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Journal articles on the topic 'Siglec-E'

Author: Grafiati
Published: 10 January 2023
Last updated: 28 January 2023

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1

Schmassmann, Philip, Tomás A. Martins, Michal Stanczak, Marie-Françoise Ritz, Tala Shekarian, Marta McDaid, Heinz Läubli, and Gregor Hutter. "EXTH-45. MICROGLIA-SPECIFIC DISRUPTION OF SIALIC ACID-SIGLEC-9/E INTERACTIONS: A NOVEL IMMUNOTHERAPY AGAINST GLIOBLASTOMA?" Neuro-Oncology 23, Supplement_6 (November 2, 2021): vi173. http://dx.doi.org/10.1093/neuonc/noab196.684.

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Abstract Recently, ‘don’t eat me’-signals like CD47 have emerged as novel innate immune checkpoints, enabling cancer cells to evade clearance by phagocytes such as monocyte-derived macrophages (MDM) or microglia (MG). Here, we aim at defining the role of inhibitory Siglec-9 in human and its mouse homologue Siglec-E in MG-centered immunotherapy against GBM. TCGA RNA-sequencing data revealed a significant correlation between high expression of immunoinhibitory SIGLEC9 and poor survival in GBM patients (log-rank p = 0.02). Siglec-E blockade increased murine MG mediated GBM cell in vitro phagocytosis (normalized phagocytosis of 1.00 in isotype vs. 1.76 in anti-Siglec-E antibody, p < 0.001). By employing a CT-2A orthotopic GBM mouse model with MG-specific spatio-temporal deletion of Siglece (Sall1 CreERT2 x Siglece flox ), we observed high MG-proliferation upon Siglec-E knockdown (Ki-67+ MG 14.8% in Cre- vs. 34.9% in Cre+, p < 0.0001) accompanied by an enhanced microglial GBM-cell uptake (5.6% in Cre- vs. 12.3% in Cre+, p < 0.001). This beneficial response was counteracted by an accentuated influx of pro-tumorigenic MDM in the Cre+ group (CD163high CD86low MDM of total MDM 47.1% in Cre- vs. 65.3% in Cre+, p = 0.002), which prevented an efficient adaptive anti-tumor immune response and survival benefit. Currently, we are investigating the cross-talk between GBM-associated MG and MDM upon Siglec-E knockdown by scRNAseq of the tumor-infiltrating immune compartment, including TCR-clonotype tracking. By genetically targeting sialic acids, the ligand for Siglec receptors, on CT-2A cells (GNE-KO), we observed a strong innate and adaptive immune response with less exhausted tumor-infiltrating CD8+ T-cells (14.8% in WT vs. 5.9% in GNE-KO, p = 0.003), which resulted in a prolonged survival (30d in WT vs. 41d post-tumor-injection in GNE-KO, p = 0.03). These data identify the sialic-acid-Siglec-E pathway as an anti-phagocytic signal in a pre-clinical GBM model, and demonstrate its therapeutic potential in GBM immunotherapy.
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2

Schmassmann, P., J. Roux, T. A. Martins, M. Ritz, T. Shekarian, M. McDaid, and H. Läubli G. Hutter. "PL02.2.A Microglia-specific disruption of sialic acid-Siglec-9/E interactions. A novel immunotherapy against glioblastoma?" Neuro-Oncology 24, Supplement_2 (September 1, 2022): ii2. http://dx.doi.org/10.1093/neuonc/noac174.005.

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Abstract Background Recently, ‘don’t eat me’-signals like CD47 have emerged as novel innate immune checkpoints, enabling cancer cells to evade clearance by phagocytes such as monocyte-derived macrophages (MdM) or microglia (MG). Here, we aim at defining the role of inhibitory Siglec-9 in human and its mouse homologue Siglec-E in MG-centered immunotherapy against GBM. Material and Methods We employed a CT-2A orthotopic GBM mouse model with MG specific (Sall1CreERT2 x Sigleceflox) and whole innate-compartment (Cx3cr1CreERT2 x Sigleceflox) spatio-temporal deletion of Siglece. We applied multi-color flow cytometry, transcriptomics and proteomics analysis to decipher the immune response upon Siglece knockout. Results TCGA RNA-sequencing data revealed a significant correlation between high expression of immunoinhibitory SIGLEC9 and poor survival in GBM patients (log-rank p = 0.02). Siglec-E blockade increased murine MG mediated GBM cell in vitro phagocytosis (normalized phagocytosis of 1.00 in isotype vs. 1.76 in anti-Siglec-E antibody, p < 0.001). In the MG specific spatio-temporal deletion of Siglece (Sall1CreERT2 xSigleceflox), we observed high MG-proliferation upon Siglec-E knockout (Ki-67+ MG 14.8% in Cre- vs. 34.9% in Cre+, p < 0.0001) accompanied by an enhanced microglial GBM-cell uptake (5.6% in Cre- vs. 12.3% in Cre+, p < 0.001). By extending the Siglece knockout to the MdM compartment in our glioma mouse model (Cx3cr1CreERT2 x Sigleceflox) we observed a significantly prolonged survival in the Cx3cr1Cre+ population (21d in Cre- vs. 27d post-tumor injection in Cre+, p = 0.018), which could be further promoted by combining Siglece knockout with CD47 blockade (30d post-tumor injection in Cre+ + anti-CD47). Unbiased proteomics analysis revealed increased antigen processing and presentation capabilities of Siglece knockout MdMs which was confirmed by ex-vivo OT-1 cross-presentation assays. This bridging of innate and adaptive responses with increased T cell priming upon MdM Siglece knockout was further promoted by addition of anti-PD1 antibody to the combined Siglece knockout and anti-CD47 treatment arm. Animals harboring CT-2A tumors, exhibited a sustained survival benefit under the triple therapy, with 23% of animals experiencing long-term remission, even after tumor re-challenge into the contra-lateral hemisphere. By genetically targeting sialic acids, the ligand for Siglec receptors, on CT-2A cells (GNE-KO), we observed a strong innate and adaptive immune response with increased GBM-cell phagocytosis by MG and MdMs and less exhausted tumor-infiltrating CD8+ T-cells (14.8% in WT vs. 5.9% in GNE-KO, p = 0.003). Conclusion These data identify the sialic-acid-Siglec-E pathway as an anti-phagocytic signal in a pre-clinical GBM model, and demonstrate its therapeutic potential in GBM immunotherapy.
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3

Siddiqui, Shoib Sarwar, Rachel Matar, Maxime Merheb, Rawad Hodeify, Cijo George Vazhappilly, John Marton, Syed Azharuddin Shamsuddin, and Hussain Al Zouabi. "Siglecs in Brain Function and Neurological Disorders." Cells 8, no. 10 (September 22, 2019): 1125. http://dx.doi.org/10.3390/cells8101125.

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Siglecs (Sialic acid-binding immunoglobulin-type lectins) are a I-type lectin that typically binds sialic acid. Siglecs are predominantly expressed in immune cells and generate activating or inhibitory signals. They are also shown to be expressed on the surface of cells in the nervous system and have been shown to play central roles in neuroinflammation. There has been a plethora of reviews outlining the studies pertaining to Siglecs in immune cells. However, this review aims to compile the articles on the role of Siglecs in brain function and neurological disorders. In humans, the most abundant Siglecs are CD33 (Siglec-3), Siglec-4 (myelin-associated glycoprotein/MAG), and Siglec-11, Whereas in mice the most abundant are Siglec-1 (sialoadhesin), Siglec-2 (CD22), Siglec-E, Siglec-F, and Siglec-H. This review is divided into three parts. Firstly, we discuss the general biological aspects of Siglecs that are expressed in nervous tissue. Secondly, we discuss about the role of Siglecs in brain function and molecular mechanism for their function. Finally, we collate the available information on Siglecs and neurological disorders. It is intriguing to study this family of proteins in neurological disorders because they carry immunoinhibitory and immunoactivating motifs that can be vital in neuroinflammation.
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4

Schmassmann, Philip, Julien Roux, Nazanin Tatari, Tomas A. Martins, Marie-Françoise Ritz, Tala Shekarian, Heinz Laeubli, and Gregor Hutter. "EXTH-26. MICROGLIA-SPECIFIC DISRUPTION OF SIALIC ACID-SIGLEC-9/E INTERACTIONS: A NOVEL IMMUNOTHERAPY AGAINST GLIOBLASTOMA?" Neuro-Oncology 24, Supplement_7 (November 1, 2022): vii215. http://dx.doi.org/10.1093/neuonc/noac209.825.

