccine delivery systems, including their advantages and limitations of their use, is provided. Gas vesicle- and archaeosome-based vaccines may be powerful next-generation tools for the prevention and treatment of a wide variety of infectious and non-infectious diseases.
, Corentin Leroy, Olivier Epaulard, Giovanna Clavarino, Antoine Vilotitch, Marion Le Marechal, Marie-Christine Jacob, Tatiana Raskovalova, Martine Pernollet, Audrey Le Gouellec, et al.
Published: 10 September 2021
Frontiers in Immunology, Volume 12; https://doi.org/10.3389/fimmu.2021.742446

Abstract:
Background The SARS-CoV-2 infection triggers excessive immune response resulting in increased levels of pro-inflammatory cytokines, endothelial injury, and intravascular coagulopathy. The complement system (CS) activation participates to this hyperinflammatory response. However, it is still unclear which activation pathways (classical, alternative, or lectin pathway) pilots the effector mechanisms that contribute to critical illness. To better understand the immune correlates of disease severity, we performed an analysis of CS activation pathways and components in samples collected from COVID-19 patients hospitalized in Grenoble Alpes University Hospital between 1 and 30 April 2020 and of their relationship with the clinical outcomes. Methods We conducted a retrospective, single-center study cohort in 74 hospitalized patients with RT-PCR-proven COVID-19. The functional activities of classical, alternative, and mannose-binding lectin (MBL) pathways and the antigenic levels of the individual components C1q, C4, C3, C5, Factor B, and MBL were measured in patients’ samples during hospital admission. Hierarchical clustering with the Ward method was performed in order to identify clusters of patients with similar characteristics of complement markers. Age was included in the model. Then, the clusters were compared with the patient clinical features: rate of intensive care unit (ICU) admission, corticoid treatment, oxygen requirement, and mortality. Results Four clusters were identified according to complement parameters. Among them, two clusters revealed remarkable profiles: in one cluster (n = 15), patients exhibited activation of alternative and lectin pathways and low antigenic levels of MBL, C4, C3, Factor B, and C5 compared to all the other clusters; this cluster had the higher proportion of patients who died (27%) and required oxygen support (80%) or ICU care (53%). In contrast, the second cluster (n = 19) presented inflammatory profile with high classical pathway activity and antigenic levels of complement components; a low proportion of patients required ICU care (26%) and no patient died in this group. Conclusion These findings argue in favor of prominent activation of the alternative and MBL complement pathways in severe COVID-19, but the spectrum of complement involvement seems to be heterogeneous requiring larger studies.
Man-Jun Yang, Ming Jiang, Xuan-Xian Peng,
Published: 10 September 2021
Frontiers in Immunology, Volume 12; https://doi.org/10.3389/fimmu.2021.682724

Abstract:
Bacterial infection presents severe challenge to tilapia farming, which is largely influenced by water temperature. However, how water temperature determines tilapias’ survival to infection is not well understood. Here, we address this issue from the perspective of metabolic state. Tilapias were more susceptible to Aeromonas sobria infection at 33°C than at 18°C, which is associated with differential metabolism of the fish. Compared to the metabolome of tilapia at 18°C, the metabolome at 33°C was characterized with increased an tricarboxylic acid cycle and a reduced level of myo-inositol which represent the most impactful pathway and crucial biomarker, respectively. These alterations were accompanied with the elevated transcriptional level of 10 innate immune genes with infection time, where il-1b, il-6, il-8, and il-10 exhibited a higher expression at 33°C than at 18°C and was attenuated by exogenous myo-inositol in both groups. Interestingly, exogenous myo-inositol inactivated the elevated TCA cycle via inhibiting the enzymatic activity of succinate dehydrogenase and malate dehydrogenase. Thus, tilapias showed a higher survival ability at 33°C. Our study reveals a previously unknown relationship among water temperature, metabolic state, and innate immunity and establishes a novel approach to eliminate bacterial pathogens in tilapia at higher water temperature.
Brandi T. Johnson-Weaver, Hae Woong Choi, Hang Yang, Josh A. Granek, Cliburn Chan, Soman N. Abraham,
Published: 10 September 2021
Frontiers in Immunology, Volume 12; https://doi.org/10.3389/fimmu.2021.730346

