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Riboldi, Elena, Roberta Daniele, Carmen Parola, Antonio Inforzato, Phoebe L. Arnold, Daniela Bosisio, Daved H. Fremont, Antonio Bastone, Marco Colonna, and Silvano Sozzani. "Human C-type Lectin Domain Family 4, Member C (CLEC4C/BDCA-2/CD303) Is a Receptor for Asialo-galactosyl-oligosaccharides." Journal of Biological Chemistry 286, no. 41 (August 31, 2011): 35329–33. http://dx.doi.org/10.1074/jbc.c111.290494.
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Plasmacytoid dendritic cells are specialized in the production of type I interferon (type I IFN), which promotes antiviral and antitumor responses, as well as autoimmune disorders. Activation of type I IFN secretion depends on the pattern recognition receptors TLR7 and TLR9, which sense microbial RNA and DNA, respectively. Type I IFN production is modulated by several receptors, including the type II C-type lectin domain family 4, member C (CLEC4C). The natural ligand of CLEC4C is unknown. To identify it, here we probed a glycan array with a soluble form of the CLEC4C ectodomain. We found that CLEC4C recognizes complex type sugars with terminal galactose. Importantly, soluble CLEC4C bound peripheral blood leukocytes and tumor cells that express glycans with galactose residues at the non-reducing ends. The positive and negative modulation of galactose residues on cell membranes was paralleled by the regulation of type I IFN secretion by plasmacytoid dendritic cells in co-culture experiments in vitro. These results suggest that the modulation in the expression of non-sialylated oligosaccharides by invading pathogens or transformed cells may affect type I IFN response and immune surveillance.
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Miller, Hannah L., Prabhakar Sairam Andhey, Melissa K. Swiecki, Bruce A. Rosa, Konstantin Zaitsev, Alexandra-Chloe Villani, Makedonka Mitreva, et al. "Altered ratio of dendritic cell subsets in skin-draining lymph nodes promotes Th2-driven contact hypersensitivity." Proceedings of the National Academy of Sciences 118, no. 3 (January 11, 2021): e2021364118. http://dx.doi.org/10.1073/pnas.2021364118.
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Plasmacytoid dendritic cells (pDCs) specialize in the production of type I IFN (IFN-I). pDCs can be depleted in vivo by injecting diphtheria toxin (DT) in a mouse in which pDCs express a diphtheria toxin receptor (DTR) transgene driven by the human CLEC4C promoter. This promoter is enriched for binding sites for TCF4, a transcription factor that promotes pDC differentiation and expression of pDC markers, including CLEC4C. Here, we found that injection of DT in CLEC4C-DTR+mice markedly augmented Th2-dependent skin inflammation in a model of contact hypersensitivity (CHS) induced by the hapten fluorescein isothiocyanate. Unexpectedly, this biased Th2 response was independent of reduced IFN-I accompanying pDC depletion. In fact, DT treatment altered the representation of conventional dendritic cells (cDCs) in the skin-draining lymph nodes during the sensitization phase of CHS; there were fewer Th1-priming CD326+CD103+cDC1 and more Th2-priming CD11b+cDC2. Single-cell RNA-sequencing of CLEC4C-DTR+cDCs revealed that CD326+DCs, like pDCs, expressed DTR and were depleted together with pDCs by DT treatment. Since CD326+DCs did not expressTcf4, DTR expression might be driven by yet-undefined transcription factors activating the CLEC4C promoter. These results demonstrate that altered DC representation in the skin-draining lymph nodes during sensitization to allergens can cause Th2-driven CHS.
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Murray, Liisa, Yang Xi, and John W. Upham. "CLEC4C gene expression can be used to quantify circulating plasmacytoid dendritic cells." Journal of Immunological Methods 464 (January 2019): 126–30. http://dx.doi.org/10.1016/j.jim.2018.11.001.
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Lim, Su Min, Young-Eun Kim, Won Jun Choi, Ki-Wook Oh, Min-Young Noh, Min-Soo Kwon, Minyeop Nahm, Namshin Kim, Chang-Seok Ki, and Seung Hyun Kim. "CLEC4C p.K210del variant causes impaired cell surface transport in plasmacytoid dendritic cells of amyotrophic lateral sclerosis." Oncotarget 7, no. 18 (March 1, 2016): 24942–49. http://dx.doi.org/10.18632/oncotarget.7886.
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Lim, Suhyeon, Monica Zhang, and Theresa L. Chang. "ACE2-Independent Alternative Receptors for SARS-CoV-2." Viruses 14, no. 11 (November 16, 2022): 2535. http://dx.doi.org/10.3390/v14112535.
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Severe acute respiratory syndrome-related coronavirus (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), is highly contagious and remains a major public health challenge despite the availability of effective vaccines. SARS-CoV-2 enters cells through the binding of its spike receptor-binding domain (RBD) to the human angiotensin-converting enzyme 2 (ACE2) receptor in concert with accessory receptors/molecules that facilitate viral attachment, internalization, and fusion. Although ACE2 plays a critical role in SARS-CoV-2 replication, its expression profiles are not completely associated with infection patterns, immune responses, and clinical manifestations. Additionally, SARS-CoV-2 infects cells that lack ACE2, and the infection is resistant to monoclonal antibodies against spike RBD in vitro, indicating that some human cells possess ACE2-independent alternative receptors, which can mediate SARS-CoV-2 entry. Here, we discuss these alternative receptors and their interactions with SARS-CoV-2 components for ACE2-independent viral entry. These receptors include CD147, AXL, CD209L/L-SIGN/CLEC4M, CD209/DC-SIGN/CLEC4L, CLEC4G/LSECtin, ASGR1/CLEC4H1, LDLRAD3, TMEM30A, and KREMEN1. Most of these receptors are known to be involved in the entry of other viruses and to modulate cellular functions and immune responses. The SARS-CoV-2 omicron variant exhibits altered cell tropism and an associated change in the cell entry pathway, indicating that emerging variants may use alternative receptors to escape the immune pressure against ACE2-dependent viral entry provided by vaccination against RBD. Understanding the role of ACE2-independent alternative receptors in SARS-CoV-2 viral entry and pathogenesis may provide avenues for the prevention of infection by SARS-CoV-2 variants and for the treatment of COVID-19.
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Steinle, Alexander, Veronika Stejfova, Sabrina Kuttruff, Birgit Schittek, and Jessica Spreu. "CLEC2A Is a Novel Skin-Specific, Stimulatory Ligand of Human NK Cells (39.8)." Journal of Immunology 182, no. 1_Supplement (April 1, 2009): 39.8. http://dx.doi.org/10.4049/jimmunol.182.supp.39.8.
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Abstract The Natural Killer Gene Complex (NKC) encodes for numerous C-type lectin-like receptors (CTLR) variably expressed on lymphocytes and myeloid cells. Well-known representatives of NKC-encoded CTLR are NKG2D, CD69, and Ly49 molecules. However, the NKC also contains a considerable number of genes which are barely characterized. Recently, we described the CLEC2A gene encoding for a new member of the human CLEC2 family of NKC-encoded CTLR. CLEC2A, in contrast to other human CLEC2 family members such as CD69/CLEC2C and AICL/CLEC2B, is virtually not expressed by peripheral leukocytes, but its expression appears restricted to skin. We now report that CLEC2A encodes for a non-disulfide-linked, homodimeric surface CTLR which is expressed on freshly isolated skin cells. Addressing a potential immune-associated function, we find that CLEC2A stimulates cytotoxicity and cytokine release of human NK cells. However, we failed to ascertain CLEC2A engagement by known activating NK receptors. Instead, we identified a hitherto undescribed NKC-encoded CTLR (NKp65) that specifically interacts with CLEC2A and activates NK cytotoxicity. In summary, we define CLEC2A as a skin-specific and NK cell-stimulating CTLR engaging NKp65, a novel activating CTLR which may allow for dedicated immunosurveillance of human skin. This work was supported by funds (SFB 685/A1) of the German Research Foundation (DFG).
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Sharma, Jyotika, Atul Sharma, Anthony Steichen, Christopher Jondle, Brandilyn Binstock, and Bibhuti Mishra. "Antibacterial and pro-resolving mechanisms in lung diseases: role of C-type lectin receptors (INM2P.430)." Journal of Immunology 192, no. 1_Supplement (May 1, 2014): 56.13. http://dx.doi.org/10.4049/jimmunol.192.supp.56.13.
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Abstract Lower respiratory tract infection with bacteria can lead to sepsis development, a complex immune disorder with systemic hyperinflammation. There are currently no effective therapies for sepsis. To understand the function of specific pulmonary components in regulation of immune responses in this immune disorder, we utilize an acute pulmonary bacterial infection model of Klebsiella pneumoniae (KPn). Nosocomial infections with this opportunistic pathogen account for 5-20% of Gram-negative sepsis cases. C-type lectin receptors (CLRs), expressed mainly by myeloid cells, can shape immune responses in diverse pathological conditions. However, their role in development of pneumonic sepsis is unknown. Our preliminary analysis of a panel of CLRs showed an upregulated expression of two CLRs, Clec4d and Clec4e in the lungs of KPn infected mice. While the wild-type mice were able to resolve a sublethal pneumonic KPn infection, the Clec4d-/- and Clec4e-/- mice displayed increased susceptibility with a progressive increase in bacterial burden, hyperinflammatory response and massive accumulation of neutrophils in lungs. Importantly, we show that coordinated function of Clec4d and Clec4e in neutrophils during bacterial pneumonia, and in a chronic lung disease, leads to control of bacterial growth and hyperinflammation by regulating phagocytosis and efferocytosis (clearance of dead cells). Our studies provide novel insights into regulation of inflammatory derangements in immune disorders.
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Uqdah, Hakim, Shelley Hankins, and Howard J. Eisen. "Something evil this way comes: Proteomic profiling identifies CLEC4C expression as a novel biomarker of primary graft dysfunction after heart transplantation." Journal of Heart and Lung Transplantation 41, no. 3 (March 2022): 269–70. http://dx.doi.org/10.1016/j.healun.2021.12.003.
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Gong, Xiaoting, and Wei Wang. "Profiles of Innate Immune Cell Infiltration and Related Core Genes in Psoriasis." BioMed Research International 2021 (February 23, 2021): 1–8. http://dx.doi.org/10.1155/2021/6656622.
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Psoriasis is an inflammatory skin disease with substantial morbidity. Numerous patients with psoriasis experience recurrence after therapy. The underlying mechanism about psoriasis is still not fully understood. Some evidences suggest that innate immunity may play an unexpected and important role in active severe psoriasis. In this work, the deconvolution algorithm CIBERSORT was conducted to identify the infiltration of innate immune cells and related core genes in psoriatic plaque. Datasets from the Gene Expression Omnibus, including skin samples from 405 psoriasis patients and 91 healthy donors, were downloaded for analysis. Considerable differences of the innate immune cell composition were uncovered between psoriatic plaque and control skin. Results revealed that γδ T cells, resting NK cells, M0 macrophages, M1 macrophages, activated dendritic cells, and neutrophils were significantly increased in psoriatic skin, while resting mast cells and active NK cells were significantly decreased. Moreover, the proportion of M0 macrophages or resting mast cells was found to be associated with disease severity. Spearman correlation analysis suggests that RORC and S100A12 genes were related to disease severity, while genes including S100A12, CLEC4C, IL-19, AIM2, IL-17F, and PPARGC1A were correlated with biologic treatment response. In conclusion, this work displays innate immune status in psoriatic skin and provides novel clues for clinical decisions and mechanism study.