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Abstract Recently, ‘don’t eat me’-signals like CD47 have emerged as novel innate immune checkpoints, enabling cancer cells to evade clearance by phagocytes such as microglia (MG) or monocyte-derived cells (MdCs). Here, we aim at defining the role of inhibitory Siglec-9 in human and its mouse homologue Siglec-E in innate-centered immunotherapy against GBM. TCGA RNA-sequencing data revealed a significant correlation between high expression of immunoinhibitory SIGLEC9 and poor survival in GBM patients (log-rank p = 0.02). Using a CT-2A orthotopic GBM mouse model with MG-specific spatio-temporal deletion of Siglece (Sall1CreERT2 x Sigleceflox) , we observed high MG-proliferation upon Siglece knockout (Ki-67+ MG 14.8% in Crenegvs. 34.9% in Creposp < 0.0001) accompanied by an enhanced microglial GBM-cell uptake (5.6% in Crenegvs. 12.3% in Crepos, p < 0.001). By extending the Siglece knockout to the MdC compartment (Cx3cr1CreERT2x Sigleceflox) we observed a significantly prolonged survival in the Crepospopulation (21d in Crenegvs. 27d post-tumor injection in Crepos, p = 0.018), which could be further promoted by combining Siglece knockout with CD47 blockade (11% long-term remission in Crepos+ anti-CD47). Proteomics analysis revealed increased antigen processing and presentation capabilities of SigleceKOMdCs which was confirmed by ex-vivo OT-1 cross-presentation assays. This increased T cell priming upon MdC SigleceKOwas further boosted by addition of anti-PD1 antibody to the SigleceKO+ anti-CD47 combination. Resulting in 23% of animals experiencing long-term remission in the triple treatment arm, even after tumor re-challenge. Genetic targeting of sialic acids, the ligand for Siglec receptors, on CT-2A cells (GNE-KO), resulted in increased GBM-cell phagocytosis by MG and MdCs and less exhausted tumor-infiltrating CD8+ T cells (14.8% in WT vs. 5.9% in GNE-KO, p = 0.003). In a translational approach, we are currently testing anti-Siglec-9 treatment regimens in patient GBM explants, cultured for 5 days in perfusion bioreactors.
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5

Maniaci, Brandon Lee, David Friedman, Sydney Crotts, Matthew Rajcula, Keith Theodore, Hyun Se Kim Lee, and Virginia Shapiro. "Accelerated tumorigenesis in a colorectal cancer model in Siglec-E knockout mice." Journal of Immunology 208, no. 1_Supplement (May 1, 2022): 61.02. http://dx.doi.org/10.4049/jimmunol.208.supp.61.02.

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Abstract The lifetime risk for colorectal cancer in the United States is approximately 4%. Individuals with Inflammatory Bowel Disease, including Ulcerative Colitis and Crohn’s Disease, have a substantially increased risk of developing colorectal cancer. The mechanisms for accelerated tumorigenesis due to enhanced inflammation are not fully characterized. Siglecs (sialic acid immunoglobulin lectin-like proteins) are a family of inhibitory receptors that are negative regulators of the immune response. Siglec-E is an inhibitory receptor that is expressed by innate immune cells, including monocytes, macrophages, neutrophils and dendritic cells. Interestingly, mice deficient in Siglec-E have accelerated development of tumors and reduced survival in a spontaneous mouse model of colorectal cancer (TS4-cre LSL-KRasG12D APClox468/wt). While tumors develop at approximately 6 months in mice with Siglec-E, tumors develop at approximately two months in Siglec-E knockout mice. Initial results indicate that Siglec-E knockout mice also have accelerated gut inflammation using the DSS colitis model as compared to WT mice. Current studies are examining inflammation that develops during tumorigenesis in Siglec-E knockout mice.
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6

YU, Zhenbao, Meryem MAOUI, Liangtang WU, Denis BANVILLE, and Shi-Hsiang SHEN. "mSiglec-E, a novel mouse CD33-related siglec (sialic acid-binding immunoglobulin-like lectin) that recruits Src homology 2 (SH2)-domain-containing protein tyrosine phosphatases SHP-1 and SHP-2." Biochemical Journal 353, no. 3 (January 25, 2001): 483–92. http://dx.doi.org/10.1042/bj3530483.

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The sialic acid-binding immunoglobulin-like lectins (siglecs) represent a recently defined distinct subset of the immunoglobulin superfamily. By using the Src homology 2 (SH2)-domain-containing protein tyrosine phosphatase SHP-1 as bait in a yeast two-hybrid screen, we have identified a new member of the mouse siglec family, mSiglec-E. The mSiglec-E cDNA encodes a protein of 467 amino acids that contains three extracellular immunoglobulin-like domains, a transmembrane region and a cytoplasmic tail bearing two immunoreceptor tyrosine-based inhibitory motifs (ITIMs). mSiglec-E is highly expressed in mouse spleen, a tissue rich in leucocytes. The ITIMs of mSiglec-E can recruit SHP-1 and SHP-2, two inhibitory regulators of immunoreceptor signal transduction. This suggests that the function of mSiglec-E is probably an involvement in haematopoietic cells and the immune system as an inhibitory receptor. When expressed in COS-7 cells, mSiglec-E was able to mediate sialic acid-dependent binding to human red blood cells, suggesting that mSiglec-E may function through cell–cell interactions. In comparison with the known members of the siglec family, mSiglec-E exhibits a high degree of sequence similarity to both human siglec-7 and siglec-9. The gene encoding mSiglec-E is localized in the same chromosome as that encoding mouse CD33. Phylogenetic analysis reveals that neither mouse mSiglec-E nor CD33 shows a clear relationship with any human siglecs so far identified.
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7

Ibarlucea-Benitez, Itziar, Polina Weitzenfeld, Patrick Smith, and Jeffrey V. Ravetch. "Siglecs-7/9 function as inhibitory immune checkpoints in vivo and can be targeted to enhance therapeutic antitumor immunity." Proceedings of the National Academy of Sciences 118, no. 26 (June 21, 2021): e2107424118. http://dx.doi.org/10.1073/pnas.2107424118.

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Given the role of myeloid cells in T cell activation and in the antitumor response, targeting checkpoint molecules expressed on this population represents a promising strategy to augment antitumor immunity. However, myeloid checkpoints that can be effectively used as immunotherapy targets are still lacking. Here, we demonstrate the therapeutic potential of targeting the myeloid receptors Siglec-7 and Siglec-9 in vivo. By using a humanized immunocompetent murine model, we demonstrate that human Siglec-7 and Siglec-9, in addition to the murine homolog Siglec-E, inhibit the endogenous antitumor immune response, as well as the response to tumor-targeting and immune checkpoint inhibiting antibodies in vivo. The impact of these Siglecs on tumor progression is highly dependent on the anatomical distribution of the tumor and, as a consequence, the local tumor microenvironment, as tumors with a more immune-suppressive tumor microenvironment are less sensitive to Siglec perturbation. Finally, to assess the potential of these two receptors as targets for immunotherapy, we developed Fc engineered blocking antibodies to Siglec-7 and Siglec-9 and demonstrate that Siglec-7 and Siglec-9 blockade can significantly reduce tumor burden in vivo, demonstrating the therapeutic potential of targeting these two receptors.
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8

Lund, Sean J., Kathryn A. Patras, Jacqueline M. Kimmey, Asami Yamamura, Lindsay D. Butcher, Pamela G. B. Del Rosario, Gilberto E. Hernandez, et al. "Developmental immaturity of sialic acid recognition mediates neonatal susceptibility to GBS pneumonia." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 231.31. http://dx.doi.org/10.4049/jimmunol.204.supp.231.31.

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Abstract Group B Streptococcus (GBS) is a major neonatal pathogen but rarely causes disease in adults. We previously showed in mice that GBS escapes killing in the neonatal lung via its heavily sialylated capsule. Immune cells detect sialic acid moieties via expression of a repertoire of Siglec receptors. Combinatory expression of proinflammatory and anti-inflammatory Siglec receptors allows differentiation between host and pathogenic microbial sialic acid modifications. We test here the hypothesis that neonatal alveolar macrophages (AMs) fail to detect and kill GBS due to developmental immaturity of Siglec receptor expression. Adult AMs express the proinflammatory sialic acid receptor Sialoadhesin (Sn, Siglec-1) and the anti-inflammatory receptors Siglec-E and Siglec-F. However, real time PCR, immunofluorescence, and FACS detected only Siglec-E in neonatal lung macrophage populations. Sn expression increased soon after birth and was restricted to AMs. The timing of increased Sn expression in newborn mice correlated with susceptibility to GBS. Mice infected with GBS on day 1 suffered early onset mortality, while mice infected on day 2 displayed late onset disease. Mice infected on day 3 survived GBS infection. Further implicating AM immaturity, Csf2−/− mice, which have defects in AM differentiation, lacked Sn expression and had reduced GBS clearance following infection. The presence of Siglec-E but absence of Sn in newborn AMs appeared to promote tolerance to GBS. Newborn SigE−/− mice had increased GBS phagocytosis and killing compared to WT controls. We therefore conclude that GBS exploits developmental immaturity of Siglec expression in AMs via its sialic acid capsule in causing neonatal disease.
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9

Chen, Guoyun, Yin wu, and Dongren Ren. "Siglec-E negatively regulates the activation of Toll-like Receptor 4 by controlling its endocytosis." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 222.22. http://dx.doi.org/10.4049/jimmunol.198.supp.222.22.