Abstract:
Mast cell activators are a novel class of mucosal vaccine adjuvants. The polymeric compound, Compound 48/80 (C48/80), and cationic peptide, Mastoparan 7 (M7) are mast cell activators that provide adjuvant activity when administered by the nasal route. However, small molecule mast cell activators may be a more cost-efficient adjuvant alternative that is easily synthesized with high purity compared to M7 or C48/80. To identify novel mast cell activating compounds that could be evaluated for mucosal vaccine adjuvant activity, we employed high-throughput screening to assess over 55,000 small molecules for mast cell degranulation activity. Fifteen mast cell activating compounds were down-selected to five compounds based on in vitro immune activation activities including cytokine production and cellular cytotoxicity, synthesis feasibility, and selection for functional diversity. These small molecule mast cell activators were evaluated for in vivo adjuvant activity and induction of protective immunity against West Nile Virus infection in BALB/c mice when combined with West Nile Virus envelope domain III (EDIII) protein in a nasal vaccine. We found that three of the five mast cell activators, ST101036, ST048871, and R529877, evoked high levels of EDIII-specific antibody and conferred comparable levels of protection against WNV challenge. The level of protection provided by these small molecule mast cell activators was comparable to the protection evoked by M7 (67%) but markedly higher than the levels seen with mice immunized with EDIII alone (no adjuvant 33%). Thus, novel small molecule mast cell activators identified by high throughput screening are as efficacious as previously described mast cell activators when used as nasal vaccine adjuvants and represent next-generation mast cell activators for evaluation in mucosal vaccine studies.
Corrigendum
Ya-Fei Qin, De-Jun Kong, Hong Qin, Yang-Lin Zhu, Guang-Ming Li, Cheng-Lu Sun, Yi-Ming Zhao, , Jing-Peng Hao,
Published: 10 September 2021
Frontiers in Immunology, Volume 12; https://doi.org/10.3389/fimmu.2021.741234

Abstract:
A Corrigendum onMelatonin Synergizes With Mesenchymal Stromal Cells Attenuates Chronic Allograft Vasculopathy By Qin Y-f, Kong D-j, Qin H, Zhu Y-l, Li G-m, Sun C-l, Zhao Y-m, Wang H-d, Hao J-p and Wang H (2021). Front. Immunol. 12:672849. doi: 10.3389/fimmu.2021.672849 In the original article, there was a mistake in Figure 3A as published. The figure was placed repeatedly in the process of copying/pasting our original images. The corrected Figure 3A appears below. In the original article, there was a mistake in Figure 6A as published. The figure was placed repeatedly in the process of copying/pasting our original images. The corrected Figure 6A appears below. Figure 3 (A) The pseudocolor of Th1 (CD4+IFN-γ+) cells and Th17 (CD4+IL-17A+) cells in vitro. Figure 6 (A) The pseudocolor of Th1 (CD4+IFN-γ+) cells, Th17 (CD4+IL-17A+) cells, and CD4+Foxp3+ Tregs in vivo. The authors apologize for these errors and state that this does not change the scientific conclusions of the article in any way. The original article has been updated. All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher Keywords: chronic allograft vasculopathy, melatonin, mesenchymal stromal cells, aorta transplantation, mice Citation: Qin Y-f, Kong D-j, Qin H, Zhu Y-l, Li G-m, Sun C-l, Zhao Y-m, Wang H-d, Hao J-p and Wang H (2021) Corrigendum: Melatonin Synergizes With Mesenchymal Stromal Cells Attenuates Chronic Allograft Vasculopathy. Front. Immunol. 12:741234. doi: 10.3389/fimmu.2021.741234 Received: 14 July 2021; Accepted: 27 August 2021;Published: 10 September 2021. Edited and reviewed by: Copyright © 2021 Qin, Kong, Qin, Zhu, Li, Sun, Zhao, Wang, Hao and Wang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. *Correspondence: Hao Wang, [email protected]; [email protected] †These authors share first authorship
Alejandro M. Palma, Mark R. Hanes,
Published: 10 September 2021
Frontiers in Immunology, Volume 12; https://doi.org/10.3389/fimmu.2021.718499

Abstract:
Mast cells are well known to be activated via cross-linking of immunoglobulins bound to surface receptors. They are also recognized as key initiators and regulators of both innate and adaptive immune responses against pathogens, especially in the skin and mucosal surfaces. Substantial attention has been given to the role of mast cells in regulating T cell function either directly or indirectly through actions on dendritic cells. In contrast, the ability of mast cells to modify B cell responses has been less explored. Several lines of evidence suggest that mast cells can greatly modify B cell generation and activities. Mast cells co-localise with B cells in many tissue settings and produce substantial amounts of cytokines, such as IL-6, with profound impacts on B cell development, class-switch recombination events, and subsequent antibody production. Mast cells have also been suggested to modulate the development and functions of regulatory B cells. In this review, we discuss the critical impacts of mast cells on B cells using information from both clinical and laboratory studies and consider the implications of these findings on the host response to infections.
Jiaheng Cheng, Yushan Yuan, Fang Zhao, Jianwei Chen, Peng Chen, Ying Li, Xia Yan, Chenglong Luo, Dingming Shu, , et al.
Published: 10 September 2021
Frontiers in Immunology, Volume 12; https://doi.org/10.3389/fimmu.2021.700603