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Ennour-Idrissi, Kaoutar, Dzevka Dragic, Elissar Issa, Annick Michaud, Sue-Ling Chang, Louise Provencher, Francine Durocher, and Caroline Diorio. "DNA Methylation and Breast Cancer Risk: An Epigenome-Wide Study of Normal Breast Tissue and Blood." Cancers 12, no. 11 (October 23, 2020): 3088. http://dx.doi.org/10.3390/cancers12113088.
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Differential DNA methylation is a potential marker of breast cancer risk. Few studies have investigated DNA methylation changes in normal breast tissue and were largely confounded by cancer field effects. To detect methylation changes in normal breast epithelium that are causally associated with breast cancer occurrence, we used a nested case–control study design based on a prospective cohort of patients diagnosed with a primary invasive hormone receptor-positive breast cancer. Twenty patients diagnosed with a contralateral breast cancer (CBC) were matched (1:1) with 20 patients who did not develop a CBC on relevant risk factors. Differentially methylated Cytosine-phosphate-Guanines (CpGs) and regions in normal breast epithelium were identified using an epigenome-wide DNA methylation assay and robust linear regressions. Analyses were replicated in two independent sets of normal breast tissue and blood. We identified 7315 CpGs (FDR < 0.05), 52 passing strict Bonferroni correction (p < 1.22 × 10−7) and 43 mapping to known genes involved in metabolic diseases with significant enrichment (p < 0.01) of pathways involving fatty acids metabolic processes. Four differentially methylated genes were detected in both site-specific and regions analyses (LHX2, TFAP2B, JAKMIP1, SEPT9), and three genes overlapped all three datasets (POM121L2, KCNQ1, CLEC4C). Once validated, the seven differentially methylated genes distinguishing women who developed and who did not develop a sporadic breast cancer could be used to enhance breast cancer risk-stratification, and allow implementation of targeted screening and preventive strategies that would ultimately improve breast cancer prognosis.
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Hsieh, Shie-Liang. "CLEC18 family are novel C-type lectins with differential binding specificity to glycans and TLR ligands." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 203.4. http://dx.doi.org/10.4049/jimmunol.196.supp.203.4.
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Abstract The human C-type lectin 18 (clec18) gene cluster, which contains clec18a, clec18b and clec18c three loci, is located in human chromosome 16q22. Even though the amino acid sequences of CLEC18A, CLEC18B, and CLEC18C are almost identical, several amino acid residues located in the C-type lectin-like domain (CTLD) and the Sperm-Coating Protein/Tpx-1/Ag5/PR-1/Sc7 (SCP/TAPS) domain, also known as the cysteine-rich secretory proteins/antigen 5/pathogenesis-related 1 proteins (CAP) domain, are distinct from each other. Genotyping by real-time PCR and sequencing further shows the presence of multiple alleles in clec18a/b/c loci. Flow cytometry analysis demonstrates that CLEC18 (CLEC18A, B and C) are expressed abundantly in human peripheral blood cells. Moreover, CLEC18 expression is further upregulated when monocytes differentiate into macrophages and dendritic cells (DCs). Immunofluorescence staining reveals that CLEC18 are localized in the endoplasmic reticulum (ER), Golgi apparatus, and endosome. Interestingly, CLEC18 are also detectable in human sera and culture supernatants from primary cells and 293T cells overexpressing CLEC18. Moreover, CLEC18 bind polysaccharide in Ca2+–independent manner, and the amino acid residues S/R339 and D/N421 in CTLD domain contribute to their differential binding abilities to polysaccharides isolated from Ganoderma lucidum (GLPS-F3). The S339 (CLEC18A) and R339 (CLEC18A-1) displayed differential binding affinity to TLR ligands. Their roles to determine host responses to virus infection are under intensive investigation now.
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Renosi, Florian, Anne Roggy, Ambre Giguelay, Lou Soret, Pierre-Julien Viailly, Meyling Cheok, Sabeha Biichle, et al. "Transcriptomic and genomic heterogeneity in blastic plasmacytoid dendritic cell neoplasms: from ontogeny to oncogenesis." Blood Advances 5, no. 5 (March 9, 2021): 1540–51. http://dx.doi.org/10.1182/bloodadvances.2020003359.
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Abstract Oncogenesis and ontogeny of blastic plasmacytoid dendritic cell neoplasm (BPDCN) remain uncertain, between canonical plasmacytoid dendritic cells (pDCs) and AXL+ SIGLEC6+ DCs (AS-DCs). We compared 12 BPDCN to 164 acute leukemia by Affymetrix HG-U133 Plus 2.0 arrays: BPDCN were closer to B-cell acute lymphoblastic leukemia (ALL), with enrichment in pDC, B-cell signatures, vesicular transport, deubiquitination pathways, and AS-DC signatures, but only in some cases. Importantly, 1 T-cell ALL clustered with BPDCN, with compatible morphology, immunophenotype (cCD3+ sCD3− CD123+ cTCL1+ CD304+), and genetics. Many oncogenetic pathways are deregulated in BPDCN compared with normal pDC, such as cell-cycle kinases, and importantly, the transcription factor SOX4, involved in B ontogeny, pDC ontogeny, and cancer cell invasion. High-throughput sequencing (HaloPlex) showed myeloid mutations (TET2, 62%; ASXL1, 46%; ZRSR2, 31%) associated with lymphoid mutations (IKZF1), whereas single-nucleotide polymorphism (SNP) array (Affymetrix SNP array 6.0) revealed frequent losses (mean: 9 per patient) involving key hematological oncogenes (RB1, IKZF1/2/3, ETV6, NR3C1, CDKN2A/B, TP53) and immune response genes (IFNGR, TGFB, CLEC4C, IFNA cluster). Various markers suggest an AS-DC origin, but not in all patients, and some of these abnormalities are related to the leukemogenesis process, such as the 9p deletion, leading to decreased expression of genes encoding type I interferons. In addition, the AS-DC profile is only found in a subgroup of patients. Overall, the cellular ontogenic origin of BPDCN remains to be characterized, and these results highlight the heterogeneity of BPDCN, with a risk of a diagnostic trap.
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Ten Cate, Vincent, Thomas Koeck, Jürgen Prochaska, Andreas Schulz, Marina Panova-Noeva, Steffen Rapp, Lisa Eggebrecht, et al. "A targeted proteomics investigation of the obesity paradox in venous thromboembolism." Blood Advances 5, no. 14 (July 26, 2021): 2909–18. http://dx.doi.org/10.1182/bloodadvances.2020003800.
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Abstract The obesity paradox, the controversial finding that obesity promotes disease development but protects against sequelae in patients, has been observed in venous thromboembolism (VTE). The aim of this investigation was to identify a body mass–related proteomic signature in VTE patients and to evaluate whether this signature mediates the obesity paradox in VTE patients. Data from the Genotyping and Molecular Phenotyping in Venous ThromboEmbolism Project, a prospective cohort study of 693 VTE patients, were analyzed. A combined end point of recurrent VTE or all-cause death was used. Relative quantification of 444 proteins was performed using high-throughput targeted proteomics technology. Measurements were performed in samples collected during the acute VTE event and at 12-month follow-up. An 11-protein signature (CLEC4C, FABP4, FLT3LG, IL-17C, LEP, LYVE1, MASP1, ST2, THBS2, THBS4, TSLP) for body mass in VTE patients was identified. The signature did not significantly mediate the obesity paradox (change in hazard ratio [HR]: 0.04; likelihood ratio test of nested models = 7.7; P = .74), but its main constituent protein, leptin, was inversely associated with recurrent VTE or death (adjusted HR [95% confidence interval] per standard deviation increase: 0.66 [0.46-0.94]). This relationship was significantly (P = .007) modified by markers of leptin resistance (ie, high body mass index and high circulating matrix metalloproteinase-2 levels). Although the signature did not substantially explain the obesity paradox, leptin appears to be protective against disease recurrence and death in VTE patients. This protective effect was abrogated under conditions of leptin resistance and hence was unrelated to the obesity paradox.
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Iwamoto, Taro, Jessica M. Dorschner, Shanmugapriya Selvaraj, Valeria Mezzano, Mark A. Jensen, Danielle Vsetecka, Shreyasee Amin, et al. "High Systemic Type I Interferon Activity Is Associated With Active Class III/IV Lupus Nephritis." Journal of Rheumatology 49, no. 4 (November 15, 2021): 388–97. http://dx.doi.org/10.3899/jrheum.210391.
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ObjectivePrevious studies suggest a link between high serum type I interferon (IFN) and lupus nephritis (LN). We determined whether serum IFN activity is associated with subtypes of LN and studied renal tissues and cells to understand the effect of IFN in LN.MethodsTwo hundred and twenty-one patients with systemic lupus erythematosus were studied. Serum IFN activity was measured by WISH bioassay. mRNA in situ hybridization was used in renal tissue to measure expression of the representative IFN-induced gene, IFN-induced protein with tetratricopeptide repeats-1 (IFIT1), and the plasmacytoid dendritic cell (pDC) marker gene C-type lectin domain family-4 member C (CLEC4C). Podocyte cell line gene expression was measured by real-time PCR.ResultsClass III/IV LN prevalence was significantly increased in patients with high serum IFN compared with those with low IFN (odds ratio 5.40, P = 0.009). In multivariate regression models, type I IFN was a stronger predictor of class III/IV LN than complement C3 or anti-dsDNA antibody, and could account for the association of these variables with LN. IFIT1 expression was increased in all classes of LN, but most in the glomerular areas of active class III/IV LN kidneys. IFIT1 expression was not closely colocalized with pDCs. IFN directly activated podocyte cell lines to induce chemokines and proapoptotic molecules.ConclusionSystemic high IFN is involved in the pathogenesis of severe LN. We did not find colocalization of pDCs with IFN signature in renal tissue, and instead observed the greatest intensity of the IFN signature in glomerular areas, which could suggest a blood source of IFN.
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Murray, Liisa M., Stephanie T. Yerkovich, Manuel A. Ferreira, and John W. Upham. "Risks for cold frequency vary by sex: role of asthma, age, TLR7 and leukocyte subsets." European Respiratory Journal 56, no. 4 (June 8, 2020): 1902453. http://dx.doi.org/10.1183/13993003.02453-2019.