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Abstract TLR4 signaling is critical for providing effective immune protection but must be tightly controlled to avoid inflammation-induced pathology. Previously, we reported extensive and direct interactions between TLR and Siglec families of Pattern Recognition Receptors. Here, we examined the biological significance of this interaction during infection. We found that Siglec-E is required for E. coli-induced endocytosis of TLR4. Siglec-E-deficient dendritic cells infected with E. coli fail to internalize TLR4. This leads to sustained TLR4 on cell surface and activation of NF-κB and MAP kinase p38, resulting in high levels of TNF-α and IL-6 compared with wild-type dendritic cells. In contrast to the signaling events occurring at the plasma membrane, as a result of the inability to internalize of TLR4, Siglec-E-deficient dendritic cells were also defective for TRIF-mediated IFN-β production in response to E. coli infection. Furthermore, we found that accumulation of ubiquitinated-TLR4 and binding of E3 ubiquitin ligase Triad3A to TLR4 was increased significantly in bone marrow-derived dendritic cells from wild-type mice, but not from Siglec-E-deficient mice, after E. coli infection. This represents a newly discovered mechanism that regulates the signaling of TLR4 during E. coli infection.
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10

Chen, Yin, David J. Friedman, Mayank Saraswat, Michael J. Shapiro, Drew Wilfahrt, Akhilesh Pandey, and Virginia Smith Shapiro. "Sialylation of CD44 by ST8sia6 is required for recognition by the inhibitory receptor Siglec-7." Journal of Immunology 208, no. 1_Supplement (May 1, 2022): 176.13. http://dx.doi.org/10.4049/jimmunol.208.supp.176.13.

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Abstract Glycans decorate almost all proteins and lipids on the cell surface, and they play a critical role in cell-cell interactions. Terminal sialic acid addition to glycans helps the immune system distinguish between “self” and “non-self.” The enzyme ST8sia6 adds alpha-2,8 disialic acids to cell surface receptors, and this sialic acid addition promotes binding to the inhibitory receptor Siglec-E. We have previously shown ST8sia6 overexpression in tumors accelerates tumor growth in a Siglec-E dependent manner. Proteomic analysis in murine tumor lines identified CD44 as a target for ST8sia6. CD44 expression on tumors is associated with metastasis and chemoresistance. Since humans and mice have different sialic acid structures, we examined whether ST8sia6 makes CD44 a ligand to the ortholog of Siglec-E in human cells, Siglec-7. When HEK293T cells overexpress ST8sia6 and CD44 together, Siglec-7 binding was significantly increased compared to ST8sia6 or CD44 overexpression alone. Thus, ST8sia6 has a conserved role from mouse to human in decorating CD44 with sialic acid. Our study proposes that ST8sia6 sialylation of CD44 could suppress immune responses and enables cancer progression in human. Supported by grant: 2T32AI007425-23 to DJF and R01 CA243545-01S1 to V.S.S.
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11

McMillan, Sarah J., Ritu S. Sharma, Emma J. McKenzie, Hannah E. Richards, Jiquan Zhang, Alan Prescott, and Paul R. Crocker. "Siglec-E is a negative regulator of acute pulmonary neutrophil inflammation and suppresses CD11b β2-integrin–dependent signaling." Blood 121, no. 11 (March 14, 2013): 2084–94. http://dx.doi.org/10.1182/blood-2012-08-449983.

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Key Points First report describing in vivo function of siglec-E as a negative regulator of neutrophil recruitment in acute lung inflammation. Implications for the human functional ortholog, siglec-9, and its potential role in regulating inflammatory lung disease.
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12

Friedman, David J., Michael J. Shapiro, Matthew Rajcula, Shaylene McCue, Khashayarsha Khazaie, Haidong Dong, and Virginia Smith Shapiro. "ST8Sia6 Overexpression Accelerates Tumorigenesis in a Siglec E Dependent Manner Through Reshaping the Tumor Immune Microenvironment." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 242.28. http://dx.doi.org/10.4049/jimmunol.204.supp.242.28.

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Abstract Checkpoint blockade has improved patient outcome through reinvigorating T cells against cancer. Despite this success, many patients don’t respond, leaving them with few options. Tumors utilize many immunosuppressive mechanisms, including altering the function of innate immune cells. Cancer cells can promote differentiation of macrophages into tolerogenic “M2-like” macrophages, which support tumor growth. Macrophage differentiation by cancer cells is influenced by many receptors, including Siglec-E. Siglec-E binds to α2,8-linked disialic acids, generated by the enzyme ST8Sia6, on O-linked glycoproteins, and functions to inhibit activation of innate immune cells. Cancer patients with high expression of ST8Sia6 exhibit reduced survival. Therefore, ST8Sia6 overexpressing tumors may engage Siglec-E, leading to immune suppression and accelerating tumor growth. Mice injected with ST8Sia6 overexpressing MC38 and B16-F10 tumors had increased tumor burden, reduced survival and an increase M2 macrophage polarization. The acceleration in tumor growth was abrogated when injected into Siglec-E knockout mice. Thus, the primary function of ST8Sia6 in tumors is an extrinsic alteration of the immune response, rather than an intrinsic effect on cell growth. Similarly, in a spontaneous colon cancer model, ST8Sia6 overexpression in a murine colon cancer model accelerated the development of tumors, decreasing survival to 2.5 months instead of 6 months. The overexpression of ST8Sia6 on tumors leads to increased Arg-1 expression by CD11b+ CD11c+Ly6C−Ly6G− cells, which suppresses the immune response. Therefore, ST8Sia6 expression in tumors inhibits the immune response to promote tumor growth in a Siglec-E dependent manner.
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Belmonte, Paul, Michael Shapiro, Shaylene McCue, Matthew Rajcula, and Virginia Smith Shapiro. "ST8Sia6 generated α2,8-disialic acids mitigate hyperglycemia in multiple low dose streptozocin-induced diabetes." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 68.16. http://dx.doi.org/10.4049/jimmunol.202.supp.68.16.

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Abstract Type 1 diabetes is an autoimmune disease that destroys insulin-producing beta cells in the pancreatic islets. Although exogenous insulin replacement therapy is lifesaving, precise blood glucose management remains a significant challenge. Experimental islet transplantation restores normoglycemia, but the lack of available islets and graft rejection present major barriers to widespread adoption as standard therapy. The islet resident macrophage (IRM) is in close contact with beta cells, efficiently presents islet antigen to autoreactive T cells, and is critical to disease occurrence. We have demonstrated that murine IRMs express high levels of Siglec-E, an immune-regulatory receptor that preferentially binds α2,8-disialic acids in cis or in trans. When islets were exposed to streptozocin (STZ)-induced stress in culture, beta cells upregulated ligands for Siglec-E. To determine the biological significance of this, we generated a mouse model where ST8Sia6, the sialyltransferase that produces α2,8-disialic acids and thus Siglec-E ligands, is constitutively overexpressed in beta cells. This increased trans Siglec-E binding affinity to the beta cell surface, and mitigated hyperglycemia in the multiple low-dose STZ model of diabetes. Significant reduction in blood sugar was evident at 14 days post-initial injection of STZ, coinciding with T cell infiltration of islets. T cells from ST8Sia6+ islets were less activated when compared to littermates. This work reveals a novel and important role for Siglec-E in autoimmune diabetes and provides insight into how rational targeting of this immune receptor may instruct islet-residing antigen presenting cells to provide local tolerance signals in the setting of islet transplantation.
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Uchiyama, Satoshi, Josh Sun, Kyoko Fukahori, Nao Ando, Mengyou Wu, Flavio Schwarz, Shoib S. Siddiqui, Ajit Varki, Jamey D. Marth, and Victor Nizet. "Dual actions of group BStreptococcuscapsular sialic acid provide resistance to platelet-mediated antimicrobial killing." Proceedings of the National Academy of Sciences 116, no. 15 (March 25, 2019): 7465–70. http://dx.doi.org/10.1073/pnas.1815572116.

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Circulating platelets have important functions in thrombosis and in modulating immune and inflammatory responses. However, the role of platelets in innate immunity to bacterial infection is largely unexplored. While human platelets rapidly killStaphylococcus aureus, we found the neonatal pathogen group BStreptococcus(GBS) to be remarkably resistant to platelet killing. GBS possesses a capsule polysaccharide (CPS) with terminal α2,3-linked sialic acid (Sia) residues that mimic a common epitope present on the human cell surface glycocalyx. A GBS mutant deficient in CPS Sia was more efficiently killed by human platelets, thrombin-activated platelet releasate, and synthetic platelet-associated antimicrobial peptides. GBS Sia is known to bind inhibitory Sia-recognizing Ig superfamily lectins (Siglecs) to block neutrophil and macrophage activation. We show that human platelets also express high levels of inhibitory Siglec-9 on their surface, and that GBS can engage this receptor in a Sia-dependent manner to suppress platelet activation. In a mouse i.v. infection model, antibody-mediated platelet depletion increased susceptibility to platelet-sensitiveS. aureusbut did not alter susceptibility to platelet-resistant GBS. Elimination of murine inhibitory Siglec-E partially reversed platelet suppression in response to GBS infection. We conclude that GBS Sia has dual roles in counteracting platelet antimicrobial immunity: conferring intrinsic resistance to platelet-derived antimicrobial components and inhibiting platelet activation through engagement of inhibitory Siglecs. We report a bacterial virulence factor for evasion of platelet-mediated innate immunity.
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Friedman, David J., Monika Kizerwetter, Paul Belmonte, Matthew Rajcula, Keith Theodore, Hyun Se Kim Lee, Michael J. Shapiro, Haidong Dong, and Virginia Smith Shapiro. "Enhanced anti-tumor immunity in ST8Sia6 knockout mice." Journal of Immunology 208, no. 1_Supplement (May 1, 2022): 61.10. http://dx.doi.org/10.4049/jimmunol.208.supp.61.10.