Abstract:
Increasing studies show that gut microbiota play a central role in immunity, although the impact of the microbiota on mediation of thymic T cells throughout life is not well understood. Chickens have been shown to be a valuable model for studying basic immunology. Here, we show that changes in the gut microbiota are associated with the development of thymic T cells in young chickens. Our results showed that T-cell numbers in newborn chicks sharply increased from day 0 and peaked at day 49. Interestingly, the α-diversity score pattern of change in gut microbiota also increased after day 0 and continued to increase until day 49. We found that early antibiotic treatment resulted in a dramatic reduction in gut alpha diversity: principal component analysis (PCA) showed that antibiotic treatment resulted in a different cluster from the controls on days 9 and 49. In the antibiotic-treated chickens, we identified eight significantly different (p < 0.05) microbes at the phylum level and 14 significantly different (p < 0.05) microbes at the genus level, compared with the controls. Importantly, we found that antibiotic treatment led to a decreased percentage and number of T cells in the thymus when measured at days 9 and 49, as evaluated by flow cytometry. Collectively, our data suggest that intestinal microbiota may be involved in the regulation of T cells in birds, presenting the possibility that interventions that actively modify the gut microbiota in early life may accelerate the maturation of humoral immunity, with resulting anti-inflammatory effects against different pathogens.
, Laureen Pohl, Birgit Weinberger, Beatrix Grubeck-Loebenstein, Andrea Wawer, Percy A. Knolle, Hedwig Roggendorf, Ulrike Protzer, Tanja Bauer
Published: 10 September 2021
Frontiers in Immunology, Volume 12; https://doi.org/10.3389/fimmu.2021.713351

Abstract:
Background The cellular mechanisms involved in the lack of protective antibody response after hepatitis B vaccination are still rather unclear. Regulatory B cells (Breg) known as modulators of B-and T-cell responses may contribute to poor vaccine responsiveness. The current study aimed to investigate the role of regulatory B cells (Breg) in hepatitis B vaccine non-responsiveness after immunization with second- or third-generation hepatitis B vaccines. Method We performed comparative phenotypic and frequency analysis of Breg subsets (CD24+CD27+ and CD24highCD38high Breg) in second-generation hepatitis B vaccine non-responders (2nd HBvac NR, n = 11) and responders (2nd HBvac R, n = 8) before (d0), on day 7 (d7), and 28 (d28) after booster vaccination. Cryopreserved peripheral blood mononuclear cells were stimulated ex vivo with a combination of CpG, PMA, and Ionomycin (CpG+P/I) and analyzed for numbers and IL-10 expression levels of Breg by flow cytometry-based analyses. Results Flow cytometry-based analyses revealed elevated frequencies of CD24+CD27+ Breg at all time points and significantly higher frequencies of CD24highCD38high Breg on d0 (p = 0.004) and 28 (p = 0.012) in 2nd HBvac NR compared to 2nd HBvac R. In parallel, we observed significantly lower levels of CpG+P/I-induced IL-10 expression levels of CD24+CD27+ and CD24highCD38high Breg (d0: p < 0.0001; d7: p = 0.0004; d28: p = 0.0003 and d0: p = 0.016; d7: p = 0.016, respectively) in 2nd HBvac NR compared to 2nd HBvac R before and after booster immunization. Frequencies of CD24+CD27+ and CD24highCD38high Breg significantly decreased after third-generation hepatitis B booster vaccination (d7: p = 0.014; d28: p = 0.032 and d7: p = 0.045, respectively), whereas IL-10 expression levels of both Breg subsets remained stable. Conclusion Here we report significantly higher frequencies of CD24highCD38high Breg in parallel with significantly lower IL-10 expression levels of CD24+CD27+ and CD24highCD38high Breg in 2nd HBvac NR compared to 2nd HBvac R. Anti-HBs seroconversion accompanied by a decrease of Breg numbers after booster immunization with a third-generation hepatitis B vaccine could indicate a positive effect of third-generation hepatitis B vaccines on Breg-mediated immunomodulation in hepatitis B vaccine non-responders.
Yiqiu Wei, Jinli Ding, Jianan Li, Songchen Cai, Su Liu, Ling Hong, Tailang Yin, Yan Zhang,
Published: 9 September 2021
Frontiers in Immunology, Volume 12; https://doi.org/10.3389/fimmu.2021.717014