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Viral respiratory infections are usually benign but can trigger asthma exacerbations. The factors associated with upper respiratory tract infection (cold) frequency are not fully understood, nor is it clear whether such factors differ between women and men.To determine which immunological and clinical variables associate with the frequency of self-reported respiratory infections (colds), 150 asthma cases and 151 controls were recruited. Associations between antiviral immune response variables: toll-like receptor (TLR)7/8 gene expression, plasmacytoid dendritic cell (pDC) numbers and interferon-α, tumour necrosis factor and interleukin-12 production, and asthma were then examined that might explain cold frequency.People with asthma cases reported more colds per year (median 3 versus 2; p<0.001) and had lower baseline TLR7 gene expression (odds ratio 0.12; p=0.02) than controls. Associations between many variables and cold frequency differed between women and men. In women, high blood neutrophil counts (β=0.096, p=0.002), and younger age (β=−0.017, p<0.001), but not exposure to children, were independently associated with more frequent colds. In men, low TLR7 expression (β=−0.96, p=0.041) and high CLEC4C gene expression (a marker of pDC; β=0.88, p=0.008) were independently associated with more frequent colds. Poor asthma symptom control was independently associated with reduced TLR8 gene expression (β=−1.4, p=0.036) and high body mass index (β=0.041, p=0.004).Asthma, age and markers of inflammation and antiviral immunity in peripheral blood are associated with frequent colds. Interestingly, the variables associated with cold frequency differed between women and men.
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Kerscher, Bernhard, Ivy M. Dambuza, Maria Christofi, Delyth M. Reid, Sho Yamasaki, Janet A. Willment, and Gordon D. Brown. "Signalling through MyD88 drives surface expression of the mycobacterial receptors MCL (Clecsf8, Clec4d) and Mincle (Clec4e) following microbial stimulation." Microbes and Infection 18, no. 7-8 (July 2016): 505–9. http://dx.doi.org/10.1016/j.micinf.2016.03.007.
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Elleisy, Nagi, Sarah Rohde, Astrid Huth, Nicole Gittel, Änne Glass, Steffen Möller, Georg Lamprecht, Holger Schäffler, and Robert Jaster. "Genetic association analysis of CLEC5A and CLEC7A gene single-nucleotide polymorphisms and Crohn’s disease." World Journal of Gastroenterology 26, no. 18 (May 14, 2020): 2194–202. http://dx.doi.org/10.3748/wjg.v26.i18.2194.
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Rozenblit, Mariya, Adriana Heguy, Luis Chiriboga, Cynthia Loomis, Farbod Darvishian, Mikala Egeblad, Yongzhao Shao, and Sylvia Adams. "Identification of differentially expressed genes associated with clinical response after treatment of breast cancer skin metastases with imiquimod." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): e12541-e12541. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e12541.
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e12541 Background: Imiquimod, a Toll-like receptor 7 agonist, activates innate immunity and has a response rate of 20% in breast cancer skin metastases. Tumor regression is associated with increased tumor infiltrating lymphocytes and increased Th1 cytokines in tumor supernatant, however gene expression changes are unknown. This is the first report of gene expression changes induced by imiquimod treatment in breast cancer skin metastases. Methods: FFPE-extracted mRNA from 8 patients pre and post 8 weeks of imiquimod treatment was analyzed using Nanostring PanCancer Immune Profiling Panel. Gene expression and pathway analysis was conducted with nSolver 3.0 with clinical response as outcome, controlling for HER2 ER/PR status, with 5% significance level used. Results: In all patients, imiquimod was associated with upregulation of genes in innate immunity such as TLR7, IL-1, T-cell, B-cell, and NK related genes. Three patients had a clinical response after imiquimod. Forty-two differentially expressed genes were identified in responders vs. non-responders after imiquimod. Reponders had up-regulation of T cell (CD2, SPN), NK cell (KLRC2), B cell (CD48), lymphocyte (LY96), and IL-2 (IL2RG) related genes. The top upregulated pathways were cytotoxicity, NK cell function, and antigen processing. Pre-treatment, the responders had upregulation of TNF and IL-17 related genes (TNFRSF10B, IL17RA) compared to non-responders. Comparing pre-treatment to post-treatment, Imiquimod was associated with mRNA expression changes in 72 genes in responders vs non responders. The top upregulated genes involved activation of lymphocytes (SH2D1A), NK cells (KLRC2), DCs (CLEC4C), several chemokines, IL7R and immune regulators PLD1 and IRF5. Conclusions: Clinical response to Imiquimod treatment of breast cancer skin metastases is associated with upregulation of genes in innate immunity suggestive of an anti-tumor immune response. Inhibition of negative feedback by addition of PLD1 inhibitors may enhance treatment response. Understanding the genetic signature of imiquimod can enhance prediction of response and inform possible combination therapies in the future.
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Chen, Kehe, Haiming Wei, Tianqi Liu, Zhenxiang Chen, Deng Pan, Jingning Huang, Ting Gao, et al. "Transcriptional characterization of microenvironment and their prediction role for the prognosis of hepatocellular carcinoma after surgery." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): e15650-e15650. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e15650.
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e15650 Background: Hepatocellular carcinoma (HCC) is one of the most common prevalent fatal cancers worldwide with poor prognosis due to high incidence of recurrence. For patients with HCC, surgical treatment is a potentially cutative therapy. However, the puzzle in the therapy was the rapid recurrence after surgery. The purpose of this study was to integrate the impact of different immune context present in HCC microenvironment on patients’ prognosis, provide the molecular prediction clue of HCC recurrence. Methods: RNA targeted sequencing was performed on 12 primary tumor specimens from HCC patients. Transcripts of 395 immune related genes expressed in FFPE tumor samples were analyzed. The lima package was used to analyze the different expressed genes (DEGs) between patients with different prognosis. The gene set variance analysis (GSVA) analysis was performed to explore gene sets enrichment related to the recurrence post-resection. Results: 15 DEGs were detected in tissue samples between the two groups (group A: patients who relapsed within one year after surgery; group B: patients who hadn't relapsed beyond two years after surgery). The Antigen processing pathway enrichment may associate with the favorable prognosis (p < 0.05). HLA-A gene expression in group A was lower than that in group B; The gene expression of IL23A, TP63, ALOX15B, BUB1, CXCR2, CCL20, CLEC4C, PTK7, MPO, IL1B, MMP9, GAGE2C, GAGE2A, GAGE2E, DMBT1, FOXM1 in group A was higher than that in group B. Additionally, the combination of 3 genes (TP63, IL23A and BUB1) can distinguish the patients recurrent within 1 year or beyond 2 years post-resection. The joint diagnostic equation is logit (Y = 1) = 0.073 +0.740 *(TP63) + 0.589 * (IL23A)+0.959(BUB1), (Optimal threshold: 0.667, specificity: 1, sensitivity: 0.833). Conclusions: Our results suggest that RNA-seq of immune related genes from FFPE sample can effectively profile the specific landscape of tumor immune microenvironment and predict the survival of HCC. 3 genes’ expression (TP63, IL23A and BUB1) might correlate with recurrence in HCC patients after surgery.
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Swystun, Laura L., Natalia Rydz, Colleen Notley, Jonathan J. Riches, Andrew D. Paterson, Robert R. Montgomery, Paula D. James, and David Lillicrap. "Genetic Variability of the CLEC4M Endothelial Lectin Receptor Modulates Binding and Internalization of Von Willebrand Factor and Contributes to Variance in Plasma VWF Levels." Blood 120, no. 21 (November 16, 2012): 16. http://dx.doi.org/10.1182/blood.v120.21.16.16.
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Abstract Abstract 16 Type 1 von Willebrand's Disease (VWD) can result from decreased synthesis or accelerated clearance of von Willebrand Factor (VWF), resulting in partial quantitative deficiency. Approximately 35% of individuals with Type 1 VWD do not have a putative mutation in their VWF gene, suggesting that genes other than VWF may contribute to the pathophysiology of this disease. Recently, the CHARGE GWAS meta-analysis identified single nucleotide polymorphisms in the gene encoding the C-type lectin domain family 4 member M (CLEC4M) as being significantly associated with plasma VWF levels in normal individuals. CLEC4M is a pathogen recognition receptor with a polymorphic extracellular neck region consisting of a variable number of tandem repeats (VNTR) (3 – 9 repeats). We hypothesize that CLEC4M binds to and clears VWF from the circulation, and that different CLEC4M VNTR alleles may contribute to differences in plasma levels of VWF in normal subjects and patients with Type 1 VWD. Previously, genotyping of 555 subjects (196 cases with type 1 VWD, and 362 family members) for the CLEC4M VNTR number showed that the most frequently documented alleles were VNTR 5 (29%), 6 (15%), and 7 (53%). Family-based association analysis on kindreds with type I VWD has demonstrated a significant excess transmission of VNTR 6 to the type I VWD phenotype (p=0.005) and an association of this VNTR allele with VWF:RCo (p=0.037). In the present studies, we have complemented this genetic association data with experiments to directly evaluate the ability of CLEC4M to bind and internalize VWF. Further, we characterized the ability of different CLEC4M VNTR alleles to facilitate VWF clearance. Binding of VWF to CLEC4M was assessed with a modified ELISA using a recombinant CLEC4M-Fc chimera. CLEC4M-Fc bound to Humate P (plasma-derived VWF-FVIII) in a dose-dependent manner. CLEC4M-Fc also bound to recombinant human VWF, and factor VIII-free plasma-derived VWF. CLEC4M-Fc demonstrated a 70% increase in binding to de-O-glycosylated Humate P (p=0.041), and a 75% decrease in binding to de-N-glycosylated Humate P (p=0.046) relative to controls. Additionally, pre-incubation of CLEC4M-Fc with the polysaccharide mannan attenuated binding to all VWF preparations by approximately 50%. Binding and internalization of VWF by HEK 293 cells stably expressing CLEC4M (VNTR allele 7) was assessed with immunofluorescence and ELISA. Binding of VWF co-localized with CLEC4M expression on HEK 293 cells. CLEC4M and VWF co-localized with early endosomal antigen-1, suggesting that CLEC4M participates in receptor-mediated endocytosis of VWF. CLEC4M-expressing cells bound and internalized VWF in a dose- and time-dependent manner relative to controls. Preincubation of CLEC4M expressing cells with mannan inhibited VWF binding and internalization by 50% (p=0.0088). The contribution of CLEC4M genetic variability to VWF binding and internalization was measured using HEK 293 cells expressing CLEC4M with 4, 6, 7, and 9 tandem repeats. Decreased binding and internalization of VWF was observed with cells expressing CLEC4M 4 and 9 tandem repeat constructs as compared to CLEC4M with 7 tandem repeats (CLEC4M 4 – 60% reduction, p < 0.001; CLEC4M 9 – 45% reduction, p=0.006). Cells expressing the CLEC4M VNTR combination 4 and 9, had a 55% decrease in binding and internalization of VWF relative to cells expressing CLEC4M with 7 VNTRs (p < 0.001). These VNTR associated differences in VWF binding/internalization were not accounted for by variances in the CLEC4M expression levels in the transfected HEK 293 cells. These studies demonstrate that the C-type lectin CLEC4M binds to and internalizes VWF through an N-glycan-dependent mechanism. Additionally, it provides further evidence that polymorphisms in the CLEC4M gene contribute to quantitative VWF deficiency. Disclosures: Montgomery: Gen-Probe/GTI Diagnostics: Consultancy; CSL Behring: Consultancy; Octapharma: Consultancy. James:CSL-Behring, Baxter, Bayer: Honoraria, Research Funding.
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Swystun, Laura L., Colleen Notley, Ilinca Georgescu, Paula D. James, and David Lillicrap. "The Endothelial Lectin Receptor CLEC4M Internalizes Factor VIII and Von Willebrand Factor Via a Clathrin-Coated Pit-Dependent Mechanism." Blood 122, no. 21 (November 15, 2013): 1091. http://dx.doi.org/10.1182/blood.v122.21.1091.1091.