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Abstract Inhibitory receptors have a critical role in the regulation of immunity. Siglecs are a family of primarily inhibitory receptors expressed by immune cells, which recognize specific sialic acid modifications on cell surface glycans. Sialyltransferases are the enzymes that catalyzing the addition of sialic acids onto glycoproteins and glycolipids. Siglec-E binds to α2,8-linked disialic acids, generated by the enzyme ST8Sia6 on O-linked glycoproteins and functions to inhibit activation of innate immune cells. Many tumors have increased sialic acid incorporation. Overexpression of the sialyltransferase ST8Sia6 on tumors led to altered macrophage polarization and increased tumor growth through engagement of ligands generated by ST8Sia6 with Siglec-E. Here, we examine the role of ST8Sia6 on immune cells in regulating anti-tumor immunity. The loss of ST8Sia6 in tumor bearing mice reduced tumor growth, increased survival, and altered the immune response as compared to ST8Sia6 sufficient tumor bearing mice. Using MC38, B16, and B16-OVA flank tumor mouse models, tumor growth was decreased in ST8Sia6 KO mice as compared to C57Bl/6 mice. Within the tumor microenvironment of tumors present in ST8Sia6 KO mice compared to tumors present in C57Bl/6 mice, macrophages and dendritic cells altered their phenotype towards enhanced immune activation. Tregs from tumors in ST8Sia6 KO mice also displayed an increase in RORγt and a reduction in TNFRII, suggesting a possible shift to a less suppressive Treg. These alterations in the immune response to tumors were due to the loss of ST8Sia6 in macrophages and dendritic cells and not T-cells. Thus, ST8Sia6 generates ligands for Siglecs that dampen anti-tumor immunity. Supported by grants from NIH (R01CA243545, 2T32AI007425) and Mayo Clinic Center of Biomedical Discovery
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Crotts, Sydney B., David J. Friedman, Zheng Wang, Michael J. Shapiro, Matthew Rajcula, Shaylene McCue, Jie Sun, and Virginia Smith Shapiro. "Regulation of the immune response by ST8Sia6." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 228.18. http://dx.doi.org/10.4049/jimmunol.204.supp.228.18.

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Abstract Sialic acids are the terminal modification on glycoproteins and glycolipids. The sialic acid transferase ST8Sia6 generates a2,8-linked disialic acids on O-linked glycoproteins, which bind to the inhibitory receptor Siglec-E on innate immune cells and suppress immune activation. Recently, our lab has shown that ST8Sia6 expression on tumor cells inhibits the immune response through Siglec-E, leading to increased tumor growth and decreased survival. Therefore, the products of ST8Sia6 can modulate the immune response to tumors. Our lab has generated ST8Sia6 knockout (KO) mice, and we seek to understand the role of ST8Sia6 in regulating the immune response to pathogens. We find that ST8Sia6 KO mice, when challenged with influenza virus, clear the infection significantly faster than wildtype controls, suggesting that absence of ST8Sia6 reduces inhibition of the innate compartment, thereby increasing immune recruitment to infection. This data suggests an important role for interactions between Siglec-E and ST8Sia6-generated disialic acids in immune regulation and recruitment to infection sites.
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Lund, Sean J., Kathryn A. Patras, Asami Yamamura, Gilberto Hernandez, Omar Lakhdari, Victor Nizet, and Lawrence S. Prince. "Alveolar macrophage maturation is required for efficient killing of GBS in the lung." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 190.43. http://dx.doi.org/10.4049/jimmunol.202.supp.190.43.

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Abstract Group B Streptococcus (GBS) is the most common pathogen in neonates but rarely causes disease in adults. GBS causes pneumonia in newborns, suggesting a defect in lung innate immunity at birth. Using a novel neonatal mouse model of GBS pneumonia, we showed that newborn mice have reduced killing of GBS in the lung and more severe and persistent lung injury. Here we test the hypothesis that defects in alveolar macrophage (AM) maturation in newborns leads to GBS susceptibility. Clodronate depletion of AM from adult mice prevented GBS killing, supporting the requirement of AM for GBS protection. AM maturation and function requires GM-CSF, which is abundantly expressed in the lung. While AM maturation occurred on day 4 in WT mice, GM-CSF knockout mice (Csf2−/−) failed to develop AM. Consistent with the role of AM in GBS immunity, neonatal Csf2−/− mice had reduced GBS killing and lung macrophages failed to phagocytose GBS. Csf2−/− macrophages also had reduced expression of multiple Siglecs, cell surface receptors implicated in protection against encapsulated bacteria. Newborn lung macrophages expressed primarily Siglec-E (SigE), whereas expression of other Siglecs were only detected in more mature AM. We used SigE−/− mice to test its role in neonatal GBS pneumonia. GBS killing in SigE−/− neonates was similar to WT. However SigE−/− macrophages appeared to phagocytose GBS more efficiently in vivo, suggesting GBS may employ SigE to avoid detection by neonatal macrophages. Our data show that mature alveolar macrophages are required for protection against pulmonary GBS infection and potentially implicate the developmental regulation of macrophage Siglec expression in neonatal lung immunity.
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Friedman, David J., Michael J. Shapiro, and Virginia Smith Shapiro. "ST8Sia6 overexpression in cancer and its effect on the tumor microenvironment." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 178.31. http://dx.doi.org/10.4049/jimmunol.200.supp.178.31.

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Abstract Modulating T-cell activity has been the primary focus in cancer immunotherapy. However, cancer cells can promote differentiation of macrophages into tolerogenic “M2” macrophages, which support tumor growth. Macrophage differentiation by cancer cells is influenced by many receptors including Siglec-E. Siglec-E recognizes α2,8-linked disialic acids on O-linked glycoproteins, and functions to inhibit activation of innate immune cells including macrophages. One enzyme that generates α2,8-linked disialic acids is ST8Sia6. COSMIC database analysis revealed that 389 tumors overexpressed, while none under-expressed, ST8Sia6, indicating a potential selective advantage for increased ST8Sia6 expression on tumors. Additionally, on a variety of cancers many patients with high expression of ST8Sia6 exhibit reduced survival as compared to patients with low expression. Therefore, we hypothesized that ST8Sia6 overexpressing tumors will engage Siglec-E, causing differentiation and expansion of M2 macrophages, and accelerating tumor growth. We demonstrated that ST8Sia6 increases M2 macrophage polarization in cell lines expressing ST8Sia6 compared to parental lines in vitro and in vivo. In vivo murine models also demonstrate increased tumor burden and reduced survival in mice injected with ST8Sia6 overexpressing MC38 tumors. Therefore, ST8Sia6 expression in tumors may suppress the immune response and promote tumor growth. ST8Sia6 may prove to be a “druggable” target for future cancer immunotherapies.
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Wu, Yin, Darong Yang, Runhua Liu, Lizhong Wang, and Guo-Yun Chen. "Selective Response to Bacterial Infection by Regulating Siglec-E Expression." iScience 23, no. 9 (September 2020): 101473. http://dx.doi.org/10.1016/j.isci.2020.101473.

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Friedman, David J., Michael Shapiro, Matthew Rajcula, Shaylene McCue, and Virginia Smith Shapiro. "ST8Sia6 Overexpression Accelerates Tumor Growth, Alters Macrophage Polarization and the Immune Response." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 135.8. http://dx.doi.org/10.4049/jimmunol.202.supp.135.8.

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Abstract T-cell targeted immunotherapy has resulted in novel treatments for multiple cancers and has been the primary focus in cancer immunotherapy. However, many patients still fail checkpoint therapies due to immune suppression mechanisms driven by cells, such as tolerogenic M2-like macrophages, which support tumor growth. ST8Sia6, a sialyltransferase, generates α2,8-linked disialic acids on O-linked glycoproteins. Cancer patients with high ST8Sia6 expression exhibit reduced survival as compared to patients with low expression, but the mechanism is unknown. We generated MC38 and B16–F10 murine cancer cell lines that overexpress ST8Sia6. Expression of ST8Sia6 accelerated flank tumor growth in both single and dual flank injection models as compared to parental tumors. In vivo, macrophage polarization was altered in ST8Sia6 expressing tumors. At day 7, tumor associated macrophages (TAMs) from ST8Sia6 negative MC38 tumors were primarily M1-like, while TAMs from ST8Sia6 expressing MC38 tumors were predominately M2-like. Tumor growth and M2-like polarization was dependent Siglec-E. Siglec-E present on innate cells bind α2,8-linked disialic acids generated by ST8Sia6 and suppress immune activation. Therefore, ST8Sia6 overexpressing tumors engage Siglec-E, suppressing the immune response and increasing tumor growth. ST8Sia6 overexpression in a spontaneous murine colon cancer model decreased survival from over 6 months to 2–3 months. Therefore, ST8Sia6 expression in tumors may promote tumor growth by promoting tolerogenic immune responses.
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CHAU, Lee-Young, Yaw-Wen Hsu, Ming-Tsai Chiang, Fu-Fei Hsu, Takashi Angata, and Paul R. Crocker. "Siglec‐E Retards Atherosclerosis by Inhibiting CD36‐Mediated Foam Cell Formation." FASEB Journal 34, S1 (April 2020): 1. http://dx.doi.org/10.1096/fasebj.2020.34.s1.02093.