Abstract:
Immunity and metabolism are interdependent and coordinated, which are the core mechanisms for the body to maintain homeostasis. In tumor immunology research, immunometabolism has been a research hotspot and has achieved groundbreaking changes in recent years. However, in the field of maternal-fetal medicine, research on immunometabolism is still lagging. Reports directly investigating the roles of immunometabolism in the endometrial microenvironment and regulation of maternal-fetal immune tolerance are relatively few. This review highlights the leading techniques used to study immunometabolism and their development, the immune cells at the maternal-fetal interface and their metabolic features required for the implementation of their functions, explores the interaction between immunometabolism and pregnancy regulation based on little evidence and clues, and attempts to propose some new research directions and perspectives.
Feifei Qiu, Junfeng Liu, Xiumei Mo, Huazhen Liu, Yuchao Chen,
Published: 9 September 2021
Frontiers in Immunology, Volume 12; https://doi.org/10.3389/fimmu.2021.751772

Abstract:
Artemisinin and its derivatives (ARTs) are known as conventional antimalarial drugs with clinical safety and efficacy. Youyou Tu was awarded a Nobel Prize in Physiology and Medicine due to her discovery of artemisinin and its therapeutic effects on malaria. Apart from antimalarial effects, mounting evidence has demonstrated that ARTs exert therapeutic effects on inflammation and autoimmune disorders because of their anti-inflammatory and immunoregulatory properties. In this aspect, tremendous progress has been made during the past five to seven years. Therefore, the present review summarizes recent studies that have explored the anti-inflammatory and immunomodulatory effects of ARTs on autoimmune diseases and transplant rejection. In this review, we also discuss the cellular and molecular mechanisms underlying the immunomodulatory effects of ARTs. Recent preclinical studies will help lay the groundwork for clinical trials using ARTs to treat various immune-based disorders, especially autoimmune diseases.
Larance Ronsard, Ashraf S. Yousif, Julianne Peabody, Vintus Okonkwo, Pascal Devant, Alemu Tekewe Mogus, Ralston M. Barnes, Daniel Rohrer, Nils Lonberg, David Peabody, et al.
Published: 9 September 2021
Frontiers in Immunology, Volume 12; https://doi.org/10.3389/fimmu.2021.730471

Abstract:
The ligand-binding surface of the B cell receptor (BCR) is formed by encoded and non-encoded antigen complementarity determining regions (CDRs). Genetically reproducible or ‘public’ antibodies can arise when the encoded CDRs play deterministic roles in antigen recognition, notably within human broadly neutralizing antibodies against HIV and influenza virus. We sought to exploit this by engineering virus-like-particle (VLP) vaccines that harbor multivalent affinity against gene-encoded moieties of the BCR antigen binding site. As proof of concept, we deployed a library of RNA bacteriophage VLPs displaying random peptides to identify a multivalent antigen that selectively triggered germline BCRs using the human VH gene IGVH1-2*02. This VLP selectively primed IGHV1-2*02 BCRs that were present within a highly diversified germline antibody repertoire within humanized mice. Our approach thus provides methodology to generate antigens that engage specific BCR configurations of interest, in the absence of structure-based information.
Xu Zhao, Yifei Zhao, Juan Du, PuJun Gao,
Published: 9 September 2021
Frontiers in Immunology, Volume 12; https://doi.org/10.3389/fimmu.2021.732775

Abstract:
Human immunodeficiency viruses (HIVs) are retroviruses that replicate effectively in human CD4+ cells and cause the development of acquired immune deficiency syndrome (AIDS). On the other hand, type 1 long interspersed elements (LINE-1s or L1s) are the only active retroelements that can replicate autonomously in human cells. They, along with other active yet nonautonomous retroelements, have been associated with autoimmune diseases. There are many similarities between HIV and LINE-1. Being derived (or evolved) from ancient retroviruses, both HIV and LINE-1 replicate through a process termed reverse transcription, activate endogenous DNA and RNA sensors, trigger innate immune activation to promote interferon (IFN) expression, and are suppressed by protein products of interferon-stimulated genes (ISGs). However, these similarities make it difficult to decipher or even speculate the relationship between HIV and LINE-1, especially regarding the involvement of the IFN signaling system. In this review, we summarize previous findings on the relationships between HIV and innate immune activation as well as between LINE-1 and IFN upregulation. We also attempt to elucidate the interplay among HIV, LINE-1, and the IFN signaling system in hopes of guiding future research directions for viral suppression and immune regulation.
Page of 414
Articles per Page
by
Show export options
  Select all
Back to Top Top