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Abstract Regulation of plasma levels of the coagulation factors von Willebrand factor (VWF) and factor VIII (FVIII) involves a dynamic balance between biosynthesis, secretion, and clearance. Clearance of VWF and FVIII occurs through receptor-mediated endocytosis, with both LDL receptor gene family (eg. LRP1), and lectin receptors (eg. asialoglycoprotein receptor, siglec-5) contributing to this process. We have previously characterized the endothelial lectin CLEC4M as an endocytic receptor for FVIII and VWF. These proteins represent the first endogenous glycoprotein ligands indentified for CLEC4M. Previous studies have characterized CLEC4M as an adhesive receptor capable of facilitating viral infection in trans. Thus, the mechanism by which CLEC4M internalizes VWF and FVIII, and the subsequent fate of these ligands, is uncharacterized. We hypothesize that CLEC4M is able to endocytose VWF and FVIII via a clathrin-coated pit-dependent mechanism. We further hypothesize that endocytosis of FVIII and VWF by CLEC4M-expressing cells targets FVIII and VWF to lysosomes for degradation. As CLEC4M is expressed exclusively on the endothelial cells of the hepatic sinusoids and lymph nodes, and commercially prepared liver sinusoidal endothelial cells do not retain CLEC4M expression, we generated a HEK 293 cell line that stably expresses CLEC4M (>90% positive by flow cytometry). We first inhibited the CLEC4M-mediated endocytic pathways by preincubating cells with methyl-β-cyclodextrin to deplete cell membrane cholesterol, dynasore hydrate to inhibit dynamin GTPase activity, and pitstop-2 to block the N-terminus of clathrin. Cells were then incubated with recombinant human FVIII, or plasma derived VWF-FVIII complex for 1 hour and internalization was visualized by immunofluorescence. A quantitative analysis of VWF or FVIII-positive objects was performed using Image Pro software. CLEC4M-expressing 293 cells internalized both FVIII as well as the VWF-FVIII complex. Binding and internalization of VWF was reduced by methyl-β-cyclodextran (65%, p=0.067), by dynasore hydrate (92%, p=0.055), and by pitstop-2 (83%, p=0.032). Binding and internalization of FVIII was similarly reduced by methyl-β-cyclodextran (50%, p=0.0050), by dynasore hydrate (60%, p=0.0225), and by pitstop-2 (90%, p=0.0086). This suggests that CLEC4M mediates endocytosis of VWF and FVIII via a clathrin-coated pit-dependent mechanism that involves lipid rafts. To visualize the endocytic pathway of VWF and FVIII, CLEC4M-expressing 293 cells were incubated with FVIII or the VWF-FVIII complex for 15, 30, or 60 minutes. Colocalization of FVIII, VWF and/or CLEC4M with markers for early endosomes (early endosomal antigen-1), late endosomes (Rab9), and lysosomes (LAMP1) was observed using immunofluorescence. For all conditions, CLEC4M-negative and isotype controls were performed. We have previously confirmed that FVIII and VWF are internalized by CLEC4M expressing cells, and that VWF colocalizes with a marker for early endosomes. When CLEC4M-expressing cells were exposed to the VWF-FVIII complex, we observed a partial colocalization of VWF and FVIII, confirming that CLEC4M is able to internalize the VWF-FVIII complex. When CLEC4M-expressing cells were exposed to FVIII, we observed colocalization between FVIII and early endosomal antigen 1 within 15 minutes, confirming that upon internalization by CLEC4M, VWF and FVIII are targeted to early endosomes. We next observed the transport of VWF and FVIII to late endosomes and lysosomes. When CLEC4M-expressing cells were incubated with VWF and FVIII for 30 minutes, we observed colocalization of both proteins with Rab9, a marker for late endosomes. When CLEC4M-expressing cells were incubated with FVIII for 1 hour, we observed colocalization of FVIII with LAMP1, a lysosomal marker, suggesting that the internalization of FVIII by CLEC4M leads to lysosome-mediated degradation of FVIII. In contrast, incubation of CLEC4M-expressing cells with VWF for up to 2 hours did not result in co-localization with LAMP1. These studies confirm that, in the context of the stable cell system used in these experiments, the cell surface lectin receptor CLEC4M mediates endocytosis of FVIII and VWF through a clathrin-coated pit-dependent pathway. Internalization of VWF and FVIII by CLEC4M targets these proteins to early and late endosomes; FVIII is subsequently targeted to lysosomes for degradation. Disclosures: James: CSL Behring: Honoraria, Research Funding; Octapharma: Honoraria, Research Funding; Baxter: Honoraria; Bayer: Honoraria.
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Aoun, Mike, Xiaojie Cai, Bingze Xu, Gonzalo Fernandez Lahore, Michael Yi Bonner, Yibo He, Liselotte Bäckdahl, and Rikard Holmdahl. "Glycan Activation of Clec4b Induces Reactive Oxygen Species Protecting against Neutrophilia and Arthritis." Antioxidants 11, no. 1 (December 22, 2021): 12. http://dx.doi.org/10.3390/antiox11010012.
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Animal models for complex diseases are needed to position and analyze the function of interacting genes. Previous positional cloning identified Ncf1 and Clec4b to be major regulators of arthritis models in rats. Here, we investigate epistasis between Ncf1 and Clec4b, two major regulators of arthritis in rats. We find that Clec4b and Ncf1 exert an additive effect on arthritis given by their joint ability to regulate neutrophils. Both genes are highly expressed in neutrophils, together regulating neutrophil availability and their capacity to generate reactive oxygen species. Using a glycan array, we identify key ligands of Clec4b and demonstrate that Clec4b-specific stimulation triggers neutrophils into oxidative burst. Our observations highlight Clec4b as an important regulator of neutrophils and demonstrate how epistatic interactions affect the susceptibility to, and severity of, autoimmune arthritis.
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Nasu, Junta, Tomofumi Uto, Tomohiro Fukaya, Hideaki Takagi, Takehito Fukui, Noriaki Miyanaga, Yotaro Nishikawa, Sho Yamasaki, Yoshihiro Yamashita, and Katsuaki Sato. "Pivotal role of the carbohydrate recognition domain in self-interaction of CLEC4A to elicit the ITIM-mediated inhibitory function in murine conventional dendritic cells in vitro." International Immunology 32, no. 10 (May 16, 2020): 673–82. http://dx.doi.org/10.1093/intimm/dxaa034.
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Abstract C-type lectin receptors (CLRs), pattern recognition receptors (PRRs) with a characteristic carbohydrate recognition domain (CRD) in the extracellular portion, mediate crucial cellular functions upon recognition of glycosylated pathogens and self-glycoproteins. CLEC4A is the only classical CLR that possesses an intracellular immunoreceptor tyrosine-based inhibitory motif (ITIM), which possibly transduces negative signals. However, how CLEC4A exerts cellular inhibition remains unclear. Here, we report that the self-interaction of CLEC4A through the CRD is required for the ITIM-mediated suppressive function in conventional dendritic cells (cDCs). Human type 2 cDCs (cDC2) and monocytes display a higher expression of CLEC4A than cDC1 and plasmacytoid DCs (pDCs) as well as B cells. The extracellular portion of CLEC4A specifically binds to a murine cDC cell line expressing CLEC4A, while its extracellular portion lacking the N-glycosylation site or the EPS motif within the CRD reduces their association. Furthermore, the deletion of the EPS motif within the CRD or ITIM in CLEC4A almost completely impairs its suppressive effect on the activation of the murine cDC cell line, whereas the absence of the N-glycosylation site within the CRD exhibits partial inhibition on their activation. On the other hand, antagonistic monoclonal antibody (mAb) to CLEC4A, which inhibits the self-interaction of CLEC4A and its downstream signaling in murine transfectants, enhances the activation of monocytes and monocyte-derived immature DCs upon stimulation with a Toll-like receptor (TLR) ligand. Thus, our findings suggest a pivotal role of the CRD in self-interaction of CLEC4A to elicit the ITIM-mediated inhibitory signal for the control of the function of cDCs.
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Araúzo-Bravo, Marcos J., Denis Delic, Daniela Gerovska, and Frank Wunderlich. "Protective Vaccination Reshapes Hepatic Response to Blood-Stage Malaria of Genes Preferentially Expressed by NK Cells." Vaccines 8, no. 4 (November 13, 2020): 677. http://dx.doi.org/10.3390/vaccines8040677.
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The role of natural killer (NK) cells in the liver as first-line post infectionem (p.i.) effectors against blood-stage malaria and their responsiveness to protective vaccination is poorly understood. Here, we investigate the effect of vaccination on NK cell-associated genes induced in the liver by blood-stage malaria of Plasmodium chabaudi. Female Balb/c mice were vaccinated at weeks 3 and 1 before being infected with 106P. chabaudi-parasitized erythrocytes. Genes preferentially expressed by NK cells were investigated in livers of vaccination-protected and non-protected mice on days 0, 1, 4, 8, and 11 p.i. using microarrays, qRT-PCR, and chromosome landscape analysis. Blood-stage malaria induces expression of specific genes in the liver at different phases of infection, i.e., Itga1 in expanding liver-resident NK (lrNK) cells, Itga2 in immigrating conventional NK (cNK) cells; Eomes and Tbx21 encoding transcription factors; Ncr1, Tnfsf10, Prf1, Gzma, Gzmb, Gzmc, Gzmm, and Gzmk encoding cytolytic effectors; natural killer gene complex (NKC)-localized genes encoding the NK cell receptors KLRG1, KLRK1, KLRAs1, 2, 5, 7, KLRD1, KLRC1, KLRC3, as well as the three receptors KLRB1A, KLRB1C, KLRB1F and their potential ligands CLEC2D and CLEC2I. Vaccination enhances this malaria-induced expression of genes, but impairs Gzmm expression, accelerates decline of Tnfsf10 and Clec2d expression, whereas it accelerates increased expression of Clec2i, taking a very similar time course as that of genes encoding plasma membrane proteins of erythroblasts, whose malaria-induced extramedullary generation in the liver is known to be accelerated by vaccination. Collectively, vaccination reshapes the response of the liver NK cell compartment to blood-stage malaria. Particularly, the malaria-induced expansion of lrNK cells peaking on day 4 p.i. is highly significantly (p < 0.0001) reduced by enhanced immigration of peripheral cNK cells, and KLRB1F:CLEC2I interactions between NK cells and erythroid cells facilitate extramedullary erythroblastosis in the liver, thus critically contributing to vaccination-induced survival of otherwise lethal blood-stage malaria of P. chabaudi.
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Ho, B. S. W., and T. Y. Tam. "Enumeration of E. coli in environmental waters and wastewater using a chromogenic medium." Water Science and Technology 35, no. 11-12 (June 1, 1997): 409–13. http://dx.doi.org/10.2166/wst.1997.0768.