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Erdmann, Hanna, Christiane Steeg, Friedrich Koch-Nolte, Bernhard Fleischer, and Thomas Jacobs. "Sialylated ligands on pathogenicTrypanosoma cruziinteract with Siglec-E (sialic acid-binding Ig-like lectin-E)." Cellular Microbiology 11, no. 11 (November 2009): 1600–1611. http://dx.doi.org/10.1111/j.1462-5822.2009.01350.x.

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Andes, F. T., S. Adam, M. Hahn, O. Aust, S. Frey, A. Grueneboom, L. Nitschke, G. Schett, and U. Steffen. "The human sialic acid-binding immunoglobulin-like lectin Siglec-9 and its murine homolog Siglec-E control osteoclast activity and bone resorption." Bone 143 (February 2021): 115665. http://dx.doi.org/10.1016/j.bone.2020.115665.

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Wu, Yin, Dongren Ren, and Guo-Yun Chen. "Siglec-E Negatively Regulates the Activation of TLR4 by Controlling Its Endocytosis." Journal of Immunology 197, no. 8 (September 12, 2016): 3336–47. http://dx.doi.org/10.4049/jimmunol.1600772.

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Egan, Hannah, Oliver Treacy, Kevin Lynch, Niamh Leonard, Amir Nader, Margaret Sheehan, Sean Hynes, et al. "865 Sugar high: Does the sialic acid profile of cancer-associated fibroblasts induce a more tumour-permissive microenvironment?" Journal for ImmunoTherapy of Cancer 8, Suppl 3 (November 2020): A918. http://dx.doi.org/10.1136/jitc-2020-sitc2020.0865.

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BackgroundImmunosuppressive tumour microenvironments (TME) inhibit the effectiveness of cancer immunotherapies. Sialic acids, which exist as terminal sugars of glyco-conjugates, are highly expressed on cancer cells and are involved in various pathological processes including increased immune evasion, tumour invasiveness and tumour cell metastasis.1 Siglecs (Sialic acid-binding immunoglobulin-type lectins) are expressed on immune cell surfaces and bind sialic acid. Siglec binding to hypersialylated tumour glycans blocks immune cell activation to promote immunosuppression.1 2Intestinal stromal cells (iSCs), precursors to cancer-associated fibroblasts (CAFs), are a key component of the TME and play a vital role in tumour progression by enhancing a tumour-promoting microenvironment. The aim of this study was therefore to investigate if iSC/CAF sialylation contributes to enhanced immunosuppression in the TME.Methods iSCs were isolated from colorectal cancer patient biopsies and cultured ex vivo. Informed consent was obtained from all patients prior to sampling. Tumour-derived iSCs were termed CAFs while control iSCs, isolated from tumour-adjacent non-cancerous tissue, were termed normal-associated fibroblasts (NAFs). NAFs/CAFs were then co-cultured with healthy allogeneic PBMCs and their immunosuppressive properties were assessed by flow cytometry.ResultsCAFs significantly supressed the proliferation of CD8+ and CD4+ T-cells and induced a more exhausted T-cell phenotype as evidenced by increased expression of the exhaustion markers TIM-3, LAG-3 and PD-1 when compared to co-culture with control NAFs, thereby demonstrating their potent immunosuppressive properties. Strikingly, CAFs also induced significantly higher expression of both Siglec-7 and Siglec-9 receptors on CD8+ T-cells specifically.To elucidate the role of sialylation on CAF-mediated immunosuppression, NAFs/CAFs were treated with the sialyltransferase inhibitor (SI) P-3FAX-Neu5Ac prior to co-culture. Reduction of sialic acid expression on NAFs/CAFs was confirmed by flow cytometry and the SI-treated NAFs/CAFs were then co-cultured with allogeneic T-cells to assess the functional consequences of reduced NAF/CAF sialylation. SI-treated CAFs induced significantly less CD4+TIM-3+ and both CD4+LAG-3+ and CD8+LAG-3+ T-cells compared to their untreated counterparts. Interestingly, SI-treated CAFs also induced significantly less Siglec-7 and -9 receptor-expressing CD8+ T-cells.ConclusionsThese results demonstrate that non-haematopoietic stromal cells in the tumour-microenvironment can suppress activated T-cells and that this immunosuppressive effect can be significantly reversed through the modulation of sialylation on the stromal cell surface. These results support the hypothesis that stromal cell sialylation plays a role in their immunosuppressive properties. Understanding how sialylation of stromal cells is regulated and functions to enhance immunosuppression in the TME could uncover novel immune checkpoints to reactivate anti-tumour immunity, allowing for tumour cell clearance.Ethics ApprovalThis study was approved by Galway University Hospitals’ Clinical Research Ethics Committee, approval number C.A 2074.ConsentN/AReferencesWang L, Liu Y, Wu L, Sun XL. Sialyltransferase inhibition and recent advances. Biochim Biophys Acta 2016 Jan; 1864(1):143-53.Munkley J, Scott E. Targeting aberrant sialylation to treat cancer. Medicines (Basel) 2019 Oct 13;6(4):102.
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Claude, J., B. Linnartz-Gerlach, A. P. Kudin, W. S. Kunz, and H. Neumann. "Microglial CD33-Related Siglec-E Inhibits Neurotoxicity by Preventing the Phagocytosis-Associated Oxidative Burst." Journal of Neuroscience 33, no. 46 (November 13, 2013): 18270–76. http://dx.doi.org/10.1523/jneurosci.2211-13.2013.

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Ishida, Takato, Masanori Nagao, Takahiro Oh, Takeshi Mori, Yu Hoshino, and Yoshiko Miura. "Synthesis of Glycopolymers Carrying 3′-Sialyllactose for Suppressing Inflammatory Reaction via Siglec-E." Chemistry Letters 51, no. 3 (March 5, 2022): 308–11. http://dx.doi.org/10.1246/cl.210740.

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Siddiqui, Shoib, Flavio Schwarz, Stevan Springer, Zahra Khedri, Hai Yu, Lingquan Deng, Andrea Verhagen, et al. "Studies on the Detection, Expression, Glycosylation, Dimerization, and Ligand Binding Properties of Mouse Siglec-E." Journal of Biological Chemistry 292, no. 3 (December 5, 2016): 1029–37. http://dx.doi.org/10.1074/jbc.m116.738351.

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Chung, Il Yup, Sae Mi Hwang, and Tae Gi Uhm. "Expression and function of Olig2 in eosinophils." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 52.17. http://dx.doi.org/10.4049/jimmunol.196.supp.52.17.

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Abstract Eosinophils are granulocytes that are associated with homeostasis and type 2 immune responses, allergy and parasitic infection. Olig2 is a basic helix loop helix transcription factor that is known to play a key role in cell fate decision and subsequent differentiation of oligodendrocytes. Herein, we report the expression and possible function of Olig2 in eosinophils. When cord blood (CB) CD34+ hematopoietic stem cells differentiated toward eosinophils during a 24 day culture period, Olig2 protein was expressed only in CB eosinophils at day 24, a time when these cells were considered fully differentiated and matured, while Olig2 protein was not detected at day 18 or at earlier time points. Olig2 protein was also abundantly expressed in human peripheral blood eosinophils, but not neutrophils, monocytes, lymphocytes or CB mast cells. RNA-seq analysis showed that numerous genes, especially those encoding eosinophil surface molecules, were highly upregulated along with OLIG2. Among the genes examined, SIGLEC-8 mRNA and protein were downregulated in parallel with OLIG2 by an Olig2 siRNA or a shRNA. In reporter gene and chromatin immunoprecipitation experiments, an E-box in the first intron was found to stimulate SIGLEC-8 gene transcription and bind Olig2. Occupancy of the E-box by Olig2 was also seen upon differentiation of immature eosinophilic AML14.3D10 cells. Hence, at least one important aspect of eosinophil differentiation is driven by Olig2, a transcription factor that has not previously been reported in normal granulocytes.
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Belmonte, Paul, Ji Young Chung, Sinibaldo Romero Arocha, Aaron Schwab, Michael J. Shapiro, Brian T. Fife, and Virginia Shapiro. "ST8Sia6 attenuates diabetes progression and severity." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 100.13. http://dx.doi.org/10.4049/jimmunol.200.supp.100.13.

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Abstract Nearly 1.25 million Americans suffer from type 1 diabetes, an autoimmune disease which destroys insulin-producing beta cells of the pancreatic islets. Although insulin therapy is a lifesaving treatment, it is not a cure and secondary complications remain a significant concern. Experimental islet transplantation as a curative measure has yet to overcome the barrier of immune-mediated destruction, as patients eventually revert back to insulin-dependency. Immunotherapies to date have focused on targeting the adaptive immune response, largely ignoring the innate immune system, and have had limited success. Siglec-E is an inhibitory receptor expressed on innate immune cells such as macrophages and dendritic cells; it is known to dampen inflammation through several mechanisms. Here, we demonstrate that the sialic acid transferase ST8Sia6, which catalyzes addition of a2,8-linked disialic acids to glycoproteins, produces cell surface ligands for Siglec-E. We selectively expressed ST8Sia6 in pancreatic beta cells, hypothesizing this would have a beneficial effect in delaying disease in the murine multiple low-dose streptozocin model of diabetes. We observe that when diabetes is induced, mice that express ST8Sia6 in beta cells have delayed onset of diabetes and less severe hyperglycemia as compared to littermate controls. Notably, expression of ST8Sia6 in beta cells does not interfere with normal glucose response. Therefore, ST8Sia6 expression in pancreatic beta cells is safe and attenuates diabetes progression and severity. Because cell surface glycans play a major role in recognition of self, this work has significance in islet-targeted gene therapy, transplantation, and graft survival.
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McMillan, Sarah J., Ritu S. Sharma, Hannah E. Richards, Vikas Hegde, and Paul R. Crocker. "Siglec-E Promotes β2-Integrin-dependent NADPH Oxidase Activation to Suppress Neutrophil Recruitment to the Lung." Journal of Biological Chemistry 289, no. 29 (June 3, 2014): 20370–76. http://dx.doi.org/10.1074/jbc.m114.574624.

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Liu, Hongmei, Yu Zheng, Yingxian Zhang, Jin Li, Steve M. Fernandes, Dongfeng Zeng, Xiaohui Li, Ronald L. Schnaar, and Yi Jia. "Immunosuppressive Siglec-E ligands on mouse aorta are up-regulated by LPS via NF-κB pathway." Biomedicine & Pharmacotherapy 122 (February 2020): 109760. http://dx.doi.org/10.1016/j.biopha.2019.109760.

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Vyas, Alka A., Ola Blixt, James C. Paulson, and Ronald L. Schnaar. "Potent Glycan Inhibitors of Myelin-associated Glycoprotein Enhance Axon Outgrowthin Vitro." Journal of Biological Chemistry 280, no. 16 (February 8, 2005): 16305–10. http://dx.doi.org/10.1074/jbc.m500250200.

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Myelin-associated glycoprotein (MAG, Siglec-4) is one of several endogenous axon regeneration inhibitors that limit recovery from central nervous system injury and disease. Molecules that block such inhibitors may enhance axon regeneration and functional recovery. MAG, a member of the Siglec family of sialic acid-binding lectins, binds to sialoglycoconjugates on axons and particularly to gangliosides GD1a and GT1b, which may mediate some of the inhibitory effects of MAG. In a prior study (Blixt, O., Collins, B. E., van den Nieuwenhof, I. M., Crocker, P. R., and Paulson, J. C. (2003)J. Biol. Chem.278, 31007-31019), we identified potent monovalent sialoside inhibitors of MAG using a novel screening platform. In the current study, the most potent of these were tested for their ability to reverse MAG-mediated inhibition of axon outgrowth from rat cerebellar granule neuronsin vitro. Monovalent sialoglycans enhanced axon regeneration in proportion to their MAG binding affinities. The most potent glycoside was disialyl T antigen (NeuAcα2–3Galβ1–3[NeuAcα2–6]GalNAc-R), followed by 3-sialyl T antigen (NeuAcα2–3Galβ1–3GalNAc-R), structures expressed onO-linked glycoproteins as well as on gangliosides. Prior studies indicated that blocking gangliosides reversed MAG inhibition (Vyas, A. A., Patel, H. V., Fromholt, S. E., Heffer-Lauc, M., Vyas, K. A., Dang, J., Schachner, M., and Schnaar, R. L. (2002)Proc. Natl. Acad. Sci. USA99, 8412–8417). In the current study, blockingO-linked glycoprotein sialylation with benzyl-α-GalNAc had no effect. The ability to reverse MAG inhibition with monovalent glycosides encourages further exploration of glycans and glycan mimetics as blockers of MAG-mediated axon outgrowth inhibition.
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Bax, M., W. Unger, S. Kaur Singh, E. J. McKenzie, M. Litjens, J. J. Garcia-Vallejo, E. Saeland, S. J. van Vliet, P. R. Crocker, and Y. van Kooyk. "Targeting siglec-E on murine dendritic cells inhibits antigen presentation and CD4 and CD8 t cell responses." Annals of the Rheumatic Diseases 69, Suppl 2 (March 1, 2010): A42. http://dx.doi.org/10.1136/ard.2010.129627s.

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Boyd, Caroline R., Selinda J. Orr, Shaun Spence, James F. Burrows, Joanne Elliott, Helen P. Carroll, Kiva Brennan, et al. "Siglec-E Is Up-Regulated and Phosphorylated Following Lipopolysaccharide Stimulation in Order to Limit TLR-Driven Cytokine Production." Journal of Immunology 183, no. 12 (November 23, 2009): 7703–9. http://dx.doi.org/10.4049/jimmunol.0902780.

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Boyd, Caroline R., Selinda J. Orr, Shaun Spence, James F. Burrows, Joanne Elliott, Helen P. Carroll, Kiva Brennan, et al. "Siglec-E is up-regulated and phosphorylated following lipopolysaccharide stimulation in order to limit TLR-driven cytokine production." Journal of Immunology 184, no. 3 (January 20, 2010): 1655. http://dx.doi.org/10.4049/jimmunol.0990117.

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Wielgat, Przemyslaw, Robert Czarnomysy, Emil Trofimiuk, and Halina Car. "The sialoglycan-Siglec-E checkpoint axis in dexamethasone-induced immune subversion in glioma-microglia transwell co-culture system." Immunologic Research 67, no. 4-5 (October 2019): 348–57. http://dx.doi.org/10.1007/s12026-019-09106-7.

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38

Perdicchio, Maurizio, Juan M. Ilarregui, Marleen I. Verstege, Lenneke A. M. Cornelissen, Sjoerd T. T. Schetters, Steef Engels, Martino Ambrosini, et al. "Sialic acid-modified antigens impose tolerance via inhibition of T-cell proliferation and de novo induction of regulatory T cells." Proceedings of the National Academy of Sciences 113, no. 12 (March 3, 2016): 3329–34. http://dx.doi.org/10.1073/pnas.1507706113.

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Sialic acids are negatively charged nine-carbon carboxylated monosaccharides that often cap glycans on glycosylated proteins and lipids. Because of their strategic location at the cell surface, sialic acids contribute to interactions that are critical for immune homeostasis via interactions with sialic acid-binding Ig-type lectins (siglecs). In particular, these interactions may be of importance in cases where sialic acids may be overexpressed, such as on certain pathogens and tumors. We now demonstrate that modification of antigens with sialic acids (Sia-antigens) regulates the generation of antigen-specific regulatory T (Treg) cells via dendritic cells (DCs). Additionally, DCs that take up Sia-antigen prevent formation of effector CD4+ and CD8+ T cells. Importantly, the regulatory properties endowed on DCs upon Sia-antigen uptake are antigen-specific: only T cells responsive to the sialylated antigen become tolerized. In vivo, injection of Sia-antigen–loaded DCs increased de novo Treg-cell numbers and dampened effector T-cell expansion and IFN-γ production. The dual tolerogenic features that Sia-antigen imposed on DCs are Siglec-E–mediated and maintained under inflammatory conditions. Moreover, loading DCs with Sia-antigens not only inhibited the function of in vitro–established Th1 and Th17 effector T cells but also significantly dampened ex vivo myelin-reactive T cells, present in the circulation of mice with experimental autoimmune encephalomyelitis. These data indicate that sialic acid-modified antigens instruct DCs in an antigen-specific tolerogenic programming, enhancing Treg cells and reducing the generation and propagation of inflammatory T cells. Our data suggest that sialylation of antigens provides an attractive way to induce antigen-specific immune tolerance.
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Yousif, N. "P495Novel therapeutic role of siglec-E in down-regulation TLR4-mediated inflammatory response after global myocardial ischemia and reperfusion." Cardiovascular Research 103, suppl 1 (June 27, 2014): S90.4—S90. http://dx.doi.org/10.1093/cvr/cvu091.169.

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Ferrero, Maximiliano R., Anja M. Heins, Luciana L. Soprano, Diana M. Acosta, Mónica I. Esteva, Thomas Jacobs, and Vilma G. Duschak. "Involvement of sulfates from cruzipain, a major antigen of Trypanosoma cruzi, in the interaction with immunomodulatory molecule Siglec-E." Medical Microbiology and Immunology 205, no. 1 (June 6, 2015): 21–35. http://dx.doi.org/10.1007/s00430-015-0421-2.

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41

Hasan, Shirin, Ameet R. Kini, Andrea Szilagyi, Peggie Conrad, Richard L. Gamelli, and Kuzhali Muthumalaiappan. "Erythropoietin Resistant Anemia Following Burn Trauma Is in Part Due to Defective Terminal Maturation of Orthochromatic Erythroblasts Influenced By Erythroblast Island Macrophages." Blood 126, no. 23 (December 3, 2015): 4776. http://dx.doi.org/10.1182/blood.v126.23.4776.4776.