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CHROMagar Liquid ECC (CLECC) was compared with membrane lauryl sulphate broth plus urea (mLS-UA) used routinely in Hong Kong for E. coli enumeration. E. coli appear as distinctive greenish-blue colonies on CLECC while other faecal coliforms are red in colour. CLECC performance was comparable to mLS with mixtures of faecal coliforms, E. coli and non-faecal coliforms. Beach, river, ground and waste water samples were used for further comparison. Results given by the two media were significantly correlated (P = <0.001). CLECC was superior to mLS-UA in sensitivity (99.1% vs 87.2%) and specificity (96.9% vs 59.8%) for detecting E. coli. On CLECC 95% of E. coli colonies were correctly identified but only 66.9% on mLS-UA. On average, time required for performing one E. coli enumeration test with CLECC was 1.2min/sample less than with mLS-UA. CLECC may enable the development of complete automation for enumerating E. coli.
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Lunghi, Barbara, Massimo Morfini, Nicola Martinelli, Silvia Linari, Giancarlo Castaman, and Francesco Bernardi. "Combination of CLEC4M rs868875 G-Carriership and ABO O Genotypes May Predict Faster Decay of FVIII Infused in Hemophilia A Patients." Journal of Clinical Medicine 11, no. 3 (January 29, 2022): 733. http://dx.doi.org/10.3390/jcm11030733.
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The C-type lectin CLEC4M binds and internalizes factor VIII (FVIII). Common CLEC4M variants have been associated with FVIII pharmacokinetic (PK) profiles in hemophilia A (HA) patients. The two-compartment PK analysis of plasma-derived (pd-) and full length recombinant FVIII concentrates was conducted in twenty-six patients (FVIII:C ≤ 2 IU/dL). F8, ABO blood-groups, and the CLEC4M rs868875A/G polymorphism were genotyped. CLEC4M genotype groups differed for the elimination rate constant K 1-0 (p < 0.001), half-life (K 1-0 HL), and the Beta rate constant. Patients treated with pd-FVIII also differed in the Alpha phase. In linear regression models, the contribution of the CLEC4M genotypes to FVIII PK parameters remained significant after correction for ABO, age, and VWF antigen levels at PK. Combined CLEC4M rs868875A/G and ABO genotypes displayed significant interaction (K 1-0, p = 0.014). Compared to other combined genotypes, the G-carriers/O genotypes showed half-reduced K 1-0 HL (p = 0.008), and faster FVIII clearance (mean 7.1 ± 2.2 mL/h/kg SE) than in the G-carriers/non-O (mean 2.4 ± 0.3 mL/h/kg SE), (p = 0.038). Comparison in HA patients recruited in several countries suggests that CLEC4M genotypes coherently influence infused FVIII half-life and clearance. Our analysis supports substantially faster FVIII decay associated with the rs868875 G-carrier/ABO O genotypes, which has potential implications for genetically tailored substitutive HA treatment.
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Rydz, Natalia, Laura L. Swystun, Colleen Notley, Andrew D. Paterson, J. Jacob Riches, Kate Sponagle, Boonchai Boonyawat, Robert R. Montgomery, Paula D. James, and David Lillicrap. "The C-type lectin receptor CLEC4M binds, internalizes, and clears von Willebrand factor and contributes to the variation in plasma von Willebrand factor levels." Blood 121, no. 26 (June 27, 2013): 5228–37. http://dx.doi.org/10.1182/blood-2012-10-457507.
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Clément, Marc, Gemma Basatemur, Leanne Masters, Lauren Baker, Patrick Bruneval, Taka Iwawaki, Manfred Kneilling, Sho Yamasaki, Jane Goodall, and Ziad Mallat. "Clec4e signaling promotes pro-atherogenic macrophage responses." Atherosclerosis 263 (August 2017): e23. http://dx.doi.org/10.1016/j.atherosclerosis.2017.06.097.
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Ito, Fumito, Mark D. Long, Ryutaro Kajihara, Satoko Matsueda, Takaaki Oba, Kazunori Kanehira, Song Liu, and Kenichi Makino. "Notch signaling is required for generation of conventional type 1 dendritic cells from human induced pluripotent stem cells." Journal of Immunology 208, no. 1_Supplement (May 1, 2022): 47.07. http://dx.doi.org/10.4049/jimmunol.208.supp.47.07.
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Abstract Compelling evidence shows a critical role of conventional type 1 dendritic cells (cDC1) in T-cell mediated antitumor immunity; however, obtaining large numbers of cDC1 is difficult. Theoretically, this limitation can be overcome by using induced pluripotent stem cells (iPSC) that could provide an unlimited source of autologous cDC1. However, generation of cDC1 from human iPSC remains elusive. Here, we hypothesized that Notch signaling would facilitate generation of cDC1 from human iPSC. We found that human iPSC gave rise to CD141+XCR1+CLEC9A+HLA-DR+ cells on OP9 feeder cells expressing the Notch ligand delta-like 1 (OP9-DL1) while the majority of iPSC-derived cells differentiated on OP9 cells were monocytic cells. Single-cell RNA sequencing analyses confirmed the presence of cDC1 as well as identified the heterogeneity of iPSC-derived CD1c+ cells; cDC2A, cDC2B, CD5+cDC2, and DC3. Inhibition of Notch signaling during co-culture of iPSC-derived CD34+ hematopoietic progenitor cells with OP9-DL1 cells abrogated generation of cDC1, and made expression of CD5, CLEC4A, CLEC10A and CD163 in CD1c+ DC similar to those differentiated on OP9 cells. Notch-activated human iPSC-derived XCR1+CLEC9A+HLA-DR+CD11c+ cells exhibited similar gene expression profile with peripheral blood cDC1, and phagocytotic, T-cell proliferative, and cytokine producing functions. Our study demonstrates that Notch signaling is required for the differentiation of cDC1-like cells, and facilitates generation of various cDC subsets from human iPSC. These findings provide insights into the future development of personalized treatment with unlimited numbers of autologous cDC1 from human iPSC. This work was supported by National Cancer Institute (NCI) grant P30CA016056 involving the use of Roswell Park’s Flow and Image Cytometry, Bioinformatics, and Genomic Shared Resources. This work was supported by the Melanoma Research Alliance and the Sarcoma Foundation of America (F. Ito), Uehara Memorial Foundation (T. Oba), and National Cancer Institute (NCI) grant, U24CA232979 (M. Long and S. Liu), K08CA197966 and R01CA255240-01A1 (F. Ito).
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Pierre, N., V. A. Huynh-Thu, D. Baiwir, G. Mazzucchelli, M. Fléron, L. Trzpiot, G. Eppe, et al. "OP02 Distinct biological profiles associated with the risk of short-term relapse and mid/long-term relapse in Crohn’s disease patients stopping infliximab." Journal of Crohn's and Colitis 17, Supplement_1 (January 30, 2023): i3—i6. http://dx.doi.org/10.1093/ecco-jcc/jjac190.0002.
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Abstract Background In Crohn’s disease (CD) patients stopping infliximab (IFX), the risk of short-term relapse (<6 months) and mid/long-term (>6 months) relapse were associated with distinct biological profiles (STORI trial). Herein, we aim to test the external validity of this finding in an independent trial (SPARE). Methods The SPARE trial has included 211 CD patients (from 64 sites in Europe and Australia) in steroid-free remission >6 months, receiving a combined therapy (IFX and immunosuppressant (IS)) >8 months and who were then randomised in three arms: continuing combo, stopping IFX or stopping IS. The arm stopping IFX was used to externally validate our findings generated in the STORI trial. To this end, the measurement of 161 proteins obtained in the baseline serum of STORI was repeated in SPARE (arm stopping IFX) with the same technologies: selected reaction monitoring (SRM, 69 proteins measured in 67 patients) or proximity extension assay (PEA, 92 proteins measured in 63 patients). Associations between serum protein levels and time to relapse (HR: hazard ratio and its associated statistics) were determined by using univariable Cox model in the stratified (relapse <6 or >6 months) and non-stratified cohort. Results The blood proteins depicting the risk of short-term or mid/long-term relapse in STORI and SPARE were selected as shown Fig. 1 (SRM) and Fig. 2 (PEA). The representation of those markers in volcano plots clearly confirmed that short-term and mid/long-term relapsers present distinct biological profiles (Fig. 3-4). This is also corroborated by the fact that only ORM1 was selected as a marker of short-term and mid/long-term relapse (Fig. 1-2). In STORI and SPARE, the risk of short-term relapse was associated (p-value<0.05) with a high serum level of inflammatory markers (IL6, CRP, HPR, ORM1, LRG1, HP, CP, APCS, ITIH3), complement components (C8B, C4B), blood coagulation proteins (F9, SERPIND1), markers of dendritic cells (LAMP3, CLEC4C) and a low serum level of a complement component (MASP1) (Fig. 1-2-3). In STORI and SPARE, the risk of mid/long-term relapse was associated (p-value<0.05) with a high serum level of a complement component (CFB) and a low serum level of a protease inhibitor (SERPINA4), a growth factor (FGF2), an anti-inflammatory cytokine (IL10) (Fig. 1-2-4). For other proteins, STORI and SPARE showed convergent tendencies (p-value<0.01; Fig. 1-2-3-4) or differences (Fig. 1-2). Conclusion We confirm that, after stopping IFX in CD patients, the risk of short-term and mid/long-term relapse are associated with distinct biological profiles. The risk of short-term relapse is deeply associated with residual inflammation while the biological picture depicting the risk of mid/long-term relapse seems less clear.
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Swystun, Laura L., Colleen Notley, Kate Sponagle, Paula D. James, and David Lillicrap. "Regulation Of Factor VIII Clearance By Mannose-Binding Lectins." Blood 122, no. 21 (November 15, 2013): 2340. http://dx.doi.org/10.1182/blood.v122.21.2340.2340.
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Abstract The coagulation factors von Willebrand factor (FVIII) and factor VIII (FVIII) circulate in the plasma in a non-covalent complex. VWF acts as a carrier for FVIII and protects it from proteolysis and accelerated clearance. However, in the absence of VWF, the molecular mechanisms that regulate FVIII clearance are largely uncharacterized. The glycosylation of FVIII may regulate its interaction with lectin clearance receptors such as the asialoglycoprotein receptor and siglec-5. The FVIII polypeptide is modified by the addition of 24 N-linked glycans and 7 O-linked glycans. The majority of N-linked glycans on FVIII are complex type and predominantly localized to the B-domain. However, two high mannose glycans are found on the A1 and C1 domains. In these studies, we characterized the ability of mannose binding lectins to interact with FVIII and mediate its clearance from the plasma. We have previously reported that the endothelial mannose binding lectin CLEC4M is a novel clearance receptor for FVIII. Removal of N-linked glycans, or pre-incubation of recombinant CLEC4M with the mannose polymer mannan attenuated binding of CLEC4M to FVIII. Additionally, the pre-incubation of CLEC4M-expressing cells with mannan significantly decreased binding and internalization of FVIII. In these studies, high mannose glycans on recombinant human FVIII were removed using the endoglycosidase endoH. Effective removal of FVIII high mannose glycans by endoH was confirmed via a lectin binding assay to Galanthus Nivalis lectin (50%, p=0.006). The binding of recombinant CLEC4M-Fc to endoH-treated FVIII was measured using a solid phase binding assay. Removal of high mannose glycans attenuated the interaction between FVIII and CLEC4M-Fc by 41% (p=0.005). A 49% decrease in the internalization of endoH-treated FVIII was observed on CLEC4M-expressing cells relative to control (p=0.046). We next sought to confirm the contribution of mannose binding lectins to the clearance of FVIII in a murine model. Although there is no murine ortholog to CLEC4M, mice express a series of CLEC4M homologs termed SIGNRs. Similar to CLEC4M, SIGNR1 is expressed on liver sinusoidal endothelial cells. While significant structural differences exist between CLEC4M and SIGNR1, they retain 59% amino acid identity between their carbohydrate recognition domains, and SIGNR1 has been shown to bind mannosylated as well as fucosylated glycoproteins. We assessed the contribution of SIGNR1 to VWF and FVIII clearance. Plasma levels of VWF:Ag, and FVIII:C were quantified in SIGNR1 deficient mice by ELISA and chromogenic assay respectively. Endogenous VWF (88% of wild type, p=0.233, n=35) and FVIII (110% of wild type, p=0.435, n=35) in SIGNR1 deficient mice were not different compared to wild type mice. SIGNR1/VWF deficient mice were bred on a C57Bl/6 background; mice received tail vein infusions of recombinant human FVIII (200 U/kg) or plasma derived VWF-FVIII complex (200 U/kg). Blood was sampled via retro-orbital puncture. VWF:Ag and FVIII:Ag levels were measured with ELISA and elimination half life was calculated using one phase exponential decay. Half-lives of infused recombinant human FVIII (VWF-/- t½=8.74 minutes, SIGNR1-/-/VWF-/- t½=10.03 minutes, p=0.898) and human plasma-derived VWF-FVIII complex (VWF-/- t½=46.09 minutes, SIGNR1-/-/VWF-/- t½=49.83 minutes, p=0.934) were not significantly different. We finally sought to characterize the contribution of other mannose-binding lectins to FVIII clearance in mice. VWF deficient mice received tail vein infusions of mannan (6 mg/kg) or saline followed after 3 minutes by tail vein infusions of recombinant human FVIII (200 U/kg). Pre-infusion of mannan into VWF deficient mice did not modify the half-life of FVIII relative to the control (control t½= 10.56 minutes, mannan t½= 9.38 minutes. p=0.33). We also assessed the clearance of endoH-treated FVIII in VWF deficient mice, and did not observe a change relative to the control (control t½=12.28 minutes, endoH FVIII t½=11.23 minutes, p=0.812). These studies suggest that CLEC4M interacts with FVIII in part through its high mannose glycans in vitro. However, our in vivo studies were unable to reveal a significant role for mannose-binding lectins in FVIII clearance in mouse models. Disclosures: James: CSL Behring: Honoraria, Research Funding; Octapharma: Honoraria, Research Funding; Baxter: Honoraria; Bayer: Honoraria.
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Qiu, Hong, Haobo Li, Ruiwen Fan, Yang Song, Xuan Pan, Chunhui Zhang, and Jing Li. "Genome-Wide DNA Methylation Profile Indicates Potential Epigenetic Regulation of Aging in the Rhesus Macaque Thymus." International Journal of Molecular Sciences 23, no. 23 (November 29, 2022): 14984. http://dx.doi.org/10.3390/ijms232314984.
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We analyzed whole-genome bisulfite sequencing (WGBS) and RNA sequencing data of two young (1 year old) and two adult (9 years old) rhesus macaques (Macaca mulatta) to characterize the genomic DNA methylation profile of the thymus and explore the molecular mechanism of age-related changes in the thymus. Combining the two-omics data, we identified correlations between DNA methylation and gene expression and found that DNA methylation played an essential role in the functional changes of the aging thymus, especially in immunity and coagulation. The hypomethylation levels of C3 and C5AR2 and the hypermethylation level of C7 may lead to the high expressions of these genes in adult rhesus macaque thymuses, thus activating the classical complement pathway and the alternative pathway and enhancing their innate immune function. Adult thymuses had an enhanced coagulation pathway, which may have resulted from the hypomethylation and upregulated expressions of seven coagulation-promoting factor genes (F13A1, CLEC4D, CLEC4E, FCN3, PDGFRA, FGF2 and FGF7) and the hypomethylation and low expression of CPB2 to inhibit the degradation of blood clots. Furthermore, the functional decline in differentiation, activation and maturation of T cells in adult thymuses was also closely related to the changes in methylation levels and gene expression levels of T cell development genes (CD3G, GAD2, ADAMDEC1 and LCK) and the thymogenic hormone gene TMPO. A comparison of the age-related methylated genes among four mammal species revealed that most of the epigenetic clocks were species-specific. Furthermore, based on the genomic landscape of allele-specific DNA methylation, we identified several age-related clustered sequence-dependent allele-specific DNA methylated (cS-ASM) genes. Overall, these DNA methylation patterns may also help to assist with understanding the mechanisms of the aging thymus with the epigenome.
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Kizuka, Yasuhiko, Shinobu Kitazume, Keiko Sato, and Naoyuki Taniguchi. "Clec4g (LSECtin) interacts with BACE1 and suppresses Aβ generation." FEBS Letters 589, no. 13 (May 7, 2015): 1418–22. http://dx.doi.org/10.1016/j.febslet.2015.04.060.
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Ceribelli, Michele, Priscilla N. Kelly, Stefania Pittaluga, Craig J. Thomas, Boris Reizis, and Louis M. Staudt. "A Druggable TCF4 and BRD4 Dependent Transcriptional Network Sustains Malignancy in Blastic Plasmacytoid Dendritic Cell Neoplasm." Blood 128, no. 22 (December 2, 2016): 1513. http://dx.doi.org/10.1182/blood.v128.22.1513.1513.
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Abstract Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive malignancy originating from neoplastic transformation of plasmacytoid dendritic cells (pDCs). Although an initial response to chemotherapy is common, BPDCN prognosis is extremely poor and most patients relapse with drug-resistant disease leading to a median overall survival of ~1 year after diagnosis. In an effort to uncover novel molecular vulnerabilities in BPDCN, we combined RNA interference screening with high-throughput drug screening to identify pathways essential for the proliferation and survival of these cancer cells. This functional/chemical genomic approach allowed us to define a master regulatory network in BPDCN that is amenable to therapeutic attack. First, the E-box transcription factor TCF4, an important regulator of normal pDCs development, emerged from our RNAi screen as a essential for BPDCN viability. Consistently, expression of TCF4 shRNAs induced a robust and time-dependent apoptotic response, specific for BPDCN cells. We defined the TCF4 regulatory network in BPDCN, by profiling gene expression changes following induction of TCF4 shRNAs and by performing TCF4 ChIP-Seq in BPDCN lines. Notably, several TCF4 targets genes were expressed at higher levels in BPDCN than in normal pDCs, including proto-oncogenes such as BCL2, TCL1A/B and MYC. Conversely, TCF4 targets encoding for important regulators of normal pDC function (BCL11A, SPIB, IL3RA and CLEC4C) were selectively expressed at low level in BPDCN cells, indicating that the pDC-specifying function of TCF4 is attenuated in BPDCN to favor oncogenic gene expression programs. Importantly, TCF4 also served as a faithful diagnostic marker of BPDCN, and TCF4 IHC could readily distinguish BPDCN from BPDCN-mimics such as cutaneous AML. Second, 3 structurally different bromodomain and extra-terminal domain inhibitors (BETi's) emerged as highly toxic to BPDCN cells from our high-throughput drug screening .This was notable since BET inhibitors block the recognition of acetylated histones by BET proteins, one of which, BRD4, was among the hits from our shRNA toxicity screening. Consistently, expression BRD4 shRNAs or treatment with the BETi JQ1 resulted in time and dose dependent induction of apoptosis in BPDCN cells. Notably, TCF4 itself was strongly downregulated by BETi treatment and ectopic TCF4 expression was sufficient to rescue BPDCN cells from JQ1 toxicity, underscoring the functionally dominant, master regulatory role played by TCF4 in BPDCN. Mechanistically, we showed that the effect of BETi on TCF4 expression is mediated by the presence of a BRD4-dependent super-enhancer (SE) that controls TCF4 expression. Surprisingly, TCF4 itself was bound to its own SE and to the majority of the BRD4-dependent SE we mapped in BPDCN, enforcing a widespread regulatory network that is required for the viability of this cancer. Altogether, we uncovered novel molecular dependencies and identified TCF4 as a lineage-survival oncogene in BPDCN. More importantly, the TCF4 network in BPDCN can be targeted by BETi. Considering that the BETi CPI 203 was well tolerated in vivo andeffective as a single agent in reducing tumor growth in two BPDCN xenograft models, our findings support the clinical evaluation of BETi in this lethal cancer. Disclosures No relevant conflicts of interest to declare.
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Fisher, James, Casey Gonzales, Zachary Chroust, Yuejin Liang, and Lynn Soong. "Orientia tsutsugamushi Infection Stimulates Syk-Dependent Responses and Innate Cytosolic Defenses in Macrophages." Pathogens 12, no. 1 (December 29, 2022): 53. http://dx.doi.org/10.3390/pathogens12010053.
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Orientia tsutsugamushi is an obligately intracellular bacterium and an etiological agent of scrub typhus. Human studies and animal models of scrub typhus have shown robust type 1-skewed proinflammatory responses during severe infection. Macrophages (MΦ) play a critical role in initiating such responses, yet mechanisms of innate recognition for O. tsutsugamushi remain unclear. In this study, we investigated whether Syk-dependent C-type lectin receptors (CLRs) contribute to innate immune recognition and the generation of proinflammatory responses. To validate the role of CLRs in scrub typhus, we infected murine bone marrow-derived MΦ with O. tsutsugamushi in the presence of selective Syk inhibitors and analyzed a panel of CLRs and proinflammatory markers via qRT-PCR. We found that Mincle/Clec4a and Clec5a transcription was significantly abrogated upon Syk inhibition at 6 h of infection. The effect of Syk inhibition on Mincle protein expression was validated via Western blot. Syk-inhibited MΦ had diminished expression of type 1 cytokines/chemokines (Il12p40, Tnf, Il27p28, Cxcl1) during infection. Additionally, expression of innate immune cytosolic sensors (Mx1 and Oas1-3) was highly induced in the brain of lethally infected mice. We established that Mx1 and Oas1 expression was reduced in Syk-inhibited MΦ, while Oas2, Oas3, and MerTK were not sensitive to Syk inhibition. This study reveals that Syk-dependent CLRs contribute to inflammatory responses against O. tsutsugamushi. It also provides the first evidence for Syk-dependent activation of intracellular defenses during infection, suggesting a role of pattern recognition receptor crosstalk in orchestrating macrophage-mediated responses to this poorly studied bacterium.
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Veltman, Denise, Ming Wu, Peter Pokreisz, Piet Claus, Hilde Gillijns, Ellen Caluwé, Maarten Vanhaverbeke, et al. "Clec4e-Receptor Signaling in Myocardial Repair After Ischemia-Reperfusion Injury." JACC: Basic to Translational Science 6, no. 8 (August 2021): 631–46. http://dx.doi.org/10.1016/j.jacbts.2021.07.001.