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Abstract Introduction: Erythropoietin resistant anemia persists for at least six months in patients discharged from intensive care unit (ICU) without any preexisting hematological disorders. Patients with greater than 10% total body surface area burn become anemic and are refractory to erythropoietin (Epo). Endogenous Epo is critical for the survival, proliferation and differentiation of erythroid progenitors during early-stage erythropoiesis. Erythropoiesis starts with the hematopoietic stem cell commitment to the erythroid lineage, and the newly developing erythroblasts are then nurtured in the erythroblastic islands (EBI), which support enucleating erythroblasts through adhesive interactions during terminal maturation. Our earlier reports in scald burn model indicate a myeloid bias following burn injury dictating bone marrow granulocyte monocyte progenitor versus megakaryocyte erythrocyte progenitors suggesting that Epo independent defects in CFU-E generation starts at the commitment stage. However, we found that Epo dependent proliferation remained intact in burn patient PBMC derived cultures, which was followed up to late erythroblast stage. Here we inquired whether erythroblast maturation stage is affected by burn injury, if so what phenotype of EBI macrophage contributes to the Epo resistant anemia in burn injury? Methods: To this end, four patients (2F and 2M), 40±7 years of age and 49.9±6.6%, TBSA burn were studied with consent and IRB approval. Blood samples collected twice at 7-10 days and 29-31 days post burn were analyzed. Age matched healthy volunteers served as controls (C). RBCs were generated ex vivo from burn patients' peripheral blood mononuclear compartment (PBMC) derived multi potent progenitors (MPPs) cultured with growth factors and autologous plasma. As it is difficult to obtain bone marrow from burn patients, parallel investigations were done in our mouse model of scald burn (15% TBSA) which causes Epo resistant anemia. To this end, bilateral femurs were harvested on post burn days (PBD) 3, 7, 14, 21 and total bone marrow erythroblasts and macrophages were investigated for ER-HR3, Siglec-1 and Vcam-1 expression. Erythroblast phenotype was characterized by flow cytometry, and validated by a pathologist. Results: We observed a defect in enucleation of orthochromatic erythroblasts (OrthoE) characterized by a significant 4-fold lower reticulocyte (CD235a+ CD71+/- Syto16-) to OrthoE (CD235a+ CD71+/- Syto16+) ratio (R/O) (P<0.05) post burn in patients compared to controls (Figure 1). In mice, peripheral hemoglobin, hematocrit and red blood cell counts were significantly lower from PBD 7 through PBD 21. In line with burn patient data, we observed similar impairment in enucleation of OrthoEs characterized by significantly lower reticulocyte (CD71+ Ter119+ Syto 16-) to OrthoE (CD71+ Ter119+ Syto 16+) ratio (R/O ratio) in the bone marrow of the burn versus control mice [2 fold lower R/O ratio from PBD 3 through PBD21 (P<0.05)]. We then investigated from both a macrophage and erythroblast perspective to understand the stage specific role of associated adhesion molecules. The mean fluorescence intensities (MFIs) of cell surface expressions of Siglec-1, and ER-HR3 were significantly decreased on F4/80+ macrophages from PBD 7 through PBD 21, (Figure 2) while changes in Vcam-1 was significantly low only on PBD 7. From the erythroblast perspective, only OrthoE expressed high intensities of macrophage adhesion molecules (Siglec1, Vcam-1 and ER-HR3) and not reticulocytes (Figure 3). However, the MFI of Siglec-1, Vcam-1 and ER-HR3 expression was significantly reduced on PBD 7, both in OrthoE and macrophages, indicating the essential role of these markers in enucleation. Conclusion: Our data demonstrate defective erythroblast maturation following burn, and identify potential mediators of this process. These findings provide a framework for further investigations to determine the mechanistic basis of erythropoietin resistant anemia in burn patients. Disclosures No relevant conflicts of interest to declare.
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Liu, Mingyue, Xu Wang, Peng Zhang, Juanjuan Su, Xuexiang Du, Yan Zhang, Yang Liu, and Pan Zheng. "813 CD24Fc ameliorates immune-related adverse events while preserving anti-tumor therapeutic effect." Journal for ImmunoTherapy of Cancer 9, Suppl 2 (November 2021): A849. http://dx.doi.org/10.1136/jitc-2021-sitc2021.813.

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BackgroundCombination therapy with anti-CTLA-4 and anti-PD-1 mAbs has emerged as the most potent and durable cancer immunotherapy, yet it is associated with frequent and severe immune-related adverse events (irAEs).1 2 A largely unmet medical need is to reduce irAEs. The CD24–Siglec 10/G interaction is an emerging immune checkpoint that regulates inflammation caused by danger-associated molecular patterns (DAMPs).3–5 It is of great interest to investigate whether CD24Fc can ameliorate severe irAEs, the hallmark of which is a severe inflammatory state in multiple organs.MethodsWe used a human CTLA-4 knock-in (Ctla4h/h) mice model that fully recapitulates human irAE in response to anti-PD-1 and anti-CTLA-4 antibodies to test if CD24Fc have therapeutic effect for irAE. We treated Ctla4h/h mice with Ipilimumab and anti-PD-1 Ab in conjunction with hIgFc or CD24Fc on day 10, 13, 16 and 19 after birth. The body weight was monitored over time, hematologic and histopathologic alterations were evaluated at 6 weeks of age. To evaluate the therapeutic effect of CD24Fc on ICIs induced tissue destruction, we performed histological analysis of internal organs and glands. Major organs were collected about 1 month after first treatment and fixed in 10% formalin, sectioned and stained with hematoxylin and eosin (H&E), and scored double blindly. To test whether CD24Fc immune modulation may interfere with the anti-tumor efficacy of the checkpoint inhibitors, we inoculated MC38 and B16-F10 tumor cells on Ctla4h/h mice, then treated with combination of Ipilimumab and anti-PD-1 Ab together with hIgFc or CD24Fc and monitored tumor growth.ResultsWe found that anti-CTLA-4 and anti-PD-1 therapy could induce growth retardation, anemia and severe inflammation in all organs examined. All of these adverse events were ameliorated by CD24Fc treatment. Moreover, in both tumor models tested CD24Fc modestly enhanced immunotherapeutic effect of anti-PD-1 and anti-CTLA-4 antibodies. CD24Fc treatment showed no effect on CD4+, CD8+ T cell or tumor associated macrophage (TAM) density intratumor. However, we observed significantly decreased Treg among CD4+T cells after CD24Fc treatment. CD24Fc treatment also decreased the TIM-3+ PD-1+ CD4+ and CD8+ T cells. These data suggest CD24Fc has the potential to optimize tumor microenvironment and augment antitumor immunity.ConclusionsOur data demonstrate that CD24Fc treatment ameliorates irAEs in multiple organs induced by combination of anti-CTLA-4 and anti-PD-1 Abs while modestly enhancing its anti-tumor activity, potentially by reducing the intratumor regulatory T cells and reverse exhaustion of tumor-infiltrating T cells.ReferencesWolchok JD, et al. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med 2017;377:1345–1356.Larkin J, et al. Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med 2019;381:1535–1546.Chen GY, Tang J, Zheng P, Liu Y. CD24 and Siglec-10 selectively repress tissue damage-induced immune responses. Science 2009;323:1722–1725.Liu Y, Chen GY, Zheng P. CD24-Siglec G/10 discriminates danger- from pathogen-associated molecular patterns. Trends Immunol 2009;30:557–561.Fang X, Zheng P, Tang J, Liu Y. CD24: from A to Z. Cell Mol Immunol 2010;7:100–103.
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Redelinghuys, Pierre, Aristotelis Antonopoulos, Yan Liu, Maria A. Campanero-Rhodes, Emma McKenzie, Stuart M. Haslam, Anne Dell, Ten Feizi, and Paul R. Crocker. "Early Murine T-lymphocyte Activation Is Accompanied by a Switch fromN-Glycolyl- toN-Acetyl-neuraminic Acid and Generation of Ligands for Siglec-E." Journal of Biological Chemistry 286, no. 40 (August 11, 2011): 34522–32. http://dx.doi.org/10.1074/jbc.m111.243410.

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Greene, MK, S. Spence, F. Fay, D. Small, D. Schmid, J. Jaworski, JF Burrows, et al. "S95 Exploiting the immunoregulatory role of Siglec-E via sialic acid-functionalised nanoparticles as a novel approach for the treatment of acute lung injury." Thorax 68, Suppl 3 (November 14, 2013): A51.1—A51. http://dx.doi.org/10.1136/thoraxjnl-2013-204457.102.

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YU, Zhenbao, Meryem MAOUI, Liangtang WU, Denis BANVILLE, and Shi-Hsiang SHEN. "mSiglec-E, a novel mouse CD33-related siglec (sialic acid-binding immunoglobulin-like lectin) that recruits Src homology 2 (SH2)-domain-containing protein tyrosine phosphatases SHP-1 and SHP-2." Biochemical Journal 353, no. 3 (February 1, 2001): 483. http://dx.doi.org/10.1042/0264-6021:3530483.