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Spillenger, Clyde, Andrew L. Kaufman, and Richard Polenberg. "Cloistered Cleric of the Law." University of Chicago Law Review 66, no. 2 (1999): 507. http://dx.doi.org/10.2307/1600474.
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Bell, Elaine. "CLEC9A: linking necrosis and immunity." Nature Reviews Immunology 9, no. 4 (April 2009): 223. http://dx.doi.org/10.1038/nri2531.
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MATTSON, DONALD L. "The Cleric in the Classroom." Counseling and Values 36, no. 3 (April 1992): 230–32. http://dx.doi.org/10.1002/j.2161-007x.1992.tb00791.x.
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Chen, Po-Ku, Shie-Liang Hsieh, Joung-Liang Lan, Chi-Chen Lin, Shih-Hsin Chang, and Der-Yuan Chen. "Elevated Expression of C-Type Lectin Domain Family 5-Member A (CLEC5A) and Its Relation to Inflammatory Parameters and Disease Course in Adult-Onset Still’s Disease." Journal of Immunology Research 2020 (April 23, 2020): 1–11. http://dx.doi.org/10.1155/2020/9473497.
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C-type lectin domain family 5-member A (CLEC5A) associates with adaptor DAP12 (DNAX activation protein 12) to form receptor complexes involved in inflammatory responses. We postulated a potential role of CLEC5A in the pathogenesis of adult-onset Still’s disease (AOSD) and aimed to investigate CLEC5A expression and its association with activity parameters and disease course. In 34 AOSD patients and 12 healthy controls (HC), circulating levels of CLEC5A-expressing monocytes or granulocytes were determined by flow cytometry analysis, the mRNA expression of CLEC5A and DAP12 on PBMCs by quantitative PCR, and plasma levels of proinflammatory cytokines by ELISA. AOSD patients had significantly higher percentages and mean fluorescence intensity (MFI) of CLEC5A-expressing monocytes (median 62.1% and 3.20, respectively) or granulocytes (72.6% and 3.22, respectively) compared with HC (in monocytes: 17.0% and 0.65, both p<0.001; in granulocytes: 67.3%, p<0.05 and 0.90, p<0.001; respectively). Patients also had significantly higher levels of CLEC5A mRNA expression on PBMCs compared with HC (median 1.77 vs. 0.68, p<0.05). The levels of CLEC5A-expressing monocytes or granulocytes were positively associated with activity scores and levels of IL-1β and IL-18 in AOSD patients. The patients with a systemic pattern had significantly higher levels of CLEC5A-expressing granulocytes and IL-18 compared to those with a chronic articular pattern of disease course. After 6 months of therapy, levels of CLEC5A-expressing monocytes and granulocytes significantly declined, paralleling the decrease of AOSD activity. Elevated CLEC5A levels and their positive association with activity parameters suggest that CLEC5A is involved in the pathogenesis and may serve as an activity indicator of AOSD.
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Caminschi, Irina, Anna I. Proietto, Fatma Ahmet, Susie Kitsoulis, Joo Shin Teh, Jennifer C. Y. Lo, Alexandra Rizzitelli, et al. "The dendritic cell subtype-restricted C-type lectin Clec9A is a target for vaccine enhancement." Blood 112, no. 8 (October 15, 2008): 3264–73. http://dx.doi.org/10.1182/blood-2008-05-155176.
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Abstract A novel dendritic cell (DC)–restricted molecule, Clec9A, was identified by gene expression profiling of mouse DC subtypes. Based on sequence similarity, a human ortholog was identified. Clec9A encodes a type II membrane protein with a single extracellular C-type lectin domain. Both the mouse Clec9A and human CLEC9A were cloned and expressed, and monoclonal antibodies (mAbs) against each were generated. Surface staining revealed that Clec9A was selective for mouse DCs and was restricted to the CD8+ conventional DC and plasmacytoid DC subtypes. A subset of human blood DCs also expressed CLEC9A. A single injection of mice with a mAb against Clec9A, which targets antigens (Ags) to the DCs, produced a striking enhancement of antibody responses in the absence of added adjuvants or danger signals, even in mice lacking Toll-like receptor signaling pathways. Such targeting also enhanced CD4 and CD8 T-cell responses. Thus, Clec9A serves as a new marker to distinguish subtypes of both mouse and human DCs. Furthermore, targeting Ags to DCs with antibodies to Clec9A is a promising strategy to enhance the efficiency of vaccines, even in the absence of adjuvants.
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Kan, Hung-Wei, Chin-Hong Chang, Ying-Shuang Chang, Yi-Ting Ko, and Yu-Lin Hsieh. "Genetic loss-of-function of activating transcription factor 3 but not C-type lectin member 5A prevents diabetic peripheral neuropathy." Laboratory Investigation 101, no. 10 (June 25, 2021): 1341–52. http://dx.doi.org/10.1038/s41374-021-00630-5.
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AbstractWe investigated the mediating roles of activating transcription factor 3 (ATF3), an injury marker, or C-type lectin member 5A (CLEC5A), an inflammatory response molecule, in the induction of endoplasmic reticulum (ER) stress and neuroinflammation in diabetic peripheral neuropathy in ATF3 and CLEC5A genetic knockout (aft3−/− and clec5a−/−, respectively) mice. ATF3 was expressed intranuclearly and was upregulated in mice with diabetic peripheral neuropathy (DN) and clec5a−/− mice. The DN and clec5a−/− groups also exhibited neuropathic behavior, but not in the aft3−/− group. The upregulation profiles of cytoplasmic polyadenylation element-binding protein, a protein translation–regulating molecule, and the ER stress-related molecules of inositol-requiring enzyme 1α and phosphorylated eukaryotic initiation factor 2α in the DN and clec5a−/− groups were correlated with neuropathic behavior. Ultrastructural evidence confirmed ER stress induction and neuroinflammation, including microglial enlargement and proinflammatory cytokine release, in the DN and clec5a−/− mice. By contrast, the induction of ER stress and neuroinflammation did not occur in the aft3−/− mice. Furthermore, the mRNA of reactive oxygen species–removing enzymes such as superoxide dismutase, heme oxygenase-1, and catalase were downregulated in the DN and clec5a−/− groups but were not changed in the aft3−/− group. Taken together, the results indicate that intraneuronal ATF3, but not CLEC5A, mediates the induction of ER stress and neuroinflammation associated with diabetic neuropathy.
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Tosiek, Milena J., Kerstin Groesser, Anton Pekcec, Monika Zwirek, Gavuthami Murugesan, and Eric Borges. "Activation of the Innate Immune Checkpoint CLEC5A on Myeloid Cells in the Absence of Danger Signals Modulates Macrophages’ Function but Does Not Trigger the Adaptive T Cell Immune Response." Journal of Immunology Research 2022 (February 25, 2022): 1–22. http://dx.doi.org/10.1155/2022/9926305.
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C-Type lectin receptor 5A (CLEC5A) is a spleen tyrosine kinase- (Syk-) coupled pattern recognition receptor expressed on myeloid cells and involved in the innate immune response to viral and bacterial infections. Activation of the CLEC5A receptor with pathogen-derived antigens leads to a secretion of proinflammatory mediators such as TNF-α and IL-6 that may provoke a systemic cytokine storm, and CLEC5A gene polymorphisms are associated with the severity of DV infection. In addition, the CLEC5A receptor was mentioned in the context of noninfectious disorders like chronic obstructive pulmonary disease (COPD) or arthritis. Altogether, CLEC5A may be considered as an innate immune checkpoint capable to amplify proinflammatory signals, and this way contributes to infection or to aseptic inflammation. In this study, we determined CLEC5A receptor expression on different macrophage subsets (in vitro and ex vivo) and the functional consequences of its activation in aseptic conditions. The CLEC5A surface expression appeared the highest on proinflammatory M1 macrophages while intermediate on tumor-associated phenotypes (M2c or TAM). In contrast, the CLEC5A expression on ex vivo-derived alveolar macrophages from healthy donors or macrophages from ovarian cancer patients was hardly detectable. Targeting CLEC5A on noninflammatory macrophages with an agonistic α-CLEC5A antibody triggered a release of proinflammatory cytokines, resembling a response to dengue virus, and led to phenotypic changes in myeloid cells that may suggest their reprogramming towards a proinflammatory phenotype, e.g., upregulation of CD80 and downregulation of CD163. Interestingly, the CLEC5A agonist upregulated immune-regulatory molecules like CD206, PD-L1, and cytokines like IL-10, macrophage-derived chemokine (MDC/CCL22), and thymus and activation chemokine (TARC/CCL17) which are associated with an anti-inflammatory or a protumorigenic macrophage phenotype. In the absence of concomitant pathogenic or endogenous danger signals, the CLEC5A receptor activation did not amplify an autologous T cell response, which may represent a protective innate mechanism to avoid an undesirable autoimmune adaptive response.
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Li, Jiabo, Xuya Wang, Steven Markwell, Tatiana Carneiro-Lobo, Cheryl Olson, Ling-Kai Shih, Luqing Tong, Xuejun Yang, and Daniel Brat. "TMIC-21. THE ROLE OF CLEC5A ON M2-LIKE TUMOR-ASSOCIATED MACROPHAGES POLARIZATION AND DISEASE PROGRESSION IN GLIOBLASTOMA." Neuro-Oncology 24, Supplement_7 (November 1, 2022): vii275—vii276. http://dx.doi.org/10.1093/neuonc/noac209.1065.
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Abstract Glioblastoma, IDH-wildtype (GBM, WHO grade 4) is the most common primary intracranial malignant tumor of adults and is characterized by an immunosuppressive tumor micro-environment (TME) and poor clinical outcomes. CLEC5A is a protein-coding gene involved in inflammatory and infectious diseases, where its activation enhances immune response. However, its role in GBM immune regulation is unclear. Seurat analysis of scRNA-seq data and CIBERSORTx analysis of GBM RNA-seq data showed that M2-like TAMs accounted for the largest proportion of immune cells in the GBM TME. Among CD163+ cells (M2-like TAM marker) in GBM, CLEC5A expression was most highly associated with overall patient survival. IHC on tumor microarrays (TMA) and analysis of Ivy GAP data indicated that CLEC5A and M2-like TAMs were preferentially expressed in tumor peri-necrotic zone. THP-1 cells exposed to GBM conditioned media showed increased CLEC5A and CD163 expression by RT-qPCR and Western blot compared to other immune-activating factors (IL-4, IL-13). CLEC5A overexpression in THP-1 cells enhanced their migration toward glioma cells in vitro, and also led to increased M2-like TAM biomarker expression. Cytokine antibody microarray results revealed that overexpressing CLEC5A in THP-1 cells also significantly increased the expression of IL-1β, IL-4, IL-6, IL-8, IL-10, IL-13, GM-CSF, and other cytokines, which all contribute to the immunosuppressive TME. In TCGA GBM data, tumors with higher CLEC5A expression were enriched in IL6-JAK-STAT3 signaling. In vivo, silencing CLEC5A delayed glioma growth and prolonged survival of tumor-bearing mice, and analysis of tumors showed reduced expression of CLEC5A, CD163 and Ki-67. Collectively, CLEC5A is expressed by M2-like TAMs and enhances M2-like TAM polarization, likely through IL6-JAK-STAT3 signaling.
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Mufa, Humaidi, Mohamad Jaenudin, and Amie Primarni. "PENGARUH KEPEMIMPINAN KYAI DAN ETOS KERJA USTADZ/USTADZAH TERHADAP KOMPETENSI PENGAJAR DI PONDOK PESANTREN QOTRUN NADA KOTA DEPOK." Jurnal Dirosah Islamiyah 1, no. 2 (November 20, 2019): 201–18. http://dx.doi.org/10.47467/jdi.v1i2.83.
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ABSTRACTThe purpose of this study is; (1) To study and analyze the influence of clerical leadership and the workethic of cleric / cleric to the professional competence of teachers at the Qotrun Nada Islamic BoardingSchool Depok jointly, (2) the influence of the cleric leadership on the Teacher Competence at the QotrunNada Islamic Boarding School in Depok, (3) the influence of the work ethic of the cleric / cleric to theTeacher Competence at the Qotrun Nada Islamic Boarding School in Depok, (4) which is more influentialbetween the clerical leadership or the work ethic of the cleric / cleric to the Teacher Competence at theQotrun Nada Islamic Boarding School in Depok.The method used in this research is quantitative descriptive method. The sample taken is the wholepopulation. The data analysis technique used is multiple linear regression analysis.From the results of the study it was found that the influence of the kyai's leadership on TeacherCompetence at Qotrun Nada Islamic Boarding School was not too significant. This is evidenced by the ttest value, sig value of 0.136 <0.05 then Ho is accepted and Ha is rejected. There is an influence of ustadz/ ustadzah's work ethic on Teacher Competence at Qotrun Nada Islamic Boarding School. This isevidenced by the t test value, sig value 0,000 <0.05 then Ho is rejected and Ha is accepted. The leadershipof the kya and the work ethic of the cleric / cleric contributed concurrently to the Teacher Competence atQotrun Nada Islamic Boarding School at 52.8%, this was evidenced by the f test.Keywords: clerical leadership, teacher competence, work ethic.
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Watson, Aleksandra A., Andrey A. Lebedev, Benjamin A. Hall, Angharad E. Fenton-May, Alexei A. Vagin, Wanwisa Dejnirattisai, James Felce, et al. "Structural Flexibility of the Macrophage Dengue Virus Receptor CLEC5A." Journal of Biological Chemistry 286, no. 27 (May 12, 2011): 24208–18. http://dx.doi.org/10.1074/jbc.m111.226142.
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The human C-type lectin-like molecule CLEC5A is a critical macrophage receptor for dengue virus. The binding of dengue virus to CLEC5A triggers signaling through the associated adapter molecule DAP12, stimulating proinflammatory cytokine release. We have crystallized an informative ensemble of CLEC5A structural conformers at 1.9-Å resolution and demonstrate how an on-off extension to a β-sheet acts as a binary switch regulating the flexibility of the molecule. This structural information together with molecular dynamics simulations suggests a mechanism whereby extracellular events may be transmitted through the membrane and influence DAP12 signaling. We demonstrate that CLEC5A is homodimeric at the cell surface and binds to dengue virus serotypes 1–4. We used blotting experiments, surface analyses, glycan microarray, and docking studies to investigate the ligand binding potential of CLEC5A with particular respect to dengue virus. This study provides a rational foundation for understanding the dengue virus-macrophage interaction and the role of CLEC5A in dengue virus-induced lethal disease.
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Bridges, Jackie, Ruth M. Pickering, Hannah Barker, Rosemary Chable, Alison Fuller, Lisa Gould, Paula Libberton, et al. "Implementing the Creating Learning Environments for Compassionate Care (CLECC) programme in acute hospital settings: a pilot RCT and feasibility study." Health Services and Delivery Research 6, no. 33 (September 2018): 1–166. http://dx.doi.org/10.3310/hsdr06330.
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BackgroundConcerns about the degree of compassion in health care have become a focus for national and international attention. However, existing research on compassionate care interventions provides scant evidence of effectiveness or the contexts in which effectiveness is achievable.ObjectivesTo assess the feasibility of implementing the Creating Learning Environments for Compassionate Care (CLECC) programme in acute hospital settings and to evaluate its impact on patient care.DesignPilot cluster randomised trial (CRT) and associated process and economic evaluations.SettingSix inpatient ward nursing teams (clusters) in two English NHS hospitals randomised to intervention (n = 4) or control (n = 2).ParticipantsPatients (n = 639), staff (n = 211) and visitors (n = 188).InterventionCLECC is a workplace educational intervention focused on developing sustainable leadership and work team practices (dialogue, reflective learning, mutual support) theorised to support the delivery of compassionate care. The control setting involved no planned staff team-based educational activity.Main outcome measuresQuality of Interaction Schedule (QuIS) for staff–patient interactions, patient-reported evaluations of emotional care in hospital (PEECH) and nurse-reported empathy (as assessed via the Jefferson Scale of Empathy).Data sourcesStructured observations of staff–patient interactions; patient, visitor and staff questionnaires and qualitative interviews; and qualitative observations of CLECC activities.ResultsThe pilot CRT proceeded as planned and randomisation was acceptable to teams. There was evidence of potential contamination between wards in the same hospital. QuIS performed well, achieving a 93% recruitment rate, with 25% of the patient sample cognitively impaired. At follow-up there were more positive (78% vs. 74%) and fewer negative (8% vs. 11%) QuIS ratings for intervention wards than for control wards. In total, 63% of intervention ward patients achieved the lowest possible (i.e. more negative) scores on the PEECH connection subscale, compared with 79% of control group patients. These differences, although supported by the qualitative findings, are not statistically significant. No statistically significant differences in nursing empathy were observed, although response rates to staff questionnaire were low (36%). Process evaluation: the CLECC intervention is feasible to implement in practice with medical and surgical nursing teams in acute care hospitals. Strong evidence of good staff participation was found in some CLECC activities and staff reported benefits throughout its introductory period and beyond. Further impact and sustainability were limited by the focus on changing ward team behaviours rather than wider system restructuring. Economic evaluation: the costs associated with using CLECC were identified and it is recommend that an impact inventory be used in any future study.LimitationsFindings are not generalisable outside hospital nursing teams, and this feasibility work is not powered to detect differences attributable to the CLECC intervention.ConclusionsUse of the experimental methods is feasible. The use of structured observation of staff–patient interaction quality is a promising primary outcome that is inclusive of patient groups often excluded from research, but further validation is required. Further development of the CLECC intervention should focus on ensuring that it is adequately supported by resources, norms and relationships in the wider system by, for instance, improving the cognitive participation of senior nurse managers. Funding is being sought for a more definitive evaluation.Trial registrationCurrent Controlled Trials ISRCTN16789770.FundingThis project was funded by the National Institute for Health Research (NIHR) Health Services and Delivery Research programme and will be published in full inHealth Services and Delivery Research; Vol. 6, No. 33. See the NIHR Journals Library website for further project information. The systematic review reported inChapter 2was funded by the NIHR Collaboration for Leadership in Applied Health Research and Care Wessex, the University of Örebro and the Karolinska Institutet.
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Hsieh, Shie-Liang Edmond, and Chi-Ya Yang. "CLEC4F, A Kupffer Cells Specific Marker, Is Critical for Presentation of Alfa-Galactoceromide to NKT Cells (78.38)." Journal of Immunology 182, no. 1_Supplement (April 1, 2009): 78.38. http://dx.doi.org/10.4049/jimmunol.182.supp.78.38.
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Abstract CLEC4F, a member of C-type lectins, was firstly purified from rat liver extract with high binding affinity to fucose, galactose and N-acetylgalactosamine, and un-sialylated glucosphingolipids with GalNAc or Gal terminus. However, the biological functions of CLEC4F have not been elucidated. To address this question, we generated mAbs to detect the expression of murine CLEC4F (mCLEC4F) in vivo, and investigated its function using mCLEC4F-deficient mice. The anti-mCLEC4F mAbs bind to 293T cells transfected with mCLEC4F cDNA as determined by flow cytometry, and the binding specificity of anti-mCLEC4F mAbs is further confirmed in mCLEC4F-deficient mice. Histochemical staining showed that mCLEC4F is only expressed on F4/80+ cells localized in liver, and is undetectable in bone marrow, spleen, lymph nodes, or other tissues in adult mice. However, mCLEC4F is detected in the liver of embryonic day 11.5 (E11.5), which is 1.5 day earlier than the formation of liver (E10) and is 3.5 day earlier than the formation of bone marrow (E15-16). Moreover, recombinant mCLEC4F.Fc binds to alpha-galactoceramide in a Ca++-dependent manner, and both galactose and ceramide can partially inhibit CLEC4F.Fc binding to alpha-galactoceramide. Interestingly, mCLEC4F-deficient (mCEC4F k/o) mice produced far less cytokines than wild type littermates after intravenous injection ofalpha-galactoceramide. This suggests that mCLEC4F is not only a specific marker for Kupffer cells, but is also critical for the presentation of glycolipid antigen to NKT cells.
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Schreibelt, Gerty, Lieke J. J. Klinkenberg, Luis J. Cruz, Paul J. Tacken, Jurjen Tel, Martin Kreutz, Gosse J. Adema, Gordon D. Brown, Carl G. Figdor, and I. Jolanda M. de Vries. "The C-type lectin receptor CLEC9A mediates antigen uptake and (cross-)presentation by human blood BDCA3+ myeloid dendritic cells." Blood 119, no. 10 (March 8, 2012): 2284–92. http://dx.doi.org/10.1182/blood-2011-08-373944.
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Abstract CLEC9A is a recently discovered C-type lectin receptor involved in sensing necrotic cells. In humans, this receptor is selectively expressed by BDCA3+ myeloid dendritic cells (mDCs), which have been proposed to be the main human cross-presenting mDCs and may represent the human homologue of murine CD8+ DCs. In mice, it was demonstrated that antigens delivered with antibodies to CLEC9A are presented by CD8+ DCs to both CD4+ and CD8+ T cells and induce antitumor immunity in a melanoma model. Here we assessed the ability of CLEC9A to mediate antigen presentation by human BDCA3+ mDCs, which represent < 0.05% of peripheral blood leukocytes. We demonstrate that CLEC9A is only expressed on immature BDCA3+ mDCs and that cell surface expression is lost after TLR-mediated maturation. CLEC9A triggering via antibody binding rapidly induces receptor internalization but does not affect TLR-induced cytokine production or expression of costimulatory molecules. More importantly, antigens delivered via CLEC9A antibodies to BDCA3+ mDCs are presented by both MHC class I (cross-presentation) and MHC class II to antigen-specific T cells. We conclude that CLEC9A is a promising target for in vivo antigen delivery in humans to increase the efficiency of vaccines against infectious or malignant diseases.
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Chan, Vera S. F., Kelvin Y. K. Chan, Yongxiong Chen, Leo L. M. Poon, Annie N. Y. Cheung, Bojian Zheng, Kwok-Hung Chan, et al. "Homozygous L-SIGN (CLEC4M) plays a protective role in SARS coronavirus infection." Nature Genetics 38, no. 1 (December 20, 2005): 38–46. http://dx.doi.org/10.1038/ng1698.
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