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Liu, M., D. Andreev, K. Kachler, J. Koelle, S. Rauber, A. Ramming, S. Finotto, G. Schett, and A. Bozec. "OP0132 ALLERGIC ASTHMA INDUCES THE ACCUMULATION OF SYNOVIAL RESIDENT EOSINOPHILS, TRIGGERING THE RESOLUTION OF INFLAMMATORY ARTHRITIS." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 86.3–86. http://dx.doi.org/10.1136/annrheumdis-2020-eular.4479.

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Background:Rheumatoid arthritis (RA) is a chronic inflammatory disorder, involving synovial joints, which affects approximately 1 percent of the world population[1]. Our former work demonstrated that the Th2-eosinophil pathway is a strong anti-inflammatory mediator of inflammatory arthritis[2]. Allergic asthma is an inflammatory disease of the airway, triggered by type 2 immune response. Hitherto, clinical observations on the impact of asthma on RA showed controversial results. Herein, we investigated the action of allergic asthma on inflammatory arthritis.Objectives:We aimed to delineate the molecular and cellular responses induced by allergic asthma on inflammatory arthritis, particularly depicting the role of eosinophil subsets in arthritic synovium.Methods:Allergic asthma was induced in wild type and genetically modified mice by ovalbumin (OVA) treatment. After the initiation of allergic asthma, K/BxN serum was transferred into the asthmatic mice or control mice to trigger serum induced arthritis (SIA). Then, arthritis severity, circulating cytokines and the cytology of lung and synovium were analyzed. Eosinophil subsets were studied by flow cytometry, single cell RNA sequencing analysis, and were isolated and transferred into the synovial cavity of eosinophil deficient arthritic mice. Clinical data of patients with both RA and asthma were collected and checked for the relapse of RA after asthma treatment with anti-interleukin (IL)-5 antibody.Results:Mice induced with allergic asthma exhibited a rapid resolution of SIA. The OVA-triggered resolution disappeared in eosinophil deficient mice (ΔdblGATA), and was partially blocked by IL-5 neutralization. We could detect that IL-5 was mainly produced by type 2 innate lymphoid cell (ILC2) in the lung. Allergic asthma exclusively induced the proliferation (Ki67+) and accumulation of synovial resident eosinophils (rEos, Siglec-Fint), which switched classical macrophages into alternatively activated macrophages. Synovial induced eosinophils (iEos, Siglec-Fhigh) appeared only in the acute phase of SIA. Single cell RNA sequencing analysis showed that rEos played an anti-inflammatory role, while iEos had pro-inflammatory properties in arthritis. The roles of rEos and iEos in arthritis were confirmed by transferring rEos/iEos into the synovial cavity of arthritic mice. Patiens with both RA and asthma showed a remission relapse of RA after using humanized monoclonal IL-5 antibody for treating sever eosinophilic asthma.Conclusion:Allergic asthma induced an IL-5 mediated proliferation and accumulation of synovial rEos. The latter triggered the resolution of inflammatory arthritis. In human, eosinophils induced by asthma were essential for the sustaining of RA remission.References:[1]Myasoedova, E., et al., Is the incidence of rheumatoid arthritis rising?: results from Olmsted County, Minnesota, 1955-2007. Arthritis Rheum, 2010.62(6): p. 1576-82.[2]Chen, Z., et al., Th2 and eosinophil responses suppress inflammatory arthritis. Nat Commun, 2016.7: p. 11596.Acknowledgments:Mengdan Liu and Darja Andreev contributed equally to this studyDisclosure of Interests:Mengdan Liu: None declared, Darja Andreev: None declared, Katerina Kachler: None declared, Julia Koelle: None declared, Simon Rauber: None declared, Andreas Ramming Grant/research support from: Pfizer, Novartis, Consultant of: Boehringer Ingelheim, Novartis, Gilead, Pfizer, Speakers bureau: Boehringer Ingelheim, Roche, Janssen, Susetta Finotto: None declared, Georg Schett Speakers bureau: AbbVie, BMS, Celgene, Janssen, Eli Lilly, Novartis, Roche and UCB, Aline Bozec: None declared
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Yoon, Soyon, Seokcheon Song, Jae Woo Shin, Sini Kang, Hye Young Kim, and Hyun Ju You. "Protective Effects of Korean Herbal Remedy against Airway Inflammation in an Allergic Asthma by Suppressing Eosinophil Recruitment and Infiltration in Lung." Antioxidants 10, no. 1 (December 23, 2020): 6. http://dx.doi.org/10.3390/antiox10010006.

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The increasing prevalence of allergic asthma has become the world’s major health issue. Current treatments for allergic asthma focus on treating symptoms, while permanent cures still remain undiscovered. In this study, we investigated the effect of Korean traditional herbal remedy, Pyunkang-tang (PGT)—composed of six plants—on asthma alleviation in a mouse model. The PGT mixture was orally gavaged to mice (PM group, 20 mg/mouse/day) from 7 days before sensitization with ovalbumin (OVA) (day −7). On day 0 and day 14, mice from OVA-control (n = 9) and PM group (n = 8) were sensitized with OVA and alum through intraperitoneal injection. On days 18~20, OVA was challenged to mice through nasal injection and sacrificed next day. Cell profile in lung tissue was analyzed by flow cytometry and RT-qPCR analysis, and the number of eosinophils and expression of siglec-F were significantly reduced in the PM group. Lung tissue was examined with hematoxylin and eosin (H&E) and Alcian blue/periodic acid–Schiff (AB-PAS) staining. Noticeably reduced eosinophil infiltration around bronchioles was displayed in the PM group compared to the OVA-control group. Furthermore, PGT-treated mice showed a significant reduction in IL-13 and a mild reduction in IL-5 in lungs. A decreasing tendency of IL-5/13 (+) CD4+ T cells and IL-13(+) innate lymphoid cells (ILCs) and a significant reduction in IL5(+) ILCs were also observed. When treating PGT on murine lung epithelial cells stimulated by papain, there was a significant reduction in IL-33 mRNA expression levels. Taken together, oral delivery of PGT successfully alleviated asthmatic responses provoked by OVA in a mouse model and could lead to novel therapies for allergic asthma.
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Ventura, Alessandro. "La pagina gialla." Medico e Bambino 40, no. 9 (November 15, 2021): 555–56. http://dx.doi.org/10.53126/meb40555.

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Bambino e adolescente con sindrome dolorosa? Pensa disforia di genere - Case pericolose: Cannabis libera e… gocce per la tosse e il raffreddore - Covid-19… in bianco e nero - Miocardite dopo vaccinazione anti-Covid a mRNA negli adolescenti: rar(issim)a e buona - Se è di bell’aspetto… si può - Pediatria in sigle associate: MICI e CRMO - MICI e infezioni
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Bonomi, Ilaria. "Ambiguità delle sigle e questione di genere: il caso di Tgr." XVI, 2021/1 (gennaio-marzo), no. 1 (March 12, 2021): 87–88. http://dx.doi.org/10.35948/2532-9006/2021.5489.

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Parecchi lettori hanno chiesto, alcuni lamentandosene, le ragioni e la liceità dell’espressione la Tgr, pensandola riferita al telegiornale: qualcuno ha anche citato un improbabile la tg3, o addirittura la tg. E qualcuno ha addirittura erroneamente inserito anche questo ‘strano’ genere femminile nella tendenza generale a creare il femminile dei nomi di professione in modalità ‘normali’ per la nostra lingua, ma che sono molto discusse: una tendenza illustrata e argomentata da Vittorio Coletti nel tema di questo mese.
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Tekavčić, Pavao. "István Jlig, A magyarországi italianistika bibliográfija - Bibliografia dell 'italiani­ stica in Ungheria, 1945-1995; Italianistica Debrecenensis V; Kossuth Lajos Tudo­ mányegyetem, Olasz Tanszek [Università Lajos Kossuth, Dipartimento di Italianistica],." Linguistica 39, no. 1 (December 1, 1999): 156. http://dx.doi.org/10.4312/linguistica.39.1.156.

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La collana Jtalianistica Debrecenensis, che esce dal 1993 (vol. I 1993-94; II 1995; III 1996; IV 1997), pubblica come vol. V l'importante raccolta bibliografica che qui presentiamo brevemente (sulla copertina posteriore c'è l'elenco delle altre edizioni, a cura dello stesso Ateneo). L'autore, dott. István Vig, slavista ungherese e docente all'Università di Debrecen, ha pubblicato vari studi e altri titoli, come risulta dalla Bibliografia. II presente volume racchiude ben 3863 unità, numerate in continuazione e uscite nel cinquantennio postbellico. Alla Prefazione, soltanto in ungherese (5-7;.si ci­ tano le pagine), segue l'Introduzione, in ungherese e in italiano (9-12), dopo la quale si trova l'Elenco delle sigle e abbreviazioni (13-27). La bibliografia (29-235) è divisa in quattro sezioni: Letteratura (29-115; recensioni 116-126), Critica e storia letteraria (127-168; recc. 169-178), Linguistica, insegnamento della lingua e della letteratura italiana (179-202; recc. 203-206), Storia (207-229; recc. 230-234), con un'Appendice (235).
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